CADTH Reimbursement Review

Tremelimumab (Imjudo) in Combination With Durvalumab (Imfinzi)

Sponsor: AstraZeneca Canada Inc.

Therapeutic area: Unresectable hepatocellular carcinoma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided Table 1.

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

^aThis submission to CADTH will be a new drug submission for tremelimumab (in combination with durvalumab), which is also under review with Health Canada as a new drug submission. Tremelimumab is not intended for monotherapy use. The durvalumab product monograph will be updated to reflect the unresectable hepatocellular carcinoma indication via a supplement to a new drug submission following approval of the tremelimumab new drug submission.

Introduction

Primary liver cancer is among the fastest rising cancers in Canada, and it is estimated that 3,500 patients will be diagnosed with primary liver cancer and 1,650 patients in Canada will die from this disease in 2022.^2-4 According to Statistics Canada’s Short-term cancer prevalence in Canada, 2018 report, the estimated 5-year prevalence of liver cancer is approximately 11.3 cases per 100,000 for both sexes.⁵ Hepatocellular carcinoma (HCC) is a severe form of liver cancer that represents about 90% of primary liver cancers globally⁶ and approximately 72% of liver cancers in Canada.² HCC is the third leading cause of cancer deaths worldwide,⁷ with a 5-year survival rate of only 20% in Canada.² It is most commonly diagnosed in people aged 70 years or older and it is 3 times more common in men than in women.⁴ Due to the insidious nature of the disease, the majority of patients are diagnosed with advanced disease, with a median survival following diagnosis of approximately 6 to 8 months, or 25% at 1 year.^6,7 The predominant risk factors for HCC include chronic infections with the hepatitis B virus (HBV) or hepatitis C virus (HCV), alcohol abuse or alcoholic steatohepatitis, and nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis.^7-9 HCC is often diagnosed using noninvasive imaging, tissue biopsies, physical examinations, or blood tests.^6,7

For advanced, unresectable HCC, the goal of treatment is to extend long-term survival, delay progression, and maintain and improve the patient’s quality of life (QoL),¹⁰ and guidelines recommend the use of systemic targeted therapies.^11,12 According to the clinical experts consulted by CADTH, systemic treatment options have improved over the past several years with the introduction of lenvatinib, sorafenib, and the combination of atezolizumab and bevacizumab as first-line systemic treatment options in Canada.^11,13-15 The clinical experts consulted by CADTH for this review identified a key limitation of the current first-line therapy of atezolizumab in combination with bevacizumab: patients with untreated or incompletely treated esophageal and/or gastric varices with bleeding or those at high risk for bleeding are not candidates for this therapy.¹³ Upper endoscopy is indicated for patients with cirrhosis or at high risk of bleeding.

The dossiers for tremelimumab in combination with durvalumab were submitted to CADTH as a pre–Notice of Compliance submission. The proposed Health Canada indication for tremelimumab in combination with durvalumab, for the first-line treatment of adult patients with unresectable HCC who require systemic therapy, generally aligns with the sponsor’s requested reimbursement criteria. Tremelimumab in combination with durvalumab received approval from the FDA in October 2022 for treatment of adult patients with unresectable HCC.¹⁶

The objective of this report Is to”revi’w and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of tremelimumab (Imjudo), 20 mg/mL, concentrate IV infusion in combination with durvalumab (Imfinzi), 50 mg/mL, concentrate for IV infusion for the treatment of unresectable HCC in adult patients.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups who responded to CADTH’s call for input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

The Colorectal Cancer Resource & Action Network (CCRAN) in collaboration with the Canadian Cancer Survivor Network (CCSN), Canadian Liver Foundation (CLF), and Gastrointestinal (GI) Society provided a collective patient input for this review. The CCRAN is a national not-for-profit patient advocacy group championing the health and well-being of patients in Canada affected by colorectal cancer and those at risk of developing the disease. The CCSN, CLF, and GI Society thoughtfully collaborated with CCRAN to ensure that the perspectives of patients with advanced HCC and their caregivers were captured, represented, and well weaved into this submission. The CCRAN gathered information for this review from in-depth interviews with 2 patients with HCC (both had experience with the currently available treatment of HCC and 1 patient had experience with the drug under review), a literature review, and online public forums for patient-reported outcomes.

According to the patient input received from CCRAN, HCC is the most common primary liver cancer. The CCRAN noted that risk factors associated with HCC include cirrhosis, HBV and HCV infections, and alcohol intake. Both patient interviews indicated that they had not been experiencing any symptoms at the time of HCC diagnosis. The CCRAN indicated that a diagnosis and symptoms of HCC represent a substantial physiological and psychological burden for patients and their caregivers and can significantly affect their health-related quality of life (HRQoL). The CCRAN pointed to various symptoms of HCC that affected patient QoL and daily activities, including sleep disorders, sexual dysfunction, ascites, gynecomastia, pruritis, fatigue, muscle cramps, and lack of appetite, even after treatment. Both patient respondents emphasized that the daily activities that were most commonly affected included the ability to work, participate in activities they enjoy, and spend time with family and friends. One of the interviewed patients (a female aged 92 years who was diagnosed with HCC diagnosis at 71 years) cycled through the same stages of cancer grief — anger, depression, guilt, anxiety, hopelessness, and fear — which hit the patient hard at the time of the initial diagnosis and subsequent relapse.

The CCRAN Indicated that patients with HCC expect any new drug or treatment to come with improvements in the key outcomes of QoL, survival time, manageable side effects, maintained functionality, and the ability to engage in society and contribute to the workforce. According to the patient input received from the CCRAN, HCC is a unique carcinoma because the majority of cases will develop in patients with cirrhosis, and therapeutic options will therefore be limited due to the patient’s overall health status. The CCRAN indicated that patients with early-stage HCC are preferred candidates for resection, transplant, and local ablation, while patients at intermediate stages may be candidates for transarterial chemoembolization (TACE) and those with advanced disease will receive systemic therapies. The CCRAN noted that the current systemic treatments for HCC include lenvatinib, sorafenib, regorafenib, cabozantinib, and atezolizumab in combination with bevacizumab. The limited treatment tolerability, in part due to the side effects, was highlighted by the CCRAN as a major challenge to available systemic therapy for advanced HCC.

One of the interviewed patients (a male 74 years of age diagnosed with HCC at 68 years) had experience with treatment with the drug under review after TACE that negatively affected his QoL. The patient respondent, who had access to tremelimumab in combination with durvalumab through a clinical trial and resided in Cranbrook, British Columbia, indicated that the drug under review has had promising and durable treatment results, with no side effects other than an occasional skin rash. The patient also mentioned that tremelimumab in combination with durvalumab helped him regain functionality and pursue a livelihood, which reduced the burden on his caregivers and loved ones. The CCRAN advocated that tremelimumab in combination with durvalumab be approved for the indication under review and suggested that it will help alleviate the gaps in current HCC therapy.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of unresectable HCC.

The clinical experts consulted by CADTH for this review stated that the treatment goals for patients with unresectable HCC Include prolonging life and delaying progression. They mentioned that treatments have improved in the past several years with the introduction of lenvatinib, which has superior efficacy and lower toxicity compared with sorafenib, and atezolizumab in combination with bevacizumab. However, the benefits of current treatments have been incremental. Moreover, the use of atezolizumab in combination with bevacizumab is limited to patients who have had a recent upper endoscopy and were found not to have symptomatic varices. The clinical experts noted that tremelimumab in combination with durvalumab would be indicated in the first line for patients who would currently be indicated for atezolizumab and bevacizumab, and that the choice of therapy would depend on clinician and patient preferences. They added that it may be indicated for patients who had started tyrosine kinase inhibitor (TKI) therapy and progressed or experienced severe toxicity.

The clinical experts agreed that tremelimumab in combination with durvalumab would be recommended for patients with unresectable HCC and preserved liver function (Childs-Pugh class A) and a good performance status (potentially up to an Eastern Cooperative Oncology Group Performance Status [ECOG PS] of 2), and who are not indicated for local therapy such as TACE. They mentioned that patients who were on TKIs and/or other therapies but had severe side effects that led to permanent discontinuation would also be eligible for tremelimumab in combination with durvalumab. Patients who are not candidates for other immune checkpoint inhibitors would not be candidates for tremelimumab in combination with durvalumab.

The clinical experts mentioned that, in clinical practice, imaging would be obtained every 3 months to assess response to treatment. The most important outcomes are prolonged survival, delayed progression, disease control, and maintained QoL with a low toxicity profile. The clinical experts note that tremelimumab in combination with durvalumab should be discontinued in the event of disease progression or intractable severe immune-related adverse effects. According to the clinical experts consulted for this review, tremelimumab in combination with durvalumab can be administered in most systemic therapy suites in which cancer patients receive chemotherapy and immunotherapy. Administration of this therapy can be supervised by most medical oncologists experienced in treating HCC.

Clinician Group Input

The clinician group input was obtained from 2 clinician groups, including the Canadian Gastrointestinal Oncology Evidence Network (CGOEN) represented by 6 clinicians; the Ontario Health (Cancer Care Ontario) Gastrointestinal Cancer Drug Advisory Committee, represented by 5 clinicians; and a clinician from the Alberta Health Services Cancer Care at the University of Alberta.

The CGOEN indicated that, with modern systemic therapy, downsizing of disease has led to newer options for local regional treatments of the liver (i.e., stereotactic radiation, embolization, ablation, resection, or transplant). The CGOEN emphasized that patients with HCC may be at increased risk of bleeding due to the underlying liver disease and the vascular nature of the disease itself, and therapy that does not increase this risk will be key in this area. The clinician groups agreed that, given an acceptable safety profile, tremelimumab in combination with durvalumab will be another first-line HCC treatment option, particularly for patients with hypertension or varices, or when upper GI endoscopy is not available. The clinician from the University of Alberta indicated that tremelimumab in combination with durvalumab may become the preferred first-line immunotherapy option for treatment of patients with unresectable HCC. The CGOEN and the clinician from the University of Alberta noted that patients receiving tremelimumab in combination with durvalumab would have fewer clinic visits and less time in the clinic as they would be treated every 4 weeks and essentially with 1 drug except for the first cycle, while for atezolizumab in combination with bevacizumab, patients are treated every 3 weeks and with 2 drugs. The clinician groups identified several reasons for discontinuing tremelimumab in combination with durvalumab, including disease progression, unacceptable drug-related toxicities, or patient preference. The clinician groups emphasized that treatment with tremelimumab in combination with durvalumab should be provided by clinicians with expertise and experience in treating HCC. The GI Drug Advisory Committee noted that treatment with tremelimumab in combination with durvalumab should be performed in outpatient infusion clinics, including satellite clinics.

Drug Program Input

The Provincial Advisory Group identified the following jurisdictional implementation issues: relevant comparators and considerations for initiation of therapy, continuation or renewal of therapy, discontinuation of therapy, and prescribing of therapy. The clinical experts consulted by CADTH weighed evidence from the HIMALAYA study and other clinical considerations to provide responses to the Provincial Advisory Group’s drug program implementation questions (Table 4).

Clinical Evidence

Pivotal Studies and Randomized Controlled Trial Evidence

Description of Studies

The HIMALAYA study was a randomized, open-label, sponsor-blind, multicentre, global, phase III study to assess the efficacy and safety of tremelimumab in combination with durvalumab versus sorafenib in the treatment of patients with unresectable HCC who are not eligible for locoregional therapy and have not received prior systemic therapy for HCC in the first-line setting. The primary objective was to compare the overall survival (OS) in all randomized patients receiving tremelimumab in combination with durvalumab versus thos receiving sorafenib. Secondary objectives included comparing OS rates (at 18, 24, and 36 months), progression-free survival (PFS), time to progression (TTP), objective response rate (ORR), disease control rate (DCR), and duration of response (DoR) as assessed by investigators, patient-reported outcomes, and safety between both treatment groups. The study was funded by AstraZeneca Canada and included 9 study centres in Canada.

Patients were randomly assigned in a 1:1:1:1 ratio using an interactive web response system into 1 of 4 treatment groups: tremelimumab in combination with durvalumab (300 mg × 1 dose plus durvalumab 1,500 mg every 4 weeks; n = 393), sorafenib (400 mg twice daily; n = 389), durvalumab monotherapy (not included in this review; n = 389), and a different dosing regimen of tremelimumab in combination with durvalumab (n = 153, recruitment to group closed due to preliminary efficacy findings). Randomization was stratified according to macrovascular invasion (MVI; yes or no), etiology of liver disease (confirmed HBV versus confirmed HCV versus others), and ECOG PS (0 versus 1). Tumour imaging assessments were to be performed at randomization and then every 8 weeks (± 1 week) for the first 48 weeks following randomization, and every 12 weeks (± 1 week) thereafter until confirmed disease progression.

Patient demographic characteristics and key disease characteristics were balanced between both treatment groups. ||| |||| ||| || |||| |||||| ||| ||||||||||||| || ||||| ||| and up to 15% of the patients in both groups were aged 75 years or older. |||| |||||||| |||| |||| |||||| ||| ||| || |||||||| |||| ||||||| |||||| |||| |||| ||||| |||||| ||||| ||||| || |||||||| |||| |||||| |||||| ||| |||||||| ||| |||||||||| ||||| ||||||||. Approximately 80% of patients had a Barcelona Clinic Liver Cancer (BCLC) stage of C, and 20% had a BCLC stage of B. Half of the patients had extrahepatic spread (EHS), and a quarter of patients had MVI. |||| ||||||| || |||||||| ||||||| ||||||| |||||||||| |||| |||||| || |||||||| ||| ||||||||| ||||||||||| |||||||||||||||||||||||||| ||| ||| ||||||||| ||| ||||||| |||||||, and 12% in the tremelimumab in combination with durvalumab group and 10% in the sorafenib group had received prior radiotherapy.

Efficacy Results

Key efficacy results of the HIMALAYA trial for all randomized patients are summarized in Table 2. As of the final primary analysis data cut-off date of August 27, 2021, ||||||| ||||||||| |||| |||||| ||||||, and the median follow-up times were 33.2 months (95% confidence interval [CI], 31.7 to 34.5) in the tremelimumab in combination with durvalumab group and 32.2 months (95% CI, 30.4 to 33.7) in the sorafenib group. The median total treatment durations were 5.5 months (range = 0.4 to 42.7) in the tremelimumab in combination with durvalumab group and 4.1 months (range = 0.1 to 38.6) in the sorafenib group.

Table 2: Summary of Key Results From the HIMALAYA Study (FAS With Final Data Cut-Off of August 27, 2021)

CI = confidence interval; CR = complete response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FAS = final analysis set; HBV = hepatitis B virus; HBC = hepatitis C virus; MVI = macrovascular invasion; NR = not reached; OS = overall survival; PFS = progression-free survival; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; vs.= versus.

^aCalculated using the Kaplan-Meier technique.

^bThe adjusted alpha levels for the 2-sided superiority test of tremelimumab in combination with durvalumab vs. sorafenib and CI were derived from the exact number of OS events for each comparison using the Lan and DeMets approach that approximates the O’Brien-Fleming spending function. Analysis performed using a stratified log-rank test adjusting for treatment, etiology of liver disease (HBV vs. HCV vs. others), ECOG PS (0 vs. 1), and MVI (yes vs. no). P value has been adjusted for multiple testing.

^cAnalysis performed using stratified log-rank test adjusting for treatment, etiology of liver disease (HBV vs. HCV vs. others), ECOG PS (0 vs. 1), and MVI (yes vs. no). P value has not been adjusted for multiple testing.

^dA confirmed response of CR/PR means that a response of CR/PR was recorded at 1 visit and confirmed by repeat imaging not less than 4 weeks after the visit where response was first observed with no evidence of progression between the initial and confirmation visit. Unconfirmed responses were not confirmed by repeat imaging.

^eAnalysis was performed using a logistic regression model adjusted for treatment with factors for etiology of liver disease, ECOG PS, and MVI. P value has not been adjusted for multiple testing.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

The efficacy analyses of OS in all randomized patients showed that patients in the tremelimumab in combination with durvalumab group had a longer OS than those in the sorafenib group. The median OS was 16.4 months (95% CI, 14.2 to 19.6) in the tremelimumab in combination with durvalumab group compared to 13.8 months (95% CI, 12.3 to 16.1) in the sorafenib group, with a hazard ratio (HR) of 0.78 (96.02% CI, 0.65 to 0.93; P = 0.0035). The OS rates at 36 months were 30.7% (95% CI, 25.8 to 35.7) in the tremelimumab in combination with durvalumab group and 20.2% (95% CI,15.8 to 25.1) in the sorafenib group. Effect estimates for all predefined subgroups were consistent with the overall OS analysis.

All secondary outcomes were based on investigator assessment according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and were not adjusted for multiplicity. Median PFS in the full analysis set (FAS) was 3.8 months in the tremelimumab in combination with durvalumab group and 4.1 months in the sorafenib group, with an HR of 0.90 (95% CI, 0.77 to 1.05). The ORRs were 20.1% (79 patients) in the tremelimumab in combination with durvalumab group and 5.1% (20 patients) in the sorafenib group. When comparing tremelimumab in combination with durvalumab against sorafenib, the || ||| ||| ||| |||| |||| ||| |||| || ||||| || |||||| || |||||||||||| || ||||||||||| |||| |||||||||||||||| |||| || |||||||| ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| || |||||||| |||||| || ||| ||||||||| ||||| ||| |||||||| ||||| ||||||||| |||||||| ||||| || |||||||| |||||||| |||| || ||||||| |||||||| |||| ||||| || ||||||||||| ||||||||| |||||| ||||||||| ||| ||||||||| || |||||| ||||||| || ||||| |||||| ||||| ||| |||||| || |||||||||||| ||||||||||. Of the patients in the tremelimumab in combination with durvalumab group, 13 (3.3%) achieved a complete response, while none in the sorafenib group achieved a similar outcome. Among the 79 responders in the tremelimumab in combination with durvalumab group and 20 responders in the sorafenib group, the median DoRs based on investigator assessment according to RECIST 1.1 were 22.3 months (interquartile range [IQR] = 8.5 to not reached) and 18.4 months (IQR = 6.5 to 26), respectively. ||| |||||||||| || |||||||| ||||||||| || |||||||| || || |||||| ||||| || ||| |||||||||||| ||||||||| ||| ||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||| || ||| ||||||||| |||||| The median times to onset of response from randomization were 2.2 months (IQR = 1.8 to 4) in the tremelimumab in combination with durvalumab group and 3.8 months (IQR = 1.9 to 8.4) in the sorafenib group. The overall DCR (complete response, partial response, or stable disease) was similar for the 2 groups, with 236 patients (60.1%) in the tremelimumab in combination with durvalumab group and 236 patients (60.7%) in the sorafenib group achieving control of the disease. ||| |||||| |||| || ||||||||||| ||| ||| |||||| |||| ||| ||| || |||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||| |||||| |||| ||| ||| || |||| || ||| ||||||||| |||||| Results from the assessment of exploratory outcomes (based on blinded independent central review [BICR] assessments using modified RECIST 1.1 for HCC and immune-related Response Evaluation Criteria in Solid Tumors [irRECIST]) were not provided by the sponsor.

Results for patient-reported outcomes as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18 (EORTC QLQ-HCC18) suggested a similar overall health status in both study groups at baseline, with no mean change scores from baseline reaching the minimal important difference (MID) of a mean change of 10 points or greater at any time point. However, |||||||||| ||||| ||||||||||| || ||| ||| ||| || |||| || || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||| ||||||||| |||||| ||||||||||||. Median time to deterioration of scores for patients favoured tremelimumab in combination with durvalumab over sorafenib in the EORTC QLQ-C30 and Global Health Status (GHS)/QoL (7.5 versus 5.7 months; HR = 0.76; 95% CI, 0.61 to 0.96); physical functioning (12.9 versus 7.4 months; HR = 0.68; 95% CI, 0.53 to 0.87), ||||||| |||| || ||| ||||||| || |||| ||||| || ||||||| |||||| ||||| || |||| ||||||| || |||| ||||| || ||||||| |||||||| |||| ||||| || ||| ||||||| || |||| ||||| || ||||||| ||| ||||| ||||||||| ||||||||| |||| ||||| || ||| ||||||| || |||| ||||| ||||||| ||| ||||||||| |||||||| ||||| || |||| ||||||| || |||| ||||| |||||||| The improvement rate in ||||||||||||||||||||| ||| |||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| |||||||| || ||| ||||||||| |||||| |||||||| ||| ||||| |||||| || ||||||| |||| ||| |||||| ||| |||||||||| ||||||||||

Harms Results

A summary of harms in the HIMALAYA trial is presented in Table 3.

A total of 378 patients (97.4%) in the tremelimumab in combination with durvalumab group and 357 patients (95.5%) in the sorafenib group experienced at least 1 adverse event (AE). The most frequently reported treatment-emergent AEs in the tremelimumab-plus-durvalumab and sorafenib groups were diarrhea (26.5% versus 44.7%, respectively), pruritis (22.9% versus 6.4%, respectively), rash (22.4% versus 13.6%, respectively), fatigue (17% versus 19%, respectively), decreased appetite (17% versus 17.9%, respectively), and palmar-plantar erythrodysesthesia syndrome (0.8% versus 46.5%, respectively). ||||| |||| ||| |||||||| ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| |||||| ||| ||| |||||||| ||||||| || ||| ||||||||| ||||| ||| ||||||||||| || ||||| ||| |||| ||||| . A total of 157 patients (40.5%) in the tremelimumab in combination with durvalumab group and 111 patients (29.7%) in the sorafenib group experienced at least 1 serious adverse event (SAE). ||| |||| |||||||||| |||||||| ||||||| ||||||| |||||| |||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||| ||||||||| |||||| |||| |||||||| ||||| || ||||| |||||||||||||| |||||| ||||| || || |||||||||||||| ||| ||||||||| ||||| || ||||| |||||||||||||| Fifty-three patients (13.7%) in the tremelimumab in combination with durvalumab group and 63 patients (16.8%) in the sorafenib group stopped treatment due to AEs.

At the final data cut-off date of August 21, 2021, in the FAS, ||||| |||| ||| |||||| ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||| |||||| ||||||| || ||| ||||||||| |||||| |||| |||||||| |||||||||| || ||| ||||||| |||||||||||. In the safety analysis set, || |||||||| |||||| ||| || |||||||| |||||| |||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||||||| |||||| |||||||||||||

||||||| |||||| || ||||||| |||||||| ||||||| |||||||| |||| |||||||||| || |||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| |||| ||| ||||||||| ||||| ||||||| |||| || |||| ||| |||||||| || ||| ||||||||||||||||||||||| ||||| |||| |||| |||||| || |||||||| |||||||| ||||||||||||||| || ||||| ||||| |||| || ||| |||||||||||||| ||| ||||| |||| |||| |||||||||| |||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| |||||| ||| |||||||| || ||||||| ||||| ||| |||| |||||||||| |||||||| || ||| ||||||||| ||||| |||| |||||| |||| |||||||||||||| Immune-mediated AEs were also more frequently reported in patients in the tremelimumab in combination with durvalumab group than in the sorafenib group (36% versus 8%, respectively). Six patients in the tremelimumab in combination with durvalumab group died due to immune-mediated AEs (|||||||||||| |||||||| ||||||| |||||||||||| ||| |||||||||| ||||||| ||| || |||||| || ||| ||||||||| |||||| |||||||| |||||||| |||||| |||||||| || || |||||||| |||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||||||| |||||| || ||| ||||||||| ||||||

There were 144 patients (37.1%) in the tremelimumab in combination with durvalumab group with any hepatic Standardized Medical Dictionary for Regulatory Activities Query (SMQ) AE compared to 121 patients (32.4%) in the sorafenib group. ||| || ||| ||||||| |||||||| ||| ||| || ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||||| || ||| ||||||||| |||||. There were 44 patients (11.3%) in the tremelimumab in combination with durvalumab group with any hemorrhage SMQ AE compared to 56 patients (15%) in the sorafenib group. ||| || ||| |||||||||| ||| ||| || ||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||||| || ||| ||||||||| |||||| In the HIMALAYA trial, tremelimumab in combination with durvalumab showed no increase in liver toxicity or risk of bleeding.

Table 3: Summary of Key Harms Results From the HIMALAYA Study (SAS With Final Data Cut-Off of August 27, 2021)

AE = adverse event; AESI = AE of special interest; SAE = serious adverse event; SAS = safety analysis set; SMQ = Standardized Medical Dictionary for Regulatory Activities Query.

^aAE with outcome of death.

^bAESIs for tremelimumab in combination with durvalumab include, but are not limited to, events with a potential inflammatory or immune-mediated mechanism and which may require more frequent monitoring and/or interventions such as steroids, immunosuppressants, and/or hormone-replacement therapy.

^cThe following hepatic SMQs were considered of relevance to the hepatocellular carcinoma patient population: cholestasis and jaundice of hepatic origin, hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions, hepatitis, noninfectious liver infections, liver malignant tumours, liver-related investigations, signs and symptoms, and liver-related coagulation and bleeding disturbances.

^dHemorrhage SMQs included hemorrhage terms and hemorrhage laboratory terms.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Critical Appraisal

Internal Validity

HIMALAYA was an open-label, sponsor-blind, randomized phase III study comparing the effect of tremelimumab in combination with durvalumab and sorafenib in adult patients with unresectable HCC who require systemic therapy. The sponsor stated that an open-label, sponsor-blind design was used due to the nature of the treatment administration (IV versus oral) and the different administration schedules (every 4 weeks versus twice daily). The study used an appropriate central randomization method sufficient for concealing allocation until assignment to the intervention. Randomization appeared to adequately balance baseline demographic and disease characteristics between the tremelimumab in combination with durvalumab and sorafenib groups. The open-label design can result in a risk of bias in the measurement of the outcomes, particularly for subjective outcomes, whether by unblinded assessors, such as PFS and ORR, or self-reported, such as HRQoL and subjective harms. With the exception of subjective harms, the bias will likely favour the experimental intervention, although the extent and direction of bias are uncertain. This bias would not be introduced into the measurement of objective outcomes such as OS, which is the primary outcome of the trial. At the first interim analysis after at least 32 weeks of follow-up, tumour response assessments were performed by BICR (which would minimize bias in the measurement of these outcomes) but in the final analysis, tumour response assessments were performed only by investigators. Results from the interim analysis were similar to those from the final analysis. In the final analysis, exploratory end points included assessment of the PFS, TTP, ORR, DCR, and DoR by BICR to mitigate this bias. However, the results of these assessments were not available. The study was powered to detect a treatment difference in the primary end point of OS between treatment group, and the enrolled sample size was adequate. However, the study was not powered for individual subgroup comparisons, and no multiplicity adjustments were made, rendering any conclusion uncertain. Multiplicity was not controlled for other outcomes, which may have increased the risk of false-positive conclusions. Patients rated maintaining and improving QoL as an important outcome, yet interpretation of results for the HRQoL instruments (i.e., the ability to assess trends over time and to make comparisons across treatment groups) is limited by the substantial decline in the number of patients available to provide assessments over time.

External Validity

According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics of the HIMALAYA study population were reflective of the Canadian population with unresectable HCC. There was a large number of screening failures in the study, as almost a third of screened patients were not randomized, most commonly due to eligibility criteria not being fulfilled. However, the eligibility criteria that were most commonly not fulfilled were clear contraindications to treatment with tremelimumab in combination with durvalumab, such as a lack of adequate organ and marrow function. The clinical experts noted that, while only including patients with a Child-Pugh class of A is reasonable in clinical trials, it may also be reasonable to include other patients (e.g., those with a Child-Pugh class of B7) in clinical practice. They also noted that, although the trial excluded patients who had received prior systemic therapy, in clinical practice a large number of patients would have already received prior systemic therapy. It is unclear if findings from this study can be generalized to patients beyond the first line of therapy. All patients in the trial had an ECOG PS of 0 or 1 due to the eligibility criteria, but the experts indicated this would not be reflective of clinical practice and that clinicians would require some flexibility in restricting treatment by performance status. The clinical experts consulted by CADTH indicated that, at the time of the HIMALAYA study design, sorafenib was the only approved treatment for unresectable HCC patients who were ineligible for locoregional therapy and who had not undergone prior systemic therapy. Sorafenib was therefore considered standard-of-care treatment for these patients and was selected as the active comparator in this study. According to the clinical experts and recent clinical guidelines, sorafenib is no longer the most common standard-of-care therapy and has been replaced by therapies that include atezolizumab in combination with bevacizumab, as well as lenvatinib.

Long-Term Extension Studies

No long-term extension studies were identified by the sponsor.

Indirect Comparisons

Description of Studies

Two matching adjusted indirect comparisons (MAICs) and a published indirect treatment comparison (ITC) submitted by the sponsor were summarized and appraised for this CADTH review.

In the absence of direct comparative evidence from trials, the aim of the MAICs conducted by the sponsor was to compare the efficacy and safety of tremelimumab in combination with durvalumab against atezolizumab in combination with bevacizumab (from the IMbrave150 trial), and lenvatinib (from the REFLECT trial) in patients with unresectable HCC. A MAIC was identified as the preferred option to adjust for suspected heterogeneity between trials with individual patient-level data for the HIMALAYA trial and aggregate data available from the comparator trials. Individual patient data from the HIMALAYA trial were used to match and adjust patients to those included in the IMbrave150 and REFLECT comparator trials). All 3 trials (HIMALAYA, IMbrave150, and REFLECT) were phase III, open-label, multicentre studies. The mean durations of follow-ups were 33.2 months in the HIMALAYA trial, 27.5 months in the REFLECT trial, and 8.5 months in the IMbrave150 trial. The efficacy end points included OS and PFS in both MAICs, and ORR and DoR were only assessed in the MAIC comparing tremelimumab in combination with durvalumab versus atezolizumab in combination with bevacizumab. For parameters related to disease progression, the HIMALAYA and IMbrave150 trials employed RECIST 1.1, while REFLECT used the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Harms related to the use of tremelimumab in combination with durvalumab were evaluated in both MAICs, including AEs, SAEs, and AEs leading to treatment discontinuation. Patient-reported outcomes were only reported in the MAIC comparing tremelimumab in combination with durvalumab versus atezolizumab in combination with bevacizumab.

Efficacy Results

This section focuses on the findings of the sponsor-submitted MAICs.

Tremelimumab in Combination With Durvalumab Versus Atezolizumab in Combination With Bevacizumab

After restriction and reweighting, the HR was 1.09 (95% CI, 0.80 to 1.48) for OS, and |||| |||| ||| ||| || ||||| ||| |||| The odds ratio (OR) was 1.18 (95% CI, 0.44 to 3.21) for ORR, and |||| |||| ||| |||| || ||||| ||| |||| ||| || ||| |||| || ||||||||||||| ||||| || |||||||||||||| ||||||| || |||| ||||||| ||| |||| |||| ||| |||| || |||||| while the HR for ||| || ||||||||| |||||||| ||| |||| |||| ||| |||| || ||||||

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Harms Results

Tremelimumab in Combination With Durvalumab Versus Atezolizumab in Combination With Bevacizumab

After restriction and reweighting, the OR was 0.73 (95% CI, 0.44 to 1.19) for AEs with a grade a 3 or 4 severity as defined by the Common Terminology Criteria for Adverse Events (CTCAE) | |||| |||| ||| |||| || ||||| ||| ||||||| |||| ||| |||| |||| ||| |||| || ||||| ||| ||| ||||||| || ||||||||||||||||||||||||.

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Critical Appraisal

Although the methodology for matching and adjustment was in line with the technical guidance, the sponsor-submitted MAICs had a number of limitations that challenge the interpretation of the internal and external validities of the findings. Overall, based on the methods detailed in the report, the systematic literature review involved a comprehensive search, and the screening strategies were sufficient to minimize error and selection bias. The risk of bias of the included studies was assessed for each study; however, it may have differed depending on the study outcomes (i.e., OS versus patient-reported outcomes). The clinical experts consulted by CADTH for this review noted that several studies published over the past year that provide updated efficacy and safety data from the IMbrave150 and REFLECT trials were not identified in this search and therefore were not included in the ITC.^18-20 As a result, MAIC analyses did not select some efficacy outcomes (i.e., PFS, ORR, DoR, and patient-reported outcomes) based on the longer follow-up data on efficacy outcomes, particularly for the IMbrave150 trial, and this may have influenced the results. While the sponsor inadvertently omitted the reference to longer follow-up data for the IMbrave150 trial in the MAIC report and the clinical evidence document, OS results from the IMbrave150 trial used in the MAIC analysis (HR = 0.66; 95% CI, 0.52 to 0.85) were reported in the Cheng et al. (2022) publication. As the matching criteria were based on the inclusion and exclusion criteria for the IMbrave150 and REFLECT trials and the availability of comparable data from the HIMALAYA trial, matching was not possible for all criteria that may remove an important portion of the patient population from the HIMALAYA trial. The effective sample size was reduced after matching and adjustment in both MAICs (65.7% to 78% of the original sample size in the HIMALAYA trial), which implies that the weighted estimates are being influenced by a subset of the patients from the HIMALAYA trial that may not be representative of the entire study population and may limit the generalizability of the results. In addition, the MAIC analysis could not account for some sources of heterogeneity in trials, such as differences in observation times or definition of end points. The clinical experts noted that, given the time gap, there is a possibility of systemic differences between patients in the HIMALAYA trial (from 2017 to 2019) and the REFLECT trial (from 2013 to 2016), such as treatments received before systemic therapy (i.e., loco-regional treatment). Furthermore, as not all trials included the same subjective and objective measurements, the comparative efficacy and safety of relevant treatments remain unknown. While OS and PFS data were available in all 3 trials, the ORR and DoR were not assessed in the REFLECT trial. In addition, DCR, considered by the clinical experts consulted for this review to be an important outcome, was assessed only in the HIMALAYA trial. Results on patient-reported outcomes (QoL and abdominal swelling), which were considered by patients to be important for this review, were only reported in the MAIC comparing tremelimumab in combination with durvalumab versus atezolizumab in combination with bevacizumab in patients with unresectable HCC. In both MAICs, results for some efficacy and harm estimates were imprecise (i.e., accompanied by wide CIs favouring either tremelimumab in combination with durvalumab or the comparators), which precluded drawing superiority conclusions.

Fulgenzi et al. (2022)

In addition to the MAICs conducted by the sponsor, a published network meta-analysis (NMA) conducted by Fulgenzi et al. (2022) was also identified. A frequentist NMA using fixed-effects models was used to compare the efficacy and safety of first-line treatments for unresectable HCC from 2007 to 2022. Two analyses were performed: the first compared the efficacy of atezolizumab in combination with bevacizumab versus all other first-line treatments, and the second compared all first-line treatments with placebo. As tremelimumab in combination with durvalumab is of interest to this report, only a comparison of atezolizumab in combination with bevacizumab versus tremelimumab in combination with durvalumab is presented here. The results of the NMA showed that the HR for OS for atezolizumab in combination with bevacizumab compared with tremelimumab in combination with durvalumab was 0.74 (95% CI, 0.52 to 1.06). The HR for PFS for atezolizumab in combination with bevacizumab compared with tremelimumab in combination with durvalumab was 0.66 (95% CI, 0.49 to 0.87). The OR for ORR for atezolizumab in combination with bevacizumab compared with tremelimumab in combination with durvalumab was 0.60 (95% CI, 0.28 to 1.25).

The results of the published NMA are highly uncertain given the heterogeneity in the baseline characteristics of patients within the included trials, data sparseness, network structure, and differences in the duration of follow for efficacy outcomes. While the use of fixed-effect models appears to be appropriate given the sparsity of data, no rationale was provided for the selection of the model in the published NMA. Furthermore, the effect estimates from the NMA are imprecise due to the sparseness of data and wide CIs, which for many outcomes included the possibility of benefit, lack of benefit, or harm for atezolizumab in combination with bevacizumab compared with tremelimumab in combination with durvalumab. Because model fit was not evaluated, it is unclear how well the model estimated treatment differences. No results on patient-reported QoL were evaluated, which was considered by patients to be an important end point. In addition, there were no comparative effect estimates for the harms. These limitations must be considered when drawing conclusions on the results of the published NMA.

Conclusions

One randomized, open-label, sponsor-blind, multicentre phase III trial provided evidence regarding the efficacy and safety of tremelimumab in combination with durvalumab compared with sorafenib in patients with unresectable HCC. Compared to sorafenib, treatment with tremelimumab in combination with durvalumab (tremelimumab 300 mg as a single priming dose in combination with 1,500 mg at day 1 of cycle 1, followed by durvalumab 1,500 mg as a single drug every 4 weeks) showed a statistically significant OS benefit. The absolute difference in median OS in patients with unresectable HCC between treatment groups (approximately 3 months) was considered clinically meaningful by the clinical experts consulted by CADTH. Because HRQoL analyses were limited by high rates of missing data, changes over time could not be interpreted. The clinical experts noted that, although sorafenib was the standard of care at the time the trial was conducted, it is now considered outdated. No definitive conclusions could be drawn from the ITCs submitted by the sponsor comparing the efficacy and safety of tremelimumab in combination with durvalumab to contemporary first-line therapies (i.e., atezolizumab in combination with bevacizumab and lenvatinib) due to methodological limitations and imprecision in the effect estimates for some outcomes. Given the lack of robust comparative data between tremelimumab in combination with durvalumab and other first-line therapies in the first-line setting (atezolizumab in combination with bevacizumab or lenvatinib), the clinical experts consulted could not draw firm conclusions about place in therapy. They noted that tremelimumab in combination with durvalumab would be suitable in patients with a higher risk of bleeding who would not be eligible for atezolizumab in combination with bevacizumab as tremelimumab in combination with durvalumab showed no increase in liver toxicity or the risk of bleeding in the HIMALAYA trial. The clinical experts would recommend funding this combination in the first-line treatment of appropriate patients with unresectable HCC as an alternative to the current options, which include lenvatinib, sorafenib, and atezolizumab in combination with bevacizumab.

The safety profile of tremelimumab in combination with durvalumab in this study was consistent with the known safety profile of other immuno-oncology checkpoint inhibitors, and no additional safety signals were identified with tremelimumab in combination with durvalumab therapy.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of tremelimumab, 20 mg/mL, concentrate for IV infusion in combination with durvalumab, 50 mg/mL, concentrate for IV infusion in the treatment of unresectable HCC in adult patients.

Disease Background

Contents within this section were informed by materials submitted by the sponsor and clinical expert input, and then summarized and validated by the CADTH review team.

Primary liver cancer is 1 of the fastest rising cancers in Canada.^2,3 In 2022, it was estimated that 3,500 patients would be diagnosed with primary liver cancer and 1,650 patients in Canada would die from this disease, with an age-standardized incidence rate of 7.1 cases per 100,000.^2,4 According to Statistics Canada’s Short-term cancer prevalence in Canada, 2018 report, the estimated 5-year prevalence of liver cancer is approximately 11.3 cases per 100,000 for both sexes.⁵ HCC, which originates from hepatocytes as a result of a complex process, is the most common type of liver cancer.^2,21 It is a severe form of liver cancer that represents about 90% of primary liver cancers globally⁶ and approximately 72% of liver cancers in Canada.² HCC is the third leading cause of cancer deaths worldwide,⁷ with a 5-year survival rate of only 20% in Canada.² It is most commonly diagnosed in people older than 70 years and it is 3 times more common in men than women.⁴

HCC classically develops and grows in a silent fashion, which makes it difficult to detect before the development of the later stages of the disease.²² In its early stages, HCC is generally asymptomatic or presents with nonspecific symptoms, including right upper abdominal or epigastric pain, weight loss, early satiety, and malaise.¹⁰ Due to the insidious nature of the disease, the majority of patients are diagnosed with advanced disease, with a median survival following diagnosis of approximately 6 to 8 months, or 25% at 1 year.^6,7 The extrahepatic manifestations of HCC may be associated with both distant metastases (most commonly to the bone, lung, and abdominal viscera) and paraneoplastic phenomena (i.e., hypoglycemia, hypocalcemia, and polycythemia).²²

The predominant risk factors for HCC include chronic infections with HBV or HCV, alcohol abuse or alcoholic steatohepatitis, and NAFLD or nonalcoholic steatohepatitis.^7-9 HBV or HCV infections in Canada are associated with increasing immigration from regions of the world where these infections are endemic, which is reflected in part by higher rates of viral hepatitis-related HCC in provinces where most immigrants settle.² Other risk factors for HCC include obesity, diabetes, and nicotine use, as well as rare conditions such as hemochromatosis or hereditary tyrosinemia type 1.^7-9 The prevalence of HCC risk factors varies geographically, with HBV predominating in Asia, HCV in Japan, and NAFLD, nonalcoholic steatohepatitis, or alcohol abuse in North America and Europe.⁷

HCC is often diagnosed using noninvasive imaging (multiphasic CT and MRI), tissue biopsies, physical examinations, or blood tests.^6,7 The Child-Pugh class, based on clinical and laboratory parameters (i.e., serum bilirubin, serum albumin, ascites, neurologic disorder, and clinical nutrition status), is now widely used to assess liver function in clinical practice.⁷ The BCLC algorithm is a well-respected staging system that subdivides patients with HCC into 5 clinical stages: very early stage (BCLC 0), early stage (BCLC A), intermediate stage (BCLC B), advanced stage (BCLC C), and terminal stage (BCLC D).^13,23,24 It is defined by the variables related to tumour burden (number and size of tumours), physical status, liver functional status, and cancer-related symptoms.^13,25 Stage B is defined as multifocal HCC with relatively preserved liver function, no cancer-related symptoms (ECOG PS 0), and no vascular invasion or extrahepatic spread.^6,13,25 Stage C comprises patients with cancer-related symptoms (symptomatic tumours, ECOG PS 1 or 2), vascular invasion (either segmental or portal invasion), or EHS (lymph node involvement or metastases), and those who have preserved liver function.^6,13,25

Standards of Therapy

Contents within this section were informed by materials submitted by the sponsor and clinical expert input and then summarized and validated by the CADTH review team.

In early stages of HCC, the primary goal for treatment is a cure, and guidelines recommend potentially curative approaches that include surgical resection, liver transplant, and/or local regional therapies such as radiofrequency ablation. The choice of therapy depends on several factors, including resectability, liver function, and patient performance status.^12,13,26 For advanced, unresectable HCC, the goal of treatment is to extend long-term survival, delay progression, and maintain and improve the patient’s QoL.¹⁰ HCC is considered to be chemotherapy-refractory; cytotoxic chemotherapy is of limited value to patients due to low tolerability and has been removed from guidelines due to modest efficacy.²⁷ Guidelines therefore recommend the use of systemic targeted therapies for patients with unresectable HCC at BCLC stage B and C.^11,12 According to the clinical experts consulted by CADTH, systemic treatment options have improved over the past several years with the introduction of lenvatinib, sorafenib, and the combination of atezolizumab and bevacizumab as first-line systemic treatment options in Canada.^11,13-15

Atezolizumab is a programmed cell death 1 ligand 1 (PD-L1) inhibitor used in combination with bevacizumab, which is an angiogenesis inhibitor targeting vascular endothelial growth factor A, and is indicated as first-line treatment for advanced HCC. Clinical evidence to support the efficacy of atezolizumab in combination with bevacizumab was demonstrated in the pivotal IMbrave150 study, in which the combination showed a superior OS benefit compared to sorafenib in unresectable HCC patients. An analysis conducted at 56% OS maturity provided an OS HR of 0.66 (95% CI, 0.52 to 0.85) with a median OS of 19.2 months (95% CI, 17.0 to 23.7) for atezolizumab in combination with bevacizumab versus 13.4 months (95% CI, 11.4 to 16.9) in the sorafenib group, with OS rates at 18 months of 52% for atezolizumab in combination with bevacizumab versus 40% for sorafenib (CIs were not reported in the published article).²⁸ Atezolizumab in combination with bevacizumab is funded widely across provincial drug programs.

Lenvatinib is also a multiple kinase inhibitor that targets vascular endothelial growth factor receptors 1, 2, and 3 and fibroblast growth factor receptors 1 through 4. Lenvatinib is indicated as first-line treatment for advanced HCC in patients without main portal vein invasion and an ECOG PS of 0 to 1. Clinical evidence to support the efficacy of lenvatinib in HCC was based on the phase III REFLECT study, in which lenvatinib demonstrated noninferiority to sorafenib. The median OS for lenvatinib was 13.6 months (95% CI 12.1 to 14.9) and the median OS for sorafenib was 12.3 months (95% CI, 10.4 to 13.9), with an HR of 0.92 (95% CI, 0.79 to 1.06; noninferiority margin = 1.08).²⁹ Lenvatinib is widely funded across Canada and may be considered for first-line treatment of patients who decline or are not appropriate candidates for atezolizumab in combination with bevacizumab or who do not have access to this combination, and second-line treatment of patients who experience disease progression following first-line treatment with atezolizumab in combination with bevacizumab.¹⁵

Sorafenib is an oral TKI that targets multiple kinases, including the vascular endothelial growth factor receptors 1, 2, and 3, and the BRAF protein. Sorafenib is indicated for the treatment of patients with advanced HCC and was the first systemic treatment available for HCC. Clinical evidence to support the efficacy of sorafenib in HCC was based on the phase III SHARP study, in which sorafenib demonstrated an improvement in median OS of 2.8 months compared to placebo (median OS of 10.7 months for sorafenib [95% CI, 9.4 to 13.3] versus 7.9 months for placebo [95% CI, 6.8 to 9.1]; HR = 0.69; 95% CI, 0.55 to 0.87; P < 0.001).³⁰ According to the clinical experts consulted by CADTH, sorafenib is now considered outdated and is no longer used by the majority of Canadian physicians, and it is recommended in the first and second lines only for patients intolerant of lenvatinib.

For patients who progress after treatment with lenvatinib or sorafenib, other multitargeted TKIs such as regorafenib and cabozantinib are funded widely in Canada as second-line therapies.

The clinical experts consulted by CADTH identified a key limitation of the current first-line therapy with atezolizumab in combination with bevacizumab: patients with untreated or incompletely treated esophageal and/or gastric varices with bleeding or who are at a high risk for bleeding are not candidates for this combination therapy.¹³ Upper endoscopy is therefore indicated for patients with cirrhosis or at high risk of bleeding.

Drug Under Review

Key characteristics of durvalumab (for injection) in combination with tremelimumab (for injection) are summarized in Table 4, along with other first-line treatments available for treatment of unresectable HCC.

Tremelimumab (for injection) in combination with durvalumab (for injection) is indicated for the first-line treatment of adult patients with unresectable HCC who require systemic therapy.¹ Durvalumab is an engineered monoclonal antibody that blocks the interaction of PD-L1 with its receptors, programmed cell death 1 protein 1 (PD-1) and CD80.³¹ Selective blockade of PD-L1/PD-1 and PD-L1/CD80 interactions leads to prolonged T-cell activation and enhanced antitumour activity.³¹ Durvalumab does not bind to programmed cell death 1 ligand 2 (PD-L2). Leaving the interaction between PD‐L2 and PD-1 may reduce the potential for relevant immune-related toxicities such as pneumonitis, given the role of PD-L2 in ameliorating airway inflammation.³² Tremelimumab is a selective, fully human immunoglobulin G2 antibody that blocks cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) interactions with CD80 and CD86, enhancing T-cell activation and proliferation and resulting in increased T-cell diversity and enhanced antitumour immune activity.¹

Targeting both the PD-1 and CTLA-4 pathways using a dual checkpoint blockade could potentially improve clinical outcomes due to this additive antitumour effect, resulting in a stronger immune response because the mechanisms of action of these pathways are nonredundant and utilized at different times of immune activation and at different locations in the body.³³ This mechanism of action could be beneficial in targeting HCC tumour cells in which a state of immune tolerance to the pathogen or tumour may exist.

The recommended dose of tremelimumab is 300 mg as a single priming dose in combination with durvalumab 1,500 mg at day 1 of cycle 1, followed by durvalumab 1,500 mg as a single drug every 4 weeks.¹ Patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to tremelimumab 4 mg/kg as a single priming dose in combination with durvalumab 20 mg/kg followed by durvalumab 20 mg/kg as a single drug every 4 weeks until weight is greater than 30 kg.¹ Treatment with tremelimumab in combination with durvalumab should continue as long as a clinical benefit is observed or until unacceptable toxicity. Dose reduction or escalation is not recommended during treatment with tremelimumab in combination with durvalumab. Treatment withholding or discontinuation may be required based on individual safety and tolerability.¹ Both durvalumab and tremelimumab should be administered under the supervision of health care practitioners experienced in the treatment of cancer.^1,31

Dossiers for tremelimumab in combination with durvalumab were submitted to CADTH as a pre–Notice of Compliance submission. The proposed Health Canada indication for tremelimumab in combination with durvalumab is for the first-line treatment of adult patients with unresectable HCC who require systemic therapy, which generally aligns with the sponsor’s requested reimbursement criteria. Tremelimumab in combination with durvalumab received approval from the FDA in October 2022 for treatment of adult patients with unresectable HCC.¹⁶

Table 4: Key Characteristics of First-line Treatments for Unresectable HCC

HCC = hepatocellular carcinoma; PD-1 = programmed cell death 1 protein 1; PD-L1 = programmed cell death 1 ligand 1; VEGF-A = vascular endothelial growth factor A; VEGFR = vascular endothelial growth factor receptor.

^aHealth Canada–approved indication.

^bHealth Canada–proposed indication.

Source: Product monographs for Imjudo,¹ Imfinzi,³¹ Nexavar,³⁴ Tecentriq,³⁵ and Lenvima.³⁶

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on input provided by patient groups. The full original patient inputs received by CADTH are included in the stakeholder section at the end of this report.

The CCRAN in collaboration with the CCSN, CLF, and GI Society provided a collective patient input for this review. The CCRAN is a national not-for-profit patient advocacy group championing the health and well-being of Canadians affected by colorectal cancer and those at risk of developing the disease. The CCSN, CLF, and GI Society collaborated with CCRAN to ensure that the perspectives of patients with advanced HCC and their caregivers were captured, represented, and well incorporated into this submission. The CCRAN gathered information for this review from in-depth interviews with 2 patients with HCC (both patients had experience with the currently available treatment of HCC, and only 1 patient had experience with drug under review), a literature review, and online public forums for patient-reported outcomes.

According to the patient input received from the CCRAN, HCC is the most common primary liver cancer. The CCRAN noted that risk factors associated with HCC include cirrhosis, HBV and HCV infections, and alcohol intake. Both patient interviews indicated that they had not been experiencing any symptoms at the time of HCC diagnosis. The CCRAN indicated that a diagnosis and symptoms of HCC represent a substantial physiological and psychological burden for patients and their caregivers and can significantly affect their HRQoL. The CCRAN pointed to various symptoms of HCC that affected QoL and daily activities, including sleep disorders, sexual dysfunction, ascites, gynecomastia, pruritis, fatigue, muscle cramps, and lack of appetite, even after treatment. Both patient respondents emphasized that the daily activities that were most commonly affected included the ability to work, participate in enjoyable activities, and spend time with family and friends. One of the interviewed patients (a female aged 92 years who was diagnosed with HCC diagnosis at 71 years) found herself cycling through the same stages of cancer grief — anger, depression, guilt, anxiety, hopelessness, and fear — which hit her hard at the time of the initial diagnosis and subsequent relapse.

The CCRAN indicated that patients with HCC expect the following key outcomes to be improved from any new drug or treatment: improved QoL, prolonged survival, manageable side effects, maintenance of functionality, and ability to engage in society and contribute to the workforce. According to the patient input received from the CCRAN, HCC is a unique carcinoma because the majority of cases will develop in patients with cirrhosis and, therapeutic options will therefore be limited due to the patient’s overall health status. The CCRAN indicted that patients with early-stage HCC are preferred candidates for resection, transplant, and local ablation, patients at intermediate stages may be candidates for TACE, and those with advanced disease will receive systemic therapies. The CCRAN noted that the current systemic treatments for HCC include atezolizumab in combination with bevacizumab, lenvatinib, sorafenib, regorafenib, and cabozantinib. Limited treatment tolerability, in part due to side effects, was identified by the CCRAN as a major challenge to available systemic therapy for advanced HCC.

One of the interviewed patients (a male aged 74 years diagnosed with HCC at 68 years) had experience with treatment with the drug under review after transarterial chemoembolization, which negatively affected his QoL. The patient had access to tremelimumab in combination with durvalumab through a clinical trial, and resided in Cranbrook, British Columbia. That patient indicated that the drug under review has had promising and durable treatment results, with no side effects other than an occasional skin rash. He also mentioned that tremelimumab in combination with durvalumab helped him regain functionality and the ability to pursue a livelihood, which reduced the burden on his caregivers and loved ones. The CCRAN advocated that use of tremelimumab in combination with durvalumab be approved for the indication under review and suggested that it will help alleviate gaps in current HCC therapy.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of unresectable HCC.

Unmet Needs

The clinical experts consulted by CADTH for this review stated that the treatment goals for patients with unresectable HCC include prolonging life and delaying progression. They mentioned that treatments have improved in the past several years with the introduction of lenvatinib, which has superior efficacy and lower toxicity compared with sorafenib, and atezolizumab in combination with bevacizumab. However, the benefits of current treatments have been incremental. Moreover, the use of atezolizumab in combination with bevacizumab is limited to patients who have had a recent upper endoscopy and no symptomatic varices.

Place in Therapy

The clinical experts noted that tremelimumab in combination with durvalumab would be indicated in the first line for patients who would currently be indicated for atezolizumab and bevacizumab, and that the choice of therapy would depend on clinician and patient preference. They added that it may be indicated for patients who had started TKI therapy and progressed or experienced severe toxicity.

Patient Population

The clinical experts agreed that tremelimumab in combination with durvalumab would be recommended for patients with unresectable HCC with preserved liver function (as indicated by a Childs-Pugh class of A) and good performance status (potentially up to an ECOG PS of 2), and those who are not indicated for local therapy such as TACE. They mentioned that patients who were on TKIs and/or other therapies but had severe side effects that led to permanent discontinuation would also be eligible for tremelimumab in combination with durvalumab. Patients who are not candidates for other immune checkpoint inhibitors would not be candidates for tremelimumab in combination with durvalumab.

Assessing the Response Treatment

The clinical experts noted that, in clinical practice, imaging would be obtained every 3 months to assess response to treatment. The most important outcomes are prolonged survival, delayed progression, disease control, and maintained QoL with a low toxicity profile.

Discontinuing Treatment

The clinical experts advised that tremelimumab in combination with durvalumab should be discontinued if there is disease progression or intractable severe immune-related adverse effects.

Prescribing Considerations

According to the clinical experts, tremelimumab in combination with durvalumab can be administered in most systemic therapy suites in which cancer patients receive chemotherapy and immunotherapy. Administration of this therapy can be supervised by most medical oncologists experienced in treating HCC.

Clinician Group Input

This section was prepared by CADTH staff based on input provided by clinician groups. The full original clinician group inputs received by CADTH are included in the stakeholder section at the end of this report.

The clinician group input was obtained from 2 clinician groups, including the CGOEN, represented by 6 clinicians; the Ontario Health (Cancer Care Ontario) GI Drug Advisory Committee, represented by 5 clinicians; and a clinician from the Alberta Health Services Cancer Care at the University of Alberta.

The clinician groups noted that the current HCC treatment paradigm includes atezolizumab in combination with bevacizumab followed by lenvatinib, or sorafenib in patients without contraindication to immunotherapy, and lenvatinib followed by cabozantinib and regorafenib in patients with autoimmune disorders or contraindications to bevacizumab. The CGOEN indicated that, with modern systemic therapy, downsizing of disease has led to newer options for locoregional treatments of the liver (i.e., stereotactic radiation, embolization, ablation, resection, or transplant). The clinical groups identified the following as key goals of new therapies in HCC: prolonging life, delaying disease progression, improving response rate, managing side effects, reducing the severity of symptoms, maintaining HRQoL, and delaying deterioration. The CGOEN emphasized that a patient with HCC may be at an increased risk of bleeding due to the underlying liver disease and the vascular nature of the disease itself, and a therapy that does not increase this risk will be key in this area.

The clinician groups agreed that, given a good safety profile, tremelimumab in combination with durvalumab will be another first-line HCC treatment option, particularly for patients with hypertension or varices, or when upper GI endoscopy is not available. The clinician from the University of Alberta indicated that tremelimumab in combination with durvalumab may become the preferred first-line immunotherapy option for treatment of patients with unresectable HCC. The CGOEN and the clinician form the University of Alberta noted that patients receiving tremelimumab in combination with durvalumab would make fewer clinic visits and spend less time in the clinic because they would be treated every 4 weeks and essentially with 1 drug except for the first cycle, while for atezolizumab in combination with bevacizumab, patients are treated every 3 weeks and with 2 drugs.

According to the input from clinician groups received for this review, treatment response should be assessed by diagnostic imaging, such as MRI or CT scans, and blood tests every 3 to 4 months or as clinically indicated. The clinician groups indicated that the outcomes used to evaluate response to treatment in patients with HCC include improved OS, improved or maintained QoL, and improved response rate, leading to a reduction of symptoms and the possibility of other modalities, such as locoregional therapies, to control the disease process. The clinician groups identified several factors that may warrant discontinuation of tremelimumab in combination with durvalumab, including disease progression, unacceptable drug-related toxicities, or patient preference. The clinician groups emphasized that treatment with tremelimumab in combination with durvalumab should be provided by clinicians with expertise and experience in treating HCC. The GI Drug Advisory Committee noted that treatment with tremelimumab in combination with durvalumab should be performed in outpatient infusion clinics, including satellite clinics.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

HCC = hepatocellular carcinoma; NAPRA = National Association of Pharmacy Regulatory Authorities; PAG = Provincial Advisory Group; pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee; q.4.w. = every 4 weeks; vs. = versus.

Clinical Evidence

The objective of CADTH’s Clinical Review is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of tremelimumab (20 mg/mL) in combination with durvalumab (50 mg/mL) for the first-line treatment of adult patients with unresectable HCC. The focus will be placed on comparing tremelimumab in combination with durvalumab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of tremelimumab in combination with durvalumab is presented in 2 sections, and CADTH’s critical appraisal of the evidence is included after each section. The first section, the systematic review, includes pivotal studies and randomized controlled trials (RCTs) that were selected according to the sponsor’s systematic review protocol. The second section includes indirect evidence from the sponsor. No long-term extension studies or studies addressing gaps in the pivotal and RCT evidence were submitted by the sponsor.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• 1 pivotal phase III trial

• 1 sponsor-conducted ITC and 1 published NMA.

Pivotal Studies and Randomized Controlled Trial Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following were summarized and validated by the CADTH review team.

Description of Studies

Characteristics of the included studies are summarized in Table 6.

Table 6: Details of Pivotal Study and Randomized Controlled Trial Evidence

BCLC = Barcelona Clinic Liver Cancer; BICR = blinded independent central review; BOR = best objective response; CTCAE = Common Terminology Criteria for Adverse Events; CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4; DBP = diastolic blood pressure; DCR = disease control rate; DCR-16w = disease control rate at 16 weeks; DCR-24w = disease control rate at 24 weeks; DoR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-HCC18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18; GI = gastrointestinal; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HDV = hepatitis D virus; HRQoL = health-related quality of life; INR = international normalized ratio; mRECIST = modified Response Evaluation Criteria in Solid Tumors; NCI = National Cancer Institute; ORR = objective response rate; OS = overall survival; PD = progressive disease; PD-1 = programmed cell death 1 protein 1; PD-L1 – programmed cell death 1 ligand 1; PFS = progression-free survival; PFSFR = progression-free survival from rechallenge; PFSNT = progression-free survival from first postdiscontinuation therapy; q.4.w. = every 4 weeks; RECIST 1.1. = Response Evaluation Criteria in Solid Tumors Version 1.1; SBP = systolic blood pressure; TTP = time to progression; ULN = upper limit or normal.

Source: HIMALAYA Clinical Study Report.¹⁷

Key characteristics of the HIMALAYA trial are summarized in Table 5. HIMALAYA is a randomized, open-label, sponsor-blind, multicentre, global, phase III study to assess the efficacy and safety of tremelimumab in combination with durvalumab versus sorafenib in the treatment of patients with unresectable HCC who are not eligible for locoregional therapy and have not received prior systemic therapy for HCC in the first-line setting. The sponsor was blinded to treatment assignment and did not have access to any aggregate summaries by treatment group during the study. Patients were enrolled up to June 19, 2019, at 181 sites and randomized at 170 study centres in 16 countries (9 study centres in Canada).¹⁷

The primary outcome was OS for tremelimumab in combination with durvalumab versus sorafenib. Noninferiority and superiority for OS for durvalumab monotherapy versus sorafenib were key secondary outcomes; however, these are not relevant to this review. Additional secondary end points included OS rates (at 18, 24, and 36 months), PFS, TTP, ORR, DCR, and DoR assessed by the investigator, patient-reported outcomes, and safety. The study was funded by AstraZeneca Canada Inc.

Randomization was stratified according to macrovascular invasion (yes or no), etiology of liver disease (confirmed HBV versus confirmed HCV versus others), and ECOG PS (0 versus 1).

Tumour assessments were performed at randomization and then every 8 weeks (± 1 week) for the first 48 weeks following randomization, and every 12 weeks (± 1 week) thereafter until confirmed disease progression. Tumors were evaluated according to RECIST 1.1. All patients were followed up for survival until the end of the study unless they withdrew consent to survival follow-up.

Patients were randomly assigned in a 1:1:1:1 ratio using an interactive web response system into 1 of 4 treatment groups:

• Tremelimumab 300 mg × 1 dose plus durvalumab 1,500 mg every 4 weeks (n = 393)

• Sorafenib 400 mg twice daily (n = 389)

• Durvalumab 1,500 mg every 4 weeks (n = 389)

• Closed treatment group: tremelimumab 75 mg every 4 weeks × 4 doses plus durvalumab 1,500 mg every 4 weeks (n = 153).

The sponsor noted that at the time of the HIMALAYA study design, sorafenib was the only approved treatment for unresectable HCC patients who were ineligible for locoregional therapy and who had not undergone prior systemic therapy. Sorafenib was therefore considered standard-of-care treatment for these patients and was selected as the active comparator.

According to the sponsor, the results from the preplanned analysis of Study 22 (a phase I and II trial conducted in patients with unresectable HCC where the primary objectives were dose-finding and safety) demonstrated that tremelimumab 75 mg plus durvalumab did not provide meaningful efficacy improvements over durvalumab monotherapy. This treatment group was therefore closed in the HIMALAYA trial following protocol amendment 3, on November 29, 2018. The remaining patients were randomly assigned 1:1:1 to receive durvalumab, sorafenib, or tremelimumab in combination with durvalumab. Patients already randomized to the tremelimumab 75 mg plus durvalumab group could continue assigned study treatment, provided the investigator and patient agreed it was in the best interest of the patient. The tremelimumab 75 mg plus durvalumab regimen is not an approved dose.

Tremelimumab in combination with durvalumab is the drug under review; results pertaining to the durvalumab monotherapy versus sorafenib are not reported as durvalumab monotherapy was out of scope of this review.

The study design is depicted in Figure 1. The final data cut-off date was August 27, 2021.

Figure 1: HIMALAYA Study Design

BCLC = Barcelona Clinic Liver Cancer; BL = baseline; D = durvalumab; ECOG = Eastern Cooperative Oncology Group; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; OS = overall survival; PD = progressive disease; S = sorafenib; T75+D = tremelimumab 75 mg plus durvalumab; T300+D = tremelimumab 300 mg plus durvalumab.

^a Patient numbers shown are approximate and correspond to the planned enrolment.

^b Enrolment into the T75+D group was closed following protocol amendment 3 (November 29, 2018) due to preliminary efficacy findings. Patients randomized to T75+D before protocol amendment 3 could continue on their assigned study treatment provided the investigator and patient agreed this was in the patient’s best interest. Patients randomized to T75+D who had not completed or started all 4 doses of tremelimumab could either complete the full schedule or continue with durvalumab monotherapy only.

^c Baseline radiological tumour assessments were performed within 28 days before the date of randomization.

^d Radiological tumour assessments were performed at randomization then every 8 weeks (± 1 week) for the first 48 weeks after randomization, and then every 12 weeks (± 1 week) until confirmed PD. The imaging schedule was followed regardless of any delays in dosing. Patients who permanently discontinued study treatment for reasons other than confirmed PD continued to have radiological scans performed following the same postrandomization schedule until confirmed PD.

^e Patients with confirmed PD who, in the investigator’s opinion, continued to receive benefit from their assigned treatment and met the criteria for treatment in the setting of PD could continue to receive their assigned treatment regimen.

Source: HIMALAYA Clinical Study Report.¹⁷

Populations

Inclusion and Exclusion Criteria

Key inclusion and exclusion criteria for the HIMALAYA study are shown in Table 5. The study population included adult patients (18 years and older) with confirmed HCC, based on histopathological findings, and with preserved liver function (Child-Pugh class A). Patients must have been BCLC stage B or C, with an ECOG PS of 0 or 1 and a life expectancy of more than 12 weeks. They were included only if they were ineligible for locoregional therapy for unresectable HCC or progressed after locoregional therapy for HCC. Locoregional therapy must have been completed 28 days or more before the baseline scan. Patients must not have received any prior systemic therapy for unresectable HCC and must not have had clinically meaningful ascites within 6 months before the first scheduled dose.

Interventions

The HIMALAYA trial was an open-label, sponsor-blinded trial. Sponsor personnel refrained from accessing treatment records whenever possible and did not view data aggregated by treatment group during the course of the study, and interim analyses were performed by an independent data monitoring committee. Patients were randomized in a 1:1:1:1 ratio to receive 300 mg of tremelimumab in combination with durvalumab (N = 393), sorafenib (N = 389), durvalumab monotherapy (N = 389), or a different 75 mg of tremelimumab in combination with durvalumab (N = 153, closed during randomization due to preliminary efficacy findings). The latter 2 groups are not included in the CADTH systematic review as the drug under review is 300 mg of tremelimumab in combination with durvalumab N = 393).

In the tremelimumab in combination with durvalumab group, patients received 1 dose of tremelimumab (300 mg) by IV infusion over 1 hour (± 5 minutes) co-administered with 1 dose of durvalumab (1,500 mg) by IV infusion on day 1, followed by durvalumab 1,500 mg every 4 weeks until confirmed progressive disease, unacceptable toxicity, or any discontinuation criteria were met. Durvalumab was available as a 500 mg vial concentrate solution for infusion after dilution (50 mg/mL) and tremelimumab as a 400 mg vial concentrate solution for infusion after dilution (20 mg/mL). The dose schedule is presented in Figure 2. In the sorafenib group, patients received 400 mg (2 × 200 mg tablets) orally twice daily until confirmed progressive disease at the investigator’s discretion, unacceptable toxicity, or any discontinuation criteria were met.

Discontinuation criteria included withdrawal of consent, AEs that contraindicated further dosing, pregnancy or intent to become pregnant, noncompliance with study protocol, initiation of alternative anticancer therapy, and clinical progression. Patients could continue treatment after progression if the investigator determined that they were benefiting from treatment and they met the criteria for continuation after progressive disease. These criteria included that progression should not have occurred after confirmed response in the target lesions (regardless of the appearance of new lesions), and that there were no significant, unacceptable, or irreversible toxicities that indicate continuing treatment would not further benefit the patient.

Patients who did not continue treatment after disease progression were followed up for survival. Patients who discontinued treatment due to toxicity or symptomatic deterioration, or who commenced subsequent anticancer therapy, were followed up until confirmed disease progression and for survival. Crossover within the study was not permitted.

Figure 2: Tremelimumab in Combination With Durvalumab Dosing Schedule in HIMALAYA

D/C = discontinuation; Durva = durvalumab; PD = progressive disease; Treme = tremelimumab.

Source: HIMALAYA Clinical Study Report.¹⁷

Dose Modifications

Weight-based dosing modifications for durvalumab (20 mg/kg every 4 weeks) and tremelimumab (4 mg/kg) were permitted if a patient’s weight decreased to 30 kg or less. If the patient regained weight to more than 30 kg, they would receive the original assigned fixed dose of durvalumab 1,500 mg every 4 weeks.

Suspected sorafenib-related toxicities were managed based on the local approved product label. In countries where sorafenib was not approved, the sorafenib dose may be reduced to 400 mg (2 × 200 mg tablets) orally once daily. If an additional dose reduction was required, the sorafenib dose could be reduced to a single 400 mg dose (2 × 200-mg tablets) orally every other day.

Rechallenge With Tremelimumab

Patients receiving tremelimumab in combination with durvalumab who had evidence of disease progression (with or without confirmation according to RECIST 1.1) after their first 4 dosing cycles, but who were benefiting from treatment according to investigator opinion, were eligible for 1 round of re-treatment with tremelimumab (300 mg) combined with durvalumab. Patients had to meet rechallenge criteria, which were identical to the criteria for treatment through progression and included that no progression should have occurred after a confirmed response in the target lesions (regardless of the appearance of new lesions), and that there were no significant, unacceptable, or irreversible toxicities that indicated continuing treatment would not further benefit the patient.

Concomitant Medication

Treatments that were prohibited for both treatment groups included any other investigational anticancer therapy or monoclonal antibodies against CTLA-4, PD-1, or PD-L1, and any concurrent chemotherapy, radiotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment. Treatments prohibited for patients in the tremelimumab in combination with durvalumab group included immunosuppressive medications (e.g., systemic corticosteroids at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and tumour necrosis factor-alpha blockers) unless clinically indicated. Sunitinib and drugs with laxative properties and herbal or natural remedies for constipation were prohibited within 90 days after the last dose of tremelimumab. Epidermal growth factor receptor TKIs were prohibited within 90 days after the last dose of durvalumab. Best supportive and prophylactic care (including antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control, and pain management) was provided as necessary for all patients.

Outcomes

A list of efficacy end points assessed in this clinical review report is provided in Table 7 and further summarized in the following section. Summarized end points are based on those included in the sponsor’s Summary of Clinical Evidence as well as any identified by stakeholders (e.g., clinical experts, clinician groups, or patient groups) as important to this review. Only outcomes for the comparison relevant to this review (i.e., tremelimumab in combination with durvalumab versus sorafenib) are included.

Primary End Point

The primary outcome of the HIMALAYA trial was OS, defined as the time from the date of randomization until death due to any cause regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy. Survival status was assessed at 2, 3, and 4 months (± 1 week), and then every 2 months (± 1 week) until the end of the study. The survival time for patients who were not known to have died at the data cut-off date was censored at the date of the last recorded date on which the patient was known to be alive. If that date or the date of death was after the data cut-off date, patients were censored at the data cut-off date.

Table 7: Outcomes Summarized From Pivotal Studies and RCT Evidence Identified by the Sponsor

BICR = blinded independent central review; BOR = best objective response; DCR = disease control rate; DCR-16w = disease control rate at 16 weeks; DCR-24w = disease control rate at 24 weeks; DoR = duration of response; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-HCC18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18; mRECIST = modified Response Evaluation Criteria in Solid Tumors; ORR = objective response rate; OS = overall survival; OS18 = OS at 18 months; OS24 = OS at 24 months; OS36 = OS at 36 months; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; TTP = time to progression.

^aOS defined as time from date of randomization to date of death due to any cause. Statistical testing for these end points was adjusted for multiple comparisons. To control the familywise error rate at 5% (2-sided), an alpha of 0.1% was spent on the interim ORR and DoR analysis (first interim analysis). The remaining 4.9% alpha level was spent on all OS analyses.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table were taken from the sponsor’s Summary of Clinical Evidence).

Secondary and Exploratory End-Point Variables

Secondary end points included PFS, TTP, ORR, best objective response (BOR), DCR, disease control rate at 16 weeks (DCR-16w), disease control rate at 24 weeks (DCR-24w), and DoR based on investigator assessments using RECIST 1.1. Disease assessment by CT or MRI was conducted at baseline within 28 days of randomization, then every 8 weeks (± 1 week) for the first 48 weeks after randomization, and then every 12 weeks (± 1 week) until radiological progression as defined by RECIST 1.1 (followed by a subsequent scan if feasible). Guidelines for evaluation of objective tumour response using RECIST 1.1 included the recommendation that the same modality (and ideally the same unit) be used for each patient across all imaging time points.

In the first interim analysis, PFS, TTP, ORR, DCR, DoR, and time to response were evaluated based on BICR assessments according to RECIST 1.1, mRECIST, and irRECIST, and ORR was also evaluated based on investigator assessments according to RECIST 1.1. Secondary end points in this analysis were ORR, BOR, and DoR based on BICRs according to mRECIST. A BICR of radiological scans was performed on patients whose scans had been reviewed by at least 2 primary radiologists.

Progression-free survival was defined as the time from randomization until date of objective disease progression or death from any cause in the absence of progression, regardless of whether or not the patient withdrew from therapy or received another anticancer therapy before progression. Patients who were alive at the data cut-off date with no documented progression were censored at the date of their last evaluable RECIST 1.1 assessment. If a patient died after 2 or more consecutive missed visits, they were censored at the date of the last evaluable RECIST 1.1 assessment before the 2 missed visits. Patients with no baseline data were censored at the randomization date.

The TTP was defined as the time from randomization until objective tumour progression in the absence of death. Patients who died without progression were censored at the date of death.

The ORR was defined as the proportion of patients with at least 1 confirmed visit response of a complete response or partial response. A confirmed response refers to a response recorded at 1 visit and confirmed by repeat imaging after 4 weeks with no evidence of progression between the 2 visits. Unconfirmed responses were not confirmed by repeat imaging. Patients who had no disease progression between 2 nonconsecutive visit responses of a partial response were defined as responders. ORR assessments included data obtained until disease progression or the last evaluable assessment in the absence of progression.

A BOR was defined as the best response a patient had following randomization but before starting any subsequent cancer therapy and up to and including RECIST 1.1 progression or the last evaluable assessment in the absence of RECIST 1.1 progression. BORs were categorized to 1 of the following response categories: complete response, partial response, stable disease, no evidence of disease (applies only to patients entering the study with no disease at baseline), progressive disease, and not evaluable.

The DCR was defined as the proportion of patients with a BOR of complete response, partial response, or stable disease. The DCR-16w and DCR-24w were defined as the proportions of patients with a BOR of CR, PR, or stable disease for at least 16 weeks (± 7 days) and at least 24 weeks (± 7 days) following the start of treatment, respectively.

The DoR was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression.

Exploratory end points included PFS, TTP, ORR, DCR, DCR-16w, DCR-24w and DoR based on BICR assessments using mRECIST for HCC and irRECIST. While RECIST 1.1 measures lesions in their longest diameter, mRECIST only measures the arterially enhanced portions of the HCC target lesions. Lesions categorized as progressive disease in RECIST 1.1 require verification in subsequent examinations to confirm progressive disease in irRECIST (to distinguish progressive disease from pseudoprogression).³⁸

Progression-free survival from rechallenge in combination therapy groups was defined as the time from the date of rechallenge (first dose date in the rechallenge period) until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from therapy or received another anticancer therapy before progression. PFS from first postdiscontinuation therapy on next treatment was defined as the time from the date of first postdiscontinuation therapy (cancer therapy drug start date on the postinvestigational-product discontinuation systemic cancer therapy form) until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient receives another anticancer therapy before progression. PFS from rechallenge (in combination therapy arms) and PFS on next treatment were determined by investigator assessments using RECIST 1.1.

Health-Related Quality of Life and Patient-Reported End Points

Health-related QoL was assessed as a secondary outcome using the EORTC QLQ-C30 and EORTC QLQ-HCC18. Exploratory outcomes included the EQ-5D 5-Level questionnaire (EQ-5D-5L), Patient’s Global Impression of Change (PGIC), and patient-reported outcome version of the CTCAE. Results of the EQ-5D 5-Level, PGIC, and patient-reported outcome of the CTCAE were not included in our review as they were not considered critical or important outcome measures for decision-making by the CADTH review team. Baseline assessments were completed at day 1 (except for PGIC), then assessments were completed every 8 weeks (± 7 days) for the first 48 weeks and every 12 weeks (± 7 days) thereafter until disease progression and up to 3 months after disease progression. The sponsor stated that approved translations of all tools underwent cultural and linguistic validation for the countries involved in the study before use.

The EORTC QLQ-C30 is a 30-item self-administered questionnaire comprising 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and/or vomiting), a GHS/QoL scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).³⁹ Most questions have 4 response options (“not at all,” “a little,” “quite a bit,” and “very much”), with scores on these items ranging from 1 to 4. For the 2 items that form the global QoL scale, the response format is a 7-point Likert-type scale with anchors at 1 (“very poor”) and 7 (“excellent”). All scale and item scores were linearly transformed to a scale from 0 to 100. For the functional scales and the global QoL scale, a high score represents a good level of functioning. Conversely, high scores on the symptom scales and single items of the EORTC QLQ-C30 correspond to more severe symptoms.⁴⁰ The sponsor defined an MID for clinically meaningful change as an absolute change in the score from baseline of 10 or more points. The main measures reported were GHS/QoL, physical function, and fatigue scales, along with the single items of appetite loss and nausea.

The EORTC QLQ-HCC18 is an 18-item self-administered additional questionnaire to the EORTC QLQ-30, which was developed and validated specifically for HCC.^41,42 It consists of 6 multi-item symptom scales (fatigue, jaundice, nutrition, pain, fever, and body image), 2 single-item symptom scales (abdominal swelling and sexual interest); and 1 multi-item functional scale (body image). All scale and item scores were linearly transformed to a scale from 0 to 100. For all scales, a higher score indicates worse symptoms or poorer HRQoL. The sponsor defined an MID for clinically meaningful change as an absolute change in the score from baseline of 10 or more points on both scales based on a patient population with breast cancer and small-cell lung cancer.⁴³ The CADTH review team did not identify any evidence for an MID among patients with unresectable HCC and the sponsor did not provide any evidence for this threshold for the EORTC QLQ-HCC18. The main measures reported were shoulder pain, abdominal pain, and abdominal swelling symptom scales.

Time to HRQoL or function deterioration was defined as the time from the date of randomization until the date of the first clinically meaningful deterioration (confirmed at a subsequent visit) or death in the absence of clinically meaningful deterioration, regardless of whether the patient discontinued study drug(s) or received another anticancer therapy before deterioration. The population for the analysis of time to GHS/QoL or function deterioration included a subset of the FAS with baseline scores of 10 or higher. Patients whose GHS/QoL or function did not show a clinically meaningful deterioration and who were alive at the time of the analysis were censored at the time of their last evaluable assessment of patient-reported outcomes. Patients whose GHS/QoL or function deteriorated or who died after 2 or more missed patient-reported outcome assessment visits were censored at the time of their last evaluable assessment. GHS or QoL and symptom improvement rates were defined as the number (%) of patients with a best overall score response of “improved” in GHS/QoL, function, or symptoms. The denominator consisted of a subset of the FAS with a baseline GHS/QoL or function score of 90 or lower, or a symptom score of 10 or higher.

Table 8: Summary of Patient-Reported Outcome Measures and Their Measurement Properties

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-HCC18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18; GHS = global health status; HCC = hepatocellular carcinoma; MID = minimal important difference; QoL = quality of life.

Harms End Points

Safety and tolerability were assessed at all visits using the incidence of AEs, serious AEs, deaths, AEs leading to discontinuation, other AEs, AEs of special interest, and immune-mediated AEs. Treatment-emergent AEs were defined as any AEs with an onset on or after the date of the first dose, or pretreatment AEs that increased in severity on or after the date of the first dose, within 90 days following the date of last dose of study drug(s) or up to the date of initiation of the first subsequent therapy (whichever occurs first).

The AEs of special interest for tremelimumab in combination with durvalumab include, but are not limited to, events with a potential inflammatory or immune-mediated mechanism and that may require more frequent monitoring and/or interventions, such as steroids, immunosuppressants, and/or hormone-replacement therapy. AEs of special interests that were managed using immunosuppressants, and/or endocrine therapy were adjudicated by as immune-mediated AEs.

The sponsor noted that, due to the nature of HCC, AEs reported in the system organ class of hepatobiliary disorders and AEs of bleeding were of particular interest. The sponsor therefore presented a detailed analysis for the hepatic SMQ and hemorrhage SMQ. The following hepatic SMQs were considered relevant to the HCC patient population: cholestasis and jaundice of hepatic origin, hepatic failure, fibrosis and cirrhosis, and other liver-damage–related conditions, hepatitis, noninfectious liver infections, liver malignant tumours, liver-related investigations, signs and symptoms, and liver-related coagulation and bleeding disturbances. Hemorrhage SMQs included hemorrhage terms and hemorrhage laboratory terms.

Statistical Analysis

A summary of statistical analyses for trial end points is presented in Table 9.

Table 9: Statistical Analysis of Efficacy End points

AE = adverse event; AESI = adverse event of special interest; BOR = best objective response; CI = confidence interval; DCR = disease control rate; DCR-16w = disease control rate at 16 weeks; DCR-24w = disease control rate at 24 weeks; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-HCC18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18; EQ-5D-5L = EQ-5D 5-Level questionnaire; HBV = hepatitis B virus; HCV = hepatitis C virus; HR = hazard ratio; NA = not applicable; NE = not evaluable; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PGIC = Patient’s Global Impression of Change; PRO-CTCAE = patient-reported outcome version of the Common Terminology Criteria for Adverse Events; RECIST = Response Evaluation Criteria in Solid Tumors Version 1.1; SAE = serious adverse event; vs. = versus; WDAE = withdrawal due to adverse event.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table were taken from the sponsor’s Summary of Clinical Evidence).

Sample Size and Power Calculation

The sample size determination considered the comparison of the primary outcome of OS for tremelimumab in combination with durvalumab versus sorafenib for superiority. Because this determination assumed an exponential distribution of OS and a 2-month delay in the separation of the OS curves, an average HR of 0.70 was used. When estimating the analysis times, a nonuniform accrual of patients with a duration of 22 months was assumed with a follow-up duration of 15.5 months and a total duration of 37.5 months. No adjustment was made for dropouts. For the efficacy comparisons, the median OS for sorafenib was assumed to be 11.5 months, with an 18-month OS rate of 33.8%. The assumed average HR of 0.70 for tremelimumab in combination with durvalumab versus sorafenib translated to an increase in median OS from 11.5 months to 16.5 months and an increase in the 18-month OS rate from 33.8% to 46.8%. The final analysis was planned for when 515 OS events occurred in both treatment groups combined (67% maturity) which was approximately 37.5 months after the first patient was randomized, providing at least 97% power to demonstrate a statistically significant difference In OS at a 2-sided 4.25% significance level. No formal sample-size calculations were associated with planned first interim analysis.

Statistical Testing and Multiple-Testing Procedure

The end points for OS were compared between treatment groups using a stratified log-rank test, stratifying by etiology of liver disease (confirmed HBV versus confirmed HCV versus others), ECOG PS (0 versus 1), and MVI (yes versus no). The P value was generated using rank tests for association as the testing approach, which corresponds to a Cox regression with the Breslow approach for handling ties. The HR was estimated using a stratified Cox proportional hazards model and the Efron method to control for ties and stratification variables, and the 95% CI was calculated using a profile-likelihood approach. The stratification variable used the values recorded in the randomization system (an interactive web response system). Kaplan-Meier plots of OS were also estimated by treatment group.

This first interim analysis was performed after 100 patients in each treatment group were followed for at least 32 weeks after randomization and after all patients had been enrolled. A second interim analysis was performed when 415 OS events had occurred in the 2 treatment groups combined (52% maturity). The OS comparison was not statistically significant at a 2-sided alpha level of 0.0244 and the study continued to the final analysis. The final analysis was performed when 555 OS events had occurred in the 2 treatment groups combined (71% maturity), which was 46 months after the first patient was randomized. The smallest treatment difference that was statistically significant at the final analysis was an average HR of 0.84 (an increase in median OS from 11.5 months to approximately 13.7 months in tremelimumab in combination with durvalumab versus sorafenib).

To control for the familywise error rate at the 5% level (2-sided), an alpha level of 0.1% was applied to the interim ORR and DoR analysis (at the first interim analysis), while the remaining 4.9% alpha level was spent on all OS analyses. If all the OS analyses for all the alternative hypotheses were considered successful, as shown in Figure 3, the 4.9% alpha level was to be passed to test the difference in the 3-year survival rates between tremelimumab in combination with durvalumab and sorafenib; however, this was not achieved. Multiplicity for other outcomes was not controlled.

The key secondary analyses for the alternative hypotheses were to compare OS for durvalumab monotherapy versus sorafenib group (first for noninferiority then superiority). Exploratory analyses compared OS for the durvalumab group versus tremelimumab in combination with durvalumab group. These analyses were not relevant and are not included in this review.

Secondary Outcomes

The ORR was calculated using exact confidence intervals at the first interim analysis, and then logistic regression was used to calculate the odds ratio (with 95% CI and P value) at the final analysis. PFS and time to response were calculated using a stratified log-rank test for P value, and HR from the Cox model (with 95% CI). BOR, DoR and DCR were reported using descriptive statistics.

For the EORTC QLQ-C30 and EORTC QLQ-HCC18, average changes from baseline were reported using a mixed model for repeated measures analysis as well as summary statistics. Time to deterioration was assessed using a stratified log-rank test for the P value, HR from the Cox model, and a Kaplan-Meier plot. The improvement rate was assessed using logistic regression with an OR, 95% CI, and P value.

Subgroup Analyses

Subgroup analysis comparing OS between the tremelimumab in combination with durvalumab and sorafenib treatment groups was conducted for the following prespecified subgroups: PD-L1 expression level, etiology of liver disease, serum alpha-fetoprotein level, MVI, EHS, MVI and EHS, ECOG PS at screening, BCLC stage at study entry, sex, age at randomization, and region. For each subgroup level, the HR and 95% CI were calculated from a Cox proportional hazards model that only contained a term for treatment.

The following subgroups, planned a priori in the statistical analyses plan, were deemed clinically meaningful by the clinical experts consulted by CADTH for this review: etiology of liver disease, MVI, ECOG PS at screening, BCLC stage at study entry, and serum alpha-fetoprotein level.

Subgroup analyses were also performed for secondary end points PFS, TTP, ORR, BOR, DoR, DCR, DCR-16w, and DCR-24w in the PD-L1 expression, etiology of liver disease, and MVI subgroups.

Figure 3: Multiple-Testing Strategy in the HIMALAYA Trial

D = durvalumab monotherapy 1,500 mg every 4 weeks; OS = overall survival; sorafenib = sorafenib 400 mg twice daily; T300+D = tremelimumab 300 mg × 1 dose + durvalumab 1,500 mg every 4 weeks.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table were taken from the sponsor’s Summary of Clinical Evidence).

Sensitivity Analyses

Sensitivity analyses for OS were conducted to rule out attrition bias using a Kaplan-Meier plot of time to censoring, where the censoring indicator for OS was reversed (0 for patients who died and 1 for censored patients). An exploratory analysis was also conducted to assess the assumption of proportionality using a stratified MaxCombo test with the same stratification factors as the primary analysis. Nonproportionality was expected due to the delayed effects of immuno-oncology drugs. An additional sensitivity analysis was planned to assess the potential impact of the COVID-19 pandemic, with patients who died from COVID-19 to be censored at their infection death date. However, the sponsor noted that the pandemic did not meaningfully affect the study and only 7 cases of COVID-19 infection were reported during the study.

Analysis Populations

Key analysis populations of interest are presented in Table 10. The FAS was used in all efficacy analyses and included all randomized patients, including those randomized in error. Patients were analyzed in the group to which they were randomized. The safety analysis set included all patients who received any number of investigational products, including those who were randomized in error or not randomized and still started on study treatment. Patients were analyzed based on the treatment received.

Table 10: Analysis Populations in the HIMALAYA Trial

FAS = full analysis set.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Protocol Changes

The major changes to the study protocol were:

• In protocol amendment 1, Protocol version 2.0 (December 20, 2017), the exploratory objective was included to assess PFS from rechallenge in the tremelimumab in combination with durvalumab group.

• In protocol amendment 3, Protocol version 4.0 (November 29, 2018), enrolment into the tremelimumab 75 mg plus durvalumab group was closed due to preliminary efficacy findings in Study 22, the primary and secondary objectives were realigned (the original primary objective of OS for tremelimumab 75 mg plus durvalumab versus sorafenib was replaced with durvalumab versus sorafenib and tremelimumab 300 mg plus durvalumab versus sorafenib for OS), the multiple-testing strategy was updated to reflect the procedure for controlling the type I error as a result of the changes to the primary and secondary objectives, patient-reported outcome end points were added to the multiple-testing procedure and updated such that the first interim analysis was performed after approximately 100 patients per treatment group had the opportunity for 32 weeks rather than 24 weeks of follow-up.

• In protocol amendment 5, Protocol version 6.0 (August 20, 2019), statistical analysis methods were revised to change dual primary objectives to a hierarchical approach with a single primary objective and 2 key secondary objectives, including ORR, following interim analysis of the ongoing Study 22 (the multiple-testing strategy was updated, ORR and patient-reported outcome end points were removed from the multiple-testing procedure, and the number of events, maturity, power and 2-sided significance levels for these analyses were updated). Efficacy assessments in the first interim analysis of patients with an opportunity for 32 weeks of follow-up were added as a secondary objective. This amendment was made before data cut-off for the first interim analysis on September 2, 2019.

Results

Patient Disposition

Patient disposition in the HIMALAYA study in the tremelimumab in combination with durvalumab and sorafenib groups is summarized in Table 11. Of ||||| |||||||| who were screened, ||||| |||||||| were randomized into 1 of the 4 original treatment groups. Of the 687 screening failures (34%), the majority (654 patients) were due to eligibility criteria not being fulfilled ||||||||| |||| || |||||||| ||||| ||| |||||| |||||||| |||| |||||||||| || ||||||||| ||| ||||| || ||||||||||||||||| |||||||| |||| ||||| ||||||| ||| ||||||||| ||| |||||||||| ||||| ||||| |||| || ||| |||| |||||||||| ||| ||||||| ||||| |||| ||| ||||| |||||||| |||||||| |||||||| || |||||||||| |||||||| ||| |||| |||||||| ||| |||||||||||||| |||| |||||| ||| ||||||||||| ||||| ||| ||||||||| |||||||||| |||| ||| |||||| |||||| || |||||||| |||||||| ||| ||||||

At the time of the data cut-off on August 27, 2021, 345 patients (88.7%) in the tremelimumab in combination with durvalumab group and 353 (94.4%) in the sorafenib group had discontinued study treatment. The most common reasons for discontinuing tremelimumab in combination with durvalumab and sorafenib were objective progressive disease (183 patients [47.0%] and 170 patients [45.5%], respectively), subjective progressive disease (61 patients [15.7%] and 66 patients [17.6%], respectively), and AEs (52 patients [13.4%] and 63 patients [16.8%], respectively).

Protocol Violations

| ||||| || ||||||||| |||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| || |||||||| |||||| || ||| ||||||||| ||||| ||| || ||||| |||||||||| |||||||| |||||||||| ||| |||| |||||||| |||||||| |||| || ||||||||| ||| |||||||| || |||||| |||||| ||| |||| |||||||| ||| |||||||||| ||| ||| ||| ||||||| ||||| ||||||||| || |||||||| |||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| || |||||||| |||| || ||| ||||||||| |||||||

Table 11: Summary of Patient Disposition in the HIMALAYA Study

^aObjective progressive disease as confirmed by Response Evaluation Criteria in Solid Tumors Version 1.1.

^bPatients confirmed alive in follow-up or on active study treatment at the time of final analysis reported “study completion” on the disposition electronic case report form.

^cPatients ongoing in study are the same as patients who completed the final analysis.

^dPercentages are calculated from the number of patients who received treatment in the global study. For combination therapy patients, durvalumab reason is reported.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Table 12: Summary of Baseline Characteristics in HIMALAYA (Full Analysis Set)

BCLC = Barcelona Clinic Liver Cancer, ECOG = Eastern Cooperative Oncology Group Performance Status, HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus, PD-L1 = programmed cell death 1 ligand 1; SD = standard deviation.

^aIncludes Brazil, Canada, France, Germany, Italy, Japan, Russia, Spain, Ukraine, and the US.

^bThe ECOG PS scale ranges from 0 to 5, with higher numbers corresponding to greater disability.

^cPatient’s ECOG PS was normal (0) at screening but deteriorated to 2 at randomization, while the Child-Pugh class was A at screening but B at randomization. The patient did not receive study treatment.

^dECOG PS was not assessed at screening. At cycle 1, the ECOG PS was normal (0).

^eThe Child-Pugh classification of liver disease severity is determined by the degree of ascites, serum concentrations of bilirubin and albumin, prothrombin time, and degree of encephalopathy and classified as follows: class A (well-compensated disease), score of 5 to 6; class B (significant functional compromise), score of 7 to 9; and class C (decompensated disease), score of 10 to 15.

^fThe BCLC staging classification system includes stages 0 (very early), A (early), B (intermediate), C (advanced), and D (end stage).

^gNo active viral hepatitis identified.

^hBaseline PD-L1 results were not available for patients who were randomly assigned but not treated.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Baseline Characteristics

The baseline demographic and disease characteristics of the tremelimumab in combination with durvalumab and sorafenib groups are summarized in Table 12. Baseline demographic and disease characteristics were generally well balanced between study groups. ||| |||| |||| || |||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||| ||||||||| |||||| |||| || ||||| ||| ||||| |||||| ||| |||| ||||| ||| ||||| ||||||| ||||||||||||| ||||||||||||| ||| || |||||||| || |||| ||||||||| |||||| |||| ||||| ||| ||| |||| ||||||| |||||| |||| || ||| |||||||| |||| ||||| |||||||| ||||| |||| |||||| ||| |||| |||| || |||| |||||||| || |||||||| |||||| Almost all patients had a Child-Pugh class A score (| |||||||| |||||||||||| || ||||| ||||| |||||||||). Approximately 80% had BCLC stage C, and 20% had BCLC stage B. Approximately half had EHS, and a quarter of patients had MVI. With regards to previous disease-related treatment, more than a third of patients had undergone therapeutic embolization, ||||||||||||| ||| ||| ||||||||| ||| ||||||| |||||||, and 48 patients (12.2%) in the tremelimumab in combination with durvalumab group and 37 patients (9.5%) in the sorafenib group had received prior radiotherapy.

Exposure to Study Treatments

Patient exposure to study treatments is presented in Table 13. For all treated patients (in the safety analysis set) the median total treatment duration was 5.5 months (range = 0.4 to 42.7) in the tremelimumab in combination with durvalumab group and 4.1 months (range = 0.1 to 38.6) in the sorafenib group. ||||| |||| || |||||||||| || |||||||||||| |||| |||||||||| |||||||| ||| |||||||||||| ||||||| |||||||||| |||||||| ||||||||||||| |||||||| || ||||||||| |||||| ||| |||||||||| |||||| |||||||| || ||| ||||| |||||||| ||||| |||||||| ||| || ||| || ||| |||||||| ||||||||| ||||| |||| || |||||||||||| |||||||| ||||||||||||| || |||||||||| ||||||| ||||||||| |||| |||||||||| |||||||| || ||||||||||||| |||| || |||||||| |||| |||||||| ||||||||| |||| |||||||| ||| || ||| |||| |||||||| |||||||||

Table 13: Redacted

NA = not applicable; SD = standard deviation.

Note: This table has been redacted at the request of the sponsor.

^aInitial treatment phase includes the start of study treatment to last treatment or last treatment before rechallenge, where rechallenge occurred.

^bTotal study exposure includes initial treatment and rechallenge phase, where rechallenge occurred.

^cTotal treatment duration for immunotherapies = (last dose date + 27 days or date of death or data cut-off, whichever occurred earlier − first dose date + 1)/(365.25/12). Total treatment duration for sorafenib = (last dose date or date of death or data cut-off, whichever occurred earlier − first dose date + 1)/(365.25/12).

^dActual treatment duration = (intended exposure – total duration of dose delays)/(365.25/12). Patients who took infusion earlier than planned were set to 0 for calculation.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Concomitant Medications

Concomitant medications used by || ||||| || || |||||||| || |||||| ||||||||| ||||| ||| |||||||||| || ||||| ||| ||| || ||||||||||| ||||||||||| ||| ||||||||| |||| |||||||| ||||||| ||||||| ||| |||| |||||||||| |||||||| ||||||||||| ||||||||||| || |||| |||| ||| || |||||||| || |||| ||||| |||||| |||| |||||||||| ||| |||||||||| ||||||| ||||||||||||| |||||||||| ||||||| ||| |||||| |||| |||||||||| ||||||||

Table 14: Redacted

ACE = angiotensin-converting-enzyme; ATC = anatomic therapeutic chemical; carbamide products = hydrogen peroxide; FAS = full analysis set; H2 = histamine type-2; HMG CoA = hydroxymethylglutaryl coenzyme A.

Note: This table has been redacted at the request of the sponsor.

^aA patient can have 1 or more generic term reported under a given ATC text. Patients with multiple concomitant medications with the same generic term under a given ATC text are counted once for that generic term. Therapy classification shown according to the WHO drug ATC classification system and mechanism of action.

Source: HIMALAYA Clinical Study Report.¹⁷

Subsequent Treatment

The details on subsequent anticancer therapy (defined as therapy started on or after the first dosing date) are presented in Table 15. Subsequent anticancer therapy was received by 40.7% of patients in the tremelimumab in combination with durvalumab group and 45% of patients in the sorafenib group. The most common therapy ||| |||||||| |||||||| ||||| ||||| || |||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| |||| || |||||||| || ||| ||||||||| ||||| |||||||| |||||||||| |||| |||||||| |||||||| |||||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| |||| || ||||| ||| |||| |||||||| || ||| ||||||||| ||||| ||||||||

Efficacy

A summary of key efficacy outcomes from the HIMALAYA trial is presented in Table 16. Detailed discussions follow.

Overall Survival

At the final OS data cut-off on August 27, 2021, ||||||| ||||||||| |||| ||| ||| ||||||, and median follow-up time in the tremelimumab in combination with durvalumab group was 33.2 months (95% CI, 31.7 to 34.5) while in the sorafenib group it was 32.2 months (95% CI, 30.4 to 33.7). OS results are presented in Table 17. In the FAS, ||||| |||| ||| |||||| ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||| |||||| ||||||| || ||| ||||||||| |||||. The HR, adjusted for stratification factors (determined by an interactive web response system), was 0.78 (96.02% CI, 0.65 to 0.93; stratified log-rank 2-sided P = 0.0035). The Kaplan-Meier estimates for median OS were 16.4 months (95% CI, 14.2 to 19.6) in the tremelimumab in combination with durvalumab group and 13.8 months (95% CI 12.3 to 16.1) in the sorafenib group. The OS rates at 36 months were 30.7% (95% CI, 25.8 to 35.7) in the tremelimumab in combination with durvalumab group and 20.2% (95% CI,15.8 to 25.1) in the sorafenib group. In the Kaplan-Meier plot of OS for tremelimumab in combination with durvalumab versus sorafenib presented in Figure 4 the curves appear to separate after 4 months, favouring tremelimumab in combination with durvalumab.

Subgroup Analysis of Overall Survival

The estimated effects in all predefined subgroups were consistent with the overall OS analysis as shown in Table 18.

||||||||||| |||||| || |||||| |||| |||||||| |||||||| |||||||||| ||||||||||||| || ||| ||||||||| ||||| ||||||| |||| ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||||||| |||||| |||| || ||| |||||||| ||| |||||||| |||||||||| ||||||| |||||||| |||| ||||||||||| ||||||| |||||| || ||| |||||||| || ||| |||||||||||| || ||||||||||| |||| ||||||||| ||||| ||| ||||| || ||| ||||||||| |||||||

||| || || |||||||| |||||||||||| |||| ||||||||||||| |||||| |||| ||| |||||||| |||||||| |||||||| |||||||||| |||||||||| |||||||| || |||||||| |||||||||| || |||||||| ||| |||| ||| |||||||||||||

Table 15: Summary of Subsequent Treatment in HIMALAYA (Full Analysis Set)

Notes: This table has been redacted at the request of the sponsor. Patients may have received more than 1 postinvestigational-product discontinuation therapy.

^aTherapies taken following discontinuation of investigational product. Only therapies used by at least 1% of patients in either group are reported.

^bIncludes intra-arterial administrations.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Table 16: HIMALAYA Key Efficacy Outcomes (FAS With Final Data Cut-Off on August 27, 2021)

CI = confidence interval; CR = complete response; FAS = final analysis set; IQR = interquartile range; OS = overall survival; PFS = progression-free survival; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; TTP = time to progression.

^aCalculated using the Kaplan-Meier technique.

^bThe adjusted alpha levels for the 2-sided superiority test of tremelimumab in combination with durvalumab vs. sorafenib and CI were derived from the exact number of OS events for each comparison using the Lan and DeMets approach that approximates the O’Brien-Fleming spending function. Analysis performed using a stratified log-rank test adjusting for treatment, etiology of liver disease (hepatitis B virus vs. hepatitis C virus vs. others), Eastern Cooperative Oncology Group Performance Status (0 vs. 1), and macrovascular invasion (yes vs. no). P value has been adjusted for multiple testing.

^cAnalysis was performed using a logistic regression model adjusted for treatment with factors for etiology of liver disease, Eastern Cooperative Oncology Group Performance Status, and macrovascular invasion. P value has not been adjusted for multiple testing.

^dA confirmed response of CR/PR means that a response of CR/PR was recorded at 1 visit and confirmed by repeat imaging not less than 4 weeks after the visit at which the response was first observed with no evidence of progression between the initial and confirmation visit. Unconfirmed responses were not confirmed by repeat imaging.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Table 17: Overall Survival (Final Analysis Set With Final Data Cut-Off on August 27, 2021)

CI = confidence interval; IQR = interquartile range; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; TTP = time to progression; vs. = versus.

^aPatients confirmed alive at follow-up or on active study treatment at the time of final analysis reported “study completion” on the disposition electronic case report form. Includes patients known to be alive at data cut-off.

^bCalculated using the Kaplan-Meier technique.

^cThe adjusted alpha levels for the 2-sided superiority test of tremelimumab in combination with durvalumab vs. sorafenib and CI were derived from the exact number of OS events for each comparison using a Lan and DeMets approach that approximates the O’Brien-Fleming spending function. Analysis performed using stratified log-rank test adjusting for treatment, etiology of liver disease (hepatitis B virus vs. hepatitis C virus vs. others), Eastern Cooperative Oncology Group Performance Status (0 vs. 1), and macrovascular invasion (yes vs. no). The values of the stratification factors were obtained from an interactive web response system.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Table 18: OS by Subgroup of Interest (FAS With Final Data Cut-Off on August 27, 2021)

CI = confidence interval; FAS = full analysis set; HBV = hepatitis B virus; HCV = hepatitis C virus; HR = hazard ratio.

^aHR and 95% CI were estimated from an unstratified Cox proportional hazards model with treatment as the only covariate and using the Efron method to control for ties.

Source: HIMALAYA Clinical Study Report.¹⁷

Sensitivity Analysis of Overall Survival

As there was a 4-month delay in the separation of Kaplan-Meier curves, an assessment of the assumption of nonproportionality was conducted. The linear interaction between treatment and time was tested, and no significant interaction was found |||||||| |||||| This was supported by a post hoc analysis that was conducted to calculate piecewise constant treatment effects for the comparison of tremelimumab in combination with durvalumab versus sorafenib. Beyond 9 months, the HR was 0.70 (95% CI, 0.56 to 0.89).

| ||||||| || |||||||| ||||| ||| |||| ||||||||||| || ||||||||| ||| |||||||| ||| ||||||| || ||| |||||||| || |||||| ||| |||||||||||| || ||||||||||| |||| |||||||||| ||| ||||||||| |||||| |||||||| ||||| || |||| ||| ||||| || ||||||| |||||||||| |||||| |||||||| ||||||||| ||| |||| |||||| || ||||| ||||| ||| || |||||||||| |||||||||| || ||| |||||| || ||||||||| ||||| ||||||| ||||||| || ||| |||||||| |||||||| |||| ||||||||| |||||||||| |||| ||||| || ||| ||||||| |||||||||

The results of another sensitivity analysis for OS based on the stratified Cox proportional hazard model, adjusted for EHS, albumin-bilirubin (ALBI) score, alpha-fetoprotein levels, and BCLC stage, were consistent with the primary OS analysis results.

Overall Survival for Patients Rechallenged With Tremelimumab

|| ||| || |||||||| ||| |||| |||||||||||| |||| |||||||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| |||||| ||| |||||| || ||| ||||| |||||| |||| ||| ||||| || |||| ||| || ||||| |||| ||| |||| ||||| ||||| || ||||| || || ||||||| ||||| ||||| || ||||| || || ||||||| ||||| ||||| || ||||| || || ||||||| ||| ||||| ||||| || ||||| || || |||||||

Overall Survival for Patients Treated After Progression

A total of 182 patients (46.3%) in the tremelimumab in combination with durvalumab group and 192 (49.4%) in the sorafenib group received at least 1 dose of the study treatment after progressive disease as defined by RECIST 1.1. ||| |||||| || ||| |||| |||||| |||| ||| |||| || ||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| |||| |||||| |||| ||| |||| || ||||| || ||| ||||||||| |||||| || ||||| |||| ||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| |||||| ||||||||| |||||| |||| ||||| ||||| || ||||| || ||||| ||||| || ||||| || || ||||||| ||||| ||||| || ||||| || ||||| ||||| || ||||| || || ||||||| ||||| ||||| || ||||| || ||||| ||||| || ||||| || || |||||| ||| ||||| ||||| || ||||| || ||||| ||||| || ||||| || || |||||||

Progression-Free Survival

At the final data cut-off on August 27, 2021, the Kaplan-Meier estimates for median PFS in the FAS were 3.8 months (95% CI, 3.7 to 5.3) in the tremelimumab in combination with durvalumab group and 4.1 months (95% CI, 3.8 to 5.5) in the sorafenib group, with an HR of 0.90 (95% CI, 0.77 to 1.05) |||||||| |||||| |||||||| A Kaplan-Meier plot for PFS is presented in Figure 5. There were 49 patients (12.5%) in the tremelimumab in combination with durvalumab group and 19 patients (4.9%) in the sorafenib group who were progression-free. PFS results are presented in Table 19.

Table 19: PFS by Investigator Assessment According to RECIST 1.1 (FAS With Final Data Cut-Off on August 27, 2021)

CI = confidence interval; FAS = full analysis set; HBV = hepatitis B virus; HCV = hepatitis C virus; PFS = progression-free survival; q.4.w. = every 4 weeks; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1.

^aCalculated using the Kaplan-Meier technique.

^bPatients who had not progressed or died, or who progressed or died after 2 or more missed visits, were censored at the latest evaluable RECIST 1.1 assessment, or day 1 if there were no evaluable visits. Patients who had no evaluable visits or baseline data were censored at day 1 unless they died within 2 visits of baseline.

^cStudy completion refers to patients who were progression-free and ongoing in the study at the data cut-off.

^dDeath occurred after 2 or more missed visits after last evaluable RECIST 1.1 assessment (or randomization).

^eRECIST 1.1 progression event occurred after 2 or more missed visits after last evaluable RECIST 1.1 assessment (or randomization).

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Objective Response Rate

At the final data cut-off on August 27, 2021, the ORRs (in patients with confirmed responses) according to RECIST 1.1 and based on investigator assessment were 20.1% (79 patients) in the tremelimumab in combination with durvalumab group and 5.1% (20 patients) in the sorafenib group. |||| ||||||||| |||||||||||| || ||||||||||| |||| |||||||||| ||| |||||||||| ||| || ||| |||| |||| ||| |||| || ||||| ||||||| |||||||| || |||||| || |||||||||||| || ||||||||||| |||| |||||||||||

Overall, the results of the additional analyses of ORR, according to RECIST 1.1 and based on investigator assessments, were consistent with the results of the main analysis. In the first additional analysis, a logistic regression model adjusted for treatment with factors for etiology of liver disease, ECOG PS, and MVI was used. The confirmed ORR was 23.9% for the tremelimumab in combination with durvalumab group and 6.7% for the sorafenib group, and ||| || ||| |||| |||| ||| |||| || |||||| || ||| |||||| |||||||||| ||||||||| |||||||||| ||||||||||||||||||||||| |||| |||||||| ||| ||| |||| ||||||| ||| |||| ||| ||| || ||| |||| |||| ||| |||| || ||||||

|||||||| || ||| || |||||||||| ||||||||| || |||||||| ||||||||| || ||||| ||||||| ||| |||| |||||||||||| |||| ||| ||||||||| ||||||| || ||| ||||||||| |||| |||||||||| |||| ||||||| ||| |||||||||

Figure 4: Kaplan-Meier Plot of Overall Survival (FAS With Final Data Cut-Off on August 27, 2021)

FAS = full analysis set; S = sorafenib; T300+D = tremelimumab 300 mg plus durvalumab.

Source: HIMALAYA Clinical Study Report.¹⁷

The descriptive results for ORR for patients at the final data cut-off and in the 32-week follow-up set (first interim analysis) are presented in Table 20. Overall, similar results were observed in terms of ORR in patients’ confirmed responses based on BICR according to RECIST 1.1 as well as in patients with unconfirmed responses (i.e., independent of imaging RECIST 1.1 methodology) based on BICR according to mRECIST, irRECIST, and RECIST 1.1.

Figure 5: Kaplan-Meier Plot for PFS (FAS With Final Data Cut-Off on August 27, 2021)

FAS = full analysis set; S = sorafenib 400 mg twice daily; T300+D = tremelimumab 300 mg × 1 dose + durvalumab 1,500 mg every 4 weeks.

Source: HIMALAYA Clinical Study Report.¹⁷

Table 20: ORR for Patients in the FAS Based on Investigator Assessment Using RECIST 1.1. (With Final Data Cut-off on August 27, 2021) and First Interim Assessment (FAS-32w With Data Cut-Off on September 2, 2019)

BICR = blinded independent central review; CI = confidence interval; CR = complete response; FAS = full analysis set; FAS-32w = full analysis set at 32-week follow-up; ORR = objective response rate; PR = partial response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1.

^aA confirmed response of CR/PR means that a response of CR/PR was recorded at 1 visit and confirmed by repeat imaging not less than 4 weeks after the visit where response was first observed with no evidence of progression between the initial and confirmation visit. Unconfirmed responses were not confirmed by repeat imaging.

^bAnalysis was performed using a logistic regression model adjusted for treatment with factors for etiology of liver disease, Eastern Cooperative Oncology Group Performance Status, and macrovascular invasion. P value has not been adjusted for multiple testing.

Source: HIMALAYA Clinical Study Report.¹⁷

Best Objective Response

|| ||| ||||| |||| ||||||| || |||||| ||| ||||| || |||||||| ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| || |||||||| |||||| |||||||| ||| || || || || ||||| || ||||||||||| ||||||||| || |||||||||||| ||||||||||| ||||| |||| || |||||||| |||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| |||||||| ||||||||| ||||||||| ||| |||| || ||| ||||||||| |||||| ||| ||||||| ||| |||||||| |||| ||||||||| ||||||||| || |||||||||||| |||||||||| |||| |||||||| Results for BOR at the first interim analysis for patients in the 32-week follow-up set based on BICR assessments were also consistent with those reported at the final analysis for patients in the FAS based on investigator assessments. Results from the final analysis and interim analysis are presented in Table 21.

Table 21: Best Objective Response Based on Investigator Assessment and BICR Assessment (Confirmed Response) According to RECIST 1.1 at the FAS (With Final Data Cut-Off on August 27, 2021) and IA1 (FAS-32w With Data Cut-Off on September 2, 2019)

BICR = blinded independent central review; FAS = full analysis set; FAS-32w = full analysis set at 32-week follow-up; IA1 = first interim assessment; RECIST 1.1 = Response Evaluation Criteria In Solid Tumors Version 1.1.

Source: HIMALAYA Clinical Study Report.¹⁷

Duration of Response

At the final data cut-off on August 27, 2021, among 79 patients with a confirmed response in the tremelimumab in combination with durvalumab group and 20 patients with a confirmed response in the sorafenib group, the median DoRs based on investigator assessments according to RECIST 1.1 were 22.3 months (IQR = 8.5 to NR) and 18.4 months (IQR = 6.5 to 26) respectively. ||| ||||||||| || |||||||| ||||||||| || |||||||| || || |||||| ||||| || ||| |||||||||||| ||||||||| ||| ||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||| || ||| ||||||||| |||||. Median time to onset of response from randomization was 2.2 months (IQR = 1.8 to 4.0) and 3.8 months (IQR = 1.9 to 8.4), respectively.

Disease Control Rate

At the final data cut-off on August 27, 2021, the overall DCR was similar between both groups, with 236 patients (60.1%) in the tremelimumab in combination with durvalumab group and 236 patients (60.7%) in the sorafenib group achieving controlled disease based on investigator assessments according to RECIST 1.1. ||| |||||||||| || |||||||| ||| |||||||| ||||||| ||||||| || || ||| || ||||| ||| ||||| ||| |||||| ||||||||||||| || ||| ||||||||||| || ||||||||||| |||| |||||||||| ||||| |||||||| |||| ||||| ||| |||||| respectively, in the sorafenib group as presented in Table 22.

Table 22: Disease Control Rate by Investigator Assessment According to RECIST 1.1 (FAS With Final Data Cut-Off August 27, 2021)

DCR-16w = disease control rate at 16 weeks; DCR-24w = disease control rate at 24 weeks; FAS = full analysis set; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1.

^aDisease control = complete response + partial response + stable disease. Responses do not require confirmation.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Table 23: Redacted

CI = confidence interval; eCRF = electronic case report form; FAS = full analysis set; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; TTP = time to progression.

Note: This table has been redacted at the request of the sponsor.

^aCalculated using the Kaplan-Meier technique.

^bPatients who had not progressed, or who progressed after 2 or more missed visits, were censored at the latest evaluable RECIST assessment, or day 1 if there were no evaluable visits. Patients who have no evaluable visits or baseline data were censored at day 1 unless they died within 2 visits of baseline. Patients who die without tumour progression will be censored at the time of death.

^cDeath occurred in the absence of progression or death occurred after 2 or more missed visits after last evaluable RECIST 1.1 assessment (or randomization).

^dOther recorded on disposition eCRF with specified status of “study terminated by sponsor.” These patients were ongoing in the study at the data cut-off.

^eRECIST 1.1 progression event occurred after 2 or more missed visits after last evaluable RECIST 1.1 assessment (or randomization).

^fNot adjusted for multiplicity.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Time to Progression

At the final data cut-off on August 27, 2021, the Kaplan-Meier estimates of median TTP according to RECIST 1.1 based on investigator assessments were ||| |||||| |||| ||| ||| || |||| in the tremelimumab in combination with durvalumab group and 5.6 months (95% CI, 5.1 to 5.8) in the sorafenib group. Results of TTP assessment are presented in Table 23.

HRQoL Measures (EORTC QLQ-C30 and EORTC QLQ-HCC)

The EORTC QLQ-C30 compliance rate (defined as the proportion of evaluable forms out of all expected forms) at baseline was 80% in the tremelimumab in combination with durvalumab group and 88% in the sorafenib group. ||||| |||||||| || ||| ||| ||| || |||| ||| ||| ||| ||| ||| || |||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||| ||||||||| |||||| ||||||||||||| ||| ||||| ||||||||| |||||||||| |||| || |||||||| ||| ||| ||| |||| ||| |||||||| || ||| ||| ||| || |||| ||| ||| ||| ||| ||| || |||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||| ||||||||| |||||| |||||||||||||

Change From Baseline

At baseline, mean scores for EORTC QLQ-C30 and QLQ-HCC items were comparable between treatment groups. Throughout follow-up, HRQoL remained stable in both treatment groups, with no mean change in scores from baseline reaching the MID (i.e., mean change ≥ 10 points) at any time point for either treatment group or between groups. Absolute scores at baseline and mean change from baseline scores using a mixed model for repeated measures at each visit up to week 60 are presented in Table 24 and Table 25.

Table 24: Redacted

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set; MMRM = mixed model for repeated measures; NE = not estimable.

Notes: This table has been redacted at the request of the sponsor. This table has been redacted at the request of the sponsor. The analysis set includes a subset of FAS with an evaluable baseline assessment and at least 1 evaluable postbaseline assessment. Change from baseline is derived using a MMRM analysis of all the postbaseline scores for each visit. The model includes treatment, visit, and treatment by visit interaction as explanatory variables and the baseline score as a covariate.

Some redacted rows have been deleted.

Source: HIMALAYA Clinical Study Report.¹⁷

Table 25: Redacted

CI = confidence interval; EORTC QLQ-HCC18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18; FAS = full analysis set; MMRM = mixed model for repeated measures; NE = not estimable.

Note: This table has been redacted at the request of the sponsor.

Some redacted rows have been deleted.

Source: HIMALAYA Clinical Study Report.¹⁷

Time to Deterioration of HRQoL and HCC Symptoms

Time to deterioration was estimated among patients with symptom scores of 10 or lower, and/or GHS and/or physical function scores of 90 or higher at baseline. || ||| ||||| |||| ||||||| || |||||| ||| ||||| |||||| ||| || |||||| ||| |||||||| |||||||| |||||||||||| || ||||||||||| |||| |||||||||| |||| ||||||||| || ||||| ||||||| ||||||| |||| |||| ||| ||| || ||||| || ||| |||| ||| ||| || |||| ||||||| || ||||| |||| ||| |||| || ||||||| |||||||| ||||||||||| ||||| |||| ||| ||| || ||||| || ||| |||| ||| ||| || ||||| ||||||| || ||||| |||| ||| |||| || ||||||| ||||||| |||| |||| || |||| || ||| |||| || |||| ||||||| || ||||| ||||| || ||||||| |||||| ||||| |||| ||| |||| || ||| || |||| |||| ||| ||| || ||||| ||||||| || ||||| ||||| || ||||||| |||||||| |||| ||||| |||| ||| ||| || ||||| || ||| |||| ||| ||| || |||| ||||||| || ||||| ||||| || ||||||| ||| ||||| ||||||||| ||||||||| |||| ||||| || ||| ||||||| || |||| ||||| ||||||| ||| ||||||||| |||||||| ||||| || |||| ||||||| || ||||| ||||| || ||||||| ||| |||||||| ||| |||||||||||| || |||| ||||||||||| ||||||| |||||| || ||| ||| |||||||| |||| || |||||||| ||| ||| ||||| ||||||||| ||||| |||| ||| ||| || ||||| || ||| |||| ||| ||| || |||||| || ||||| |||| ||| |||| || ||||||| Time-to-deterioration results are presented in Table 26 and Table 27.

Table 26: Analysis of Time to Deterioration of EORTC QLQ-30 (FAS With Final Data Cut-Off on August 27, 2021)

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-HCC18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18; FAS = full analysis set; GHS = global health status; HBV = hepatitis B virus; HCV = hepatitis C virus; MVI = macrovascular invasion; NR = not reached; QoL = quality of life; vs. = versus.

Note: The analysis includes a subset of the FAS with baseline scores of 10 or higher for EORTC QLQ-C30 GHS/QoL and functioning domains while baseline scores of up to 90 for EORTC QLQ-C30 and EORTC QLQ-HCC18 symptom domains or items.

^aPatients who have not shown a clinically meaningful deterioration or died, or who shows a clinically meaningful deterioration or die after 2 or more missed visits, are censored at the latest evaluable patient-reported outcome assessment, or day 1 if there are no evaluable visits. Patients with a clinically meaningful deterioration within 2 visits of baseline who do not have any evaluable visits or do not have a baseline assessment are censored at day 1.

^bCalculated using the Kaplan-Meier technique.

^cAnalysis performed using a Cox proportional hazards model adjusting for treatment, etiology of liver disease (HBV vs. HCV vs. others), ECOG PS (0 vs. 1), and MVI (yes vs. no). A hazard ratio less than 1 favours immune-oncology treatment groups to be associated with a longer time to QoL deterioration than sorafenib.

^dAnalysis was performed using a stratified log-rank test adjusting for treatment, etiology of liver disease (HBV vs. HCV vs. others), ECOG PS (0 vs. 1), and MVI (yes vs. no). P values were not adjusted for multiplicity.

Source: HIMALAYA Clinical Study Report.¹⁷

Table 27: Analysis of Time to Deterioration of EORTC QLQ-HCC18 (FAS With Final Data Cut-Off on August 27, 2021)

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-HCC18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18; GHS = global health status; HBV = hepatitis B virus; HCV = hepatitis C virus; FAS = full analysis set; MVI = macrovascular invasion; NR = not reached; QoL = quality of life; vs. = versus.

Notes: Others (for etiology of liver disease) is defined as no active viral hepatitis identified. The analysis includes a subset of the FAS who have baseline scores of 10 or higher for EORTC QLQ-C30 GHS/QoL and functioning domains while baseline scores of 90 or lower for EORTC QLQ-C30 and QLQ-HCC18 symptom domains/items.

^aPatients who have not shown a clinically meaningful deterioration or died, or who show a clinically meaningful deterioration or die after 2 or more missed visits, are censored at the latest evaluable patient-reported outcome assessment, or day 1 if there are no evaluable visits.

^bCalculated using the Kaplan-Meier technique.

^cThe analysis was performed using a Cox proportional hazards model adjusting for treatment, etiology of liver disease (HBV vs. HCV vs. others), ECOG PS (0 vs. 1), and MVI (yes vs. no). A hazard ratio of less than 1 favours immune-oncology treatment groups to be associated with a longer QoL deterioration than sorafenib.

^dThe analysis was performed using stratified log-rank test adjusting for treatment, etiology of liver disease (HBV vs. HCV vs. others), ECOG PS (0 vs. 1), and MVI (yes vs. no). P values were not adjusted for multiplicity.

Source: HIMALAYA Clinical Study Report.¹⁷

Improvement Rate

Improvement rate was estimated in the trial among patients with symptom scores of 10 or greater, and/or GHS and/or physical function scores less than or equal to 90 at baseline. At the final data cut-off on August 27, 2021, the odds of improvement (defined as the number of patients with a best overall score response of “improved”) were higher in the tremelimumab-plus-durvalumab group compared to the sorafenib group for fatigue according to the EORTC QLQ-C30 results (OR = 1.67; 95% CI, 1.13 to 2.47) and abdominal swelling according to the EORTC QLQ-HCC18 (OR = 2.28; 95% CI, 1.19 to 4.44) as shown in Table 28 and Table 29. For the improvement rate for all other HRQoL domains, the evidence was insufficient to show a difference between groups. The differences between groups were not tested statistically.

Table 28: EORTC QLQ-C30 Improvement Rate (FAS With Final Data Cut-Off on August 27, 2021)

CI = confidence interval; EORTC = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set.

Notes: This table has been redacted at the request of the sponsor. The analysis was performed using logistic regression model adjusted for treatment with factors for etiology of liver disease, Eastern Cooperative Oncology Group Performance Status, and macrovascular invasion.

^aSubset of the FAS who have baseline scores of 90 or lower.

^bSubset of the FAS who have baseline scores of 10 or higher.

Source: HIMALAYA Clinical Study Report.¹⁷

Table 29: EORTC QLQ-HCC18 Improvement Rate (FAS With Final Data Cut-Off on August 27, 2021)

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-HCC18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18; FAS = full analysis set.

Notes: This table has been redacted at the request of the sponsor. The analysis was performed using logistic regression model adjusted for treatment with factors for etiology of liver disease, ECOG PS, and macrovascular invasion.

^aSubset of the FAS who have baseline scores of 10 or greater.

Source: HIMALAYA Clinical Study Report.¹⁷

Harms

Table 30 provides detailed harms data from the August 27, 2021, data cut-off. Safety was analyzed in all treated patients in the group corresponding to the treatment received.

Adverse Events

Totals of 378 patients (97.4%) in the tremelimumab in combination with durvalumab group and 357 patients (95.5%) in the sorafenib group experienced at least 1 AE. The most frequently reported treatment-emergent AEs in the tremelimumab in combination with durvalumab and sorafenib groups, respectively, were diarrhea (26.5% versus 44.7%), pruritis (22.9% versus 6.4%), rash (22.4% versus 13.6%), fatigue (17% versus 19%), decreased appetite (17% versus 17.9%), and palmar-plantar erythrodysesthesia syndrome (0.8% versus 46.5%).

||||||||||| ||| |||||| |||||||| ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| |||||| ||| ||| |||||||| ||||||| || ||| ||||||||| ||||| ||||||||||| || ||||| ||| |||| ||||| ||| ||| |||| |||||||||| |||||||| ||||||||| || ||| ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||| ||||||||| ||||||| |||||||||||| |||| ||||||||| ||||||||| |||||||||||||||| ||||| ||| |||||| ||||||||| |||||| ||||| ||| |||||| |||||||||||| ||||| ||| |||||| ||| |||||||||||||| |||||||||||||||||| |||||||| || |||||||| || ||||||

Serious Adverse Events

A total of 157 patients (40.5%) in the tremelimumab in combination with durvalumab group and 111 patients (29.7%) in the sorafenib group experienced at least 1 SAE. ||| |||| |||||||||| |||||||| |||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||| ||||||||| |||||| |||| |||||||| ||||| || |||||| |||||| ||||| || ||| ||| ||||||||| ||||| || |||||| ||| ||||| |||| |||||||| || |||| |||| || || |||||||| || |||| |||||

Withdrawals Due to Adverse Events

There were 53 patients (13.7%) in the tremelimumab in combination with durvalumab group and 63 patients (16.8%) in the sorafenib group stopped treatment due to AEs. No AEs led to discontinuation in more than 2% of patients in either study group.

Mortality

At the final data cut-off date of August 21, 2021, in the FAS, there was a total of ||| |||||| ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||| |||||| ||||||| || ||| ||||||||| |||||| |||| |||||||| |||||||||| || ||| ||||||| ||||||||||| || |||||||||||| ||||||||||| ||| |||||| |||||||| |||| ||||| |||| || |||||||| |||||| ||| || |||||||| |||||| ||| ||||||||||| || ||||||| |||| ||| ||||||| ||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||||||| |||||| ||||||||||||| ||| |||| |||||| ||||| || ||||| ||| ||||||| ||||||| ||||| || |||||| || ||||| ||||| ||| |||||||| || |||| |||| || || |||||||| || |||||| ||||||||| |||||.

Adverse Events of Special Interest

||||| |||||||| |||| |||||||||| || |||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| |||| ||| ||||||||| ||||| ||||||| |||| || ||||| |||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| |||| |||| |||| |||||| || ||||||| |||||||| ||||||||||||||| ||| ||||| |||| || |||| ||| ||||||||||||| ||||| |||| |||| |||||||||| |||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| |||||| ||| |||||||||||||||| |||| ||| |||| |||||||||| |||||||| || ||| ||||||||| ||||| |||| |||||| |||||

Immune-mediated AEs were reported in 36% of patients in the tremelimumab in combination with durvalumab group and 8% of patients in the sorafenib group. Six patients in the tremelimumab in combination with durvalumab group died due to immune-mediated AEs (|||||||||||| |||||||| ||||||| |||||||||||| ||| |||||||||| ||||||) and no deaths were reported in the sorafenib group.

|||||||| |||||||| |||||| |||||||| || || |||||||| |||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||||| |||||| || ||| ||||||||| ||||||

Other Significant Adverse Events

There were 144 patients (37.1%) in the tremelimumab in combination with durvalumab group with any hepatic SMQ AE compared to 121 patients (32.4%) in the sorafenib group. ||| || ||| ||||||| |||||||| ||| ||| || ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| |||||| || ||| ||||||||| ||||||

There were 44 patients (11.3%) in the tremelimumab in combination with durvalumab group with any hemorrhage SMQ AE compared to 56 patients (15%) in the sorafenib group. ||| || ||| |||||||||| ||| ||| || ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| |||||| || ||| |||||||||||||||

In the HIMALAYA trial, tremelimumab in combination with durvalumab showed no increase in liver toxicity or risk of bleeding.

Table 30: Summary of Harms in the HIMALAYA Trial (Safety Analysis Set)

SAE = serious adverse event.

Some redacted rows have been deleted.

^a15% or greater of patients in either group.

^b5% or greater of patients in either group.

^c2% or greater of patients in either group.

^d1% or greater of patients in either group.

^eAdverse event with outcome of death.

Source: HIMALAYA Clinical Study Report¹⁷ (details from the table have been taken from the sponsor’s Summary of Clinical Evidence).

Pooled Safety Analysis

The sponsor also provided a pooled safety analysis of tremelimumab in combination with durvalumab in patients from the |||||||| ||||||||| ||| |||| ||||| || || ||||| ||||| ||||||||| || |||||||| |||| |||| ||| ||| |||||| |||||||||| ||| |||| |||||||||| ||| || ||| ||||||| ||||||||| |||| |||||||||| || ||| |||||| || ||| |||||||| ||||||| ||||||||||| || |||||||||||||| ||||||| ||||||||||| || || ||||| ||| || ||| |||||||| ||||||| || |||||||| ||||||||||| || |||| ||| ||| ||||||| || ||||||||||||||| || ||| ||||| ||||||||| |||| |||||||| || || |||||||| ||||||||

Critical Appraisal

Internal Validity

HIMALAYA was an open-label, sponsor-blind, randomized phase III study comparing tremelimumab in combination with durvalumab and sorafenib in adult patients with unresectable HCC. The study also included 2 additional treatment groups who received durvalumab monotherapy and a lower dose of tremelimumab in combination with durvalumab. These were not relevant to this review and closed before the end of randomization, respectively, and were not included in this report. The sponsor stated that an open-label design was used due to the nature of the treatment administration (IV versus oral) and the different administration schedules (every 4 weeks versus twice daily), which made blinding infeasible. Protocol amendments occurred after recruitment had started but before the first interim analysis, and do not appear to have influenced results. The study used an appropriate central randomization method sufficient for concealing allocation until assignment to the intervention (1:1:1:1 using an interactive web response system until the fourth treatment group was closed, after which patients were randomized at 1:1:1). Randomization appeared adequate in balancing baseline demographic and disease characteristics between the tremelimumab in combination with durvalumab and the sorafenib groups. Concomitant therapy use was also similar across the treatment groups.

||||| |||| |||||| ||||| || |||| ||||||||| |||||||| |||||||||| || ||| ||||||||| ||||| |||||| || || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||||||| |||| |||||||| ||||||| |||||||| ||| |||||||||| ||| ||| |||||||||| ||||| |||||||||. Due to the limited number of patients who were affected by protocol deviations, no substantial impact on the comparative clinical efficacy of tremelimumab in combination with durvalumab versus sorafenib would be expected.

An open-label design can result in a risk of bias in the study, including the measurement of the outcomes, whether by unblinded assessor, such as PFS and ORR, or self-reported, such as HRQoL or harms. With the exception of harms, the bias will likely favour the experimental intervention, although the extent of bias is uncertain. This bias would not be introduced into the measurement of objective outcomes such as OS, which is the primary outcome of the trial. At the first interim analysis after at least 32 weeks of follow-up, tumour response was assessed by BICR to minimize bias in their measurement due to the investigators’ knowledge of the assigned interventions. Results from the interim analysis were similar to results from the final analysis. In the final analysis, tumour response assessments were performed only by investigators. In the final analysis, exploratory end points included assessment of PFS, TTP, ORR, DCR, and DoR by BICR to mitigate this bias; however, as the results of these assessments were not available it is not possible to determine the extent of any bias in the measurement of these outcomes. The trial used RECIST 1.1 primarily to assess tumour response, while some guidelines recommend the use of mRECIST, which more accurately measures tumour viability to targeted therapies (which are cytostatic rather than cytotoxic).²⁷ However, the clinical experts consulted for this review noted that radiological reporting differs between the academic and clinical settings, and neither RECIST 1.1 nor mRECIST are used in clinical practice.

Statistical analyses were in general appropriate for the outcomes evaluated. Intention-to-treat (ITT) analyses (i.e., using the FAS) were used for efficacy outcomes, which is appropriate for estimating the effect of assignment to the intervention. At the time of the final analysis, 555 OS events had occurred across the groups, which, according to the prespecified analysis plan, provided greater than 97% power to demonstrate a statistically significant difference in OS (assuming a HR of 0.70). However, the study was not sized for individual subgroup comparisons and no multiplicity adjustments were made, rendering any conclusion uncertain. Moreover, although OS was assessed in the ITT population, it would still be influenced by treatments received after progression. Because of the 4-month delay in the separation of the Kaplan-Meier curves, the sponsor conducted additional analysis to assess the assumption of nonproportionality, finding no significant interactions. The study was not sized for secondary end points. ||| ||||||| ||||| |||||| ||||| ||||| || |||| ||| ||||| || ||| ||||||| |||||||| || ||| ||| ||| || ||||||| ||| |||||||||| ||||| |||| || ||| || ||||| ||||||||| ||||| ||| |||| ||| ||||| || ||| || ||||||||. However, only descriptive statistics were presented for ORR and DoR. The lack of multiplicity control for other outcomes may have increased the risk of false-positive conclusions.

Maintaining and improving QoL overall was rated as an important outcome by patients, yet the interpretation of results for the HRQoL instruments (i.e., the ability to assess trends over time and to make comparisons across treatment groups) is limited by the missing data at baseline and significant decline in the number of patients available to provide assessment over time. There was no evidence of validity or MID of the EORTC QLQ-C30 and EORTC QLQ-HCC18 in patients with HCC. However, the sponsor provided literature on patients with other cancers that supported the choice of MID. The clinical experts consulted by CADTH pointed out that HRQoL instruments are not used routinely in clinical practice and more weight is placed on clinical outcomes.

External Validity

According to the clinical experts CADTH consulted for this review, the HIMALAYA study population is considered reflective of the requested reimbursement population. The following considerations are of importance regarding the external validity of the study.

Population: According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics of the HIMALAYA study population were reflective of the Canadian population with unresectable HCC. There was a large number of screening failures in the study, with almost a third of screened patients not randomized, most commonly due to eligibility criteria not being fulfilled. However, the eligibility criteria that were most commonly not fulfilled |||| ||||| ||||||||||||||||| || ||||||||| |||| |||||||||||| || ||||||||||| |||||||||||||| |||| || |||| || |||||||| ||||| ||| |||||| |||||||| ||| || ||||||||| ||| ||||| || ||||||||||||||||| |||||||| |||| ||||| |||||||. It was required that patients have a Child-Pugh class of A, which excluded 87 patients after screening. The clinical experts noted that, while only including patients with a Child-Pugh class of A is reasonable in clinical trials, it may also be reasonable to include other patients (e.g., those with a Child-Pugh class of B7) in clinical practice. It is unclear if findings from this study can be generalized to patients beyond the first line of therapy. All patients in the trial had an ECOG PS of 0 or 1 as specified by the eligibility criteria, but the experts indicated this would not be reflective of clinical practice and that clinicians would require some flexibility in restricting treatment by performance status. The clinical experts noted that, while almost ||| || |||||||| || |||| ||||||||| |||||| ||| |||||||| |||||||||||| ||||||| ||| |||| this proportion would be lower for patients in Canada. Although most participants were Asian, the clinical experts noted that this is consistent with other HCC trials, and they did not expect this would limit generalizability to patients in Canadian clinical practice.

Appropriateness of comparator: The clinical experts consulted by CADTH indicated that at the time of the HIMALAYA study design, sorafenib was the only approved treatment for unresectable HCC patients who were ineligible for locoregional therapy or who had progressed after locoregional therapy and who had not undergone prior systemic therapy. In this study, sorafenib was considered standard-of-care treatment for these patients and was selected as the active comparator. According to the clinical experts and recent clinical guidelines, sorafenib is no longer the most common standard-of-care therapy and has been replaced by more effective therapies, including atezolizumab in combination with bevacizumab and lenvatinib. As such, the results of the trial may not be directly generalizable to current standard of care.

Relevance of end points: The clinical experts consulted by CADTH and clinician groups providing input agreed that, ideally, prolonging survival and delaying progression are the most important end points, followed by ORR, DCR, and toxicity profile with maintained HRQoL. Although information about HRQoL was collected, interpretation is limited due to missing data and increased risk of type I error. The clinical experts noted that, in clinical practice, imaging would be obtained every 3 to 4 months to assess response to treatment.

Setting: This study was a multinational, multicentre trial. The study population was drawn from a wide variety of sites across the globe, with 9 study centres (out of 170) and ||||||||||||| |||| || |||||||| || ||||||. The clinical experts indicated that there is no concern regarding generalizing the findings from the pivotal study to the Canadian clinical setting.

Long-Term Extension Studies

No long-term extension studies were identified by the sponsor.

Indirect Evidence

The contents within this section were informed by materials submitted by the sponsor and summarized and validated by the CADTH review team.

Objectives and Methods for the Summary of Indirect Evidence of the Sponsor-Submitted Indirect Treatment Comparison

The objective of this section is to summarize and critically appraise available indirect evidence comparing tremelimumab in combination with durvalumab to other relevant first-line treatments for unresectable HCC currently used in Canadian settings.

Description of the Sponsor-Submitted Indirect Treatment Comparison

The efficacy and safety of tremelimumab in combination with durvalumab against sorafenib have been previously assessed in the HIMALAYA trial.¹⁷ However, no head-to-head comparison of tremelimumab in combination with durvalumab against other first-line treatments for unresectable HCC was available for this review. Due to this gap in evidence, the sponsor submitted an ITC that included a systematic literature review⁴⁹ with an ITC in the form of 2 MAICs^50,51 submitted in separate reports that provide comparative evidence of the efficacy and safety of tremelimumab in combination with durvalumab relative to atezolizumab in combination with bevacizumab, and tremelimumab in combination with durvalumab relative to lenvatinib. Data from this ITC were used to inform the pharmacoeconomic model.

Study Selection Method

Table 31 shows the study selection criteria and key aspects of the methods for the systematic review.

Based on the prespecified eligibility criteria outlined in Table 31, the sponsor conducted a systematic literature search to assess first-line systemic treatments in patients diagnosed with unresectable HCC and to evaluate the comparative efficacy and safety of tremelimumab in combination with durvalumab and alternative treatments in this patient setting. The systematic literature review was conducted on |||||| ||| ||||| ||| ||||||| || |||||||| || ||||| Systematic literature searches were conducted in electronic databases (i.e., Ovid Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews). In addition, hand searches were conducted, including a reference list of eligible studies, conference proceedings (i.e., American Society of Clinical Oncology, American Association for the Study of Liver Diseases [AASLD]), clinical trial registries, and global health technology assessment bodies (i.e., National Institute for Health and Care Excellence [NICE]).

The study screening, selection, and data-extraction processes were conducted by 2 independent reviewers. Studies identified by the systematic literature search were first screened based on the title and abstract. Full-text screening was then carried out for studies selected from the title and abstract screening stage. A third reviewer was involved to resolve any discrepancies during the title, abstract, and full-text review. An independent reviewer performed a data-extraction quality check by reviewing 20% of the extracted articles. Two independent reviewers assessed the risk of bias of the included studies using the checklist of the NICE single-technology appraisal user guide.⁵² A list of excluded studies was reported with reasons for exclusion.

| ||||| || ||| ||||||| |||| |||||||| || ||||| ||| ||||||||| || |||||| || |||||||||||| |||| |||||||| || |||| ||||| ||||| |||| ||||||||| ||| ||||||||||| |||||||| ||| |||||| || |||||||||| |||||||| || ||| |||||| |||||||||||||||||||| ||||| |||||||| ||| ||||||||||| || ||| |||||||||| ||| ||| |||||||||| ||||||||| || |||||||| |||| |||||||| || |||||||||| |||| || |||||| || |||||||||||| |||| |||||||||| || || |||||||| |||||||| || ||| |||||| |||| ||||||| || |||||| ||||||||| || |||||||| |||| |||||||| || |||||||||| ||| ||||||||| ||||||||| |||| ||||||||||| |||||| ||||||||| ||| || || ||| |||||| || |||||||| || ||| |||||||| |||||| ||| ||||||||| |||||||||||||||||||| || |||||||| |||||||||| ||||| |||| ||| ||| ||||| || ||| ||| |||||| |||||||| ||||| |||| || |||||| |||||||| |||| ||||||||||| ||| || |||| ||||||| |||||||||| || ||||| || |||||||| ||| ||| |||||||| |||||||||||||||||||| |||||||| || |||||||||||| ||||||||

To be eligible to be included in the ITC, the population, the control treatment, and the study design of studies identified from the systematic literature review had to be aligned with those from the HIMALAYA trial conducted by the sponsor. The studies that were potentially eligible for the ITC were assessed for feasibility:

• Decision set trials: trials assessing only treatments included in the decision set of comparators, including both an intervention and a comparator of interest. |||| ||| |||||||| |||| |||| |||| || |||||||||||| || |||| || ||||||||||| || |||||||| ||| ||| |||| |||||||| ||||||||| |||| the IMbrave150 trial, and the HIMALAYA trial.

• Analysis set trials: trials included in the decision set trials as well as additional trials that could be of interest to connect the network. |||| ||| |||||||| ||||| || ||||| |||| |||| |||| ||| |||||||| |||| ||| ||||||||||| ||||||| ||||| || || ||||||||| |||||||| || ||||||| ||| ||||||| || |||| ||||||| ||||||||| || |||||||||||| ||| ||||||| |||||| |||||||||| |||| || |||||||||| ||||||| ||||||||| ||| ||| || || ||| |||||||

After assessing the publications identified in the systematic literature review and based on the decision set, || |||||||||||| ||||||| || ||||| |||||||||||| || || |||||||| || ||| ||| ||||||||| ||||||||| |||| and the IMbrave150 trial) with the sponsor-conducted HIMALAYA trial (Table 32).

Table 31: Study Selection Criteria and Methods for ITC Submitted by Sponsor

AE = adverse event; HCC = hepatocellular carcinoma; HTA = health technology assessment; ITC = indirect treatment comparison; NICE = National Institute for Health and Care Excellence; PFS = progressive-free survival; SLR = systematic literature review.

Note: Details from the table were taken from the sponsor’s Summary of Clinical Evidence.

Source: Sponsor systematic literature review⁴⁹ and ITC reports.^50,51

Table 32: Studies Included in the Sponsor-Conducted Indirect Treatment Comparison

| ||||||||| || ||| ||||||||||| ||| ||| |||||||||| ||||||||| ||| ||| || ||||||| ||| || ||| ||||||||| ||||||| || |||| ||| |||||

Source: Sponsor indirect treatment comparison reports.^50,51

Design of Indirect Treatment Comparison Conducted by Sponsor

Evidence Network

The overall evidence network was constructed as part of a feasibility assessment, which was built for each outcome of interest based on data availability. The availability of hazard ratios or Kaplan-Meier curves was considered for time-to-event outcomes including OS, |||| |||| ||| |||| For binary outcomes, such as ORR, AEs of grade 3 || ||||||| ||||||| |||| and AEs leading to discontinuation, the availability of rates and/or number of patients with response or experiencing the AEs were considered to build the networks. Figure 6 presents the overall network of evidence for efficacy, patient-reported, and safety outcomes. However, MAIC analyses were performed by the sponsor to compare tremelimumab in combination with durvalumab relative to atezolizumab in combination with bevacizumab, ||| |||||||||||| || ||||||||||| |||| |||||||||| |||||||| || ||||||||||| ||||| ||||||||| || ||| ||||||||||| ||| ||| |||||||||| ||||||||| ||| ||| || ||||||| || || ||| ||||||||| ||||||| || |||| |||||||| ||| |||||||| ||||| |||||||| |||||||| |||||||||||| || ||||||||||| |||| |||||||||| || ||| |||| ||||| ||||||| ||||||||| ||||||| |||||||||| || ||| |||||||||| ||||||||||| |||||| ||||||||| ||| ||| ||||||||||||||||||||||| ||||||||||| ||| ||| || ||||| || |||| ||||||| ||| |||| |||||||| ||| |||||| |||||||||| || |||||||| |||| ||||||||| || |||||||||| ||||| |||| || |||||| |||||| OS and ||| were reported in all trials, while 2 additional efficacy outcomes, ORR and DoR, were only included in the MAIC comparing tremelimumab in combination with durvalumab versus atezolizumab in combination with bevacizumab, || ||||| |||||||| |||| ||| |||||||| || ||| ||||||| ||||||

Figure 6: Redacted

Note: This figure has been redacted at the request of the sponsor.

Source: Sponsor indirect treatment comparison reports.^50,51

Analysis Methods

Matching Adjusted Indirect Comparison Rationale

A feasibility assessment was performed to determine the method of the ITC. The comparability of the HIMALAYA trial with trials involving comparators was examined by comparing eligibility criteria and patients’ characteristics. Observed differences across eligible trials included region (specifically the proportion of patients from China mainland), etiology, and macrovascular invasion. There was also a limited amount of evidence in the network in terms of number of trials per comparison, leading to insufficient data to consider meta-regression to adjust for treatment-effect modifiers. In addition, individual patient-level data were available only for the HIMALAYA trial, and the authors concluded that ITCs based on summary-level data were likely to provide misleading results due to the presence of heterogeneity between trials. A MAIC was therefore chosen to adjust for suspected heterogeneity with aggregate data available from the trials involving comparators and individual patient-level data for the HIMALAYA trial. A simulated treatment comparison could also be applied but, given the additional assumptions required by the simulated treatment comparison related to the parametric fit of the time-to-event curves and the associated risk of bias in some instances, the MAIC was preferred.

||| anchored MAICs were performed to compare tremelimumab in combination with durvalumab versus atezolizumab in combination with bevacizumab (using the IMbrave150 trial), ||| |||||||||||| || ||||||||||| |||| |||||||||| |||||| |||||||||| |||||| ||| ||||||| ||||||| The sources of heterogeneity are discussed in the following sections.

Treatment-Effect Modifiers

Potential treatment-effect modifiers in unresectable or advanced HCC were identified to assess sources of heterogeneity between studies. Table 33 presents a summary of the lists of potential treatment-effect modifiers identified through a targeted literature review and the final list of potential treatment-effect modifiers identified based on the sponsor’s clinical expert’s opinion, and the review of relative treatment effect by subgroup reported in the trials included in the network of evidence.

Overview of Matching Adjusted Indirect Comparison Methods

An overview of the MAIC methods is provided in Table 34.

Table 33: List of Treatment-Effect Modifiers

ECOG PS = Eastern Cooperative Oncology Group Performance Status; TLR = targeted literature review; vs. = versus.

Source: Sponsor indirect treatment comparison reports.^50,51

Table 34: Matching Adjusted Indirect Comparison Analysis Methods