Reimbursement Review

Nivolumab and Ipilimumab (Opdivo and Yervoy)

Sponsor: Bristol-Myers Squibb Canada Co.

Therapeutic area: Unresectable or metastatic MSI-H or dMMR colorectal cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

dMMR = deficient mismatch repair; MSI-H = metastatic microsatellite instability-high; NOC = Notice Of Compliance.

Introduction

In Canada, colorectal cancer (CRC) was the third most prevalent cancer overall in 2024. CRC is also the fourth most commonly diagnosed cancer, as well as the second leading cause of cancer-related death (11% of all cancer deaths) among people living in Canada.¹ In 2024, the incidence was 11,000 and 14,100 cases among males and females, respectively.² Presenting symptoms can be nonspecific (diarrhea, constipation, abdominal pain, rectal bleeding or pain, unexplained weight loss, unexplained iron deficiency anemia, nausea, vomiting), contributing to delays in diagnosis.^3,4 Around 20% to 25% of patients with CRC present with metastasis at diagnosis, and almost 50% of patients with nonmetastatic CRC will eventually develop metastases. Metastatic CRC (mCRC) is largely incurable, with a 5-year overall survival (OS) of less than 15%.^5,6 The metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) subtype of CRC arises from germline or sporadic impairments of the mismatch repair (MMR) system, the protein complex responsible for correcting errors during DNA replication.⁷ Overall, MSI-H and/or dMMR tumours account for 15% of CRC cases. However, the prevalence of microsatellite instability (MSI) differs across disease stages. It can range from 10% in stage II and 20% in stage III to approximately 5% to 7% in stage IV.^8,9 According to the clinical experts consulted by the review team, testing for MMR and MSI status is currently part of the standard of care (SOC) for unresectable or mCRC, and testing is not anticipated to be a barrier to implementation.

Currently, pembrolizumab is the recommended first-line therapy in Canada indicated for patients with MSI- H or dMMR mCRC.¹⁰ Multiagent chemotherapy, along with targeted therapies against VEGFR and EGFR are the principle first-line therapies in patients with metastatic proficient MMR or microsatellite stable CRC. These agents may be used as the first-line treatment in a limited number of patients with dMMR or MSI-H mCRC in whom there is a severe contraindication to immunotherapy.

Nivolumab in combination with ipilimumab has been previously reviewed by Canada’s Drug Agency (CDA-AMC) in the population with melanoma,^11,12 malignant pleural mesothelioma,¹³ non–small cell lung cancer,^14,15 advanced or metastatic renal cell carcinoma,¹⁶ and metastatic melanoma.¹⁷ The combination is also currently under review for another indication in people with unresectable or advanced hepatocellular carcinoma.¹⁸

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of nivolumab plus ipilimumab (nivolumab: 40 mg/4 mL [10 mg/mL] and 100 mg/10 mL [10 mg/mL]; ipilimumab: 50 mg/10 mL [5 mg/mL] and 200 mg/40 mL [5 mg/mL], IV) in the first-line treatment of adult patients with unresectable or metastatic MSI-H or dMMR CRC.

Perspectives of Patients, Clinicians, and Drug Programs

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

Patient Input

Two patient groups, Colorectal Cancer Resource and Action Network (CCRAN) and Colorectal Cancer Canada (CCC), provided input for this submission. CCRAN is a national, not-for-profit, patient advocacy group championing the health and well-being of people living in Canada by providing support, education, and advocacy to help improve patient outcomes, longevity, and quality of life. CCRAN used a multifaceted approach to contact medical oncologists based in Canada, Europe, and the US between July 24, 2024, to February 19, 2025, to gather lived patient experience. None of the clinicians in Canada had treated patients with MSI-H CRC. In collaboration with the Canadian Cancer Survivor Network, a social media campaign was conducted from July 16, 2024, to March 15, 2025. Patients from France (n = 2), Italy (n = 2), and the US (n = 2) shared their experience with nivolumab plus ipilimumab through either telephone interviews or written inputs. One patient from Canada with MSI-H mCRC without access to nivolumab plus ipilimumab provided input. Further, responses from a previous CRC survey distributed from March 17, 2024, to April 17, 2024, comprising 77 patients with CRC or their respective caregivers, were submitted.

CCC is a not-for-profit organization for patients with CRC dedicated to raising awareness, education, supporting patients and their caregivers, and advocating on their behalf. Patient and caregiver perspectives regarding nivolumab plus ipilimumab were gathered through an online survey and semistructured interviews from August 2024 to April 2025. Of the 11 patients and 1 caregiver who responded to the online survey, 1 patient lived in Australia, 3 patients lived in Canada, 1 caregiver lived in England, and 7 patients lived in the US. Among the 4 patients interviewed, 3 lived in Canada, and 1 lived in the US.

Those who responded to both patient group surveys highlighted how the inability to work, exercise, and participate in social activities and/or family obligations significantly impacted quality of life. They also highlighted that the inability to plan about the future, fear of recurrence, constant worry, and fatigue resulted in significant psychological impacts. Caregivers reported challenges caring for patients with CRC, including the inability to work outside, difficulty managing treatment-induced side effects, loss of income, and/or financial strain, time spent on medical appointments, and medication administration. Those who responded to the CCC survey indicated that symptoms such as abdominal cramps, gas, feeling bloated, abdominal pain, fatigue, and diarrhea were important to control.

Those who responded to both patient group surveys indicated the following side effects from available systemic treatments: fatigue, brain fog, diarrhea, loss of appetite, hair loss, peripheral neuropathy, nausea, and low white blood cell count. In addition, those who responded to the CCC survey highlighted that diarrhea, hand-foot syndrome, and fatigue are the most difficult side effects to tolerate. Those who responded to the CCRAN survey noted the burden of out-of-pocket expenses for additional mediations required to manage treatment-induced side effects. In addition, patients who were interviewed reported that ineffective chemotherapeutics to control cancer caused poor quality of life and negatively impacted mental health. The CCC survey results noted that 30% of those who responded to the survey believed that their needs were not met by currently available treatments. Five percent of patients indicated “no” and 45% indicated “somewhat” when asked whether available drug therapies were effective in controlling disease progression.

Both patient groups noted tumour shrinkage, tumour stability, reduced pain, improved breathing, and quality of life (e.g., improved mobility, improved sense of wellness, relief from side effects) as important outcomes with new treatments. Caregivers who responded to the CCRAN survey indicated that preventing death (i.e., survival) and stopping the spread of the illness were important treatment outcomes. Those who responded to the CCC survey (53%) indicated a willingness to accept a treatment with significant yet tolerable side effects (i.e., nausea, anemia, neutropenia) if it offered an OS of at least 3 or 4 months.

Four patients interviewed by CCRAN who received the combination therapy achieved a durable and complete response and maintained no evidence of disease for more than 5 years. Patients also noted that side effects were manageable, treatment administration was easily managed, and they were able to maintain a high quality of life. Those who responded to the CCC survey (11 of 12) indicated that nivolumab plus ipilimumab controlled their cancer and its spread to other organs. Sixty-four percent indicated that they were able to continue their daily activities while undergoing treatment. Most patients were able to complete treatment without interruptions, whereas 25% stopped treatment earlier or skipped doses due to side effects and/or complications. Anxiety and/or worry, fatigue, and management of side effects were noted as the most difficult adverse events (AEs) of receiving nivolumab plus ipilimumab. The top 5 side effects included skin itchiness, skin rash, joint stiffness, vomiting, and diarrhea. Several patients considered side effects with nivolumab plus ipilimumab as more manageable than those associated with chemotherapy. All patients interviewed experienced tumour shrinkage and/or stabilization during treatment with nivolumab plus ipilimumab and were able to return to daily activities. Patients noted that although there were considerable side effects, they resolved over time.

Clinician Input

Input From Clinical Experts Consulted for This Review

The clinical experts highlighted that the 3 most important goals of all therapies for metastatic MSI-H or dMMR CRC are to improve OS, to improve quality of life, and to reduce AEs and toxicity.

The clinical experts indicated that for patients with unresectable or metastatic MSI-H or dMMR CRC, pembrolizumab is the current funded standard first-line treatment. According to the clinical expert, a concern with the pembrolizumab monotherapy is that only approximately 40% of patients will respond to treatment, and patients with liver metastases may derive significantly less benefit. The clinical experts emphasized that nivolumab plus ipilimumab will likely replace pembrolizumab, particularly in the population of patients with liver metastases, given that the CheckMate-8HW trial showed consistent treatment benefit in this population of patients. However, the enhanced efficacy of using nivolumab plus ipilimumab comes at the expense of a higher risk of side effects and/or toxicity. Therefore, single-drug pembrolizumab will remain an important therapeutic alternative for patients experiencing frailty and who have comorbidities. The clinical experts noted that following disease progression on first-line therapy, the SOC second-line systemic treatment in Canada is chemotherapy (leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride [FOLFIRI] or leucovorin calcium [folinic acid], fluorouracil, oxaliplatin [FOLFOX]) in combination with bevacizumab. Following disease progression on 2 lines of therapy, the third-line treatment options become very limited in number and efficacy.

The clinical experts stated that patients with treatment-naive unresectable or metastatic MSI-H or dMMR CRC, with no contraindications to immunotherapy, reasonable performance status, and no concerns about the immunotherapy-related side effects, would be the ideal candidates for treatment with nivolumab plus ipilimumab. The clinical experts highlighted that while OS is the most important treatment outcome in this disease, progression-free survival (PFS) is considered an accepted surrogate outcome for OS in this setting. They noted that based on the statistically significant and clinical meaningful improvement in PFS reported in the CheckMate-8HW trial, OS improvement is very much expected. The clinical experts noted that patients should be assessed by a clinician after every 2 to 3 cycles of treatment, and more frequently if bothersome symptoms or side effects are occurring. Radiological assessment (e.g., CT scans) should be completed every 2 to 3 months. Tumour markers should be completed at least once every 4 weeks.

The clinical experts indicated that disease progression and/or unacceptable toxicities are the 2 main reasons to discontinue treatment with nivolumab plus ipilimumab.

The clinical experts noted that treatment with nivolumab plus ipilimumab could be safely administered in a hospital and should only be prescribed by or under the supervision of a specialist in medical oncology with expertise in managing immunotherapy-related side effects. One clinical expert further indicated that in some jurisdictions in Canada, private-pay immunotherapy is allowed to be administered in outpatient private infusion centres.

Clinician Group Input

Two clinician groups, Ontario Health (Cancer Care Ontario) (OH [CCO]) Gastrointestinal Cancer Drug Advisory Committee, and Canadian Gastrointestinal Oncology Evidence Network (CGOEN), in collaboration with the CCC Medical Advisory Board, provided their input for this submission. The OH (CCO) provides evidence-based clinical and health system guidance on drug-related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. The group gathered information via emails, and 5 clinicians provided their input. The CGOEN is a network of gastrointestinal oncology clinicians in Canada who contribute to the knowledge of gastrointestinal cancer and its treatments by participating in clinical trials, conducting observational research, and engaging in local, provincial, and national clinical guideline development and health technology assessment. The Medical Advisory Board of CCC works alongside the patient group to ensure its activities and health information are relevant and useful for patients and caregivers. For this submission, 11 clinicians provided input based on relevant information from the CheckMate-8DW trial and evidence-based expert opinions.

Clinician groups agreed that improving survival and quality of life were important treatment goals. The OH (CCO) further noted the following treatment goals: prolong PFS, delay disease progression, potentially convert some patients to surgery, reduce the severity of symptoms, and minimize AEs. The CGOEN clinician group noted that about 30% to 40% of patients do not respond to pembrolizumab and progress within the first 2 to 3 months of treatment.

Clinician groups agreed that treatment with nivolumab plus ipilimumab would be the new standard first-line for patients with dMMR or MSI-H tumours. The CGOEN further mentioned that the treatment may be administered in any centre and by any specialist experienced in treating patients with mCRC using systemic therapy.

The CGOEN noted that the treatment should be limited to patients not amenable for surgical resection or with metastatic disease. They highlighted that patients would require regular clinical evaluations to assess clinical response and toxicity. They also noted routine imaging would be required at timed intervals for objective assessment and suggested that patient preference, tolerability of treatment, and quality of life be considered when assessing meaningful response to treatment. The CGOEN noted that disease progression (radiological or clinical), toxicity, clinician discretion, or patient request should be considered reasons for treatment discontinuation.

Drug Program Input

The drug programs provide input on each drug under review through the reimbursement review process by identifying issues that may affect their ability to implement a recommendation. The drug programs’ input, along with the corresponding responses from the clinical experts consulted by CDA-AMC, is summarized in Table 5.

Clinical Evidence

Systematic Review

Description of Studies

One pivotal trial (CheckMate-8HW) is included in this review. CheckMate-8HW is an ongoing multinational, phase III, open-label, active-controlled randomized controlled trial (RCT) to evaluate the efficacy and safety of nivolumab plus ipilimumab (N = 202) compared with chemotherapy (N = 101) in adult patients with unresectable or MSI-H or dMMR CRC. Key inclusion criteria included histologically confirmed recurrent or mCRC with no prior treatment history with chemotherapy and/or targeted drugs for metastatic disease and not amenable to surgery; locally confirmed MSI-H or dMMR status, and Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 1 or less. A total of 303 patients in 22 countries, including 204 patients (67.3%) from Canada, Europe, and the US, were randomized to receive treatment with nivolumab plus ipilimumab or chemotherapy (2:1 randomization). Randomization was conducted using an interactive response technology system and stratified by primary tumour location (sidedness: left versus right). The baseline demographic and disease characteristics were largely balanced between treatment groups. The median age of all patients was 63.0 years, ranging from 21 to 87 years. Most of the patients were white (86.1%), followed by Asian (10.6%), other (2.0%), and Black or African American (1.3%). Females represented 53.8% of all participants and males were 46.2%. An ECOG PS score of 0 was reported in 53.8% of patients, and an ECOG PS score of 1 was reported in 46.2% of patients. The primary efficacy outcome was PFS, assessed per a blinded independent central review (BICR) based on centrally confirmed MSI-H or dMMR mCRC. The secondary efficacy outcome was PFS, assessed per a BICR based on locally confirmed MSI-H or dMMR mCRC. The exploratory outcome included the health-related quality of life (HRQoL) (e.g., European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30]). The harm outcomes included AEs, serious adverse events (SAEs), discontinuation from the treatment due to AEs, immune-mediated adverse events (IMAEs), and other events of special interest (OESIs). The results of PFS presented in this report are based on the data cut-off on August 28, 2024 (with a median follow-up time of 42.05 months). Results of HRQoL were based on the data cut-off on October 12, 2023 (median follow-up of 31.57 months). Safety outcomes results were based on the safety population at the data cut-off on both October 12, 2023, and August 28, 2024.

Efficacy Results

Progression-Free Survival

After a median follow-up of 42.05 months, a total of 53 (31.0%) PFS events were observed in the nivolumab plus ipilimumab arm and 54 (64.3%) in the chemotherapy arm. The median PFS was 54.08 months (95% CI, 54.08 months to not available) in the nivolumab plus ipilimumab arm and 5.85 months (95% CI, 4.37 months to 7.79 months) in the chemotherapy arm (hazard ratio [HR] = 0.21, 95% CI, 0.14 to 0.31). In the landmark time points, compared with the chemotherapy, nivolumab plus ipilimumab showed a clinical meaningful higher PFS probability starting from 6 months and sustained to 36 months. Based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment, nivolumab plus ipilimumab results in a clinically important increase in the probability of being progression-free at 12 months compared to chemotherapy. The PFS results for patients with MSI-H or dMMR mCRC were consistent whether the patients were centrally confirmed (primary outcome) or locally confirmed (a key secondary outcome).

The results of the predefined subgroup analysis showed a statistically significant improvement in PFS probability with nivolumab plus ipilimumab compared with chemotherapy in patients with liver metastasis (HR = 0.11; 95% CI, 0.05 to 0.25) and patients without liver metastasis (HR = 0.28; 95% CI, 0.17 to 0.46). Sensitivity analyses of PFS were consistent with the primary analysis.

HRQoL Assessed With EORTC QLQ-C30

Compared with chemotherapy, treatment with nivolumab plus ipilimumab demonstrated a statistically significant improvement from week 13 to week 37. The GRADE assessment suggested nivolumab plus ipilimumab may result in a clinically important improvement in EORTC QLQ-C30 global health status (GHS) score compared with chemotherapies at week 37.

Harms Results

After a median follow-up of 42.05 months, the overall proportion of patients with AEs were similar in both nivolumab plus ipilimumab compared with chemotherapy arm (nivolumab plus ipilimumab versus chemotherapy: 99.0% versus 98.9%). Compared to those in the nivolumab plus ipilimumab arm, more patients receiving chemotherapy reported all-cause grade 3 or 4 AEs (nivolumab plus ipilimumab versus chemotherapy: 50.5% versus 67.0%), all-causality SAEs (nivolumab plus ipilimumab versus chemotherapy: 35.5% versus 42.0%), and death (nivolumab plus ipilimumab versus chemotherapy: 25.5% versus 47.7%). The proportion of patients who discontinued treatment because of AEs was similar (nivolumab plus ipilimumab versus chemotherapy: 15.0% versus 15.9%). However, it should be noted that the AEs of special interest (AESIs) such as all-causality grade 3 to 4 IMAEs were much higher in the nivolumab plus ipilimumab arm than in the chemotherapy arm (nivolumab plus ipilimumab versus chemotherapy: 17.0% versus 1.1%). The between-group difference was 15.9% (95% CI, not reported). The GRADE assessment suggested that nivolumab plus ipilimumab likely result in clinically important increases in grade 3 or 4 IMAEs, compared with chemotherapies. The clinical experts consulted for this review indicated that the safety profile of nivolumab plus ipilimumab has been well established. The harms profile of nivolumab plus ipilimumab observed in the CheckMate-8HW trial was generally consistent with that of previously known AEs associated with nivolumab plus ipilimumab. No new safety signals were identified. Overall, most AEs were predictable and clinically manageable in most patients.

Critical Appraisal

The CheckMate-8HW study was a phase III, open-label RCT. Appropriate methods for randomization were reported. The outcomes assessed are clinically relevant, and statistical analyses were done using standard methods. Overall, the risk of selection bias and detection bias is considered very low for the key outcome (i.e., PFS per BICR). However, the open-label design introduces a potential bias in the subjective outcomes of HRQoL (e.g., EORTC QLQ-C30) and AEs (such as fatigue and nausea). However, the extent and direction of bias due to treatment knowledge is uncertain. In addition, the EORTC QLQ-C30 assessment may be further biased due to high attrition, particularly at a longer follow-up (e.g., at week 37).

The clinical experts highlighted that the inclusion and exclusion criteria of the CheckMate-8HW trial are standard for clinical trials, but stricter than what pertains in clinical practice. For example, they noted that patients with an ECOG PS score of more than 1 were not eligible for the trial, whereas patients with an ECOG PS score of 2 would be considered potential candidates for nivolumab plus ipilimumab in the clinical experience. However, the clinical experts considered that overall, the inclusion and exclusion criteria of the CheckMate-8HW trial are consistent with the clinical practice setting in Canada, and its findings present no major concerns regarding generalizability in terms of clinical practice in Canada.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^19,20 Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect. The target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold (minimal important difference [MID]) for a clinically important effect. In this review, the threshold (MID) assessment of between-group difference for PFS was based on published information^21,22 in combination with the MID suggested by clinical experts consulted for this review. The threshold (MID) for HRQoL (i.e., EORTC QLQ-C30 GHS) assessment of between-group difference was based on the published information,²³ which was aligned with the suggestion by the clinical experts consulted for this review. The threshold (MID) for assessment of between-group difference for harms (i.e., IMAEs) was suggested by clinical experts consulted for this review.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• PFS

• HRQoL

• safety.

Table 2 presents the GRADE summary of findings for nivolumab plus ipilimumab versus chemotherapy for the first-line treatment of adult patients with unresectable or metastatic MSI-H or dMMR CRC.

Table 2: Summary of Findings of Nivolumab Plus Ipilimumab Combination Therapy vs. Chemotherapies for Patients With Unresectable or Metastatic MSI-H or dMMR CRC Receiving First-Line Treatment With Unresectable or Metastatic MSI-H or dMMR Colorectal Cancer

AE = adverse event; AESI = adverse event of special interest; CI = confidence interval; CRC = colorectal cancer; dMMR = deficient mismatch repair; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; IMAE = immune-mediated adverse event; MID = minimal important difference; MSI-H = microsatellite instability-high; NR = not reported; PFS = progression-free survival; RCT = randomized controlled trial; vs. = versus.

Notes: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

The between-group MID for PFS at 12 months was based on the publications (≥ 10%),^21,22 in combination with the MID suggested by the clinical experts consulted for this review. (i.e., 10% to 20% for PFS probabilities at 12 months).

Musoro et al. reported that the between-group MID for EORTC QLQ-C30 GHS total score was 6 points.²³ The clinical experts consulted for this review suggested between-group difference MIDs for EORTC QLQ-C30 GHS total score at 37 weeks is 5 to 7 points.

There is no established between-group MID for the proportion of patients with grade 3 or 4 IMAEs after an overall median follow-up of 42.05 months. The clinical experts consulted for this review suggested a MID of 5% for the odds experiencing grade 3 or 4 IMAEs after an overall median follow-up of 42.05 months.

^aRated down 2 levels for very serious study limitations for this outcome: There is risk of bias in measurement of the outcome due to open-label study design and risk of bias due to a substantial attrition rate; that is, only 119 patients (59%) in the nivolumab plus ipilimumab arm and 15 patients (15%) in the chemotherapy arm were included for the analysis at week 37.

^bRated down 2 levels for very serious study limitations for this outcome: Because no 95% CI for between-group difference was reported, it was rated down 2 levels for imprecision.

^cRated up 1 level for very large between-group difference.

^dDespite it being an open-label study design, the evidence certainty is not rated down for the grade 3 or 4 IMAEs because the grade 3 or 4 IMAEs reported in the review are all objective), which were unlikely biased due to the open-label design.

Long-Term Extension Studies

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

Indirect Comparisons

Description of Studies

The sponsor conducted an indirect treatment comparison (ITC) using a matching-adjusted indirect comparison (MAIC) to estimate the relative efficacy (i.e., PFS) and network meta-analysis (NMA) for safety outcomes comparing nivolumab plus ipilimumab with pembrolizumab for the first-line treatment of MSI-H or dMMR mCRC.

Efficacy Results

Anchored MAIC: The point estimate of the time-varying HR of PFS is lower than 1 over the estimated 10-year period (HR < 1 indicates in favour of nivolumab plus ipilimumab compared with pembrolizumab). ███ ██ ██████ ███████ ████ ██ ██ ██████ ███ ████ ██ ██ ███████ The 95% CIs do not cross the null value (i.e., 1) at 12 months and 24 months, which indicates that PFS for nivolumab plus ipilimumab is favourable compared with pembrolizumab. However, starting from 36 months until 120 months, the 95% CI of HR includes the null value (i.e., 1), indicating the estimation of the HR is uncertain.

Constant HR-based scenario NMA: ███ ███ ██ ██ ████ ████ ████ ████ ██ ██████ ███ ██████ ████ ███ █████ ██ ███████ █████████ █ ██████████ ██ ███████ █████████ ████ ██████████████ ███ ██████ ██ ██████████ ████ ███ ████████████ ████████ ██ ██ ██████ ███ ██ ███████

Unanchored MAIC: ███ █████ ████████ ██ ███ ████████████ ██ ███ ███ ██ █████ ████ █ ████ ███ █████████ ███████ ███████ ███ ██ ██████ ████ ████ ██ ██ ██████ ██ ████ ██ ██ ███████ ███ ███ ███ ██ ██ ██ ███ █████ ███ ████ █████ ████ ██ ██████ ██ ██ ██ ███████ █████ █████████ ████ ███ ███ █████████ █ ██████████ ██ ██████████ ████████ ████ ██████████████ ████████ ██████ ██ ███████ ███ ██████ ██ ██ ███████ ███ ████ ██████ ██████████ ███ ██████████ ██ ███ ██ ███ ███ ██ ██████████

Constant HR-based scenario NMA analysis: ███ ███ ██ ██ ████ ███████ ████ ██ ██████ ███ ██████ ████ ███ █████ ██ ███████ █████████ █ ██████████ ██ ████████ ████ █████████ ██ ██████████████ ███ ██████ ██ ██████████ ████ ███ ████████████ ████████ ████ ██ ██████ ██ ██ ███████

In summary, all results of the ITC analysis (i.e., anchored MAIC using a time-varying HR approach, unanchored MAIC using a time-varying HR approach, and the scenario NMAs using constant HR approach) suggested a favourable PFS improvement in patients with nivolumab plus ipilimumab treatment compared with pembrolizumab, despite certain key limitations (e.g., not able to adjust all treatment effect modifiers [TEMs] and prognostic modifiers).

Harms Results

The evidence of the NMA was not sufficient to demonstrate the difference of grade 3 or higher AEs (█████ ███████ ███████████ █████████ ███ █████████) between the 2 treatments. It should be noted that no ITC was done for the overall AEs, overall SAEs, and discontinuation due to AEs, especially for the proportion of patients with total IMAEs.

Critical Appraisal

The key limitation for the MAICs was their inability to balance all (known or unknown) TEMs due to the unavailability of published summary statistics in the KEYNOTE-177 trial. Another key limitation for the NMA was that the heterogeneity in terms of TEMs between the 2 studies were not adjusted, which may threaten the transitivity assumption for the NMA analysis.

Studies Addressing Gaps in the Evidence From the Systematic Review

The sponsor-submitted evidence from the CheckMate-8HW trial comparing nivolumab plus ipilimumab to nivolumab monotherapy in patients with MSI-H or dMMR mCRC receiving treatment across all lines of therapy to inform questions on the contribution of ipilimumab in addition to nivolumab. Per the CDA-AMC Procedures for Reimbursement Reviews, nivolumab monotherapy does not meet the CDA-AMC definition of relevant comparator because it is neither approved by Health Canada nor reimbursed by participating drug plans in Canada for the first-line treatment of MSI-H or dMMR mCRC. Therefore, the evidence was considered out of scope for this review.

Conclusions

Evidence from the CheckMate-8HW trial showed that nivolumab plus ipilimumab results in a clinically important increase in the probability of being progression-free at 12 months, compared to chemotherapy in the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR CRC. Based on the EORTC QLQ-C30 GHS, nivolumab plus ipilimumab may result in a clinically important improvement in patients’ HRQoL compared with chemotherapy, which was expected in this population. The evidence indicates that nivolumab plus ipilimumab likely results in a clinically important increase in grade 3 to 4 IMAEs, compared with chemotherapies. The harms profile of nivolumab plus ipilimumab reported in the CheckMate-8HW trial was generally consistent with that of previously known AEs associated with nivolumab plus ipilimumab. No new safety signal was identified. Overall, most AEs were predictable, and clinically manageable in most patients.

The results of the ITC suggested a more favourable PFS improvement with nivolumab plus ipilimumab treatment compared with pembrolizumab, despite certain limitations associated with the ITC methods. Due to the limitations associated with the NMA, a definitive conclusion could not be drawn on the comparative safety of nivolumab plus ipilimumab versus pembrolizumab in patients with MSI-H or dMMR mCRC. However, according to the clinical experts consulted on this review, nivolumab plus ipilimumab, being a double-drug immunotherapy, is expected to have an increased risk of side effects compared with the single-drug immunotherapy, and likely unsuitable for patients experiencing frailty or who have comorbidities.

Introduction

Disease Background

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

In Canada, CRC was the third most prevalent cancer overall in 2024. CRC is also the fourth most commonly diagnosed cancer, as well as the second leading cause of cancer-related death (11% of all cancer deaths) among residents of Canada.¹ In 2024, the incidence was 11,000 and 14,100 cases among males and females, respectively.² Presenting symptoms can be nonspecific (diarrhea, constipation, abdominal pain, rectal bleeding or pain, unexplained weight loss, unexplained iron deficiency anemia, nausea, vomiting), contributing to delays in diagnosis.^3,4

Around 20% to 25% of patients with CRC present with metastasis at diagnosis, and almost 50% of patients with non-mCRC will eventually develop metastases. Based on the extent of metastasis, CRC can be either regional with metastasis limited to specific nodes, or distant with metastasis to distant organs.⁷ mCRC is largely incurable, with a 5-year OS of less than 15%.^5,6 The MSI-H and/or dMMR subtype of CRC arises from germline or sporadic impairments of the MMR system, the protein complex responsible for correcting errors during DNA replication.⁷ Overall, MSI-H and/or dMMR accounts for 15% of CRC cases. However, the prevalence of MSI differs across disease stages. It can range from 10% in stage II and 20% in stage III to approximately 5% to 7% in stage IV.^8,9

Diagnosis of CRC begins with a histologic examination of the colon, usually obtained from a biopsy,²⁴ followed by a colonoscopy if CRC is suspected. Once a diagnosis of CRC is established, the local and distant extent of disease needs to be determined.^24,25 The stage at diagnosis is the most important prognostic factor. The American Joint Committee on Cancer has defined 1 of the most common staging systems for CRC based on tumour, node, and metastases criteria. In Ontario, approximately 23% of patients present with stage IV CRC at diagnosis.²⁶

MSI can be detected in fresh or fixed tumour specimens by amplification of specific microsatellite markers using polymerase chain reaction (PCR) or next generation sequencing (NGS).²⁷ Immunohistochemistry (IHC) is a useful alternative strategy for identifying tumours with dMMR activity by searching for loss of expression of 1 of the proteins of the MMR system (generally MSH2, MLH1, MSH6, or PMS2).²⁷ In Canada, between 95% to 100% of patients with CRC undergo MMR or MSI testing.²⁸ The availability of MMR or MSI testing is not expected to be limited by access.

Standards of Therapy

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

Currently, pembrolizumab is the recommended first-line therapy in Canada that is indicated for patients with unresectable or metastatic MSI-H or dMMR CRC regardless of any other biomarker status.¹⁰ Multiagent chemotherapy, along with targeted therapies against VEGFR and EGFR are the principle first-line therapies in patients with metastatic proficient MMR and microsatellite stable CRC. These agents may be used as the first-line treatment in a limited number of patients with deficient MMR or MSI-H mCRC in whom there is a severe contraindication to immunotherapy.¹⁰

Per the CDA-AMC and the Institut national d’excellence en santé et en service sociaux (INESSS) treatment algorithms, a patient with mCRC with both MSI-H or dMMR and BRAF V600E mutations should receive pembrolizumab as first-line therapy. The use of encorafenib in combination with cetuximab or panitumumab²⁹ should be reserved for use as a second-line regimen.¹⁰

Drug Under Review

Key characteristics of nivolumab plus ipilimumab are summarized in Table 3 with other treatments available for CRC.

According to the product monograph,³⁰ 240 mg nivolumab and 1 mg/kg ipilimumab are to be administered every 3 weeks for a maximum of 4 dosing cycles. The combination is administered intravenously over 30 minutes. Following the combination phase, nivolumab is administered as a single drug at a dose of 480 mg every 4 weeks or 240 mg every 2 weeks up to 2 years (unless disease progression or unacceptable toxicity occurs).

Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response.³⁰ Ipilimumab is a fully human monoclonal antibody to the CTLA-4 antigen.³¹ Combined nivolumab (anti–PD-1) and ipilimumab (anti–CTLA-4) mediated inhibition results in enhanced T-cell function and results in improved antitumour responses.

The Health Canada indication is “nivolumab in combination with ipilimumab for the first-line treatment of adult patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer.”³⁰ The sponsor’s reimbursement request aligns with the Health Canada indication.

Nivolumab plus ipilimumab for the first-line treatment of unresectable or mCRC was approved by the European Medicines Agency in December 2024.³² The FDA approved nivolumab plus ipilimumab in patients aged 12 years and older with unresectable or metastatic MSI-H or dMMR CRC in April 2025.³³ On May 8, 2025, the National Institute of Health and Care Excellence in England approved the use of nivolumab plus ipilimumab in adults with untreated unresectable or mCRC with MSI-H or dMMR.³⁴ In May 2025, nivolumab plus ipilimumab was approved by regulatory agencies in Australia for the treatment of unresectable or mCRC, that is MSI-H or dMMR as determined by a validated test.³⁵ The combination is under review by health technology agencies in Australia (Pharmaceutical Benefits Advisory Committee), and France (Haute Autorité de Santé).

Nivolumab plus ipilimumab has been previously reviewed by CDA-AMC in the population with melanoma,^11,12 malignant pleural mesothelioma,¹³ non–small cell lung cancer,^14,15 advanced or metastatic renal cell carcinoma,¹⁶ and metastatic melanoma.¹⁷ The combination is also currently under review for another indication in people with unresectable or advanced hepatocellular carcinoma.¹⁸

Table 3: Key Characteristics of Nivolumab, Ipilimumab, Pembrolizumab, mFOLFOX6, FOLFIRI, Bevacizumab, Panitumumab, and Cetuximab

dMMR = deficient mismatch repair; FOLFORI = leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride; FOLFOX = leucovorin calcium (folinic acid), fluorouracil, oxaliplatin; ; mCRC = metastatic colorectal cancer; mFOLFOX6 = modified leucovorin calcium (folinic acid), fluorouracil, oxaliplatin; MSI-H = microsatellite instability-high.

Note: Clinical experts noted that for patients with MSI-H or dMMR colorectal cancer, single-drug pembrolizumab was the standard of care first-line treatment in Canada. Following disease progression while receiving first-line therapy, the standard of care for patients with MSI-H or dMMR colorectal cancer requiring second-line treatment in Canada is chemotherapy (FOLFIRI or FOLFOX) in combination with bevacizumab. Following disease progression on 2 lines of therapy, treatment options are limited.

^aHealth Canada–approved indication.

Sources: Product monographs of nivolumab (draft),³⁰ ipilimumab,³¹ pembrolizumab,³⁶ mFOLFOX6,^37-39 FOLFIRI,^38-40 bevacizumab,⁴¹ panitumumab,⁴² and cetuximab.⁴³

Testing Procedure Considerations

MMR and MSI mutation status is an important prognostic factor in patients with CRC and can be used in clinical decision-making to determine eligibility for targeted treatments (e.g., immunotherapies).^44-46 Current guidelines in Canada recommend testing all patients with CRC for MMR or MSI status, or both MMR and MSI status.^44-46 The clinical experts consulted for this review indicated that reflexive MMR testing using IHC is currently done in jurisdictions across Canada as the SOC to identify dMMR or MSI-H tumours upon diagnosis with CRC. IHC is recommended for MMR testing instead of other methods, such as NGS or PCR testing of the MSI status, due to factors such as lower costs, shorter turnaround times, and being less resource intensive.^47,48 However, the clinical experts noted that MSI testing is readily available and funded, but funding of NGS versus PCR testing may vary between jurisdictions.

Potential impacts were considered for MMR and MSI testing to ascertain eligibility for nivolumab plus ipilimumab for the first-line treatment of adult patients with unresectable or metastatic MSI-H or dMMR CRC, including those to health systems, patients (including families and caregivers), and costs. Because testing for MMR and MSI status is currently performed as the SOC for adult patients with CRC across jurisdictions in Canada, no new impacts are anticipated. Key considerations and relevant information available from materials submitted by the sponsor, input from the clinical experts consulted by the review team, and sources from the literature were validated by the review team when possible and are summarized in Table 4.

Table 4: Considerations for MMR and MSI Testing for Establishing Treatment Eligibility With Nivolumab Plus Ipilimumab in mCRC

BIA = budget impact analysis; CRC = colorectal cancer; IHC = immunohistochemistry; mCRC = metastatic colorectal cancer; MMR = mismatch repair; MSI = microsatellite instability; MSI-H = microsatellite instability-high; NGS = next generation sequencing; PCR = polymerase chain reaction.

^aCDA-AMC has not evaluated or critically appraised this evidence to determine its validity or reliability.

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

Two patient groups, CCRAN and CCC, provided input for this submission. CCRAN is a national, not-for-profit, patient advocacy group championing the health and well-being of people living in Canada by providing support, education, and advocacy to help improve patient outcomes, longevity, and quality of life. CCRAN used a multifaceted approach to contact medical oncologists based in Canada, Europe, and the US between July 24, 2024, and February 19, 2025, to gather lived patient experience. None of the clinicians practising in Canada had treated any patients with MSI-H CRC. In collaboration with the Canadian Cancer Survivor Network, a social media campaign was conducted from July 16, 2024, to March 15, 2025. Patients from France (n = 2), Italy (n = 2), and the US (n = 2) shared their experience with nivolumab plus ipilimumab through either telephone interviews or written inputs. One patient from Canada with MSI-H mCRC without access to nivolumab and ipilimumab provided input. Further, responses from a previous CRC survey distributed from March 17, 2024, to April 17, 2024, comprising 77 patients with CRC or their respective caregivers, were submitted. CCC is a not-for-profit organization for patients with CRC dedicated to raising awareness, education, supporting patients and their caregivers, and advocating on their behalf. Patient and caregiver perspectives regarding nivolumab and ipilimumab were gathered through an online survey and semistructured interviews from August 2024 to April 2025. Of the 11 patients and 1 caregiver who responded to the online survey, 1 patient lived in Australia, 3 patients lived in Canada, 1 caregiver lived in England, and 7 patients lived in the US. Among the 4 patients interviewed, 3 lived in Canada, and 1 lived in the US.

Both patient group survey respondents highlighted how the inability to work, exercise, and participate in social activities and/or family obligations significantly impacted quality of life. They also highlighted that the inability to plan about the future, fear of recurrence, constant worry, and fatigue resulted in significant psychological impacts. Caregivers reported challenges caring for patients with CRC, including the inability to work outside, difficulty managing treatment-induced side effects, loss of income, and/or financial strain, time spent on medical appointments, and medication administration. Those who responded to the CCC survey indicated that symptoms such as abdominal cramps, gas, feeling bloated, abdominal pain, fatigue, and diarrhea were important to control.

Patients who responded to both patient group surveys indicated the following side effects from available systemic treatments: fatigue, brain fog, diarrhea, loss of appetite, hair loss, peripheral neuropathy, nausea, and low white blood cell count. In addition, those who responded to the CCC survey highlighted that diarrhea, hand-foot syndrome, and fatigue are the most difficult side effects to tolerate. Patients who responded to the CCRAN survey noted the burden of out-of-pocket expenses for additional mediations required to manage treatment-induced side effects. In addition, patients who were interviewed reported that ineffective chemotherapeutics to control cancer caused poor quality of life and negatively impacted mental health. The CCC survey results noted that 30% of patients who responded believed that their needs were not met by currently available treatments. Five percent of patients indicated “no” and 45% indicated “somewhat” when asked whether available drug therapies were effective in controlling disease progression.

Both patient groups noted tumour shrinkage, tumour stability, reduced pain, improved breathing, and quality of life (e.g., improved mobility, improved sense of wellness, relief from side effects) as important outcomes with new treatments. Caregivers who responded to the CCRAN survey indicated that preventing death (i.e., survival) and stopping the spread of the illness were important treatment outcomes. Those who responded to the CCC survey (53%) indicated a willingness to accept a treatment with significant yet tolerable side effects (i.e., nausea, anemia, neutropenia) if it offered an OS of at least 3 or 4 months.

Four patients interviewed by CCRAN who received the combination therapy achieved a durable and complete response and maintained no evidence of disease for more than 5 years. Patients also noted that side effects were manageable, treatment administration was easily managed, and they were able to maintain a high quality of life. Patients (11 of 12) who responded to the CCC survey indicated that nivolumab plus ipilimumab controlled their cancer and its spread to other organs. Sixty-four percent of patients indicated that they were able to continue their daily activities while undergoing treatment. Most were able to complete treatment without interruptions, whereas 25% stopped treatment earlier or skipped doses due to side effects and/or complications. Anxiety and/or worry, fatigue, and management of side effects were noted as the most difficult AEs of receiving nivolumab plus ipilimumab. The top 5 side effects included skin itchiness, skin rash, joint stiffness, vomiting, and diarrhea. Several patients considered side effects with nivolumab plus ipilimumab as more manageable than those associated with chemotherapy. All patients interviewed experienced tumour shrinkage and/or stabilization during treatment with nivolumab plus ipilimumab and were able to return to daily activities. Patients noted that although there were considerable side effects, they resolved over time.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding 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 adult patients with unresectable or metastatic MSI-H or dMMR CRC.

Unmet Needs

The clinical experts highlighted that the 3 most important goals of all therapies for metastatic MSI-H or dMMR CRC are to improve OS, to improve quality of life, and to reduce AEs and toxicity. The clinical experts indicated that for patients with unresectable or metastatic MSI-H or dMMR CRC, pembrolizumab is the current funded standard first-line treatment. According to the clinical experts, a concern with pembrolizumab monotherapy is that only approximately 40% of patients will respond to treatment, and patients with liver metastases may derive significantly less benefit. The clinical experts emphasized that nivolumab plus ipilimumab will likely replace pembrolizumab, particularly in the population of patients with liver metastases, as the CheckMate-8HW trial showed consistent treatment benefit in this population of patients.

Place in Therapy

The clinical experts indicated that, in eligible patients without a contraindication to immunotherapy, the current first-line treatment with pembrolizumab is the funded SOC in these cases. This recommendation is based on the results of the KEYNOTE-177 phase III RCT.⁴⁹

The clinical experts noted that following disease progression on first-line therapy, the SOC second-line systemic treatment in Canada is chemotherapy (FOLFIRI or FOLFOX) with or without bevacizumab. There is no high-quality evidence to support this recommendation. Following disease progression on first-line therapy, for patients with BRAF V600E mutations (whether they have comutations in MMR or MSI or not), the SOC second-line systemic treatment in Canada is encorafenib plus cetuximab based on the results of the BEACON phase III RCT. Following disease progression on first-line therapy for patients without a BRAF V600E mutation, the SOC treatment in Canada is to switch the chemotherapy regimen backbone. This recommendation is based on a GERCOR phase III RCT.⁵⁰ In Canada, in the second-line setting, additional therapies on top of the chemotherapy backbone are not routinely used. It may vary across the jurisdictions.

The clinical experts indicated that following disease progression on 2 lines of therapy, treatment options become very limited in number and efficacy. The present SOC for most patients is TAS-102 plus bevacizumab based on the SUNLIGHT clinical trial.⁵¹ For patients with extended RAS wild-type tumours who have not previously been treated with EGFR inhibition, options could include single-drug panitumumab⁵² or irinotecan in combination with cetuximab.⁵³ For other patients, treatment with either regorafenib monotherapy or TAS-102 (trifluridine-tipiracil) monotherapy are the treatment options in Canada based on the results of the phase III CORRECT RCT and the phase III RECOURSE RCT respectively, but these are very infrequently used due to their limited effectiveness and substantial toxicity.

Fruquintinib is another treatment option for patients with treatment-refractory mCRC based on the results of the phase III FRESCO-2 trial.⁵⁴ However, access to this medication is very limited in Canada. Best supportive care without anticancer systemic therapy is a treatment option in all lines of treatment depending on patients’ performance status, values, and preferences. However, best supportive care is often given higher consideration after progression on second-line therapies due to the limited anticancer efficacy of these treatments in this setting.

The clinical experts stated that combining CTLA-4 inhibition (ipilimumab) to PD-1 inhibition (nivolumab) seems to be associated with a better response rate and PFS compared to PD-1 inhibition alone, as per the most recent update of the landmark phase III CheckMate-8HW trial. Very importantly, the findings in the CheckMate-8HW trial demonstrated that patients with liver metastases derived excellent benefit from the dual immunotherapy treatment. According to the clinical experts, this is not the first drug to address this disease process, but the hope is that it will represent a far more effective way to address this disease process, used as a first-line treatment. They considered the reported improvement in outcomes remarkable and expected that some patients can have a very durable response with stabilization of their cancer (i.e., delaying the need for a second-line treatment). The clinical experts further noted that if nivolumab plus ipilimumab is available, it would be appropriate to give eligible patients that treatment option.

The clinical experts further indicated that while nivolumab plus ipilimumab will likely become the preferred first-line therapy, the enhanced efficacy of using the double-drug immunotherapy comes at the expense of an increased risk of side effects or toxicity and may not be suitable for patients experiencing frailty and who have comorbidities. However, single-drug pembrolizumab will remain an important therapeutic alternative for such patients.

Patient Population

The clinical experts stated that patients with treatment-naive unresectable and/or metastatic MSI-H or dMMR CRC, with no contraindications to immuno-oncology, reasonable performance status, and no concerns about the immuno-oncology–related side effects would be the ideal candidates for this treatment option. These patients should be identified based on clinician assessment in addition to diagnostic testing.

Assessing the Response Treatment

Both clinical experts highlighted that 3 important outcomes measurements for this setting are HRQoL (e.g., EORTC QLC-30), safety, and PFS. They also noted that while OS is the most important treatment outcome in this disease, PFS is considered an accepted surrogate outcome for OS in this setting. The clinical experts noted that no mature OS data are yet available from the CheckMate-8HW trial. The magnitude of improvement in PFS from this study is remarkable. With such an improvement in PFS, OS improvement is expected. A delay in the need for a second-line treatment in patients with MSI-H mCRC would be expected. This is a substantial development. One expert noted that although OS and quality of life are most important outcomes, response rate is an important end point that should be considered in the mCRC setting. The clinical experts noted that patients should be assessed by a clinician after every 2 to 3 cycles of treatment, or more frequently if bothersome symptoms or side effects are occurring. Radiological assessment (e.g., CT scans) should be completed every 2 to 3 months. Tumour markers should be completed at least once every 4 weeks.

The clinical experts mentioned that there are 3 factors used to determine the response to treatment: patient-reported symptoms or side effects, cross-sectional imaging (e.g., CT scan or MRI), and tumour markers (e.g., CEA and Ca 19 to 9). In general, those factors are listed in descending hierarchical importance. The only truly clinically meaningful end points in all of oncology are OS and quality of life. PFS should be considered a surrogate outcome. However, it is of little relevance if PFS does not predict better OS or quality of life. Nevertheless, the early and dramatic separation of the PFS curves (in both the nivolumab plus ipilimumab versus chemotherapy) makes an OS benefit highly likely, especially due to the fact that there are no other dramatically effective therapies available for this population of patients.

Discontinuing Treatment

The clinical experts indicated that disease progression and/or unacceptable toxicities are the 2 main reasons to discontinue treatment with nivolumab plus ipilimumab. Principally, patient-reported symptoms, side effects, and well-being would be the major determinants for discontinuing therapy. Additionally, the results of the cross-sectional imaging and serum tumour markers would be used to provide context of how well the treatment was working to fully inform treatment decision-making. However, progression on imaging alone would be insufficient reason to discontinue therapy with immunotherapy due to concerns about “pseudo-progression.” The results of the imaging must be interpreted in the context of the patient’s general status, their symptoms or side effect, and the timing of imaging in relation to treatment.

Prescribing Considerations

The clinical experts noted that treatment with nivolumab plus ipilimumab could be safely administered in a hospital and should only be prescribed by or under the supervision of a specialist in medical oncology with expertise in managing immunotherapy-related side effects. One clinical expert further indicated that in some jurisdictions in Canada, private-pay immunotherapy is allowed to be administered in outpatient private infusion centres.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Two clinician groups, OH (CCO) Gastrointestinal Cancer Drug Advisory Committee and CGOEN, in collaboration with the CCC Medical Advisory Board, provided their input for this submission. The OH (CCO) provides evidence-based clinical and health system guidance on drug-related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. The group gathered information via emails, and 5 clinicians provided their input. The CGOEN is a network of gastrointestinal oncology clinicians in Canada who contribute to the knowledge of gastrointestinal cancer and its treatments by participating in clinical trials, conducting observational research, and engaging in local, provincial, and national clinical guideline development and health technology assessment. The Medical Advisory Board of CCC works alongside the patient group to ensure its activities and health information are relevant and useful for patients and caregivers. For this submission, 11 clinicians provided input based on relevant information from the CheckMate 8HW trial and evidence-based expert opinions.

Clinician groups agreed that improving survival and quality of life were important treatment goals. The OH (CCO) further noted the following treatment goals: prolong PFS, delay disease progression, potentially convert some patients to surgery, reduce the severity of symptoms, and minimize AEs. The CGOEN clinician group noted that about 30% to 40% of patients do not respond to pembrolizumab and progress within the first 2 to 3 months of treatment.

Clinician groups agreed that treatment with nivolumab plus ipilimumab would be the new standard first-line for patients with dMMR or MSI-H tumours. The CGOEN further mentioned that the treatment may be administered in any centre and by any specialist experienced in treating patients with mCRC using systemic therapy.

The CGOEN noted that the treatment should be limited to patients not amenable for surgical resection or with metastatic disease. They highlighted that patients would require regular clinical evaluations to assess clinical response and toxicity. They also noted routine imaging would be required at timed intervals for objective assessment and suggested that patient preference, tolerability of treatment, and quality of life be considered when assessing meaningful response to treatment. The CGOEN noted that disease progression (radiological or clinical), toxicity, clinician discretion, or patient request should be considered reasons for treatment discontinuation.

Drug Program Input

The drug programs provide input on each drug under review through the reimbursement review process by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted for this review are summarized in Table 5.

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

CDA-AMC = Canada’s Drug Agency; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FOLFIRI = leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride; FOLFOX = leucovorin calcium (folinic acid), fluorouracil, oxaliplatin; mCRC = metastatic colorectal cancer; MMR = mismatch repair; MSI = microsatellite instability; MSI-H = microsatellite instability-high; pERC = pan-Canadian Oncology Drug Review Expert Review Committee.

Clinical Evidence

The objective of this Clinical Review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of nivolumab plus ipilimumab, IV infusion for the first-line treatment of adult patients with unresectable or MSI-H or dMMR CRC. The focus will be placed on comparing nivolumab plus ipilimumab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of nivolumab plus ipilimumab is presented in 2 sections with a critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. The assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes indirect evidence from the sponsor.

Included Studies

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

• 1 pivotal study (i.e., RCT) identified in the systematic review

• 1 ITC.

Systematic Review

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

Description of Studies

Characteristics of the included studies are summarized in Table 6. A schematic of the CheckMate-8HW study design is shown in Figure 1.

Table 6: Details of Studies Included in the Systematic Review

1L = first line; AE = adverse event; BICR = blinded independent central review; CDA-AMC = Canada’s Drug Agency; CRC = colorectal cancer; dMMR = deficient mismatch repair; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IMAE = immune-mediated adverse event; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; OESI = other event of special interest; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; q.2.w. = every 2 weeks; q.3.w. = every 3 weeks; q.4.w. = every 4 weeks; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; SAE = serious adverse event; vs. = versus.

Notes: For all patients receiving first-line therapy in this study (data cut-off: October 12, 2023), prior surgery related to the current cancer and prior radiotherapy was allowed.⁵⁷ Prior treatment with chemotherapy and/or targeted agents for metastatic disease was not allowed; however, patients treated with neoadjuvant and/or adjuvant chemotherapy were eligible if disease progression occurred 6 months or later following completion of chemotherapy.⁵⁷

For key secondary outcomes and exploratory outcomes, only information and/or outcomes relevant to and reported in this review (i.e., the first-line treatment for patients who are treatment-naive; nivolumab plus ipilimumab vs. chemotherapy) are presented in this table.

^aPer CDA-AMC Procedures for Reimbursement Reviews, the definition of relevant comparators, the nivolumab monotherapy arm, and all lines population are not relevant to this review.

^bOS data were not provided for this review because OS data were not mature.

^CORR data were not yet available for the nivolumab plus ipilimumab vs. chemotherapy comparison due to the hierarchical testing approach.

^dThe crossover cohort included patients in the chemotherapy arm who experienced documented progression of disease (per RECIST 1.1) by BICR and crossed over to receive nivolumab plus ipilimumab therapy (nivolumab 240 mg q.2.w. + ipilimumab 1 mg/kg every 6 weeks for 2 cycles followed by nivolumab 480 mg q.4.w. + ipilimumab 1 mg/kg every 6 weeks). Patients must have completed at least 1 follow-up visit and met all other crossover criteria outlined in the protocol.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁵⁸

Figure 1: Study Design of CheckMate-8HW

1L = first-line; 2L = second line; 3L = third line; BICR = blinded independent central review; CRC = colorectal cancer; CSR = Clinical Study Report; dMMR = deficient mismatch repair; FOLFORI = leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride; F/U = follow-up; IC = informed consent; Ipi = ipilimumab; mCRC = metastatic CRC; mFOLFOX6 = modified leucovorin calcium (folinic acid), fluorouracil, oxaliplatin; MSI-H = microsatellite instability-high; Nivo = nivolumab; PD = pharmacodynamics; PFS = progression-free survival; q.2.w. = every 2 weeks; q.3.w. = every 3 weeks; q.4.w. = every 4 weeks; vs. = versus.

Notes: First line is defined as 0 prior lines of systemic therapy); second line is defined as 1 prior line of systemic therapy; third line or later is defined as 2 or more prior lines of systemic therapy. Line of therapy was not a stratification factor during part 2 enrolment. The populations for the dual primary end points were patients receiving first-line treatment and randomized (arm B vs. arm C) with centrally confirmed MSI-H or dMMR mCRC or patients who were randomized (arm B vs. arm A) with centrally confirmed MSI-H/dMMR mCRC. Investigator’s choice chemotherapy included mFOLFOX6 or FOLFIRI with or without bevacizumab or cetuximab. Maximum treatment duration was not applicable for patients in arm C.

*Patients who had received 2 or more prior lines of therapy were randomized only to arm A or arm B during part 1; only patients with 0 prior lines of therapy were randomized during part 2.

**Optional crossover for arm C with 6 doses of nivolumab 240 mg every 2 weeks, then nivolumab 480 mg every 4 weeks plus ipilimumab 1 mg/kg every 6 weeks.

***Part 1 enrolment allowed randomization of approximately 560 patients across lines of therapy with locally confirmed MSI-H or dMMR mCRC. Part 2 enrolment allowed randomization of approximately 271 additional patients with locally confirmed MSI-H or dMMR who had not received prior therapy for metastatic disease (first line).

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence and interim CSR.⁵⁷

Populations

Inclusion and Exclusion Criteria

Eligibility Criteria

Patients included in the CheckMate-8HW trial were aged 18 years or older. Among the first-line treatment population (i.e., the Health Canada population of indication), patients had histologically confirmed recurrent or metastatic CRC with no prior treatment history with chemotherapy and/or targeted drugs for metastatic disease and not amenable to surgery. Patients were also required to have known dMMR or MSI-H status per local standard of practice testing and an ECOG PS score of 1 or lower. Patients were excluded from the trial if they had an active, known, or suspected autoimmune disease, history of interstitial lung disease or pneumonitis, or a known history of a positive test for HIV or known AIDS.

Interventions

Eligible patients receiving first-line treatment were randomized (2:1 ratio) to receive nivolumab plus ipilimumab or chemotherapy, respectively. Patients in the chemotherapy arm who experienced documented progression of disease per the Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1) by BICR had an option to crossover to receive nivolumab plus ipilimumab therapy if they had completed at least 1 follow-up visit and met all other crossover criteria; crossover started when the patients started nivolumab plus ipilimumab treatment.

Interventions were as follows:

• Nivolumabplus plus ipilimumab arm: Nivolumab (240 mg) plus ipilimumab (1 mg/kg) were both administered as IV infusion every 3 weeks for up to 4 doses, followed by 480 mg of nivolumab administered as IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or until reaching the maximum treatment duration of 2 years.

• Chemotherapy arm: Patients received 1 of 6 investigator’s choice chemotherapy regimens (modified leucovorin calcium [folinic acid], fluorouracil, oxaliplatin [mFOLFOX6], mFOLFOX6 plus bevacizumab, mFOLFOX6 plus cetuximab, FOLFIRI, FOLFIRI plus bevacizumab, or FOLFIRI plus cetuximab) administered every 2 weeks until disease progression, unacceptable toxicity, or withdrawal of consent.

• Crossover cohort (nivolumab plus ipilimumab): Patients received 240 mg of nivolumab every 2 weeks for up to 6 doses plus ipilimumab 1 mg/kg every 6 weeks for 2 doses, both administered as IV infusion, followed by 480 mg of nivolumab every 4 weeks plus ipilimumab 1 mg/kg every 6 weeks, both administered as IV infusion.

Dose reductions or escalations of nivolumab were not permitted. However, dose adjustments of ipilimumab (1 mg/kg) were permitted if the participant’s weight on the day of dosing differed by greater than 10% from the weight used to calculate the initial dose; in such cases, the dose was recalculated. Dose reductions were permitted for chemotherapy. Doses could be delayed or interrupted and/or the IV infusion rate reduced.

Outcomes

Table 7 summarizes the outcome measures assessed in patients receiving first-line treatment in the CheckMate-8HW trial available at the time of the data cut-off date of October 12, 2023, and August 28, 2024. Of note, per the hierarchical testing strategy, not all outcomes planned for analysis have yet been evaluated for statistical significance at this time. For example, because statistically significant PFS results of nivolumab plus ipilimumab versus nivolumab monotherapy were not available (refer to Figure 2, although nivolumab monotherapy is not the relevant comparator to this review), the results for the objective response rate (ORR) are not yet available for the nivolumab plus ipilimumab arm compared with the chemotherapy arm.

Table 7: Summary of Outcomes Relevant to the Systematic Review

BICR = blinded independent central review; CSR = Clinical Study Report; dMMR = deficient mismatch repair; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; PFS = progression-free survival; UI = utility index; VAS = visual analogue scale.

Note: Only relevant outcomes reported in the section of results in this review were presented in this table.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence, Bristol-Myers Squibb, 2024 (Interim CSR);⁵⁷ Bristol-Myers Squibb, 2025 (Supplemental Analysis).⁵⁹

Progression-Free Survival

The primary outcome was BICR-assessed PFS based on the centrally confirmed MSI-H or dMMR mCRC, defined as the time from randomization to the date of the first documented disease progression per RECIST 1.1 or death due to any cause, whichever occurred first. Patients who did not progress and remained alive were censored on the date of their last tumour assessment. Patients who did not have any on-study tumour assessments and remained alive were censored on their randomization date. Patients who started any subsequent anticancer therapy or switched to crossover without a prior reported progression or before death were censored at the last tumour assessment conducted on or before initiation of the subsequent anticancer therapy or crossover.⁶⁰

The sponsor submitted 3 publications^61-63 as evidence to support the use of PFS as a surrogate end point for OS in the population with mCRC. Roodhart et al. (2025),⁶¹ examined previously untreated patients with mCRC and reported a correlation between PFS and OS. In the Cicero et al. (2018)⁶² study, results aggregated from multiple mCRC trials supported the use of PFS as a surrogate, particularly in first-line and second-line settings. A study by Sidhu et al. (2013),⁶³ with pooled data (n = 20,438) from 24 randomized mCRC trials evaluated chemotherapy and targeted drugs (panitumumab, cetuximab, bevacizumab, and aflibercept), and the results indicated that PFS efficacy reasonably predicted a benefit in OS in the mCRC setting.⁶³

The sponsor noted that the CheckMate-8HW trial measured PFS using a predefined criterion of progression, such as RECIST 1.1 criteria, and the use of central reviewers blinded to study treatments to ascertain lack of assessment bias, as per FDA recommendations.⁶⁴

BICR-assessed PFS based on locally confirmed MSI-H or dMMR mCRC was a key secondary outcome of interest. It was defined the same way as the primary outcome, and conditions (e.g., patients who were censored) applied in a similar manner.

Exploratory Outcomes

The exploratory outcomes in the CheckMate-8HW trial included the following:

• EORTC QLQ-C30 (cancer-specific) includes GHS, 5 functional scales, 3 multi-item symptom scales, and 6 symptom single items. The sponsor did not submit any information regarding the psychometric properties (validity, reliability, and responsiveness) of the EORTC QLQ-C30 in the population with metastatic colorectal disease (Table 8).

• EQ-5D-3L (visual analogue scale [VAS] and utility index [UI]) descriptive systems have 5 dimensions with 3 levels: “no problems” (level 1), “some problems” (level 2), and “extreme problems” (level 3).” Responses to the descriptive system were converted to a single UI score. Respondents used VAS to rate their current health on a 101-point scale: 0 = “worst” to 100 = “best imaginable health.” The sponsor did not submit any information regarding the psychometric properties of EQ-5D-3L in the population of mCRC (Table 8).

A description of the EORTC QLQ-C30 and EQ-5D-3L outcome measures is presented in Table 8.

Table 8: Summary of the EORTC QLQ-C30 and EQ-5D-3L Outcome Measures and Their Measurement Properties

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; HRQoL = health-related quality of life; mCRC = metastatic colorectal cancer; MID = minimal important difference; QoL = quality of life; UI = utility index; VAS = visual analogue scale.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Safety End Points

The assessment of safety was based on the incidence of AEs, SAEs, AEs leading to discontinuation, AEs leading to dose modification, select AEs, IMAEs, OESIs, and deaths.

Statistical Analysis

A summary of statistical analyses used in the CheckMate-8HW trial is provided in Table 9.

Table 9: Statistical Analysis of Efficacy and Safety End Points

BICR = blinded independent central review; CI = confidence interval; CTCAE = Common Terminology Criteria for Adverse Events; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; HR = hazard ratio; KM = Kaplan-Meier; MID = minimally important difference; MMRM = mixed models for repeated measures; NA = not applicable; NCI = National Cancer Institute; NR = not reported; PFS = progression-free survival; QoL = quality of life; SD = standard deviation; UI = utility index; VAS = visual analogue scale; vs. = versus.

Note: Only relevant outcomes reported in the Results section in this review were presented.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence - Bristol-Myers Squibb, 2023 [Statistical Analysis Plan].⁷⁰

Sample Size and Power Calculation

The study characteristics, design, and statistical testing strategy of the CheckMate-8HW trial are described in Table 6, Figure 1, and Figure 2, respectively. The following description focuses on content from the study considered relevant to this Reimbursement Review report.

To control the overall type I error of 0.05, alpha was split among various hypotheses. An alpha of 0.044 was used for PFS (nivolumab plus ipilimumab versus chemotherapy) in first-line treatment and the remaining 0.006 was used for all lines. Sample size determination for PFS was calculated assuming a piecewise exponential distribution in the nivolumab plus ipilimumab arm and exponential distribution in the chemotherapy arm. Based on simulations, approximately 125 PFS events in first-line treatment would provide about 99% power to reject an alternative hypothesis of a model-averaged HR of 0.55 with an overall type I error of 0.044 (2-sided). Under the assumption of a staggered enrolment and the assumed event distribution, it would require randomizing approximately 230 patients receiving first-line treatment with nivolumab plus ipilimumab compared with chemotherapy at a 2:1 ratio. An interim analysis was planned to be conducted when 85% of the total number of events were observed (approximately 106 events) and after the last participant was randomized.

Statistical Testing

Statistical analysis of efficacy outcomes in the CheckMate-8HW trial was controlled for overall type I error by using a hierarchical testing strategy. The testing strategy in Figure 2 controlled the family wise error rate at an alpha level of 5% for the primary and key secondary end points. The testing procedure only allowed testing of secondary outcomes if all the precedent outcomes completed their tests. Testing was only performed in the forwarding path (no retrospective testing).

Figure 2: Testing Strategy for the Primary and Secondary Outcomes

1L = first line; dMMR = deficient mismatch repair; MSI-H = microsatellite instability-high; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; vs. = versus.

Sources: Bristol-Myers Squibb, 2023 (Statistical Analysis Plan).⁷⁰ Details included in the figure are from the sponsor’s Summary of Clinical Evidence.

PFS by BICR

Primary Analyses

The primary outcome PFS analysis based on centrally confirmed MSI-H or dMMR mCRC was conducted using a log-rank test stratified on tumour sidedness (left versus right). The HR across treatment groups along with its corresponding CI were estimated using a stratified Cox model. Ties were handled using the exact method. The PFS survival curve within each treatment arm was estimated using the Kaplan-Meier (KM) estimator. A 2-sided 95% confidence interval (CI) for median PFS in each treatment arm was computed via a log-log transformation. PFS probability at fixed time points (e.g., 6 and 12 months) were presented along with their corresponding 95% CIs calculated using Greenwood’s formula.⁷¹

PFS based on locally confirmed MSI-H or dMMR mCRC (a key secondary outcome) was assessed using the same method as the primary outcome analysis.

Subgroup Analyses

Prespecified subgroup analyses for PFS by BICR was conducted based on important baseline and demographic characteristics including age, sex, race, region, ECOG PS, disease stage at initial diagnosis, tumour sidedness, time from initial disease diagnosis to randomization, liver metastasis per BICR, and BRAF, KRAS, NRAS mutation status, and so forth. For each comparison, the median PFS based on the KM product-limit method along with 2-sided 95% CIs were produced. Forest plots of the unstratified PFS HRs (along with the 95% CIs) were produced. Median and HRs were not reported if the number of patients in the subgroup category per treatment arm was less than 10.

Sensitivity Analysis

Sensitivity analyses were conducted, including analysis of PFS per BICR including imbalanced baseline characteristics as covariates; analysis of PFS per BICR using unstratified Cox model; analysis of PFS per BICR using stratification factors as covariates; and analysis of PFS per BICR accounting for missing tumour assessment before PFS event (Table 9).

EORTC QLQ-C30 (Exploratory Outcomes)

For EORTC QLQ-C30, all scales and single items were scored on categorical scales and linearly transformed to 0 to 100 scales with higher scores for functional scales or items (and EORTC QLQ-C30 GHS) representing higher levels of functioning or quality of life and higher scores for symptom scales or items representing a higher level of symptoms. For EORTC QLQ-30, a meaningful difference in the change from baseline was defined as a change of 10 or more points.^68,72

For EORTC QLQ-C30, the following descriptive analyses were conducted:

• The EORTC QLQ-C30 questionnaire completion rate was analyzed, defined as the proportion of questionnaires received out of the expected number (i.e., number of patients receiving treatment or in follow-up), and summaries for each assessment time point by treatment group, based on all patients who were randomized and all patients with locally confirmed MSI-H or dMMR status who were randomized.

• The mean score and mean change from baseline in EORTC QLQ-C30 GHS, functional scales, and symptom scales were summarized using descriptive statistics (N, mean with standard deviation, and 95% CI) for all scales at each assessment time point).

• A mixed model repeated measures model was used to generate the results.

EQ-5D-3L (Exploratory End Point)

For EQ-5D-3L VAS, patients rated their general health using a scale ranging from 0 to 100 with 0 being the worst imaginable health state and 100 being the best imaginable health state. The MID from baseline was 7 points for EQ-5D-3L VAS scores.⁷³

For the EQ-5D-3L UI, patients rated their health state for each of the 5 dimensions in the descriptive system (mobility, self-care, usual activities, pain or discomfort, anxiety or depression). Responses to the descriptive system then define 1 of 243 possible health states. A single UI score was calculated by applying a value or weight to each of the levels in each dimension. The UK time trade-off value set was used to calculate UI scores, which range from −0.594 to 1.000, where 1 reflects full health, 0 reflects death, and negative scores reflect a health state perceived to be worse than death.⁷⁴ The MID was 0.08 for EQ-5D-3L UI scores.⁷³

Safety Analyses

All safety analyses were based on the safety analysis set. Safety assessments included the frequency of deaths, AEs, SAEs, AEs leading to discontinuation of study treatment or dose modification, IMAEs, and OESIs. Descriptive statistics of safety were presented by treatment arm for all patients who were treated. Analyses were conducted using the 30 day and/or 100-day safety window from the day of the last dose received (data cut-off date: October 12, 2023, and data cut-off date: August 28, 2024).

Analysis Populations

The analysis populations for patients receiving first-line treatment randomized to nivolumab plus ipilimumab and chemotherapy are defined in Table 10.

Table 10: Analysis Populations

dMMR = deficient mismatch repair; IHC = immunohistochemistry; ITT = intention to treat; MSI-H = microsatellite instability-high; PCR = polymerase chain reaction.

Sources: Bristol-Myers Squibb, 2023 [Statistical Analysis Plan].⁷⁰ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

The patient disposition for the CheckMate-8HW trial is presented in Table 11. At the data cut-off date on October 12, 2023, the median follow-up for patients who were randomized and receiving first-line treatment was 31.57 months (range, 6.1 months to 48.4 months).⁵⁷ A total of 303 patients were randomized to the nivolumab plus ipilimumab arm (n = 202) or to chemotherapy arm (N = 101). Of these patients, 288 patients (95.0%) were treated: 200 with nivolumab plus ipilimumab and 88 with chemotherapy. The most common reason for discontinuation of treatment was disease progression in both treatment arms (19% in the nivolumab plus ipilimumab arm and 69% in the chemotherapy arm). Of the 303 patients who were randomized and receiving first-line treatment, 255 had centrally confirmed MSI-H or dMMR status: 171 in the nivolumab plus ipilimumab arm and 84 in the chemotherapy arm. The overall patient disposition was consistent between all patients randomized to receive first-line treatment (i.e., locally confirmed MSI-H or dMMR, intention-to-treat [ITT] population) and patients who were randomized and receiving first-line treatment with centrally confirmed MSI-H or dMMR.

Table 11: Patient Disposition — Patients Randomized to Receive First-Line Treatment in the Nivolumab Plus Ipilimumab and Chemotherapy Arms (ITT)

AE = adverse event; CDA-AMC = Canada’s Drug Agency; CSR = Clinical Study Report; DCO = data cut-off; ITT = intent to treat; PP = per protocol.

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^aThe reasons include randomized in error for the participant in the nivolumab plus ipilimumab arm and the following in the chemotherapy arm: participant refused chemotherapy (3 patients); participant changed their mind (1 participant); and participant requested to discontinue (1 participant).

^bIncludes data from crossover period or cohort. The crossover cohort included patients in the chemotherapy arm who experienced documented progression of disease and crossed over to receive nivolumab plus ipilimumab therapy. Percentages are based on patients entering the period. End of treatment status was evaluated at the end of the main period treatment for patients who continued to crossover.

^cThe ITT population corresponds to the population who were randomized.

^dThe safety population included all patients who were treated (i.e., the population who were treated).

Sources: Bristol-Myers Squibb, 2024 (Interim CSR).⁵⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence, as well as additional information provided by the sponsor at the request of CDA-AMC.

Baseline Characteristics

Baseline characteristics of all patients randomized to receive first-line treatment in the CheckMate-8HW trial for the ITT population (i.e., locally confirmed MSI-H or dMMR) are presented in Table 12. The baseline characteristics outlined in Table 12 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. Baseline characteristics for patients randomized to receive first-line treatment with centrally confirmed MSI-H or dMMR were consistent with those for all patients randomized to receive first-line treatment. The 2 treatment arms had generally similar demographic, clinical, and disease characteristics. No major imbalances were noted. Among all patients, the median age was 63 years (range, 21 to 87 years). More patients were aged 65 years or older in the chemotherapy arm than in the nivolumab plus ipilimumab arm (54.5% versus 42.1%). Slightly more patients were female (53.8%), and a majority were white (86.1%). Patients were distributed across Asia (9.9%); Canada, Europe, or the US (67.3%); and the rest of the world (22.8%). The number of patients who were enrolled from Canada was not reported. A total of 53.8% patients had an ECOG PS score of 0, and 46.2% had an ECOG PS score of 1. Overall, 44.2% of patients had stage IV disease at initial diagnosis. Overall tumour sidedness was 32% in the left side and 68% in the right side. The proportion of patients who had liver metastasis, lung metastasis, and peritoneal metastasis at baseline were 38.9%, 22.8% and 41.9% respectively.

Table 12: Baseline Characteristics of Patients Randomized to Receive First-Line Treatment in the Nivolumab Plus Ipilimumab and Chemotherapy Arms (ITT)

BICR = blinded independent central review; CSR = Clinical Study Report; dMMR = deficient mismatch repair; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ITT = intention to treat; MMR = mismatch repair; MSI = microsatellite instability; NA = not applicable; NE = not evaluable; NGS = next generation sequencing; PCR = polymerase chain reaction; pMMR = proficient mismatch repair.

Notes: For local and central MSI or MMR assessment, “not available” includes both not evaluable and not tested. MSI test per local assessment includes both PCR and NGS test.

Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

^aInformation on Lynch syndrome was collected based on the participant’s medical history.

Sources: Bristol-Myers Squibb, 2024 (Interim CSR);⁵⁷ Andre et al. (2024).⁵⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

Study Treatments

Patient exposure data for first-line treatment only supplemental analysis with a data cut-off date of August 28, 2024, is provided in Table 13. At the data cut-off, the median duration of therapy was 19.04 months in the nivolumab plus ipilimumab arm (nivolumab: 19.04 months; ipilimumab: 2.10 months) and 3.96 months in the chemotherapy arm.⁵⁹ Detailed patient exposure information for the first-line treatment only interim analysis with a data cut-off on October 12, 2023, is provided in Table 31 in Appendix 1.

Table 13: Duration of Study Therapy in Patients Receiving First-Line Treatment in the Nivolumab Plus Ipilimumab and Chemotherapy Arms (ITT)

ITT = intention to treat.

Source: Bristol-Myers Squibb, 2025 (Supplemental Analyses).⁵⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Prior Treatment

For all patients receiving first-line treatment in this study, prior surgery related to the current cancer and prior radiotherapy was allowed.⁵⁷ Prior treatment with chemotherapy and/or targeted drugs for metastatic disease was not allowed; however, patients treated with neoadjuvant and/or adjuvant chemotherapy were eligible if disease progression occurred 6 months or later after completion of chemotherapy. Most patients (96.7%) randomized to first-line treatment received prior cancer therapy.⁵⁷

Concomitant Medications and Cointerventions

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Table 14: Concomitant Medications Used in 10% or More of Patients Randomized to Receive First-Line Treatment in the Nivolumab Plus Ipilimumab and Chemotherapy Arms (ITT)

CSR = Clinical Study Report; ITT = intention to treat.

Note: Concomitant medications are listed in order of most used in the nivolumab plus ipilimumab arm.

Source: Bristol-Myers Squibb, 2024 (Interim CSR).⁵⁷

Subsequent Treatment

Subsequent cancer therapy was defined as any systemic therapy, surgery, or radiotherapy for the treatment of tumours occurring after discontinuation of the study treatment. Among all patients randomized to first-line treatment (data cut-off date was on October 12, 2023), a lower proportion of patients received subsequent cancer therapy (systemic therapy in majority) in the nivolumab plus ipilimumab arm than in the chemotherapy arm (22.3% versus 68.3%). Crossover treatment (nivolumab plus ipilimumab) was received by 45 patients (44.6%) in the chemotherapy arm who experienced BICR-documented disease progression; this crossover treatment was included under subsequent systemic therapy. An additional 20.8% of patients received subsequent immuno-oncology therapy outside of the crossover cohort. Taken together, 65.4% of patients in the chemotherapy arm received subsequent immuno-oncology therapy. A summary of subsequent cancer therapy for all patients randomized to first-line treatment is provided in Table 15.

Table 15: Subsequent Cancer Treatment — Patients Randomized to Receive First-Line Treatment in the Nivolumab Plus Ipilimumab and Chemotherapy Arms (ITT)

CSR = Clinical Study Report; ITT = intention to treat.

^aParticipant may have received more than 1 type of subsequent therapy. Subsequent therapy was defined as therapy started on or after first dosing date (randomization date if the participant was never treated).

^bPatients who received crossover treatment in chemotherapy are included.

Source: Bristol-Myers Squibb, 2024 (Interim CSR).⁵⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Efficacy

The primary outcome was defined as PFS per BICR based on centrally confirmed MSI-H or dMMR mCRC, with a data cut-off of August 28, 2024.

The median PFS was 54.08 months (95% CI, 54.08 months to not available) in the nivolumab plus ipilimumab arm and 5.85 months (95% CI, 4.37 months to 7.79 months) in the chemotherapy arm. The HR was 0.21 (95% CI, 0.14 to 0.31) (Table 16). The between-group difference in PFS at 12 months for nivolumab plus ipilimumab versus chemotherapy was 57.45% (95%CI, 45.41% to 69.49%). PFS results are presented in Figure 3, Table 16, and Table 17.

Figure 3: PFS per BICR for Nivolumab Plus Ipilimumab Versus Chemotherapy in Patients With Centrally Confirmed MSI-H or dMMR mCRC Randomized to Receive First-Line Treatment (DCO: August 28, 2024)

1L = first line; BICR = blinded independent central review; CI = confidence interval; DCO = data cut-off date; dMMR = deficient mismatch repair; HR = hazard ratio; IRT = interactive response technology; KM = Kaplan-Meier; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; NE = not estimable; PFS = progression-free survival.

Notes: Statistical model for HR and P value: stratified Cox proportional hazard model and stratified log-rank test by tumour sidedness (left versus right) as per IRT. Symbols represent censored observations. Excludes data collected on or after first crossover dose date. KM plot was generated only if there were at least 10 patients in each treatment arm in population or subgroup.

Source: Andre et al., Lancet 2025 – supplement.⁵⁶ Bristol-Myers Squibb, 2025 [Supplemental Analyses.].⁵⁹ Reprinted from The Lancet, 405(10476), Andre T, Elez E, Lenz H-J, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomized, open-label, phase 3 trial., Pages No.383 to 395, Copyright (2025), with permission from Elsevier. doi: https://doi.org/10.1016/S0140-6736(24)02848-4. Details included in the figure are from the sponsor’s Summary of Clinical Evidence.

Table 16: Results of PFS per BICR, Patients Randomized to First-Line Treatment With Centrally Confirmed MSI-H or dMMR mCRC

BICR = blinded independent central review; CI = confidence interval; dMMR = deficient mismatch repair; HR = hazard ratio; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; NR = not retested; PFS = progression-free survival.

^aBased on Kaplan-Meier estimates.

^bNot retested because P < 0.0001 was reported based on the data cut off date of October 12, 2023.

Source: Bristol-Myers Squibb, 2025 (Supplemental Analyses).⁵⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 17: Reason for Censoring, PFS per BICR for Nivolumab Plus Ipilimumab vs. Chemotherapy in Patients With Centrally Confirmed MSI-H or dMMR mCRC Randomized to Receive First-Line Treatment (Data Cut-off Date: August 28, 2024)

BICR = blinded independent central review; dMMR = deficient mismatch repair; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; vs. = versus.

Note: Excludes data collected on or after first crossover dose date.

^aRECIST 1.1 criteria.

^bTumour assessments and death if any, occurring after the start of subsequent anticancer therapy were not considered.

^cPatients who received subsequent anticancer therapy before first on-study scan were censored on randomization date.

^dIncludes patients, regardless of treatment status, who received subsequent anticancer therapy without a prior reported PFS event. Those patients were censored at the last evaluable tumour assessment before or on the start date of subsequent anticancer therapy.

Sources: Bristol-Myers Squibb, 2025 [Supplemental Analyses].⁵⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Subgroup Analyses

Most subgroup analyses of PFS per BICR for patients with centrally confirmed MSI-H or dMMR mCRC were consistent with the primary analysis. Specifically, HRs were less than 1 in favour of nivolumab plus ipilimumab, and the corresponding 95% CIs did not include 1 (Figure 4). Of note, statistically significant improvements in PFS were observed in both patients with liver metastases (HR = 0.11; 95% CI, 0.05 to 0.25) and those without liver metastases (HR = 0.28; 95% CI, 0.17 to 0.46).

Figure 4: PFS per BICR in Predefined Subgroups for Nivolumab Plus Ipilimumab Versus Chemotherapy in Patients With Centrally Confirmed MSI-H or dMMR mCRC Randomized to Receive First-Line Treatment [Redacted]

BICR = blinded independent central review; dMMR = deficient mismatch repair; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; PFS = progression-free survival.

Sensitivity Analyses

Sensitivity analyses for PFS per BICR based on centrally confirmed MSI-H or dMMR mCRC were consistent with primary analysis (Table 18).

Table 18: Sensitivity Analysis for PFS per BICR for Nivolumab Plus Ipilimumab vs. Chemotherapy in Patients With Centrally Confirmed MSI-H or dMMR mCRC Randomized to Receive First-Line Treatment

BICR = blinded independent central review; CI = confidence interval; dMMR = deficient mismatch repair; HR = hazard ratio; IRT = interactive response technology; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; PFS = progression-free survival; PD-L1 = programmed death-ligand 1 vs. = versus.

Note: Excludes data collected on or after first crossover dose date.

^aCox proportional hazard model stratified by time-dependent Cox model by tumour sidedness (left versus right) per IRT.

^bThe following imbalanced baseline characteristics are included in the model: PD-L1.

Sources: Bristol-Myers Squibb, data on file. Data cut-off date: October 12, 2023.⁵⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The secondary outcome was PFS per BICR results based on locally confirmed dMMR or MSI-H mCRC in the ITT population (data cut-off date: August 28, 2024).

The median PFS was 54.08 months (95% CI, 38.44 months to not achieved) in the nivolumab plus ipilimumab arm and 5.95 months (95% CI, 4.86 months to 9.03 months) in the chemotherapy arm. The HR was 0.30 (95% CI, 0.21 to 0.43) (Table 19). The between-group difference in PFS at 12 months for nivolumab plus ipilimumab versus chemotherapy was 47.01% (95% CI, 36.57% to 57.45%). PFS results are presented in Figure 5 and Table 19.

Figure 5: PFS per BICR for Nivolumab Plus Ipilimumab Versus Chemotherapy in Patients With Locally Confirmed MSI-H or dMMR mCRC Randomized to Receive First-Line Treatment (ITT) (DCO: August 28, 2024) [Redacted]

BICR = blinded independent central review; DCO = data cut-off; dMMR = deficient mismatch repair; ITT = intention to treat; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; PFS = progression-free survival.

Table 19: PFS per BICR for Nivolumab Plus Ipilimumab vs. Chemotherapy in Patients With Locally Confirmed MSI-H or dMMR mCRC Randomized to Receive First-Line Treatment (ITT)

███ █████ █████ ████ █ ███████ ███████████ ███████ ███████ ██ █ ██████████ █████████ ███ █ ████ ████████ ████ █ █████████ ████████ ███████ ████ █ ██████████ ██████████ ███████ █████ █ ██████████████ ███████████ █████ ██ █ ███ ███████████ ████ █ ███ █ █████████ █ ██████████████ ██████████ ██ ████████ ████ ██████ ████████████████ ██ ████████ ██████████ █████ ██ ████████████ ███████████ █████ ████ █████████ ██ ██ █████ █████ █████████ ████ ████ ███ █████████ ████████ █████████████ ███████ ████ ██████████████ ████████████ ███ ████ ███ ██████████ ███████████ ████████ ██ ███ ███████ ██ ███ ███████ ██ ████████

BICR = blinded independent central review; dMMR = deficient mismatch repair; ITT = intention to treat; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; PFS = progression-free survival; vs. = versus.

The results observed in the August 28, 2024, data cut-off date (median follow-up: 42.05 months) were consistent with the PFS results from the primary analysis, sensitivity analysis, and subgroup analysis based on the October 12, 2023, data cut-off date (median follow-up: 31.57 months).

Health-Related Quality of Life

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30

At the data cut-off for the first-line treatment interim analysis (data cut-off: October 12, 2023), the completion rates for the EORTC QLQ-C30 at baseline were 95.3% for patients in the nivolumab plus ipilimumab arm and 86.9% in the chemotherapy arm.⁵⁷

Mean baseline EORTC QLQ-C30 scores were generally similar in the 2 treatment arms (Figure 6 and Table 20). The results for EORTC QLQ-C30 GHS in the nivolumab plus ipilimumab arm showed a trend for improvement from baseline during the treatment period (Figure 6). In contrast, EORTC QLQ-C30 GHS results for the chemotherapy arm were either stable or showed a trend for worsening from baseline during the treatment period (Figure 6). At week 37, the between-group mean differences of change from baseline was 14.0 (95% CI, 5.9 to 22.1).

No subgroup or sensitivity analyses were conducted for EORTC QLQ-C30.

Figure 6: Mean Change From Baseline for EORTC QLQ-C30 GHS Scores by Time Points in Patients With Locally Confirmed MSI-H or dMMR mCRC Randomized to Receive First-Line Treatment in the Nivolumab Plus Ipilimumab and Chemotherapy Arms (ITT) (Data Cut-Off Date: October 12, 2023) [Redacted]

dMMR = deficient mismatch repair; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Core 30; GHS = global health status; ITT = intention to treat; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high.

Table 20: EORTC QLQ-C30 GHS, EQ-5D-3L VAS, and EQ-5D-3L UI Scores — Longitudinal Analysis (MMRM) Change From Baseline Results by Time Points (Patients With Locally Confirmed MSI-H or dMMR mCRC Randomized to Receive First-Line Treatment) (ITT)

CDA-AMC = Canada’s Drug Agency; CI = confidence interval; dMMR = deficient mismatch repair; EORTC QLQ-C30 = European Organization for Research and Treatment of Care Quality of Life Questionnaire Core 30; GHS = global health status; ITT = intention to treat; mCRC = metastatic colorectal cancer; MMRM = mixed model repeated measure; MSI-H = microsatellite instability-high; VAS = visual analogue scale; UI = utility index.

Note: A mixed model repeated measures model was used to generate the results in this table.

Source: Additional information was provided by the sponsor at the request of CDA-AMC.

The results of EORTC QLQ-C30 GHS based on the centrally confirmed patient population was consistent with the locally confirmed patient population.

EQ-5D-3L Questionnaire

████████ ███ ████ ████████ ███ ███ ██ ██████ ███ ███ ██ ██████████ ████████████ ████ ███████ █████████ ██████████ ████ ████████ ███████████ ████ ████ ██████ █████████ ██ ████ █████ ███ ██ █ ███████ ██████ ██ ███ █████████ ████ ██████████ ███ ████████ ████ ███ ████████████ ██████████ ███

Harms

At the October 12, 2023, data cut-off for the first-line treatment interim analysis, patients had a median treatment duration of 13.52 months for the nivolumab plus ipilimumab arm (nivolumab: 13.52 months; ipilimumab: 2.10 months) and 3.96 months for the chemotherapy arm.⁵⁷ At the August 28, 2024, data cut-off, patients had a median treatment duration of 19.04 months for the nivolumab plus ipilimumab arm (nivolumab: 19.04 months; ipilimumab: 2.10 months) and 3.96 months for the chemotherapy arm.⁵⁷ The median follow-up time was 31.57 months and 42.05 months as of the October 12, 2023, and the August 28, 2024, data cut-offs, respectively. The narrative that follows will focus on the updated data from the August 28, 2024, data cut-off, except where that information was not provided. The harms outcomes are summarized in Table 21.

Table 21: Safety Results for Patients Receiving First-Line Treatment (Safety Population)

AEs = adverse event; CI = confidence interval; CSR = Clinical Study Report; DCO = data cut-off; IMAE = immune-mediated adverse event; OESI = other event of special interest; SAE = serious adverse event; vs. = versus.

Notes: AE included events reported between first dose and 30 days after last dose of study therapy, unless otherwise indicated. Excluded data collected on or after first crossover dose date, except for the summary of deaths.

^aDiscontinuation of any drug in the regimen.

^bNo OESIs were reported in the following categories: demyelination, Guillain-Barre syndrome, graft vs. host disease, autoimmune eye disorder, and immune-mediated arthritis. All-causality OESIs within 100 days of last dose with or without immune modulating medication by category.

^cOne patient with grade 5 OESIs was observed in the nivolumab plus ipilimumab arm on top of the grade 3 to 4 OESIs events.

Sources: Bristol-Myers Squibb, 2024 (Interim CSR);⁵⁷ Bristol-Myers Squibb, 2025 (Supplemental analyses).⁵⁹

Adverse Events

The overall frequency of grade 3 to 4 all-causality AEs were reported in █████ ███ █████ in the nivolumab plus ipilimumab arm and in the chemotherapy arm, respectively (data cut-off: August 28, 2024) (Table 21). The most frequently reported all-causality grade 3 to 4 AEs (occurred in 6% or more of patients in either arm) were neutropenia (nivolumab plus ipilimumab versus chemotherapy: 1.0% versus 10.2%), decreased neutrophil count (0.5% versus 6.8%), and hypertension (1.5% versus 6.8%) (data cut-off: October 12, 2023) (Table 21).

Serious Adverse Events

The overall frequency of grade 3 to 4 SAEs was █████ ███ █████ in the nivolumab plus ipilimumab arm and in the chemotherapy arm, respectively (data cut-off: August 28, 2024) (Table 21). The most frequently reported all-causality grade 3 to 4 SAEs (occurred in more than 3% of patients in either arm) were adrenal insufficiency (nivolumab plus ipilimumab versus chemotherapy: 3% versus 0%) and pneumonia (1.5% versus 3.4%) (data cut-off: October 12, 2023) (Table 21).

Withdrawals Due to AEs

The overall frequency of all-causality AEs leading to discontinuation of treatment was █████ in the nivolumab plus ipilimumab arm and █████ in the chemotherapy arm, respectively (data cut-off: August 28, 2024) (Table 21). Grade 3 to 4 AEs leading to discontinuation of study drug were reported in a similar proportion of patients (nivolumab plus ipilimumab versus chemotherapy: █████ ███ █████) in both arms (data cut-off: August 28, 2024) (Table 21). ███ ████ ██████████ ████████ ███ ███████ ██ █████████ ███████████████ ██ ███ █████████ █ ██████████ ███ ████ █████████ ████ ████ ███████ █████████████ ██████ ███ ███████████████ █████████████ █████████ ██ ███ ████████████ ████ ███ ████ ██████████ ████████ ███ ███████ ██ █████████ ███████████████ ████ ██████████ ██████████ ███ █████████████ █████ ██████ ███ ██████████ ███████ ██████████ ███████ ███ █████████ ███ ███████ ██ █ ████ █████ ██ █████████ ████ ████████ ██ ██ ███████ ████████ ██ ███ █████████ █ ██████████ ███ ███ ██ ███████ ████████ ██ ███ ████████████ ██████ ███ ████ ██████████ ████████ ███ ███████ ██ █ ████ █████ ██ █████████ ████ ████████ ███████ ████████ ███████ ███ █████████ ███ ███ █████████ ███ █████ █████ ██ ███ █████████ █ ██████████ ███ ███ ███████████ ████████ ████████ ████████ ████████ ████████ ███ █████████ ██████████ █████ ███████ ██ ███ ████████████ ██████

Notable Harms (AESIs)

The AESIs of special interest reported in this report include IMAEs and OESIs.

Immune-Mediated AEs

A total of ███ patients in the nivolumab plus ipilimumab arm and ████ patients in the chemotherapy arm experienced grade 3 to 4 IMAEs. The difference between groups (nivolumab plus ipilimumab versus chemotherapy) was ████ | (95% CI, not reported). The most frequently reported grade 3 to 4 IMAEs (occurred in 3% or more of patients in either arm) were ████████████████ ███████████ ██████████ ███ █████████████ ████ ███ ████ █████████ █████ ███ ████ ███ ███████ █████████████ █████ ███ ███

These results were consistent with those reported in the data cut-off on October 12, 2023 (Table 21).

Other Events of Special Interest

A total of 2% patients in the nivolumab plus ipilimumab arm and 0% of patients in the chemotherapy arm experienced grade 3 to 4 OESIs. ███ ████ ██████████ ████████ █████ ███ ████ █████████ ██ | | | ████████ ██ ██████ ████ ████ ████████████ ███████████ ██████████ ███ █████████████ ████ ███ ████ ███ ███████████ █████ ███ ████

Mortality

All-cause mortality was █████ in the nivolumab plus ipilimumab arm and █████ in the chemotherapy arm (Table 21).

Critical Appraisal

Internal Validity

The CheckMate-8HW study was a phase III, open-label RCT. Stratified randomization via interactive response technology ensured concealment of the randomized groups until allocation. Baseline characteristics were balanced across the treatment groups, suggesting that the randomization was reasonably successful. The clinical experts consulted for this review indicated that the concomitant treatments used in both arms are reflective of practice in Canada, and it is unlikely to have introduced bias in efficacy for PFS. The open-label design introduces a potential bias in the assessment of PFS; however, this bias was mitigated by using BICR for disease assessment. Knowledge of the assigned treatment could have led to bias in the reporting and measurement of subjective outcomes, including patient-reported outcomes (e.g., EORTC QLQ-C30) and subjective AEs (such as fatigue and nausea). Two patients (1%) randomized in the nivolumab plus ipilimumab arm and 13 patients (12.9%) in the chemotherapy arm did not receive the treatment. Protocol deviations were low and balanced in both arms (nivolumab plus ipilimumab versus chemotherapy: 4.95% versus 5.94%). Overall, the risk of selection bias and detection bias are considered low.

The clinical experts CDA-AMC consulted for this review indicated that OS is the most important end point in this disease setting. The primary efficacy end point of PFS was considered appropriate for the disease setting and was considered a valid surrogate for OS in this indication in the patient population with mCRC.^61-63 A longer-term follow-up is needed to inform the true effect of nivolumab plus ipilimumab compared with chemotherapy on OS. Most subgroup results for PFS were consistent with the primary analysis, favouring nivolumab plus ipilimumab, although some of these analyses were limited by small sample sizes. However, there was no multiplicity control for the subgroup analyses.

█████ ███ █ ███████████ █████████ ████ ███ █████ █████ ██████ ███████ █████ █████ ███ ████████ ████ ██ ███ █████████ █████ ███████ ██████ ████ ███████ █████ ███ ███████ ███ ███ █████ ██ █████ ██ █████ ████ ███ █████ ███ ██████████ █████████ ████ █████████ ████████ ██ ███ █████ ███ █████████ █████████ █████ ██ ████ ███ ███ ███ ██ ██████████████ ██ ███ ███████ ███████ ███████████ ██ ██████ ███████████ █████ ██ █████ █████ ███ ██████ ██ ██████████ ██████████ ████████ ████ ████████████ ██ █████ ███ ██ █ ████ ████ ██ █████████ █████ ████████████ ██ ██████ █████████ ██████ ██ ████ ████

External Validity

The clinical experts highlighted that the inclusion and exclusion criteria of the CheckMate-8HW trial are standard for clinical trials, but stricter than what pertains in clinical practice. For example, they noted that patients with an ECOG PS score of greater than 1 were not eligible for the trial, whereas patients with an ECOG PS score of 2 would be considered potential candidates for nivolumab plus ipilimumab in the clinical experience. However, the clinical experts considered that overall, the inclusion and exclusion criteria of the CheckMate-8HW trial are consistent with the clinical practice setting in Canada and present no major generalizability concern of its findings in clinical practice in Canada.

The clinical experts indicated that the enrolment of the patients based on the locally confirmed MSI-H or dMMR mCRC is aligned with the clinical practice. In addition, according to the clinical experts consulted, the demographic and disease characteristics of the CheckMate-8HW trial population were reflective of patients living in Canada with mCRC. The drugs and dose regimens used in the chemotherapy arm were also consistent with that used in practice in Canada. Therefore, the results are considered to be generalizable to clinical practice in Canada.

GRADE Assessment Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE assessment was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^19,20

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — the true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — the true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect. The target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold (MID) for a clinically important effect. In this review, the threshold (MID) assessment of between-group difference for PFS were based on published information^21,22 in combination with the MID suggested by clinical experts consulted for this review. The threshold (MID) for HRQoL (i.e., EORTC QLQ-C30 GHS) assessment of between-group difference was based on the published information,²³ which was aligned with the suggestion by the clinical experts consulted for this review. The threshold (MID) for assessment of between-group difference for harms (i.e., IMAEs) was suggested by clinical experts consulted for this review.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for nivolumab plus ipilimumab combination therapy versus chemotherapies for the first-line treatment of patients with unresectable or MSI-H or dMMR CRC. The reference points for the certainty of evidence assessment for PFS, HRQoL, and harms were set according to the presence of an important effect based on thresholds identified from the literature and agreed or suggested by clinical experts consulted for this review.

Long-Term Extension Studies

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

Indirect Evidence

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

Objectives for the Summary of Indirect Evidence

In the absence of evidence from a direct head-to-head comparison, the sponsor submitted an ITC using MAIC for PFS and NMA for safety outcomes to compare nivolumab plus ipilimumab versus other comparators. The scope of the sponsor’s search strategy and study selection criteria for the systematic literature review (SLR) that informed the ITC were broader than that of this review, which focuses on pembrolizumab considered the current relevant comparator in Canada. The objective of this section is to summarize and critically appraise the sponsor-submitted ITC in patients receiving first-line treatment for MSI-H or dMMR mCRC.

Description of Indirect Comparison

Objectives

The objective of this ITC was to compare the efficacy in terms of PFS and safety outcomes of nivolumab plus ipilimumab with that of pembrolizumab for patients with MSI-H or dMMR mCRC receiving first-line treatment.

ITC Design

Study Selection Methods

An SLR was conducted following the recommendations of the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols checklist.^76,77 A summary of the methods used to conduct the SLR is provided in Table 22.

Table 22: Study Selection Criteria and Methods for Indirect Comparisons

1L = first line; AE = adverse event; ASCO = American Society of Clinical Oncology; ASCO GI = American Society of Clinical Oncology Gastrointestinal Cancers; CR = complete response; DFS = disease-free survival; dMMR = deficient mismatch repair; DOR = duration of response; ESCP = European Society of Coloproctology; ESMO GI = European Society for Medical Oncology Gastrointestinal Cancers; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; RFS = recurrence-free survival; SAE = serious adverse event; SD = stable disease; SLR = systematic literature review; TRM = treatment-related mortality; TTP = time to progression; TTTF = time to treatment failure.

^aRelevant SLRs or meta-analyses were included for bibliographic checks for primary publications that were not retrieved via other search methods. Once reviewed at the full-text screening stage, SLRs or meta-analyses were excluded from this review.

Source: Bristol-Myers Squibb, 2022.⁷⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

SLR Results and ITC Feasibility Assessment

Based on the similarity of the studies (population, intervention, comparator, outcome, and study design), the phase III RCTs KEYNOTE-177 and CheckMate-8HW were included for the ITC. The feasibility assessment found the 2 trials to be comparable across study designs, inclusion and exclusion criteria, most baseline characteristics assessed (minor differences in patient-reported race), common comparator treatments, and outcome definitions. Therefore, an indirect comparison was deemed feasible.

Identification of TEMs

A multistep approach, incorporating a literature review and input or validation from clinical experts consulted by the ITC team (including input from a clinical expert in Canada), was used to identify important prognostic factors in MSI-H or dMMR mCRC. The subgroup forest plots used to inform TEM selection are presented in Figure 9 and Figure 10 in Appendix 1. Seven TEMs were finally identified for matching based on the forest plots and availability of published data from the KEYNOTE-177 trial, namely, age, ECOG PS, BRAF, KRAS, and NRAS mutation status, side of primary tumour (left or right), liver metastasis, liver or lung metastasis, and region.

Proportional Hazards Assumption Validation

The proportional hazards assumption (PHA) for PFS in the KEYNOTE-177 trial was tested using the pseudoindividual patient data generated from the published KM curves. The results of the test suggested that the PHA was violated, indicating that the use of a constant HR-based ITC method may be biased.

ITC Analysis Methods

A summary of the analytical approaches used to conduct the ITC is provided in Table 23. Both an anchored and unanchored MAIC were conducted for efficacy analyses.⁷⁹

Table 23: Indirect Comparison Analysis Methods

AIC = Akaike information criterion; BIC = Bayesian information criterion; DSU = Decision Support Unit; HR = hazard ratio; ITC = indirect treatment comparison; KM = Kaplan-Meier; MAIC = matching-adjusted indirect comparison; NA = not available; NICE = National Institute for Health and Care Excellence; NMA = network meta-analysis; PFS = progression-free survival.

^aAnalyses involving overall survival could not be conducted at the time as this data from the CheckMate-8HW trial was still immature.

Source: Bristol-Myers Squibb, 2025 [ITC Report].⁷⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The detailed information of the assessment of homogeneity for the ITC is presented in Table 24 and Table 25.

Table 24: Assessment of Homogeneity for ITC

DCO = data cut-off; HR = hazard ratio; IPD = individual patient data; ITC = indirect treatment comparison; KM = Kaplan-Meier; PFS = progression-free survival.

Source: The sponsor’s submission.⁵⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The key baseline characteristics of the KEYNOTE-177 and CheckMate-8HW trials are presented in Table 25.

Baseline characteristics for first-line treatment trials in mCRC were classified according to 1 of 3 levels: most relevant (i.e., suggested stratification factors), recommended set, and suggested set.⁸² The distribution of these baseline characteristics were compared between the CheckMate-8HW and KN-177 trials, with a specific focus on the distribution of TEMs across trials to assess any potential imbalances (Table 25). The 2 trials were comparable across most of the baseline characteristics assessed with only minor differences noticed in the distribution of race of patients (i.e., with the CheckMate-8HW trial having a greater proportion of patients who were white and fewer patients who were Asian compared to the KEYNOTE-177 trial). Table 25 compares the patients’ baseline characteristics based on each trial’s population with locally confirmed MSI-H or dMMR mCRC status.

Table 25: Assessment of Heterogeneity in mCRC-Specific Baseline Characteristics

ECOG PS = Eastern Cooperative Oncology Group Performance Status; ITC = indirect treatment comparison; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; NR = not reported; TEM = treatment-effect modifier; vs. = versus.

Note: Three recommended and 14 suggested prognostic variables are not listed in the table as data on distributions in the KEYNOTE-177 trial were unavailable.

Race and ethnicity categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

^aPotential TEMs.

^bNot reported, but liver involvement (under recommended prognostic variables) was reported.

^cThree patients from the KEYNOTE-177 trial and 7 patients from the CheckMate-8HW trial who had both a BRAF mutation and a KRAS or NRAS mutation are included. Totals do not add up to 100%.

^dThe CheckMate-8HW trial reported the number of patients who received prior systemic therapy in adjuvant or neoadjuvant setting.

Sources: Bristol-Myers Squibb, 2024 (ITC Report Appendix).⁷⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Treatments of the chemotherapy arm in the KEYNOTE-177 trial and the CheckMate-8HW trial consisted of the same 6 chemotherapy treatments with or without targeted therapies, with the same dosing regimens. The distribution of treatments in the SOC (i.e., chemotherapy) arm for the KEYNOTE-177 trial and the CheckMate-8HW trial are comparable (Table 32 in Appendix 1). In both the KEYNOTE-177 trial and the CheckMate-8HW trial, PFS was similarly defined. Both trials were phase III, randomized, open-label studies with blinded independent review for assessing PFS. Both trials allowed crossover after disease progression. The KEYNOTE-177 trial had a median follow-up of 73.3 months and the CheckMate-8HW trial had a median follow-up of 42.05 months (based on individual patient data from the data cut-off of August 28, 2024.^56,59,80,81

Based on the feasibility assessment, 2 approaches were recommended for the ITC: an anchored MAIC that allows for adjustment of present heterogeneity in TEMs without requiring PHA to hold, and a proportional HR-based NMA that serves as a scenario analysis even though PHA is violated. The anchored MAIC is the methodologically preferred method, relying on fewer assumptions compared to the unanchored MAIC as randomization is preserved. Therefore, unanchored MAIC was performed as a sensitivity analysis. Unanchored MAIC matched the nivolumab plus ipilimumab trial arm to the pembrolizumab trial arm in terms of TEMs and prognostic variables.

Estimation of MAIC Weights

For the weighted analyses, inverse odds for trial inclusion were estimated for each patient in the CheckMate-8HW trial. These weights were estimated using a matching approach.

Anchored MAIC

Weighting

TEMs were matched in the MAIC methodology and the patient population in the CheckMate-8HW trial was reweighted such that the resulting population aligned with the KEYNOTE-177 population with regards to TEM distribution. Baseline characteristics used for matching and their distribution before and after matching of the CheckMate-8HW trial to the KEYNOTE-177 trial are provided in Table 26. Following matching, an effective sample size corresponding to █████ ███ of the original CheckMate-8HW trial sample size was observed.

Table 26: Patient Characteristics Included in the Anchored MAIC

ECOG PS = Eastern Cooperative Oncology Group Performance Status; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; TEM = treatment-effect modifier.

^aIncludes 10 patients who were classified as “both sided.”

^bThe CheckMate-8HW trial reported patients classified as “Canada, Europe, or US” from Czech Republic and Romania were reclassified to the rest of the world.

Source: Bristol-Myers Squibb, 2025 (ITC Report).⁷⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Weighting did not change the survival estimates significantly (Figure 11 in Appendix 1).

Unanchored MAIC

The unanchored MAIC methodology is similar to the methodology described in the preceding section for the anchored analyses. However, in the unanchored MAIC, only the intervention arm populations of interest (e.g., nivolumab plus ipilimumab and pembrolizumab) were matched. The unanchored analysis adjusted for both the chosen TEMs and 2 prognostic variables (prior chemotherapy and synchronous or recurrent metachronous metastasis).⁷⁹

Baseline characteristics before and after matching the CheckMate-8HW trial to the KEYNOTE-177 trial are provided in Table 27. Following matching, an effective sample size corresponding with about █████ of the original nivolumab plus ipilimumab arm sample size was observed.

Table 27: Patient Characteristics Included in the Unanchored MAIC

ECOG PS = Eastern Cooperative Oncology Group Performance Status; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; TEM = treatment effect modifier.

^aIncludes 5 patients who were classified as “both sided.”

^bThe CheckMate-8HW trial reported patients classified as “Canada, Europe, or US” from Czech Republic and Romania were reclassified to the rest of the world.

Source: Bristol-Myers Squibb, 2025 (ITC Report).⁷⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Weighting did not change the survival estimates significantly (Figure 12 in Appendix 1).

Adverse Events NMA

A Bayesian fixed effect NMA of AEs was conducted comparing the incidence of the following AEs in the CheckMate-8HW trial and the KEYNOTE-177 trial: any AEs of grade 3 or higher occurring in 5% or more of a treatment arm and immuno-oncology therapy related AEs recommended by clinical experts for inclusion in the analysis (diarrhea, hypophysitis, rash, adrenal insufficiency, hepatitis, hyperthyroidism, and pneumonia).⁸³

Results of ITC

Summary of Included Studies

Two studies, KEYNOTE-177 and CheckMate-8HW, were included in the ITC.

Evidence Networks

CheckMate-8HW and KEYNOTE-177 were the 2 trials included in the evidence base for which chemotherapy (SOC) was the common comparator. The network diagram is presented in Figure 13 in Appendix 1.

Efficacy

Anchored MAIC

Seven parametric survival distributions were fitted. The PFS KM curves for weighted CheckMate-8HW and KEYNOTE-177 trials, as well as the long-term extrapolation based on the best-fitting generalized gamma distribution, are shown in Figure 14 in Appendix 1.

Base-Case Analysis: Time-Varying HR of Nivolumab Plus Ipilimumab Versus Pembrolizumab

███ █████████ ████████████ ██████ █████ ██ ███ ███ █████████ █ ██████████ ███ █████████████ ██ ██████████ ██ ██████ █ ███ █████ ███ ███ █████ ████████ ██ ███ ████████████ ██ ██ ███ ██ █████ ████ █ ████ ███ █████████ ███████ ███████ ████ ██ ███████ ███████ ████ ██ ██ ██████ ███ ████ ██ ██ ███████ █████ █████████ ████ ███ ███ █████████ █ ██████████ ██ ██████████ █████████ ████ ██████████████ ████████ ████████ ████ ██ ██████ █████ ██ ███████ ███ █████ ██ ██ ███████ ███ ████ █████ ██████ ███

Figure 7: Results of the Generalized Gamma Model Anchored MAIC — Time-Varying PFS HR of Nivolumab Plus Ipilimumab Versus Pembrolizumab [Redacted]

HR = hazard ratio; MAIC = matching-adjusted indirect comparison; PFS = progression-free survival.

Table 28: Results of Anchored MAIC (Time-Varying PFS HR) and NMA (Constant PFS HR)

██ █ ██████████ █████████ ███ █ ████████ █████████ ██ █ ██████ █████ ███ █ ███████████ ████ █ ██████████ ███ █ ███████ ██████████████ ████ █ ██████████████ ███ █ ███████████████ ██████████| ████ ████ █████████ █████ ███████████ ████████| ████████ █████████ ████████ █████████ █████████ ██ ██ ███ ███ ███ █████ ██ █████ ██████ ████████ ███ █████████ ████████ ████████████ █████████████ ███████ ████ ████ ██████████ ████████ ████████ ██ ███ █████ ███ ████ ███ █████████ ███████ ██ ████████ █████████

CI = confidence interval; HR = hazard ratio; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; PFS = progression-free survival; NMA = network meta-analysis; vs. = versus.

Scenario Analysis Using a Constant HR-Based NMA for Anchored MAIC

A constant HR-based NMA was performed as a scenario analysis. The estimated PFS HR is ████ ████ ████ ████ ██ ██████

Unanchored MAIC

The results of a generalized gamma model in the unanchored MAIC for PFS is presented in Figure 15 in Appendix 1. As a sensitivity analysis, an unanchored MAIC analysis of PFS using time-varying HRs was also estimated. The estimated time-varying PFS for nivolumab plus ipilimumab versus pembrolizumab is presented in Figure 8 and Table 29. The estimated HRs are ██ ██ ██████ ███ ████ ██ ██ ██████, which indicates that PFS for nivolumab plus ipilimumab is favourable comparing with pembrolizumab. However, ██████ ██ ███████ the HR efficacy of nivolumab plus ipilimumab compared to pembrolizumab is uncertain because the 95% CI for the HR include the null value (i.e., 1).

Figure 8: Results of the Generalized Gamma Model Unanchored MAIC — Time-Varying PFS HR of Nivolumab Plus Ipilimumab Versus Pembrolizumab [Redacted]

HR = hazard ratio; MAIC = matching-adjusted indirect comparison; PFS = progression-free survival.

Table 29: Results of Unanchored MAIC (Time-Varying PFS HRs) and NMA (Constant PFS HR)

CDA-AMC = Canada’s Drug Agency; CI = confidence interval; Crl = credible interval; HR = hazard ratio; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; NMA = network meta-analysis; PFS = progression-free survival; vs. = versus.

^aBase-case analysis, using frequentist approach.

^bScenario analysis: Estimates of HR and 95% CI based on Cox proportional hazards model (assuming constant HRs).

Source: Bristol-Myers Squibb, 2025 (ITC Report).⁷⁹ Details included in the table are from the additional information provided by the sponsor at the request of CDA-AMC.

Scenario NMA Analysis Using Constant PFS HR Approach for Unanchored MAIC

A constant HR-based NMA was performed as a scenario analysis. The PFS HR is ████ ███████ ████ ██ ██████. The result was consistent with the time-varying analyses (Table 29).

Harms

Estimated ORs (95% CrI) are provided in Table 30.

The 95% CrIs of all ORs of all assessed individual AEs include 1, which indicates the uncertainty of the comparative safety findings when comparing nivolumab plus ipilimumab with pembrolizumab in all assessed individual AEs.

Table 30: Main Results of AEs in the NMA (Grade ≥ 3 AEs Occurring in ≥ 5% in Either of the Treatment Arms)

██ █ ███████ ██████ ███ █ ████████ █████████ ███ █ ███████████ ████ ███████████ ██ █ ████ ██████ ████ █ ███████████████| ███ ████████ ███ ███ ███████ █ ████ ████████████████ ██ ████ █████████ ████ █████████████ ███ █ █████ ████ ██ ███████████ █████████████ ███████ ████ ████ ██████ ████████████████ ████████ ██ ███ █████ ███ ████ ███ █████████ ███████ ██ ████████ █████████

AE = adverse event; Crl = credible interval; MAIC = matching-adjusted indirect comparison; OR = odds ratio; NMA = network meta-analysis; vs. = versus.

Critical Appraisal of ITC

The search for eligible studies was comprehensive, and the methods used to select relevant studies, extract data, and assessment of the risk of bias of included studies were adequate. The use of an MAIC estimation procedure was conducted according to existing standards. In the ITC, the anchored MAIC was considered the preferred method because it relied on fewer methods assumptions compared with an unanchored MAIC. However, the sponsor indicated that the anchored analysis did not sufficiently match the chemotherapy comparator arms across studies, with the chemotherapy arm of CheckMate-8HW displaying a poorer PFS than the KEYNOTE-177 chemotherapy arm. In either case, at least 3 known potential TEMS were not included in the analysis, which could contribute to bias of the results. In the unanchored setting, 14 suggested prognostic variables were not adjusted because these data on distributions in KEYNOTE-177 were unavailable. Consequently, the bias of the effects in the unanchored MAIC can be substantial and the CI may be overly optimistic.

In addition to the anchored and unanchored MAIC time-varying HR models, 2 Bayesian NMAs using a constant HR model were conducted. The estimates from these models are considered to be biased and challenging to interpret except as supportive evidence of the time-varying model estimates. The differences across trials and imbalances in the distribution of TEMs and prognostic factors introduces substantial differences in the populations being compared. Furthermore, any long-term extrapolation beyond the support of observed follow-up is uncertain,⁷⁹ and relies exclusively on the model fit rather than data.

Finally, for the harms outcome, a fixed effects Bayesian NMA of AEs was conducted comparing the incidence of any AEs of grade 3 or higher occurring in 5% or more of a treatment arm and immuno-oncology therapy related AEs reported in the CheckMate-8HW trial and KEYNOTE-177 trial, including diarrhea, hypophysitis, rash, adrenal insufficiency, hepatitis, hyperthyroidism, and pneumonia.⁸³ As the sponsor pointed out, AEs were not consistently reported or measured across trials, and differences between these measurements may persist, potentially biasing the NMA. ███ ███████ ███ ████ ████████ ███ ██ ████ ████ ██████████ █████████ ███ █████████ ███ ███████ ███ ███ ███████████ ████████ ██ █████████ ██ ███ ███ ████ ███ ██████ █████ ███████████████ ███ ██ ███████ ███████ ████

Studies Addressing Gaps in the Systematic Review Evidence

The sponsor-submitted evidence from the CheckMate-8HW trial comparing nivolumab plus ipilimumab to nivolumab monotherapy in patients with MSI-H or dMMR mCRC receiving treatment across all lines of therapy to inform questions on the contribution of ipilimumab in addition to nivolumab. Per the CDA-AMC Procedures for Reimbursement Reviews, nivolumab monotherapy does not meet the CDA-AMC definition of relevant comparator because it is neither approved by Health Canada nor reimbursed by participating drug plans in Canada for the first-line treatment of MSI-H or dMMR mCRC. Therefore, the evidence was considered out of scope for this review.

Discussion

Summary of Available Evidence

The evidence included in this review consisted of 1 pivotal study (CheckMate-8HW) and 1 ITC. The CheckMate-8HW trial is an ongoing multinational, phase III, open-label, active-controlled RCT evaluating the efficacy and safety of nivolumab plus ipilimumab (N = 202) versus chemotherapy (N = 101) in adult patients with unresectable or metastatic MSI-H or dMMR CRC. A total of 303 patients across 22 countries, including 204 patients (67.3%) from Canada, Europe, and the US, were randomized (2:1 randomization) to receive treatment with nivolumab plus ipilimumab compared with chemotherapy. Key inclusion criteria included histologically confirmed recurrent or metastatic CRC with no prior treatment history with chemotherapy and/or targeted drugs for metastatic disease and not amenable to surgery; locally confirmed MSI-H or dMMR status, ECOG PS score of 1 or less. The median age of all patients was 63.0 years, ranging from 21 to 87 years. Most of the patients were white (86.1%), and 53.8% of all participants were female. Patients had an ECOG PS score of 0 (53.8%) or 1 (46.2%). The primary efficacy outcome was PFS per BICR based on centrally confirmed MSI-H or dMMR mCRC. The secondary efficacy outcome was PFS per BICR based on locally confirmed MSI-H or dMMR mCRC. The exploratory outcome includes HRQoL (e.g., EORTC QLQ-C30). The harms outcomes included AEs, SAEs, discontinuation from the treatment due to AEs, IMAEs, and OESI, and so forth.

In the absence of direct comparative evidence of nivolumab plus ipilimumab versus the relevant comparator, pembrolizumab (considered the current relevant comparator in Canada), the sponsor submitted an ITC using a MAIC to estimate the comparative efficacy (i.e., PFS) and NMA for safety of nivolumab plus ipilimumab versus pembrolizumab as the first-line treatment in adult patients with unresectable or metastatic MSI-H or dMMR CRC. The outcomes of interest in the ITC included PFS and safety outcomes.

Interpretation of Results

Efficacy

After a median follow-up of 42.05 months, the use of nivolumab plus ipilimumab results in a clinically important increase in the probability of being progression free at 12 months compared with chemotherapy, with a between-group difference of 57.45% (95% CI, 45.41% to 69.49%) in favour of nivolumab plus ipilimumab. The patients in the nivolumab plus ipilimumab arm demonstrated a clinically meaningful longer median PFS than that in chemotherapy arm (treatment group difference: 48.23 months). At landmark time points, compared with the chemotherapy, nivolumab plus ipilimumab showed a clinically important increase in the probability of being progression free starting from 6 months (between-group difference, 34.44% [95% CI, 21.00% to 47.87%]) and sustained to 36 months (between-group difference, 57.80% [95% CI, 46.34% to 69.49%]) in favour of nivolumab plus ipilimumab. Similarly, the results of the prespecified subgroup and sensitivity analyses were overall consistent with the results of primary analyses, indicating rigour in the finding and suggesting that the open-label trial design of the CheckMate-8HW study was unlikely to have biased the estimates.

The clinical experts CDA-AMC consulted for this review indicated that a particular concern of the current standard treatment (i.e., single-drug pembrolizumab) is that the patients with liver metastases may derive significantly less benefit. However, the predefined subgroup analysis in the CheckMate-8HW trial demonstrated that treatment with nivolumab plus ipilimumab resulted in a statistically significant improvement PFS probability in both patients with liver metastasis (HR = 0.11; 95% CI, 0.05 to 0.25) and patients without liver metastasis (HR = 0.28; 95% CI, 0.17 to 0.46).

One of the enrolment criteria in the CheckMate-8HW trial was MSI-H or dMMR status per local standard of practice. The clinical experts CDA-AMC consulted for this review noted that eligibility for the treatment based on the locally confirmed MSI-H or dMMR status reflects the current standard practice in Canada. However, they also expressed ongoing concerns about the accuracy of MMR testing. Notably, approximately 16% of patients were not centrally confirmed to have MSI-H or dMMR mCRC, and the potential false-positives could not be ruled out. Despite this, the PFS results for patients with MSI-H or dMMR mCRC were consistent whether the patients were centrally confirmed (primary outcome) or locally confirmed (a key secondary outcome), further supporting the robustness and reliability of the findings from the CheckMate-8HW trial.

Input from patient group, clinician group, and clinical experts CDA-AMC consulted for this review noted improvements in OS and quality of life as part of the most important treatment goals for unresectable or metastatic MSI-H or dMMR CRC. OS data from the CheckMate-8HW trial was immature at the cut-off dates for analyses, and a conclusive determination could not be made about the comparative OS benefit of nivolumab plus ipilimumab. However, evidence from the literature indicate that the PFS is an acceptable surrogate for OS in this setting.^61-63 Furthermore, the clinical experts noted that the magnitude of improvement in PFS in nivolumab plus ipilimumab compared with chemotherapy reported in the CheckMate-8HW trial is remarkable and suggests that improvement in OS is expected.

The EORTC QLQ-C30 results from the CheckMate-8HW trial suggest that treatment with nivolumab plus ipilimumab may result in clinically important HRQoL improvement compared with chemotherapy from week 13 to week 37. However, EORTC QLQ-C30 is based on subjective patient-reported outcomes, and the open-label design of the CheckMate-8HW trial could have introduced performance bias, potentially favouring the nivolumab plus ipilimumab arm regarding these outcomes. Additionally, the nivolumab plus ipilimumab arm had significantly more patients than the chemotherapy arm (64% versus 13%, respectively), contributing data to the week 37 assessment. This discrepancy raises concerns about attrition bias, which could further skew results in favour of the treatment with nivolumab plus ipilimumab.

The clinical experts highlighted that the inclusion and exclusion criteria of the CheckMate-8HW trial are standard for clinical trials, but stricter than what pertains in clinical practice. For example, they noted that patients with an ECOG PS score of greater than 1 were not eligible for the trial, whereas patients with an ECOG PS score of 2 would be considered potential candidates for nivolumab plus ipilimumab in the clinical experience. However, the clinical experts considered that overall, the inclusion and exclusion criteria of the CheckMate-8HW trial are consistent with clinical practice in the setting in Canada and present no major generalizability concern of its findings in clinical practice in Canada.

There was no direct evidence comparing nivolumab plus ipilimumab with pembrolizumab identified in a literature review. The sponsor submitted an ITC using a MAIC to estimate the relative efficacy comparing nivolumab plus ipilimumab with pembrolizumab on PFS and NMA for safety outcomes. Results of the ITC analyses suggested a favourable PFS improvement in patients with nivolumab plus ipilimumab treatment compared with that in pembrolizumab, despite certain key limitations such as inability to adjust for some relevant treatment effect and prognostic modifiers. The clinical experts consulted for this review indicated that the findings of the ITC are aligned with expected use in clinical practice in Canada.

Harms

The overall proportion of patients with AEs were similar in both the nivolumab plus ipilimumab compared with chemotherapy arms. More patients in the hemotherapy arm reported all-cause grade 3 to 4 AEs than in the nivolumab plus ipilimumab arm, all-causality SAEs, and deaths. The proportion of patients who discontinued treatment because of AEs was similar. However, AESIs — specifically, all-cause grade 3 to 4 IMAEs — were significantly more frequent in the nivolumab plus ipilimumab arm ███████ compared to chemotherapy ███████ with a between-group difference of ██████ The 95% CI for this difference was not reported, introducing uncertainty regarding the precision of this estimate. The GRADE assessment suggested that nivolumab plus ipilimumab likely result in a clinically important increase in grade 3 to 4 IMAEs, compared with chemotherapies. The clinical experts consulted for this review indicated that the safety profile of nivolumab plus ipilimumab has been well established. The harms profile of nivolumab plus ipilimumab reported in the CheckMate-8HW trial was generally consistent with that of previously known AEs associated with nivolumab plus ipilimumab, with no new safety signals identified. According to the clinical experts consulted for this review, most AEs were predictable, and clinically manageable in most patients.

Results from the NMA showed odds ratios (ORs) with wide CIs for the assessed grade 3 or higher AEs, indicating uncertainty. In addition, due to the limitations of the NMA methods (e.g., potential heterogeneity between the 2 trials), the evidence of the NMA was insufficient to demonstrate the difference of grade 3 or higher AEs (e.g., ███████ ███████████ █████████ ███ █████████) between nivolumab plus ipilimumab compared with pembrolizumab. A definitive conclusion could not be drawn on the comparative safety of the 2 therapies in patients with MSI-H or dMMR mCRC. The clinical experts noted that the use of double-drug immunotherapy (e.g., nivolumab plus ipilimumab) is expected to cause an increased risk of side effects or toxicity compared with the single-drug immunotherapy (e.g., pembrolizumab).

Conclusion

Evidence from the CheckMate-8HW trial showed that nivolumab plus ipilimumab results in a clinically important increase in the probability of being progression free at 12 months, compared to chemotherapy in the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR CRC. Based on the EORTC QLQ-C30 GHS, nivolumab plus ipilimumab may result in clinically important improvement in patients’ HRQoL compared with chemotherapy, which was expected in this population. The evidence indicates that nivolumab plus ipilimumab likely result in a clinically important increase in grade 3 to 4 IMAEs, compared with chemotherapies. The harms profile of nivolumab plus ipilimumab reported in the CheckMate-8HW trial was generally consistent with that of previously known AEs associated with nivolumab plus ipilimumab. No new safety signal was identified. Overall, most AEs were predictable, and clinically manageable in most patients.

The results of the ITC suggested a more favourable PFS improvement with nivolumab plus ipilimumab treatment compared with pembrolizumab, despite certain limitations associated with the ITC methods. Due to the limitations associated with the NMA, a definitive conclusion could not be drawn on the comparative safety of nivolumab plus ipilimumab versus pembrolizumab in patients with MSI-H or dMMR mCRC. However, according to the clinical experts consulted on this review, nivolumab plus ipilimumab, being a double-drug immunotherapy, is expected to have an increased risk of side effects compared with the single-drug immunotherapy, and likely unsuitable for patients experiencing frailty or who have comorbidities.

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