Reimbursement Review

Durvalumab (Imfinzi), Carboplatin, Paclitaxel

Sponsor: AstraZeneca Canada Inc.

Therapeutic area: Endometrial cancer that is mismatch repair deficient (dMMR)

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

NOC = Notice of Compliance.

Introduction

Endometrial cancer is a type of uterine cancer originating in the lining of the uterus and is the most common gynecological malignancy,¹ accounting for approximately 95% of uterine cancers.² In Ontario, 2,909 new endometrial cancer cases were diagnosed in 2018, with an age-standardized incidence rate of 36.2 per 100,000.³ In 2024, the Canadian Cancer Society estimated that 8,600 females would be diagnosed with uterine cancer that year, and 1,600 would die from it.⁴ Endometrial cancer primarily affects females who are postmenopausal, with an average age at diagnosis of 60 years.⁵

Endometrial cancer is staged using the International Federation of Gynecology and Obstetrics (FIGO) system, ranging from stage I (tumour confined to the uterus), to stage IV (cancer has spread to bladder, bowel, or distant organs).⁶ In Canada, the overall 5-year net survival for uterine cancer is 82%, with stage-specific survival rates of 70% for stage I, 45% for stage II, 30% for stage III, and 15% for stage IV.⁷

The symptoms of advanced (stage III or IV) and recurrent (return following primary treatment) disease are variable, but include abnormal vaginal bleeding,^8,9 pelvic or back pain, the presence of a palpable mass in the lower abdomen, and unintentional weight loss.⁸ Patients often experience additional issues like sexual dysfunction, anxiety, depression, and the long-term effects of chemotherapy, all of which further reduce health-related quality of life (HRQoL).^1,10,11

The diagnosis of endometrial cancer involves clinical assessments, radiological imaging, and histopathological analysis of biopsy samples. For recurrent endometrial cancer cases, biopsies may help identify molecular subtypes of the cancer.^12,13 Molecular testing during endometrial biopsy is crucial for treatment decisions and risk assessment.¹⁴ Endometrial cancer is characterized as microsatellite instability (MSI)-high (MSI-H), MSI-low, or microsatellite stable (MSS) based on MSI testing,¹⁵ and mismatch repair (MMR) proficient (pMMR) or MMR deficient (dMMR) based on MMR testing.¹⁶ According to the clinical experts consulted by the review team, MMR testing, assessed by immunohistochemistry (IHC), is currently performed as the standard of care (SOC) for patients with endometrial cancer in Canada.

Durvalumab is a fully human, high-affinity, immunoglobulin G1 kappa monoclonal antibody that selectively blocks the interaction of PD-L1, a protein expressed on tumour cells, with PD-1 and CD80 on T cells. PD-L1 binds to PD-1 and CD80 on T cells, inhibiting their activation and reducing their ability to detect and destroy cancer cells. The selective blockade of PD-L1 and PD-1 and PD-L1 and CD80 interactions releases the inhibition of immune responses and enhances antitumour immune responses.^17,18 It is administered at 1,120 mg every 3 weeks in combination with platinum-based chemotherapy for 4 to 6 cycles. This is followed by maintenance therapy at 1,500 mg every 4 weeks, as monotherapy, until disease progression or unacceptable toxicity.¹⁹

Durvalumab was reviewed by Health Canada (Notice of Compliance issued January 17, 2025) as a first-line treatment for adult patients with primary advanced or recurrent endometrial cancer who are eligible for systemic therapy. The sponsor’s indication and reimbursement request is for durvalumab in combination with carboplatin and paclitaxel for the first-line treatment of adults with primary advanced or recurrent dMMR endometrial cancer who are candidates for systemic therapy, followed by durvalumab as monotherapy. Durvalumab was previously reviewed by Canada’s Drug Agency (CDA-AMC) for extensive-stage small-cell lung cancer; locally advanced, unresectable non–small cell lung cancer; biliary tract cancer; and unresectable hepatocellular carcinoma, all of which received conditional reimbursement recommendations.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of durvalumab (concentrate for solution for IV infusion, 50 mg/mL) in combination with platinum-based chemotherapy, followed by maintenance with durvalumab as monotherapy for the first-line treatment of patients with advanced or recurrent endometrial cancer that is dMMR.

Perspectives of Patients, Clinicians, and Drug Programs

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

Patient Input

One patient group, the Colorectal Cancer Resource & Action Network (CCRAN), in collaboration with the Canadian Cancer Survivor Network and HPV Global Action, submitted input on durvalumab for endometrial cancer. Information for this submission was gathered through outreach by CCRAN to 12 clinicians in Canada in September 2024, 17 US-based clinician investigators involved in the DUO-E clinical trial in October 2024, and the Society of Gynecologic Oncology and the Gynecologic Cancer Initiative. Additionally, HPV Global Action collaborated with several medical advisors to identify patients with experience using the therapy under review. These efforts led to 2 telephone interviews with patients with MSS endometrial cancer who participated in the DUO-E trial. Also, data from a 2023 online survey, which generated 6 responses and gathered information on the experiences of 4 patients, were used for this input.

The patient group input highlighted that patients with endometrial cancer face significant inequities, including research underfunding; rising incidence rates, particularly among females who are postmenopausal; and increasing mortality rates, despite advancements in oncology. According to the patient group input, a diagnosis of endometrial cancer is profoundly distressing, placing significant emotional strain on both patients and their caregivers and triggering fears related to personal health and family welfare.

Respondents to the survey reported using various treatment options, including radiation, surgical resection, targeted therapy, hormonal therapy, immunotherapy, chemotherapy, and complementary medicines. Common symptoms included neuropathy, fatigue, vaginal dryness, itching, burning sensations, changes in sexual function, fluid retention, nausea, constipation, and cognitive impairment known as “chemo brain.” Many patients described chemotherapy as “tough,” with significant nausea and fatigue impacting daily life. The effects of treatment often extend to sexual health, which is frequently overlooked in clinical care and research.

The input highlighted that early-stage endometrial cancer is typically treated with surgery, often combined with chemotherapy, radiation, or hormone therapy. However, treatment options for patients with recurrent or metastatic endometrial cancer are limited, and the prognosis remains poor due to stagnant access to new therapeutics over the past decades. Patient groups highlighted an urgent unmet need for additional precision therapeutics in advanced or recurrent endometrial cancer in Canada, with 60% of patients with endometrial cancer ranking “prolong life” as the most important issue they hope new treatments will address.

The 2 patients who participated in telephone interviews shared their experiences with durvalumab in combination with olaparib during the DUO-E trial, reporting complete responses (CRs) and minimal side effects, while a third patient receiving durvalumab treatment in Australia highlighted the positive impact of targeted therapies on their quality of life.

Clinician Input

Input From the Clinical Experts Consulted for This Review

The clinical experts consulted for this review noted that the goals of treatment for advanced or metastatic endometrial cancer are to improve quality of life by reducing pain and suffering, improve disease-related symptoms, control the cancer proliferation, and improve survival, if possible. They noted that achieving a longer duration of response would be strongly linked to improvement in relevant patient outcomes. In dMMR endometrial cancer, 1 expert noted that between 20% and 40% of patients do not experience a response to the current first-line treatment paradigm; for context, they noted that, in general, approximately 40% of patients are not expected to experience a response to chemotherapy, and the duration of response (DOR) to chemotherapy alone is often very short. While the addition of an immune checkpoint inhibitor (ICI) improves the overall treatment response rate, it has the most significant impact on the improvement in DOR. The unmet needs in patients with dMMR endometrial cancer include better identification of potential nonresponders, determining the therapy their cancer might respond to, and determining the ideal duration of maintenance treatment among the patients with cancer that does respond to therapy.

The experts indicated that durvalumab would be an additional first-line ICI option, alongside dostarlimab, that could be added to chemotherapy and used as maintenance monotherapy in patients with dMMR endometrial cancer. In general, the clinical experts noted that the choice of ICI is often based on availability but, when multiple approved options are available, any of them could be offered. If a patient did not experience a response to ICI therapy, the clinical experts noted it was unlikely they would trial the drug class again; however, if a patient had a recurrence more than 12 months after therapy and had previously experienced a response, then re-treatment might be considered.

The clinical experts noted that the DUO-E trial results did not identify specific molecular subtypes of cancer (beyond dMMR) that could respond to the new treatments; therefore, all patients who meet the other clinical trial criteria would likely be candidates for treatment with durvalumab.

According to the experts, the outcomes from the DUO-E trial corresponded to standard clinical assessments, with the exception of HRQoL measures, which are not routinely used in clinical practice. In general, symptomatic benefit would be assessed every cycle through conversations with the patient, and radiologic treatment response would be assessed every 2 to 3 cycles. They noted that the ideal outcome to assess response would be survival but, in the face of measurable disease, achieving stability (i.e., prolongation of progression-free survival [PFS]) while being tolerated well would be a minimum response to continue therapy. They indicated that the definition of a treatment benefit may vary across physicians and patients.

Disease progression and serious adverse events (SAEs) would be grounds to discontinue therapy, according to the experts. Examples of SAEs could include grade 3 or 4 toxicities such as hepatitis, colitis, or pneumonitis, as well as any other significant immune-related toxicity. Both clinical experts agreed that an oncologist or specialist in administering chemotherapy or biologic therapy would be essential to manage the complexities of treatment toxicity.

Clinician Group Input

Two inputs, 1 from the Ontario Health (Cancer Care Ontario) (OH [CCO]) Gynecologic Cancer Drug Advisory Committee (7 clinicians contributed to the input) and 1 from the Gynecologic Oncology Society of Canada (GOC) (1 clinician contributed to the input) were provided for this review. The OH (CCO) input was gathered through conference calls and emails, while the GOC input was based on data from completed clinical trials and expert opinions from board members on treating advanced or recurrent endometrial cancer.

According to the clinician groups, treatment for dMMR endometrial cancer involves platinum-based chemotherapy (carboplatin and paclitaxel) and radiation, with pembrolizumab funded for recurrent dMMR disease after failure of chemotherapy. There are no publicly funded first-line immunotherapies for patients with dMMR endometrial cancer, although compassionate access to dostarlimab in combination with chemotherapy is available.

The clinician groups agreed with the experts consulted for this review that the primary treatment goals are to prolong survival, delay disease progression, control symptoms, improve HRQoL and, when possible, cure the disease. Both the clinician input and the clinical experts agreed that chemotherapy alone fails to provide a durable response in patients with dMMR endometrial cancer. The input from both the clinician groups and the clinical experts also agreed that durvalumab would be suitable as a first-line option for patients with advanced (stage III or IV) or recurrent endometrial cancer. They also noted that patients with dMMR endometrial cancer can receive durvalumab treatment without prior chemotherapy.

The clinician groups agreed that treatment response is assessed through imaging (CT or MRI) and clinical evaluations. The GOC added that tolerability is evaluated before each treatment cycle (i.e., every 3 weeks) with radiologic assessments every 6 to 9 weeks. A clinically meaningful response includes tolerable toxicity and improved PFS.

The clinician groups indicated that treatment may be withheld due to disease progression and intolerable toxicity or adverse events (AEs). The GOC further mentioned that such decisions could also be related to patient preference. In line with the clinical experts consulted for this review, the clinician groups stated that durvalumab plus carboplatin and paclitaxel should be administered in an outpatient setting and is best prescribed by specialist physicians experienced in systemic therapy.

Drug Program Input

Input was obtained from the drug programs that participate in the CDA-AMC Reimbursement Review process. The following were identified as key factors that could potentially impact the implementation of a recommendation for durvalumab combined with carboplatin and paclitaxel followed by durvalumab monotherapy:

• relevant comparators

• considerations for initiation of therapy

• considerations for continuation or renewal of therapy

• considerations for prescribing of therapy

• generalizability

• care provision issues.

The clinical experts provided advice on the potential implementation issues raised by the drug program input. Refer to Table 5 for more details.

Clinical Evidence

Systematic Review

Description of Studies

The DUO-E study is an ongoing phase III, multicentre, double-blind, placebo-controlled randomized controlled trial (RCT) of durvalumab in combination with platinum-based chemotherapy (carboplatin and paclitaxel) followed by maintenance with durvalumab monotherapy or with durvalumab in combination with olaparib in patients with recurrent or newly diagnosed advanced endometrial cancer compared with SOC alone (carboplatin and paclitaxel). Enrolment for the DUO-E study ended in March 2022; however, treatment and follow-up are still ongoing. In total, 718 patients were randomized 1:1:1 to SOC (arm A; N = 241), durvalumab plus SOC (arm B; N = 239), or durvalumab plus olaparib plus SOC (arm C; N = 238). In the chemotherapy phase, arm A received a regimen of platinum-based chemotherapy consisting of carboplatin and paclitaxel plus durvalumab placebo for 6 cycles; after the chemotherapy phase, patients who had no evidence of progressive disease then received maintenance-phase therapy consisting of durvalumab placebo IV every 4 weeks plus olaparib placebo tablets twice daily. Patients in arms B and C received the same platinum-based chemotherapy as those in the SOC arm plus durvalumab for 6 cycles, then arm B received maintenance-phase therapy consisting of durvalumab plus olaparib placebo tablets twice daily, while arm C received both durvalumab and olaparib. The primary end point of the DUO-E study was PFS, with secondary end points consisting of overall survival (OS), objective response rate (ORR), DOR, time to study treatment discontinuation or death (TDT), and HRQoL.

Of note, the DUO-E trial randomized patients with pMMR and dMMR status to all 3 study arms. To align with the Health Canada indication and reimbursement request (durvalumab in combination with carboplatin and paclitaxel in patients with dMMR endometrial cancer, followed by maintenance durvalumab), this Clinical Review Report focuses only on the population of patients from the DUO-E trial with dMMR endometrial cancer who received durvalumab in combination with carboplatin and paclitaxel (i.e., only a subset of the patients included in arm B of the DUO-E study).

Efficacy Results

Progression-Free Survival

In the dMMR subgroup, there were a total of 25 PFS-related events in the SOC arm (51.0%; N = 49 patients) and 15 PFS-related events in the SOC plus durvalumab arm (32.6%; N = 46 patients). There were ██████ censored deaths in the SOC arm and ██████ in the SOC plus durvalumab arm. The median PFS in the SOC arm was 7.0 months (95% confidence interval [CI], 6.7 to 14.8), while the median PFS was not calculable in the SOC plus durvalumab arm (hazard ratio [HR], 0.42; 95% CI, 0.22 to 0.80 in favour of durvalumab). The risk difference between study arms for the proportion of patients with progression-free disease was █████ (95% CI, ████ ██ ██████) at 6 months; █████ (95% CI, ████ ██ ██████) at 12 months; and █████ (95% CI, █████ ██ ██████) at 18 months.

Overall Survival

In the dMMR subgroup, there were a total of ██ ███████ deaths in the SOC arm and ███████ deaths in the SOC plus durvalumab arm. The median OS in the SOC arm was ████ months (95% CI ███ ██████████), while the median OS was ███ ██████████ in the SOC plus durvalumab arm (HR, ████; 95% CI, ████ ██ ████ in favour of durvalumab). The risk difference between study arms for the proportion of patients who were alive was █████ (95% CI, █████ ██ ██████) at 6 months, ████% (95% CI, ████ ██ █████) at 12 months, and █████ (95% CI, ████ ██ ██████) at 18 months.

Objective Response Rate

In the dMMR subgroup, a total of ██ patients (████%) had a response out of ██ patients with measurable disease at baseline in the SOC arm, and ██ patients (████%) had a response out of ██ with measurable disease at baseline in the SOC plus durvalumab arm. The odds ratio (OR) for response was ████ (95% CI, ████ ██ ████) in favour of durvalumab.

Duration of Response

In the dMMR subgroup, █ patients (████%) out of the ██ patients in the SOC arm who experienced a response subsequently died or experienced disease progression. The median DOR (measured from the onset of response) was 10.5 months. Out of the ██ patients in the SOC plus durvalumab arm who experienced a response, █ patients (████%) subsequently died or experienced disease progression; the median DOR was not calculable. The difference between study arms for the proportion of patients who continued to experience a response was ████% (95% CI, ████% to ████%) at 6 months, ████% (95% CI, █████ ██ ████%) at 12 months, and ████% (95% CI, █████ ██ ████%) at 18 months.

Time to Treatment Discontinuation or Death

In the dMMR subgroup, ██ ███████ patients in the SOC arm and ██ ███████ patients in the SOC plus durvalumab arm had an event of treatment discontinuation or death (HR, ████; 95% CI, ████ ██ ████ in favour of durvalumab).

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

The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) functional scales range from 0 to 100, with higher scores indicating better functioning. In the dMMR subgroup, the mean baseline score was █████ points (standard deviation [SD] = █████) in the SOC arm and █████ points (SD = █████) in the SOC plus durvalumab arm. At week 18 (corresponding to the sixth cycle of the chemotherapy phase), the mean change in score from baseline was ██████ points (SD = █████) in the SOC arm (N = ██) and █████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was █████ points (95% CI, –█████ ██ ████). At week 42 (corresponding to the sixth month of the maintenance phase), the mean change in scores from baseline was ██████ points (SD = █████) in the SOC arm (N = ██) and ████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was █████ points (95% CI, ████ ██ █████).

EORTC Quality of Life Questionnaire – Endometrial Cancer Module Pain in Back and Pelvis Score

The EORTC Quality of Life Questionnaire – Endometrial Cancer Module (EORTC QLQ-EN24) functional scales range from 0 to 100, with higher scores indicating better functioning, and the 10 symptom scales range from 0 to 100, with higher scores indicating more severe symptoms. In the dMMR subgroup, the mean baseline score was █████ points (SD = █████) in the SOC arm and █████ points (SD = █████) in the SOC plus durvalumab arm. At week 18, the mean change in score from baseline was ████ points (SD = █████) in the SOC arm (N = ██) and ████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was ████ points (95% CI, █████ ██ █████). At week 42, the mean change in scores from baseline was █████ points (SD = █████) in the SOC arm (N = ██) and ████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was ████ points (95% CI, █████ ██████).

EORTC QLQ-EN24 Urological Symptoms Score

In the dMMR subgroup, the mean baseline score was █████ points (SD = █████) in the SOC arm and █████ points (SD = █████) in the SOC plus durvalumab arm. At week 18, the mean change in score from baseline was ████ points (SD = █████) in the SOC arm (N = ██) and █████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was ████ points (95% CI, █████ ██████). At week 42, the mean change in scores from baseline was ████ points (SD = █████) in the SOC arm (N = ██) and ████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was ████ points (95% CI, █████ ██ ████).

Harms Results

Adverse Events

In the dMMR subgroup, all patients in each study arm experienced an AE during the DUO-E trial. A total of ████% of patients in the SOC arm and ████% of patients in the SOC plus durvalumab arm experienced an AE with a maximum grade of 3 or 4. The most common AEs were nausea (████% of patients in the SOC plus durvalumab arm, ████% of patients in the SOC arm), alopecia (█████ in the SOC plus durvalumab arm, █████ in the SOC arm), arthralgia (█████ in the SOC plus durvalumab arm, █████ in the SOC arm), and anemia (█████ in the SOC plus durvalumab arm, █████ in the SOC arm).

There were differences between study arms in the proportion of patients with several AEs. Of note, a numerically higher proportion of patients in the SOC plus durvalumab arm reported nausea (█████ versus █████ in the SOC arm), alopecia (█████ versus █████ in the SOC arm), arthralgia (█████ versus █████ in the SOC arm), hypomagnesemia (█████ versus █████ in the SOC arm), cough (█████ versus █████ in the SOC arm), peripheral neuropathy (█████ versus █████ in the SOC arm), dyspnea (█████ versus ████ in the SOC arm), and injury, poisoning, or procedural complications (█████ versus █████ in the SOC arm).

Serious Adverse Events

In the dMMR subgroup, a total of █████ patients in the SOC arm and █████ patients in the SOC plus durvalumab arm experienced an SAE during the DUO-E trial. The most common SAEs were as follows: gastrointestinal disorders (█████ in the SOC plus durvalumab arm consisting of █ reports of fecaloma and █ report each of abdominal hernia, colitis, intestinal obstruction, and nausea, and ███% in the SOC arm consisting of █ report each of diarrhea, nausea, and vomiting), blood and lymphatic system disorders (████% in the SOC arm consisting of █ reports of anemia, █ reports of febrile neutropenia, and █ reports of neutropenia, and ███% in the SOC plus durvalumab arm consisting of █ report of autoimmune hemolytic anemia), infections and infestations (███% in the SOC arm consisting of █ report each of COVID-19, neutropenic sepsis, urinary tract infection and urosepsis, and ███% in the SOC plus durvalumab arm consisting of █ report each of appendicitis, gastroenteritis, and sepsis), and renal and urinary disorders (███% in the SOC arm consisting of █ report each of acute kidney injury, renal failure, ureteric obstruction and urinary bladder hemorrhage, and █% in the SOC plus durvalumab arm).

Withdrawals Due to Adverse Events

In the dMMR subgroup. a total of ████% of patients experienced AEs leading to the withdrawal of durvalumab in the SOC plus durvalumab arm, and ████% reported this in the SOC arm (durvalumab placebo). In the SOC plus durvalumab arm, the reasons for discontinuation were anemia, interstitial lung disease, maculopapular rash, symmetric drug-related intertriginous and flexural exanthema, fatigue, and procedural pain (each reported in █ patient). In the SOC arm, the reasons for discontinuation of durvalumab placebo were anemia (█ patients), cerebrovascular accident, tinnitus, and asthenia (each reported in █ patient). A total of ████% of patients in the SOC plus durvalumab arm and ███% of patients in the SOC arm experienced an AE leading to discontinuation of SOC.

Mortality

In the dMMR subgroup, a total of ██ ███████ patients died in the SOC arm and ███████ patients died in the SOC plus durvalumab arm. The submission did not provide details on the specific causes of death in patients in the dMMR subgroup.

Notable Harms

Immune-mediated AEs (exact conditions not specified) and infusion reactions were identified by the clinical experts as adverse events of special interest (AESIs). In the dMMR subgroup, ████% of patients experienced an immune-mediated AE in the SOC plus durvalumab arm and ████% experienced this in the SOC arm. A total of ███% of patients experienced infusion reactions in the SOC plus durvalumab arm compared with ████% of patients in the SOC arm.

A total of ████% of patients in the SOC plus durvalumab arm and ████% of patients in the SOC arm experienced an AESI for durvalumab (or its placebo). The most common AEs in both arms were diarrhea (████% in the SOC plus durvalumab arm, ████% in the SOC arm) and rash (████% in the SOC plus durvalumab arm, ████% in the SOC arm). Hypothyroidism (████% of patients) was the next most common AE in the SOC plus durvalumab arm, and hyperthyroidism (███% of patients) was the next most common AE in the SOC arm.

Critical Appraisal

The DUO-E study is an ongoing phase III trial assessing the efficacy and safety of durvalumab plus SOC compared with SOC alone in the treatment of primary advanced or recurrent endometrial cancer. Despite the adequate randomization, concealment, and blinding, there were numerically higher numbers of patients in the SOC arm who discontinued treatment relative to the number in the SOC plus durvalumab arm, which suggests the possibility that patients may have become unblinded to their treatment assignment and discontinued treatment more readily than those in the SOC plus durvalumab arm. As part of the study design, patients with no evidence of progressive disease during the 6-cycle chemotherapy phase were eligible to proceed to the maintenance phase. Results separating the efficacy outcomes in the chemotherapy and maintenance phases were not provided; thus, the impact of the chemotherapy phase versus the maintenance phase individually on response to treatment remains unknown. The design of the DUO-E trial included patients with either dMMR and pMMR endometrial cancer. However, given the Health Canada indication and reimbursement request, the focus of this review is on the subgroup of patients with dMMR endometrial cancer. Therefore, all results focusing on the dMMR subgroup can only be considered exploratory and supportive of the overall effect of durvalumab. Furthermore, the subgroup was not controlled for multiple comparisons and there is an increased risk of type I error, which is particularly important, given that the sample sizes in each study arm were small. The results from the DUO-E trial were from an interim analysis (IA), and the P value cut-off for the IA of the subgroups themselves is not known; this carries an increased risk of overestimating the true effect. While the primary end point was reached for the intention-to-treat (ITT) population, the median PFS and OS were not estimable for the dMMR subgroup in the respective analyses. In the ITT population, this analysis was based on an information fraction of 61.0% while, in the dMMR subgroup, only ████% of PFS events had occurred, suggesting the data were immature, particularly for OS. As a result, there is increased uncertainty in the PFS and OS results, and it is therefore unclear how confidently the long-term results associated with durvalumab can be predicted. For the HRQoL end points, the baseline estimates and the estimates at weeks 18 and 42 have a substantial amount of missing data. The end points were analyzed using a mixed model for repeated measures, which assumes the missing data are missing at random; however, given the nature of the disease and the design of the trial, the missing-at-random assumption is not appropriate. Because patients are censored at disease progression or death, among other reasons, it is likely that these patients are systematically different from the patients who are included in the analysis; thus, there is a likelihood of bias in the results.

Per the clinical experts, the inclusion and exclusion criteria were broadly representative of patients who would be candidates for durvalumab. However, the study is subject to some limitations impacting external validity. The results of patient screening were not available for the dMMR subgroup; therefore, the reasons for screening failure and the distribution of screening failures between study arms is not known, so it is unclear whether there are systematic differences between the patients who failed screening and those who did not. Similarly, the exact causes of death in participants who died during the study were not reported, and it is therefore not known whether there are systematic differences between the patients who died and those who did not. Patients with an Eastern Cooperative Oncology Group (ECOG) status greater than 1 were not included in the trial; however, according to the clinical experts consulted for this review, these patients would likely be considered for treatment with durvalumab in clinical practice. Apart from this, the study did not assess whether other molecular subtypes (e.g., POLE mutation, HER expression, p53 mutation) would have an impact on the results observed. The clinical experts noted that additional molecular classifications are usually undertaken in clinical practice and that there is a proportion of patients with dMMR cancer that does not respond to current ICI therapy, the reason for which is not always clear. Therefore, it is possible the same nonresponder population may also exist for patients treated with durvalumab.

GRADE Summary of Findings and Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development and Evaluation (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.^20,21

Following the GRADE approach, the evidence from the RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer 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; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty-of-evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. For the PFS and OS outcomes, the target of the assessment was the presence or absence of an important effect based on thresholds provided by the clinical experts. For the HRQoL outcomes, the target of the assessment was the presence or absence of any effect based on a null threshold.

The selection of outcomes for GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with clinical experts, and the 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 (difference in the proportion of patients with progression-free disease at 12 months and 18 months)

• OS (difference in the proportion of patients alive at 12 months and 18 months)

• EORTC QLQ-C30 (change from baseline to 18 weeks and change from baseline to 42 weeks)

• EORTC QLQ-EN24 (change from baseline to 18 weeks and change from baseline to 42 weeks)

• Notable harms: infusion-mediated AEs and infusion-related reactions.

Table 2: Summary of Findings for Durvalumab in Combination With Carboplatin-Paclitaxel Versus Placebo in Combination With Carboplatin-Paclitaxel for Patients With Primary Advanced or Recurrent dMMR Endometrial Cancer

CI = confidence interval; dMMR = mismatch repair deficient; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-EN24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Endometrial Cancer Module; HRQoL = health-related quality of life; NR = not reported; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; SOC = standard of care.

Note: 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.

^aIn the trial, testing for this outcome in the dMMR subgroup was not adjusted for multiplicity. The results are considered supportive evidence.

^bFollow-up presented as durvalumab + carboplatin and paclitaxel vs. placebo + carboplatin and paclitaxel.

^cAdditional information was requested from the sponsor to obtain absolute differences and 95% CIs. This information was not necessarily part of the sponsor’s statistical plan and is considered exploratory evidence.

^dRated down 1 level for serious indirectness. At the time of data cut-off, median PFS was not reached and the study did not meet the primary end point in the dMMR subgroup. This implies that the PFS data are immature and there is high uncertainty in the trends observed to date; therefore, the confidence with which the results predict the outcome in the long-term is not clear.

^eRated down 1 level for serious imprecision. Based on a nontrivial target certainty assessment with a minimal important difference threshold of 150 per 1,000 at 12 months and 100 per 1,000 at 18 months provided by the clinical experts, the point estimate of the effect is larger than the threshold but the 95% CI includes the possibility of a trivial effect as well as a nontrivial effect at 12 months, the number of PFS events in each arm were not provided by the sponsor, and the sample size is very small, raising concern for prognostic imbalance and potential overestimation of the true effect.

^fRated down 1 level for serious indirectness. At the time of data cut-off, median OS was not reached and the study did not meet the secondary end point in the dMMR subgroup. This implies that the OS data are immature and there is high uncertainty in the trends observed to date; therefore, the confidence with which the results predict the outcome in the long-term is not clear.

^gRated down 1 level for serious imprecision. Based on a nontrivial target certainty assessment with a minimal important difference threshold of 100 per 1,000 provided by the clinical experts, the point estimate of the effect is larger than the threshold but the 95% CI includes the possibility of a trivial effect as well as a nontrivial effect, the number of OS events at 12 months and 18 months in each arm were not provided by the sponsor, and the sample size is very small, raising concern for prognostic imbalance and potential overestimation of the true effect.

^hRated down 2 levels for serious study limitations. A considerable amount of patient data was missing at the time points and, based on the study design, it is likely that the missingness is informative.

^IRated down 1 level for serious imprecision. Based on a non-null target certainty assessment, the CI for the estimate contains the possibility of reduced HRQoL as well as improved HRQoL.

^jRated down 2 levels for very serious imprecision due to the small number of events in a small patient population and the lack of specified follow-up duration.

Sources: Details included in the table are from the sponsor’s summary of clinical evidence²² and additional information provided by the sponsor.^23,24

Long-Term Extension Studies

The submission did not contain any long-term extension studies.

Indirect Comparisons

The DUO-E trial included SOC chemotherapy (carboplatin and paclitaxel) but did not include a comparison with dostarlimab, a relevant first-line comparator for patients with dMMR endometrial cancer, and information from indirect comparisons was included in the pharmacoeconomic model. Therefore, a review of the indirect evidence was undertaken. The body of indirect evidence consisted of 2 sponsor-submitted multiple-adjusted indirect comparisons (MAICs).

Description of Studies

A systematic literature review (SLR) was conducted with a focus on systemic anticancer treatments and which excluded all other therapies. The patient population of interest comprised those newly diagnosed with stage III or IV disease or recurrent disease who were either naive to first-line therapy or had been treated with 1 prior line of chemotherapy. The submission did not provide details on the date when the SLR was conducted, the range of publication dates that were used in the search terms, or the search terms used.

An anchored MAIC was performed using a frequentist approach and Bucher methodology. The treatment effects for the 2 efficacy outcomes, PFS and OS, were reported as HRs and associated 95% CIs for SOC plus durvalumab versus SOC plus dostarlimab, with an HR of less than 1 favouring SOC plus durvalumab. For the safety end points, the ORs were calculated for SOC plus durvalumab versus SOC plus dostarlimab, with ORs of less than 1 favouring SOC plus durvalumab. ORs were estimated from AE frequency data and the number of patients included in the safety analysis sets.

Efficacy Results

The submission did not provide a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram of the results from the SLR but reported that the SLR identified 2 phase III, double-blind, placebo-controlled RCTs relevant to the indirect treatment comparison: the DUO-E study and the RUBY Part 1 study. Differences were noted in the median duration of follow-up as well as the molecular characteristics of the patients’ cancer; the primary analysis for the MAICs used data from the post hoc subgroup of the DUO-E trial, which contained only patients with dMMR and/or MSI-H cancer (and therefore could contain patients with MSI-H pMMR endometrial cancer), and the main analysis in the RUBY Part 1 study enrolled patients who had either dMMR or MSI-H tumours. The submission did not provide a breakdown of other baseline characteristics before and after matching. Of note, after the matching procedure, minor differences remained in the proportion of patients who were Black or African American (███% in the DUO-E study after weighting, and 8.5% in the RUBY Part 1 study), and the proportion of patients who were aged 65 years and older (████% in the DUO-E trial after weighting, and 49.2% in the RUBY Part 1 study).

The results for PFS from the anchored, weighted MAIC suggested there was insufficient evidence to detect a difference between durvalumab plus SOC and dostarlimab plus SOC (adjusted HR, ████ ████ ███ ████ ██ ██████; effective sample size [ESS] = ████). Similarly, the results of OS using the anchored, unweighted MAIC suggested there was insufficient evidence to detect a difference between durvalumab plus SOC and dostarlimab plus SOC (adjusted HR, ████ ████ ███ ████ ██ ██████).

Harms Results

The harms results from the anchored, unweighted MAIC suggested there was insufficient evidence to detect a difference between durvalumab plus SOC and dostarlimab plus SOC for AEs leading to discontinuation (adjusted OR, ████ ████ ███ ████ ██ ████) and any SAEs (adjusted OR, ████ ████ ███ ████ ██ █████); however, for grade 3 or greater AEs, durvalumab plus SOC was favoured over dostarlimab plus SOC (adjusted OR, ████ ████ ███ ████ ██ ███████).

Critical Appraisal

The procedures as described for screening, data extraction, and the quality assessment steps used were considered generally accepted methods. However, the date on which the SLR was undertaken is not provided, and it is not known whether the most recent publications on any relevant comparators would have been captured in the search. The submission did not provide the results of the quality assessment; therefore, the risk of bias in the studies is not known. However, because the DUO-E and RUBY Part 1 trials were phase III trials, the risk of bias may be lower. For both MAIC analyses, data from a subgroup of the RUBY Part 1 study and a subgroup from the DUO-E trial were used (patients with dMMR and/or MSI-H cancer). In the case of the DUO-E trial, this resulted in the inclusion of some patients with pMMR MSI-H cancer in the subgroup used for the analysis, which is likely to somewhat bias the results because MMR status is a known treatment-effect modifier. The 2 studies also differ considerably in the median follow-up time because the follow-up in the RUBY Part 1 study was longer than in the DUO-E trial (twice as long follow-up time for PFS). This increases the likelihood of bias to possibly favour durvalumab because there was a shorter follow-up period over which events could accrue. Lastly, in both studies, the subgroup arms had small sample sizes and a low number of events, which impacts the power of the analysis. In addition, other baseline characteristics not included in the matching were not reported and, therefore, it is not known whether there are other potential sources of confounding in these characteristics. There were also no details reported on model fit, convergence, or model selection, which is another potential source of bias or uncertainty.

In addition to the limitations in the comparability of the studies and matching, there are additional limitations specific to each efficacy outcome. The MAIC for PFS was a weighted, anchored MAIC, and the weighting procedure was largely able to balance the baseline characteristics reported. However, the ESS was approximately ███ smaller (N = ████) than the number of patients prematching (N = ███), suggesting that data from a smaller number of patients may be driving the results, which increases the imprecision. These results are subject to high uncertainty due to the limitations in the comparability of the studies as well as the limitations around the size of the ESS. The analyses undertaken for OS and harms were unweighted, anchored MAICs, which did not employ the propensity score measurement process to reweight the results and was considered a naive comparison of the DUO-E and RUBY Part 1 trials. For OS, this was due to the small number of events observed (8 events for dMMR or MSI-H in SOC plus durvalumab and 7 events for SOC plus dostarlimab), which would generate potentially unstable results if reweighted and compared using MAIC methodology. There were still notable differences between the 2 studies at baseline, and it is not known how the sample size in the 2 studies compares with the sample in the MAIC for OS. It is highly likely that not all possible effect modifiers were controlled for in the analysis for these outcomes. The limitations in the comparability of the studies and analysis method significantly undermines the validity of the results for OS and harms.

Studies Addressing Gaps in the Evidence From the Systematic Review

The submission did not contain any studies addressing gaps in the evidence from the systematic review.

Conclusions

One phase III ongoing multicentre, double-blind, placebo-controlled RCT (the DUO-E trial) provided evidence for the efficacy and safety of durvalumab plus SOC for 6 cycles followed by durvalumab maintenance therapy as first-line treatment in the subgroup of 95 adult patients with primary advanced or recurrent dMMR endometrial cancer.

Patients and clinicians identified a need for new treatments for primary advanced or recurrent endometrial cancer — which is the most common gynecological malignancy — and prolonged survival was considered the most important outcome. In the subgroup of patients with dMMR endometrial cancer, the subgroup results of the DUO-E trial suggested improved PFS and OS in patients treated with durvalumab. The clinical experts consulted for this review considered these results compelling, and the results of the GRADE assessment suggested that the minimal important differences (MIDs) for the proportion of patients with progression-free disease or alive at 12 and 18 months were surpassed. However, because these results were based on a subgroup of the ITT population, the statistical analyses were not powered to detect differences in this subgroup, and no adjustments were made for multiple testing. Furthermore, although the median results for the time-to-event end points were not reached, the certainty in the magnitude of benefit was reduced because they were based on a small sample size and an IA with largely immature data and based on an information fraction of 42.1% for the subgroup and treatment arms presented. Furthermore, despite results for HRQoL that suggested no detriment in patients receiving durvalumab, there was a high rate of attrition. As such, the results of these important efficacy outcomes can be considered only as supportive of the overall effect of durvalumab, and causal conclusions cannot be drawn. Indirect evidence comparing durvalumab with dostarlimab, a relevant comparator in the Canadian clinical setting, suggested no difference between the 2 treatment regimens for PFS; however, the considerable limitations in the indirect evidence preclude conclusions on efficacy (as measured by OS) and harms. While the reporting of harms in the DUO-E study is also immature and lacks important details, in particular with regard to AESIs and the specific causes of death, the clinical experts consulted for this review considered the harms to be typical for patients undergoing chemotherapy with an ICI.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of durvalumab 1,120 mg administered intravenously every 3 weeks in combination with carboplatin and paclitaxel, followed by durvalumab 1,500 mg IV every 4 weeks until disease progression or unacceptable toxicity, in the treatment of primary advanced or recurrent endometrial cancer in adult patients who are candidates for systemic therapy.

Disease Background

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

Endometrial cancer is a type of uterine cancer originating in the lining of the uterus and is the most common gynecological malignancy,¹ accounting for approximately 95% of uterine cancers.² In Ontario, 2,909 new endometrial cancer cases were diagnosed in 2018, with an age-standardized incidence rate of 36.2 per 100,000.³ In 2024, the Canadian Cancer Society estimated that 8,600 females would be diagnosed with uterine cancer that year, and 1,600 would die from it.⁴ Endometrial cancer primarily affects females who are postmenopausal, with an average age of diagnosis of 60 years.⁵

Endometrial cancer is staged using the FIGO system: stage I (tumour confined to the uterus), stage II (cervical stroma invasion), stage III (regional spread), and stage IV (spread to bladder, bowel, or distant organs).⁶ In Canada, the overall 5-year net survival for uterine cancer is 82%, with stage-specific survival rates of 70% for stage I, 45% for stage II, 30% for stage III, and 15% for stage IV, highlighting significant variability based on disease progression.⁷

Both primary advanced (stage III or IV) and recurrent (return following primary treatment) endometrial cancer are associated with numerous debilitating symptoms that significantly impair physical functioning and HRQoL. Key symptoms include abnormal vaginal bleeding, which may be periodic or continuous.^8,9 Additional manifestations encompass pelvic or lower back pain, the presence of a palpable mass in the lower abdomen, and unintentional weight loss.⁸ Patients often experience abdominal distension, early satiety, alterations in bowel or bladder habits, and dyspareunia.¹⁰ The debilitating nature of the disease has a profound impact on daily activities, confidence, and self-esteem. Symptoms such as menopausal-like effects, sexual dysfunction, anxiety, depression, and long-term side effects of chemotherapy further diminish HRQoL.^1,10,11

A diagnosis of endometrial cancer relies on clinical assessments to evaluate tumour location, size, and spread, supported by radiological imaging of the uterus and histopathological analysis of biopsy samples to determine histological type and grade. In cases of recurrent endometrial cancer, biopsies may also be used to identify molecular subtypes of the cancer.^12,13

Molecular testing during endometrial biopsy is crucial for treatment decisions and risk assessment.¹⁴ MMR protein expression and MSI are key biomarkers for evaluating DNA repair functionality.²⁵ Endometrial cancer is categorized as MSI-H, microsatellite instability-low, or MSS based on MSI testing,¹⁵ and as either pMMR or dMMR based on MMR status.¹⁶ Additional molecular tests are also recommended to assess for other molecular subtypes such as mutations in p53, DNA POLE, and estrogen receptor and HER2 expression.

MMR dysfunction results in MSI-H, marked by defective DNA repair and elevated mutation rates. IHC is a standard technique for detecting the expression of MMR proteins (hMLH1, hPMS2, hMSH2, and hMSH6). Loss of any protein indicates dMMR, while intact expression signifies pMMR.¹⁶ Clinically, dMMR endometrial cancer, which accounts for 20% to 30% of endometrial cancer cases,²⁷ is linked to higher tumour mutation burdens and greater sensitivity to immunotherapies, such as PD-1 inhibitors.

Standards of Therapy

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

The goals of treatment for advanced or metastatic endometrial cancer, according to the clinical experts consulted for this review, are to improve quality of life by reducing pain and suffering, reduce disease-related symptoms, control cancer proliferation, and improve survival, if possible.

The National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines recommend surgery, if possible, and adjuvant chemotherapy treatment for advanced endometrial cancer (advanced being stage III or IV) upon initial diagnosis of metastatic disease.^28,29 The clinical experts consulted for this review noted that targeted radiation therapy is also an option in some cases (e.g., cancer confined to the pelvis); the NCCN does not recommend whole-abdomen radiotherapy due to toxicity. Surgery is recommended to be accompanied by adjuvant chemotherapy rather than observation alone.³⁰

Patients who are not surgical candidates, or patients with recurrent or metastatic endometrial cancer (e.g., after treatment of localized disease) typically undergo systemic therapy. ESMO guidelines recommend platinum-based chemotherapy, doxorubicin or paclitaxel, dostarlimab, or pembrolizumab plus lenvatinib as treatment options for dMMR endometrial cancer that is recurrent or metastatic. According to the clinical experts, the current treatment paradigm in Canada for patients with dMMR endometrial cancer is to treat all eligible patients with platinum-taxane chemotherapy (i.e., carboplatin and paclitaxel or, in rare cases, with a substitution of 1 of the 2 agents) plus an ICI for up to 6 cycles followed by maintenance ICI alone. Dostarlimab is the only ICI therapy currently recommended for reimbursement for this indication. It is used alongside chemotherapy and then as maintenance monotherapy for up to 3 years if well tolerated and there is no evidence of disease progression. If patients with dMMR endometrial cancer do not receive an ICI in the first line, they are eligible to receive it in the second line. If there is disease progression, patients who did not receive an ICI in the first-line setting would receive a single-drug ICI in the second-line setting.

Other potential first-line treatments for advanced recurrent endometrial cancer include hormone therapies, which may be considered for specific patients with indolent or low-volume disease and with low-grade carcinomas.²⁶ The clinical experts noted that patients with low-grade endometrioid histologies may receive hormone therapies such as letrozole or medroxyprogesterone acetate, either on their own or in combination with tamoxifen. For patients with HER2-overexpressing serous tumours, trastuzumab and chemotherapy are suggested over other regimens.³⁰

Re-treatment with platinum-based chemotherapy is considered an acceptable approach for those experiencing relapse more than 6 months after initiating their last platinum-based chemotherapy because their disease is considered platinum-sensitive.²⁹ The clinical experts consulted for this review noted that if a patient’s cancer does not respond to therapy, they are unlikely to be re-treated with the same class of treatment but, if the cancer recurs more than 12 months after treatment in a patient who initially experienced a response, then re-treatment with the same therapy may be considered. If a patient’s cancer progresses after an interval of less than 6 months, then treatment with second-line therapies such as pembrolizumab are options.³¹

Drug Under Review

The Health Canada indication for durvalumab (Notice of Compliance date: January 17, 2025), in combination with carboplatin and paclitaxel, is as a first-line treatment for adult patients with primary advanced or recurrent dMMR endometrial cancer who are eligible for systemic therapy. Durvalumab is administered at 1,120 mg every 3 weeks in combination with platinum-based chemotherapy for 4 to 6 cycles. This is followed by maintenance therapy at 1,500 mg every 4 weeks as monotherapy until disease progression or unacceptable toxicity.¹⁹

The sponsor’s reimbursement request is the same as the Health Canada indication. Durvalumab was previously reviewed by CDA-AMC for extensive-stage small-cell lung cancer; locally advanced, unresectable non–small cell lung cancer; biliary tract cancer; and unresectable hepatocellular carcinoma, all of which received conditional reimbursement recommendations.

Durvalumab is a fully human, high-affinity, immunoglobulin G1 kappa monoclonal antibody that selectively blocks the interaction of PD-L1 (a protein expressed on tumour cells) with PD-1 and CD80 on T cells. PD-L1 binds to PD-1 and CD80 on T cells, inhibiting their activation and reducing their ability to detect and destroy cancer cells. Selective blockade of PD-L1 and PD-1 interactions and PD-L1 and CD80 interactions releases the inhibition of immune responses and enhances antitumour immune responses.^17,18

The key characteristics of durvalumab and other treatments available for primary advanced or recurrent endometrial cancer are summarized in Table 3.

Table 3: Key Characteristics of Durvalumab, Dostarlimab, Carboplatin, and Paclitaxel

dMMR = deficient mismatch repair; MSI-H = microsatellite instability-high.

^aHealth Canada–approved indication.

Sources: Product monographs for durvalumab,¹⁹ dostarlimab,³⁴ carboplatin,³⁵ and paclitaxel.³⁶

Testing Procedure Considerations

In patients with endometrial cancer, MMR status is considered an important prognostic factor, and its determination can help in clinical decision-making.^29,37,38 Confirmation of the molecular subtype based on MMR status (i.e., dMMR or pMMR) can inform risk stratification, eligibility for ICI therapy, and further germline testing for inherited conditions such as Lynch syndrome.³⁹ Current international guidelines recommend testing all endometrial cancer tumours for MMR status along with other molecular or genetic tests, such as those for p53 status and, when indicated, POLE mutations.^29,38

MMR status can be determined using IHC. This technique uses antibodies to target and stain specific MMR proteins such as MLH1, MSH2, MSH6, and PMS2, which are the most clinically relevant in cancer.^39,40 MMR is considered deficient (i.e., dMMR) if there is an absence of staining in any of the 4 MMR proteins.³⁹ Each of the MMR proteins pair with another to form heterodimers (i.e., PMS2 with MLH1 and MSH6 with MSH2); using a 2-antibody approach targeting PMS2 and MSH6 first, instead of targeting all 4 proteins, is a more cost-effective and quicker method for determining MMR status that is already being implemented in some jurisdictions in Canada.^41,42 To offset a potential decrease in accuracy with the 2-antibody method, dMMR samples are further tested using IHC for MLH1 and MSH2 expression if PMS2 or MSH6 expression appears abnormal.⁴² IHC for MMR testing is conducted using tissue samples obtained through biopsies or surgical resections. IHC is widely available and relatively inexpensive. When considering ICI therapy, using IHC to determine MMR status is recommended over other methods, such as next-generation sequencing or polymerase chain reaction, due to factors such as lower costs, shorter turnaround times, and being less resource-intensive.^42-44

The clinical experts consulted for this review noted that testing for MMR status with IHC using the diagnostic biopsy sample is routine in most jurisdictions in Canada and is the SOC for endometrial cancer. Jurisdictions that are not currently using IHC testing for MMR in patients with endometrial cancer should already have the capability (e.g., availability of antibodies) and the technical expertise in place. The clinical experts stated that the results of MMR testing are usually reported simultaneously with the diagnostic pathology report and that MMR testing can also be ordered by the treating oncologist.

The potential impacts of MMR testing for establishing treatment eligibility for durvalumab in adult patients with primary advanced or recurrent endometrial cancer were considered for this review, including impacts to health systems, patients (including families and caregivers), and costs. No new impacts are anticipated because MMR testing is currently performed as the SOC for endometrial cancer in Canada. 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 Testing for Establishing Treatment Eligibility With Durvalumab in Primary Advanced or Recurrent Endometrial Cancer

dMMR = mismatch repair deficient; EC = endometrial cancer; IHC = immunohistochemistry; MMR = mismatch repair.

^aCanada’s Drug Agency 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 for durvalumab (Imfinzi) in combination with carboplatin and paclitaxel.

Patient Group Input

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

One patient group, CCRAN, in collaboration with the Canadian Cancer Survivor Network and HPV Global Action, submitted input on durvalumab for endometrial cancer. CCRAN gathered information for this submission in September 2024 through outreach to 12 clinical trial investigators and/or clinicians in Canada to identify patients with experience using durvalumab in combination with carboplatin and paclitaxel for dMMR and/or MSI-H cancer, followed by olaparib in patients with pMMR or MSS cancer. CCRAN also reached out to 17 US-based clinician investigators involved in the DUO-E clinical trial via email in October 2024, as well as to the Society of Gynecologic Oncology and the Gynecologic Cancer Initiative. Additionally, HPV Global Action collaborated with several of its medical advisors to identify patients with experience using the therapy under review. These efforts led to 2 telephone interviews with patients with MSS endometrial cancer who participated in the DUO-E trial. Also, data from a 2023 online survey, which generated 6 responses and gathered information on the experiences of 4 patients, were used for this input.

The patient group input highlighted that patients with endometrial cancer face significant inequities, including research underfunding; rising incidence rates, particularly among females who are postmenopausal; and increasing mortality rates, despite advancements in oncology. According to the patient group input, a diagnosis of endometrial cancer is profoundly distressing, placing significant emotional strain on both patients and their caregivers, and triggering fears related to personal health and family welfare.

Respondents to the survey reported using various treatment options, including radiation, surgical resection, targeted therapy, hormonal therapy, immunotherapy, chemotherapy, and complementary medicines. Common symptoms included neuropathy, fatigue, vaginal dryness, itching, burning sensations, changes in sexual function, fluid retention, nausea, constipation, and cognitive impairment known as “chemo brain.” Many patients described chemotherapy as “tough,” with significant nausea and fatigue impacting daily life. The effects of treatment often extend to sexual health, which is frequently overlooked in clinical care and research.

The input highlighted that early-stage endometrial cancer is typically treated with surgery, often combined with chemotherapy, hormone therapy, or radiation. However, treatment options for patients with recurrent or metastatic endometrial cancer are limited, and the prognosis remains poor due to stagnant access to new therapeutics over the past decades. Thus, the patient groups highlighted an urgent unmet need for additional precision therapeutics in advanced or recurrent endometrial cancer in Canada. When asked about desired improvements in cancer treatment, the 2 patients who participated in telephone interviews emphasized the necessity of timely access to new therapies for patients with similar genomic markers in different tumour types. Among the survey respondents, 60% of patients with endometrial cancer ranked “prolong life” as the most important issue they hope new treatments will address.

The 2 patients who were interviewed shared their experiences with durvalumab in combination with olaparib during the DUO-E trial, reporting CRs and minimal side effects, while a third patient who was receiving durvalumab treatment in Australia highlighted, in their survey response, the positive impact of targeted therapies on their quality of life.

Clinician Input

Input From the 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 endometrial cancer.

Unmet Needs

The goals of treatment for advanced or metastatic endometrial cancer, according to the clinical experts, are to improve quality of life by reducing pain and suffering, improve disease-related symptoms, control the cancer proliferation, and improve survival, if possible. They noted that achieving a longer DOR would be strongly linked to improvement in relevant patient outcomes.

In dMMR endometrial cancer, 1 expert noted that between 20% and 40% of patients do not experience a response to the current first-line treatment paradigm; for context, they noted that, in general, approximately 40% of patients are not expected to experience a response to chemotherapy, and the DOR to chemotherapy alone is often very short. While the addition of an ICI improves the overall treatment response rate, it has the most significant impact on the improvement in DOR. The unmet needs in patients with dMMR endometrial cancer include better identification of potential nonresponders, determining the therapy their cancer might respond to, and determining the ideal duration of maintenance treatment among the patients with cancer that does respond to therapy.

Place in Therapy

The experts indicated that durvalumab would be an additional first-line ICI option, alongside dostarlimab, that could be added to chemotherapy and used as maintenance monotherapy in patients with dMMR endometrial cancer. In general, the clinical experts noted that the choice of ICI is often based on availability but, in a situation when multiple approved options are available, any of them could be offered. If a patient did not experience a response to ICI therapy, the clinical experts noted it was unlikely they would trial the same drug class again; however, if a patient had a recurrence more than 12 months after therapy and had previously experienced a response, then re-treatment might be considered.

Patient Population

Endometrial cancer is not considered a rare disease, and the indication places durvalumab as first-line therapy. The clinical experts noted that the DUO-E trial results did not identify specific molecular subtypes of cancers (beyond dMMR) that could respond to the new treatments; therefore, all patients who meet the other clinical trial criteria would likely be candidates for treatment with durvalumab.

Assessing the Response to Treatment

The clinical experts consulted for this review noted that the outcomes from the DUO-E trial corresponded to standard clinical assessments, with the exception of HRQoL measures, which are not routinely used in clinical practice. In general, symptomatic benefit would be assessed every treatment cycle through conversations with the patient, and radiologic treatment response would be assessed every 2 to 3 cycles. They noted that the ideal outcome to assess response would be survival but, in the face of measurable disease, achieving stability (i.e., prolongation of PFS) while being tolerated well would be a minimum response to continue therapy. They indicated that the definition of a treatment benefit may vary across physicians and patients.

Discontinuing Treatment

The clinical experts noted that disease progression and SAEs would be grounds to discontinue therapy. Examples of SAEs could include grade 3 or 4 toxicities such as hepatitis, colitis, or pneumonitis as well as any other significant immune-related toxicity.

Prescribing Considerations

Both clinical experts agreed that an oncologist or specialist in administering chemotherapy or biologic therapy would be essential to manage the complexities of treatment toxicity.

Clinician Group Input

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

Two inputs, 1 from the OH (CCO) Gynecologic Cancer Drug Advisory Committee (7 clinicians contributed to the input) and 1 from the GOC (1 clinician contributed to the input), were provided for this review. The OH (CCO) input was gathered through conference calls and emails, while the GOC input was based on data from completed clinical trials and expert opinions from its board members on treating advanced or recurrent endometrial cancer.

According to the clinician groups, treatment for dMMR endometrial cancer involves platinum-based chemotherapy (carboplatin and paclitaxel) and radiation. The clinician groups underscored the lack of publicly funded first-line immunotherapy options, though both groups acknowledged that pembrolizumab is funded for recurrent dMMR disease after failure of chemotherapy. The OH (CCO) noted that compassionate access to dostarlimab in combination with chemotherapy is available.

According to both clinician groups, the primary goals of treatment are to prolong survival, delay disease progression, control symptoms, improve HRQoL and, when possible, cure the disease. The OH (CCO) emphasized that chemotherapy fails to provide a durable response in patients with dMMR endometrial cancer.

Both clinician groups recommended durvalumab as a first-line option for patients with advanced (stage III or IV) or recurrent endometrial cancer. The OH (CCO) noted its suitability for patients with dMMR endometrial cancer, specifically highlighting that patients with dMMR endometrial cancer can receive durvalumab treatment without prior chemotherapy. The GOC emphasized that treatment suitability is determined by pathologic and radiologic staging, underscoring that it is best suited for patients with stage III or IV disease.

The clinician groups noted that treatment response is assessed through imaging (CT or MRI) and clinical evaluations. The GOC added that tolerability is evaluated before each treatment cycle (i.e., every 3 weeks) and that radiologic assessments occur every 2 to 3 cycles (i.e., every 6 to 9 weeks). The GOC highlighted that a clinically meaningful response includes tolerable toxicity and improved PFS. However, the clinician groups indicated that treatment may be withheld due to disease progression and intolerable toxicity or AEs. The GOC further mentioned that such decisions could also be related to patient preference.

In line with the clinical experts consulted for this review, the clinician groups stated that durvalumab plus carboplatin and paclitaxel should be administered in an outpatient setting and is best prescribed by specialist physicians experienced in systemic therapy.

Drug Program Input

The drug programs provide input on each drug being reviewed through the Reimbursement Review processes 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 Responses

dMMR = mismatch repair deficient; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ICI = immune checkpoint inhibitor; MMR = mismatch repair; PAG = Provincial Advisory Group; pCPA = pan-Canadian Pharmaceutical Alliance; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; QoL = quality of life; vs. = versus.

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 durvalumab plus carboplatin and paclitaxel, and durvalumab monotherapy in the treatment of advanced or recurrent endometrial cancer in adult patients aged 18 years or older. The focus will be placed on comparing durvalumab with relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of durvalumab plus carboplatin and paclitaxel is presented in 2 sections, with the CDA-AMC 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 review team’s 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. No long-term extension studies or studies addressing gaps in the evidence were included.

Included Studies

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

• 1 pivotal study or RCT identified in systematic review

• 1 indirect treatment comparison consisting of 2 MAICs.

Systematic Review

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

Description of Studies

One study (the DUO-E study) was included in this review. Characteristics of the DUO-E study are summarized in Table 6.

The DUO-E study is an ongoing phase III, multicentre, double-blind, placebo-controlled RCT of durvalumab in combination with platinum-based chemotherapy (carboplatin and paclitaxel), followed by maintenance durvalumab or maintenance durvalumab in combination with olaparib, in patients with newly diagnosed advanced or recurrent endometrial cancer compared with SOC alone (carboplatin and paclitaxel). The primary end point of the DUO-E study was PFS, with secondary end points consisting of OS, ORR, DOR, TTD, and HRQoL. In total, 718 patients were randomized 1:1:1 to SOC (arm A; N = 241), durvalumab plus SOC (arm B; N = 239), or durvalumab plus olaparib plus SOC (arm C; N = 238). Randomization was stratified according to MMR status (dMMR versus pMMR), disease status (recurrent versus newly diagnosed), and geographic region (Asia versus the rest of the world), and was undertaken using an interactive voice response system (IVRS) or interactive web response system. The study took place in 22 countries worldwide and included 7 centres in Canada. Enrolment for the DUO-E study ended in March 2022; however, treatment and follow-up are still ongoing. Full details of the DUO-E study design are included in Figure 1.

Of note, the DUO-E trial randomized patients with either pMMR or dMMR status to all 3 study arms. To align with the Health Canada indication and reimbursement request (durvalumab in combination with carboplatin and paclitaxel in patients with dMMR endometrial cancer, followed by maintenance durvalumab), this Clinical Review Report focuses only on the population of patients from the DUO-E study with dMMR status who received durvalumab in combination with carboplatin and paclitaxel (i.e., only a subset of patients included in arm B of the DUO-E study).

Other trial results, such as the use of concomitant medications and efficacy and safety results for the full ITT population (i.e., all patients with either dMMR or pMMR endometrial cancer) are presented in Appendix 1.

Table 6: Details of Studies Included in the Systematic Review

ALT = alanine aminotransferase; AML = acute myeloid anemia; ANC = absolute neutrophil count; anti-HBc = hepatitis B core antibody; AST = aspartate transferase; AUC = area under the curve; CrCl = creatinine clearance; DOR = duration of response; dMMR = mismatch repair deficient; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-EN24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Endometrial Cancer Module; FFPE = formalin-fixed paraffin-embedded; HbsAg = hepatitis B virus surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HRD = homologous recombination deficiency; IP = investigational product; MDS = myelodysplastic syndrome; MMR = mismatch repair; MSI = microsatellite instability; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; ORR = objective response rate; q.3.w. = every 3 weeks; q.4.w. = every 4 weeks; QT = electrocardiogram interval measured from the beginning of the QRS complex to the end of the T wave; PFS = progression-free survival; PGI-BR = Patient Global Impression of Benefit–Risk; PGI-S = Patient Global Impression–Severity; PGI-TT = Patient Global Impression of Treatment Tolerability; PGIC = Patient Global Impression of Change; PR = partial response; PRO-CTCAE = Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events; RCT = randomized controlled trial; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; SOC = standard of care; TDT = time to study treatment discontinuation or death; TFST = time to first subsequent therapy or death; TMB = tumour mutational burden; TSST = time to second subsequent therapy or death; ULN = upper limit of normal; vs. = versus.

^aThese inclusion and exclusion criteria were checked during prescreening; the remainder were verified during screening.

Sources: Details included in the table are from the sponsor’s summary of clinical evidence²² and the DUO-E Clinical Study Report.⁴⁸

The data provided in the submission were from a global population data cut-off of April 12, 2023, when clinical study protocol version 5.0 was in effect. The study design for the DUO-E trial consisted of a prescreening phase, screening phase, on-treatment phase (split into chemotherapy and maintenance phases) as well as a postdiscontinuation follow-up phase. During prescreening, tissue for MMR screening at a central laboratory was collected and the main inclusion and exclusion criteria (indicated as footnote “a” in Table 6) were checked. Patients underwent the screening phase while the MMR status of their sample was being tested and, following this, were randomized to begin treatment on day 1 of the study. Investigators and patients were to remain blinded to treatment assignment throughout the course of the study, except in specific circumstances. Washout periods or prespecified lengths of time were required for patients taking concomitant moderate or strong CYP3A4 inhibitors or inducers.

Figure 1: DUO-E Study Design — ITT

bd = twice a day; CTX = platinum-based chemotherapy; MMR = mismatch repair; Q3W = every 3 weeks; Q4W = every 4 weeks.

^aChemotherapy was to have been administered for a maximum of 6 cycles.

^bMaintenance treatment was to continue until progression of disease or other discontinuation criteria were met.

^cMMR status was to be known before randomization.

Source: details included in the figure are from the sponsor’s summary of clinical evidence.²²

Notable changes to the protocol between versions 1.0 and 5.0 included: the definitions for end of treatment and when a patient was considered to have completed the study (April 2021) were revised, the PFS futility boundary and analysis time point were updated (June 2022), and the statistical analysis was updated so that 2 PFS comparisons (durvalumab plus SOC versus SOC alone, and durvalumab plus olaparib plus SOC versus SOC alone) could be tested independently. Other updates to the statistical analysis included updates to the statistical analysis method, sample size assumptions, timing of the primary analysis of PFS, multiplicity testing strategy, and an assumption of a 3-month lag for durvalumab plus SOC (June 2022). Version 6.0 of the study protocol was implemented in January 2023.

Populations

Inclusion and Exclusion Criteria

The DUO-E study enrolled adult (aged 18 years or older) female patients with a histologically confirmed diagnosis of epithelial endometrial carcinoma (excluding sarcomas). The cancer status was measurable per Response Evaluation Criteria in Solid Tumours Version 1 (RECIST 1.1) and could be in any of the following categories: newly diagnosed stage III following surgery or diagnostic biopsy, newly diagnosed stage IV with or without disease following surgery or diagnostic biopsy, or recurrent disease when the potential for cure by surgery alone or in combination was poor. Patients had to be naive to first-line systemic anticancer therapy, except when prior adjuvant chemotherapy had been used (e.g., in the context of prior surgery or radiotherapy) and at least 12 months or more had elapsed from the last treatment to the recurrence of disease. Key exclusion criteria included unresolved toxicities from prior anticancer therapy (with exceptions), prior radiotherapy administered to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of beginning the study, any previous immune-mediated therapy, concurrent hormonal therapy for noncancer conditions, history of another primary malignancy (with exceptions) or major surgeries within 2 weeks of starting the study treatment. Full detailed inclusion and exclusion criteria are in Table 6.

Tumour markers were not used for determining patient eligibility, but were used to allow for stratification by MMR status. Other putative DNA damage response markers (BRCA gene mutation status, presence of HRR gene mutation, and so forth) and putative immune-oncology markers (for example, PD-L1 expression on tumour and immune cells) were tested retrospectively for subgroup analyses.

Interventions

Patients began treatment on the day of randomization or, in the event of logistical challenges, no later than 3 calendar days following randomization. Treatment in each group was divided into an initial chemotherapy phase for up to 6 cycles, followed by a maintenance phase for cycles 7 and beyond in patients who experienced a response. Patients received the following interventions based on their assigned treatment arm:

• Arm A (SOC): A chemotherapy phase regimen of platinum-based chemotherapy consisting of carboplatin (area under the curve [AUC] 5 mg/mL/min or 6 mg/mL/min once every 3 weeks for 6 cycles) and paclitaxel (175 mg/m² once every 3 weeks for 6 cycles) plus durvalumab placebo for 6 cycles. After the chemotherapy phase, patients who had no evidence of progressive disease (per RECIST 1.1) then received maintenance-phase therapy consisting of durvalumab placebo IV every 4 weeks plus olaparib placebo tablets twice daily.

• Arm B (SOC plus durvalumab): A chemotherapy phase regimen of the same platinum-based chemotherapy as the SOC arm plus durvalumab 1,120 mg IV every 3 weeks for 6 cycles. After the chemotherapy phase, patients who had no evidence of progressive disease (per RECIST 1.1) then received maintenance-phase therapy consisting of durvalumab 1,500 mg IV every 4 weeks plus olaparib placebo tablets twice daily.

• Arm C (SOC plus durvalumab plus olaparib): The same chemotherapy phase regimen as arm B. After the chemotherapy phase, patients who had no evidence of progressive disease (per RECIST 1.1) then received maintenance-phase therapy consisting of durvalumab 1,500 mg IV every 4 weeks plus olaparib 300 mg twice daily. This study arm was not appraised in this review.

The carboplatin and paclitaxel regimens were to be continued for a maximum of 6 cycles but could be reduced to a minimum of 4 cycles if required due to toxicity.

Durvalumab or its placebo were available in a 500 mg vial containing 50 mg/mL solution for IV infusion after dilution. The dose was administered using an IV bag with 0.9% (w/v) saline or 5% (w/v) dextrose. If a patient’s weight fell to 30 kg or less using treatment, weight-based dosing of 20 mg/kg was administered. Dose delays of up to 12 weeks were permitted for durvalumab under prespecified circumstances, but dose reductions were not permitted. A cycle was counted if treatment was started, even if the full dose was not delivered.

The order of infusions for the chemotherapy phase was durvalumab or placebo followed by paclitaxel and then carboplatin. Dosing intervals in the maintenance phase were permitted to be shortened as clinically feasible to align treatment cycles with the schedule for the assessments of tumour efficacy (RECIST 1.1) and HRQoL. The subsequent time between 2 consecutive doses was not permitted to be less than 21 days, based on the half-life of durvalumab. Maintenance treatments were continued until objective disease progression (per RECIST 1.1), unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. In cases of doubt regarding radiological disease progression, patients could continue study treatment(s) for the purpose of confirming disease progression, with a follow-up scan in 4 weeks or less if they were not experiencing any significant, unacceptable, or irreversible toxicities, in the opinion of the investigator. The discontinuation criteria were any of the following occurrences:

• Objective disease progression according to RECIST 1.1 criteria.

• Clinical deterioration was used as a reason for discontinuation only when objective disease progression had not yet been or could not be determined. Patients with symptomatic or clinical deterioration requiring discontinuation of treatment without objective radiologic evidence of disease progression at that time were to continue undergoing tumour assessments.

• Withdrawal of consent from further treatment. Per the submission, patients could discontinue treatment at any time; patients who discontinued would be expected to continue to participate in the study (e.g., for safety and survival follow-up) unless they specifically withdrew consent to all further participation in any study procedures and assessments.

• An AE that, in the opinion of the investigator or the sponsor, contraindicated further dosing.

• Any AE that met criteria for discontinuation as defined in the study’s dosing modification and toxicity management guidelines or as defined in the local prescribing information for the chemotherapy agents (carboplatin and paclitaxel).

• Pregnancy or intent to become pregnant.

• Nonadherence with the study protocol that, in the opinion of the investigator or the sponsor, warranted withdrawal from treatment.

• Bone marrow findings consistent with myelodysplastic syndrome or acute myeloid leukemia.

• Initiation of an alternative anticancer therapy, including another investigational drug.

All patients continued to be assessed for radiological tumours, according to the study schedule, until objective radiological disease progression, irrespective of any treatment delays or discontinuation of study treatment. Once a patient progressed, they were followed as per local clinical practice; in the case of a second progression, assessments were planned for every 12 weeks and survival status was to be assessed every 2 months until the final analysis of the study.

Restrictions, Concomitant Medications, and Rescue Medications During the DUO-E Trial

Patients who were enrolled in the study and had been on moderate or strong cytochrome P450 3A (CYP3A) inducers or inhibitors were required to discontinue them during a 2-week washout period before beginning the study. The consumption of grapefruit juice was prohibited during the maintenance phase of the study (i.e., during the administration of olaparib or its placebo). Strong and moderate CYP3A inhibitors or inducers were prespecified not to be taken with olaparib, but if no suitable alternative was found, then the dose of olaparib was reduced for the period of concomitant administration. Medications that are substrates for CYP3A4, including CYP2B6, OATP1B1, OACT3, OCT1, OCT2, MATE1, and MATEK1, were to be used with caution. Warfarin was permitted with a recommendation to monitor the international normalized ratio at prespecified intervals. Palliative radiotherapy was permitted for the treatment of pain at the site of bony metastases that were present at baseline, provided the investigator did not feel they were indicative of clinical disease progression, and the study treatment was to be discontinued and resumed at prespecified time points.

Prohibited medications included other anticancer drugs, immunosuppressive medications (e.g., systemic corticosteroids at doses exceeding 10 mg/kg/day of prednisone or equivalent, methotrexate, tumour necrosis factor alpha blockers), EGFR tyrosine kinase inhibitors, live virus vaccines, live bacterial vaccines, and herbal or natural remedies that may have immunomodulating effects. Patients were permitted to continue the use of denosumab or bisphosphonate for bone disease provided these were started at least 4 weeks before beginning study treatment. For each prohibited medication class, prespecified guidance was provided in the study protocol. Full details of the restricted concomitant therapies are in Table 7.

Two rescue treatments, infliximab (e.g., for colitis) and mycophenolate mofetil (e.g., for hepatitis), were permitted for any immune-mediated AEs experienced by patients. Dose modifications for the management of AEs (including renal impairment) for durvalumab were prespecified in the study protocol.

Table 7: Relevant Prohibited and Restricted Medications for the DUO-E Study — dMMR Subgroup

dMMR = mismatch repair deficient; mAb = monoclonal antibody.

Note: Hormone replacement therapy was acceptable.

Source: Details included in the table are from the DUO-E study protocol.⁴⁹

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 8, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review according to the clinical experts consulted for this review and input from patient and clinician groups and public drug plans. Using the same considerations, the review team selected end points that were considered to be most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee.

The included time-to-event end point outcomes for PFS and OS have been summarized in this report and assessed at 12- and 18-month time points using GRADE; these measures and time points were chosen because they are standard measures of response to treatment in oncology and provide the longest follow-up available from the DUO-E trial. To provide additional context for efficacy, ORR, DOR, and TDT have been summarized in this report but were not included in GRADE. The EORTC QLQ-C30 and EORTC QLQ-EN24 scores were summarized in this report and included in GRADE; these measures were chosen as they measure quality of life in patients with cancer and with endometrial cancer, respectively. The HRQoL outcomes at 18 weeks, which corresponds to the last infusion of the chemotherapy phase, have been summarized, and summarized again at 42 weeks, which corresponds to the sixth month of maintenance therapy. Select notable harms outcomes considered important for informing expert committee deliberations were also assessed using GRADE; these included immune-mediated AEs and infusion-related reactions.

Of note, results for arm B relative to arm A, and arm C relative to arm A, were reported separately in the ITT population. Results for arm B relative to arm A are reported only for the dMMR subgroup in this review. The submission also included a post hoc analysis of arm B versus arm C, but this was not appraised in the review because the comparison was not relevant to the reimbursement request.

Table 8: Outcomes Summarized From the DUO-E Study

CR = complete response; dMMR = mismatch repair deficient; DOR = duration of response; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-EN24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Endometrial Cancer Module; ITT = intention to treat; ORR = objective response rate; OS = overall survival; PD = progressive disease; PR = partial response; q.3.w. = every 3 weeks; q.4.w. = every 4 weeks; QoL = quality of life; PFS = progression-free survival; TDT = time to study treatment discontinuation or death.

^aStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchal testing) in the ITT analysis. Statistical testing was not controlled for multiplicity in the dMMR subgroup analysis.

Sources: Details included in the table are from the sponsor’s summary of clinical evidence²² and additional information provided by the sponsor.⁵⁰

Survival Outcomes

All patients were given radiological tumour assessments according to the study schedule (every 9 weeks for the first 18 weeks relative to randomization, then every 12 weeks, plus or minus 1 week, until RECIST 1.1–defined radiological progression).

Progression-Free Survival

PFS was defined as the time from randomization to the date of objective disease progression or death from any cause in the absence of progression, regardless of whether the patient withdrew from therapy or received another anticancer therapy before progression. PFS determined by the investigator was the primary outcome in the DUO-E trial; PFS assessment by blinded independent central review (BICR) was used as a prespecified sensitivity analysis. The PFS time was always derived based on scan/assessment dates and not visit dates. RECIST 1.1 assessments or scans contributing toward a particular visit were performed on different dates. The following rules were applied:

• For investigator assessments, the date of progression was determined based on the earliest of the scan dates of the component that triggered progression.

• For BICR assessments, the date of progression was determined based on the earliest of the scan dates of the component that triggered the determination of progression by the adjudicated reviewer who assessed progressive disease, or by the reviewer who read the baseline data first if there was no adjudication for BICR data.

• For both BICR and investigator assessments, when censoring a patient for PFS, the patient was censored at the latest of the scan dates contributing to a particular overall visit assessment.

Overall Survival

OS was defined as the time from the date of randomization until death due to any cause, regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy (i.e., date of death or censoring minus date of randomization plus 1). OS determined by the investigator was a secondary outcome.

Objective Response Rate

ORR was defined as the proportion of patients with measurable disease at baseline who had a CR or partial response (PR), as determined by the investigator. A confirmed response of CR or PR meant that the response had been recorded at 1 visit and confirmed by repeat imaging no sooner than 4 weeks after the visit when the response was first observed, with no evidence of progression between the initial and confirmation visit. Patients who discontinued treatment without progression, or who received a subsequent anticancer therapy and then experienced a response, were not included as responders in the ORR assessment. If PRs were recorded for a patient at 2 nonconsecutive visits, the patient was defined as a responder if the time between the 2 visits was greater than 4 weeks and there was no progressive disease between the 2 visits. Similarly, if a patient had a response of “CR not evaluable” recorded at 1 visit, and then a CR was recorded at another visit, then a best response of CR was assigned if the time between the 2 visits was greater than 4 weeks.

Duration of Response

DOR was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression (i.e., date of PFS event or censoring minus the date of first response plus 1). DOR was defined only for patients classified as responders in the ORR analysis. The end of response had to have coincided with the date of progression or death from any cause that was used for the PFS outcome. The time of the initial response was defined as the latest of the visit dates at which the first CR or PR was recorded and subsequently confirmed. If a patient’s cancer did not progress following a response, then their DOR used the PFS censoring time.

Time to Study Treatment Discontinuation or Death

TDT was defined as the time from randomization to the earlier of either the date of study treatment discontinuation or death. Treatment discontinuation was defined as all investigational products being discontinued. For example, if a patient had received both durvalumab and olaparib and they were discontinued on different dates, the date of discontinuation was the later date; if a patient had received only 1 of the study treatments, then the date of discontinuation was the date that drug was discontinued; if a patient had not received either study treatment, they were censored at day 1.

HRQoL Outcomes

HRQoL measures, including the EORTC QLQ-C30 and EORTC QLQ-EN24, were assessed at baseline (before dosing on day 1 of cycle 1), then every 3 weeks (± 3 days) for the first 18 weeks, and then every 4 weeks (± 3 days) until a second disease progression or death. Patients were also assessed at the study treatment discontinuation visit (+ 2 days) unless an assessment had been completed within 3 days before the visit; for those who discontinued for reasons other than progressive disease, HRQoL was assessed for patients at the progressive disease assessment visit (+ 2 days) unless an assessment had been completed within 3 days before the visit. Patients also had an HRQoL assessment at the visit marking the start of maintenance therapy, unless an assessment had been completed within 3 days before the visit. Full details of the HRQoL measures, including validation and MIDs, are presented in Table 9.

EORTC Quality of Life Questionnaire Core 30

The EORTC QLQ-C30 is a 30-item, cancer-specific, patient-reported HRQoL questionnaire designed to assess the physical, psychological, and social functioning of patients with cancer.⁵¹ The functional scales range from 0 to 100, with higher scores indicating better functioning. An MID of 10 points, based on the recommendation to use 10% of the scale as a cut-off of meaningful change, has been identified in patients with breast and small-cell lung cancer.⁵² No MID was available in the literature for patients with endometrial cancer.

EORTC Quality of Life Questionnaire – Endometrial Cancer Module

The EORTC QLQ-EN24 is a 24-item, cancer-specific patient-reported outcome measure designed to assess the HRQoL of patients with endometrial cancer. It is intended to be used alongside the EORTC QLQ-C30 to capture both disease and treatment-specific aspects of quality of life in patients with endometrial cancer. All questions are rated on a 4-point Likert scale.⁵³ The functional scales range from 0 to 100, with higher scores indicating better functioning. The 10 symptom scales range from 0 to 100, with higher scores indicating more severe symptoms. The pain in back and pelvis score and the urological symptoms score are included in this review. No MID was identified for patients with endometrial cancer.

Table 9: Summary of Outcome Measures and Their Measurement Properties

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-EN24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Endometrial Cancer Module; HRQoL = health-related quality of life; ICC = interclass correlation; MID = minimal important difference.

Statistical Analysis

Sample Size and Power Calculations

Sample size calculations were performed for the overall study following the prespecified statistical analysis plan and included patients with either pMMR or dMMR endometrial cancer. No prespecified sample size calculations were performed for patients with a specific MMR status; thus, none of the comparisons for the dMMR cohort were sufficiently powered to detect statistically significant differences between durvalumab plus carboplatin and paclitaxel versus SOC.

Globally, the aim was to randomize approximately 699 eligible patients with endometrial cancer at a 1:1:1 ratio to the study treatments. The sample size calculations were based on the following assumptions:

• A median PFS of 12 months was assumed for the control arm, which is in line with the data reported for carboplatin plus paclitaxel in first-line endometrial cancer from the GOG-209 study,⁶³ as reported in the GOG-86P manuscript.⁶⁴

• The sample size was derived on the assumption of a 3-month delay in the separation of the PFS curves between arm B versus arm A and between arm C versus arm A. The true average HR for arm B versus arm A was assumed to be 0.70 (corresponding to an improvement in median PFS of 5.5 months over the assumed median PFS of 12 months in the control arm), and 0.55 for arm C (corresponding to an improvement in median PFS of 11.2 months).

If the average true PFS HR was 0.70 for arm B versus arm A, the study would provide 80% power to demonstrate a statistically significant difference for PFS with an overall 2-sided significance level of 2.5%, which would translate to a 5.5-month benefit in median PFS over 12 months relative to arm A. The smallest treatment difference that would be statistically significant would be an HR of 0.77. If the average true PFS HR was 0.55 for arm C versus arm A, the study would provide more than 99% power to demonstrate a statistically significant difference for PFS with an overall 2-sided significance level of 2.5%; this would translate to a 11.2-month benefit in median PFS over 12 months relative to the control arm. The smallest treatment difference that would be statistically significant would be an HR of 0.76.

In addition, the sample size was derived on the following assumptions:

• 27-month period of recruitment

• approximately 10% uniform dropout rate over the study period.

The power calculations for OS were based on the following assumptions:

• The median OS for the control arm was assumed to be 22.7 months.

• The sample size was derived on the assumption of a 3-month delay in separation of the OS curves between arm B versus arm A, and arm C versus arm A, hence the use of an average HR for OS. The assumed true average OS HR was 0.75 for both comparisons, corresponding to an improvement in median OS of approximately 7.9 months over the assumed median OS of 22.7 months in arm A.

The first IA of OS was performed at the time of the primary PFS analysis. For the comparison of arm B versus arm A and arm C versus arm A, the submission anticipated that 74% of the target number of OS events would have occurred at this time (i.e., approximately 208 of 280 OS events per comparison). A further analysis of OS was performed at the same calendar time when approximately 244 OS events (87% of the target number of OS events) occurred for the comparisons of interest, approximately 51 months after the first patient was randomized. A final analysis of OS was performed at the same calendar time when approximately 280 OS events occurred (60% maturity) for the comparisons of interest, approximately 63 months after the first patient was randomized.

If the average true OS HR was 0.75 for the comparison of the experimental arm versus control, the study would provide 55% power to demonstrate a statistically significant difference for OS with an overall 2-sided significance level of 2.5%, or a 7.9-month benefit in median OS over 22.7 months relative to arm A. The smallest treatment difference that would be statistically significant is an HR of 0.76. These estimates were based on the assumption that no confounding would occur.

Statistical and Analytical Plans

Details of the statistical analyses for both the primary analysis (i.e., the ITT population) and the dMMR subgroup for the included outcomes are summarized in Table 10. Briefly, the primary analyses separately compared arm B (durvalumab plus SOC) with arm A (SOC), and arm C (durvalumab plus olaparib plus SOC) with arm A (SOC). As previously noted, the results for the analysis comparing arm C with arm A are not included in this report. The study protocol was modified in June 2022, updating the ITT population statistical analysis so that 2 PFS comparisons could be tested independently; the changes included updates to the statistical analysis method, sample size assumptions, timing of the primary analysis PFS, multiplicity testing strategy, and an assumption of a 3-month lag for arm B. The primary analysis was prespecified to be undertaken when approximately 299 PFS events had occurred (64% maturity) for the arm B versus arm A comparison, and when approximately 281 PFS events had occurred (60% maturity) for the comparison of arm C versus arm A. No information was provided on any prespecified statistical analyses of the dMMR subgroup indicated in the reimbursement request, and no outcomes were adjusted for multiple testing in this cohort of patients. The data cut-off for the primary analysis of PFS was April 12, 2023; the first IA for OS was also performed using this data.

Statistical Tests and Models

Some general principles were prespecified in the submission and followed for the statistical analysis. Among the key principles were the following: for safety end points, the last observation before the first dose of study treatment was considered the baseline measurement, unless otherwise specified; for the efficacy and HRQoL end points, baseline was defined as the last assessment before randomization. However, if an evaluable assessment was not available before randomization but was available before the first dose of study treatment, then this assessment was to be used as baseline. Change from baseline was calculated as the posttreatment value of the variable minus the value at baseline. The results of all statistical analyses were presented using corresponding CIs and 2-sided P values, unless otherwise stated.

Time-to-Event Analyses: All time-to-event end points, including the primary end point of PFS, were analyzed in the ITT population using a log-rank test stratified by MMR status (proficient versus deficient), disease status (recurrent versus newly diagnosed), and geographic region (Asia versus rest of world) for each pairwise comparison independently. Of note, stratification factors were excluded from the model (region first, followed by MMR status and then disease status) until there were at least 5 events in each stratum of interest across the 3 treatment arms. The HR and its CI were estimated from a stratified Cox proportional hazards model that included the same stratification factors as strata. The CIs were calculated using a profile likelihood approach. In the dMMR subgroup, the HR and corresponding 95% CI were estimated from an unstratified Cox proportional hazards model. Details on patient censoring are described in Table 10 under Handling of missing data.

HRQoL and Descriptive Analyses: Descriptive statistics were used for all variables, as appropriate, and were presented by treatment group. Continuous variables were summarized by the number of observations, mean, SD, median, minimum, and maximum. For log-transformed data, the geometric mean, coefficient of variation, and the median, minimum, and maximum were reported. Categorical variables were summarized by frequency counts and percentages for each category. Unless otherwise stated, percentages were calculated out of the total population for the corresponding treatment arm.

Analysis models were stratified by the randomization stratification factors: MMR status (MMR-proficient tumours versus dMMR tumours), disease status (recurrent endometrial cancer versus newly diagnosed endometrial cancer), and geographic region (Asia versus rest of world). The strata obtained from the randomization code were used, as opposed to the values recorded in the electronic case report form. The submission provided rationales for the choice of stratification factors. Specifically, it was noted that MMR status and disease recurrence status impact treatment response, and Asian countries may have different approaches to managing advanced disease (e.g., greater emphasis on surgery versus systemic therapy). The submission did not contain details on whether other factors were considered for stratification and what the results of those deliberations might be.

Table 10: Statistical Analysis of Efficacy End Points for the DUO-E Study

BICR = blinded independent central review; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; CR = complete response; dMMR = mismatch repair deficient; DOR = duration of response; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-EN24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Endometrial Cancer Module; HR = hazard ratio; ITT = intention to treat; IVRS = interactive voice response system; KM = Kaplan-Meier; MMR = mismatch repair; MMRM = mixed model for repeated measures; NA = not applicable; OR = odds ratio; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; SOC = standard of care; TDT = time to study treatment discontinuation or death; vs. = versus.

^aFor the analysis of the PFS primary end point, if there were fewer than 5 events per stratum, the following pooling strategy was applied across all 3 arms: Strata were calculated as stratum 1 × stratum 2 × …stratum X × treatment; so, with 3 stratification factors for every 2 levels and 3 treatments, the total was 24 strata (2 × 2 × 2 × 3). Stratification factors were removed in the following order until there were at least 5 events in each stratum: Region (Asia vs. rest of world), MMR status (proficient vs. deficient), and disease status (recurrent vs. newly diagnosed). The same pooling was applied for both primary comparisons (arm B vs. arm A and arm C vs. arm A). All analyses were then conducted with the same stratification factors that were used for the primary analysis of PFS in the ITT population. If there were secondary end points or sensitivity analyses that still did not conform to the 5-event rule per stratum, an unstratified analysis was conducted.

Source: Details included in the table are from the sponsor’s summary of clinical evidence.²²

Sensitivity and Subgroup Analyses

Prespecified subgroup analyses of the ITT population were conducted for several end points. The subgroup analyses for the stratification factors were based on the values entered into the IVRS; all other factors were based on values recorded on the electronic case report form, as indicated previously, or third-party vendor data. No adjustment to the significance level for testing was made. Because the subgroup analyses were undertaken for the ITT population, the results were not included in the report.

Multiple-Testing Procedure

A multiple-testing procedure with a gatekeeping strategy was used for PFS and OS and for the treatment comparisons of interest for the ITT population. Details of the multiple-comparisons strategy are in Figure 2. An alpha-exhaustive recycling strategy was employed in which the test mass that became available after each rejected null hypothesis was recycled to a secondary hypothesis not yet rejected. If 1 test in the family could be rejected, the family was rejected and the total alpha assigned to the family was recycled to the next multiple-testing level. The testing procedure stopped when the entire test mass was allocated to nonrejected null hypotheses.

Timing of Efficacy Analyses

The timing of the efficacy analyses for PFS and OS in the ITT population is summarized in Table 11. Briefly, the analyses were prespecified to occur after specific thresholds for PFS events were reached. Once a PFS threshold was reached, the OS IA was undertaken. Two IAs and a final analysis for OS were planned.

In the ITT population analysis, the OS tests for the same comparison were to be considered as 1 test family. The alpha level allocated to OS was controlled at the interim and primary time points by using the Lan DeMets⁶⁶ spending function that approximated an O’Brien-Fleming approach; with this method, the alpha level applied at the interim time point depends on the proportion of information available. If an IA or primary analysis was found to be statistically significant, the overall 2-sided alpha was to be allocated to the next level. For a given hypothesis, if the IA did not meet the criterion for stopping for superiority, the follow-up would continue until the final target number of OS events for that comparison had been observed, following which the hypothesis would be retested. If the null hypothesis was rejected, subsequent testing would continue hierarchically.

Included in the sponsor’s current submission were the results from the primary PFS analysis and first IA for the OS analysis in the ITT population. The dMMR subgroup was derived from the same data cut-off; however, no information was provided on whether similar testing methods (i.e., the Lan DeMets and O’Brien-Fleming approach) were undertaken for the analysis of this subgroup.

Figure 2: Multiple-Comparisons Strategy — DUO-E Study ITT Population

H = hypothesis; ITT = intention to treat; OS = overall survival; PFS = progression-free survival; vs = versus.

Note: The alpha levels presented in the figure are 2-sided.

Source: Details included in the figure are from the sponsor’s summary of clinical evidence.²²

The submission noted that the IA and primary analysis boundaries for the OS analysis would be derived from the number of events observed in the study, and that the numbers in this figure are for reference only. As noted, no multiple testing was conducted for the dMMR subgroup.

Table 11: Timing of Efficacy Analyses for PFS and OS in the DUO-E Study — ITT Population

IA = interim analysis; ITT = intention to treat; OS = overall survival; PFS = progression-free survival.

Sources: Details included in the table are from the sponsor’s summary of clinical evidence²² and the DUO-E Clinical Study Report.⁴⁸

Analysis Populations

Details of the analysis sets are available in Table 12. Briefly, the full analysis set (FAS) included all randomized patients within treatment arms assigned in accordance with the randomization, regardless of the treatment actually received. Patients who were randomized but did not subsequently receive treatment were included in the FAS. The analysis of data using the FAS comprised an ITT population. Study population, demographic data, and efficacy and HRQoL results were summarized and analyzed based on the FAS, and patients were summarized based on the treatment arm they were assigned to, regardless of the treatment they received.

The safety analysis set consisted of all randomized patients who received any amount of study treatment (durvalumab or its placebo, or olaparib or its placebo). Patients who initially received a dose of durvalumab or durvalumab placebo were summarized according to the arm to which they had been randomized. Safety and treatment exposure were summarized based on the safety analysis set. For the maintenance phase, the number of patients in the safety analysis set who entered the maintenance phase (defined as having received at least 1 dose of olaparib or olaparib placebo) were also summarized.

Table 12: DUO-E Study Analysis Populations

ADA = antidrug antibody; dMMR = mismatch repair deficient; ECG = electrocardiogram; FAS = full analysis set; HRQoL = health-related quality of life; PK = pharmacokinetic; SAS = safety analysis set; SOC = standard of care.

Source: Details included in the table are from the sponsor’s summary of clinical evidence.²²

Results

Patient Disposition

Results of the patient disposition for the ITT population, including the number of screening failures and other reasons for nonrandomization, are shown in Table 13. Specific reasons for screen failure were not provided. Briefly, out of 875 patients enrolled, a total of 718 were randomized into the study and comprised the ITT population (containing patients with either pMMR or dMMR cancers). A summary of the efficacy and harms results for the ITT population is included in Appendix 1.

Table 13: Summary of Patient Disposition From the DUO-E Study — ITT Population

ITT = intention to treat; SOC = standard of care.

Source: Details included in the table are from the sponsor’s DUO-E Clinical Study Report.⁴⁸

A subset of the enrolled population (i.e., patients with dMMR status) within arm A (SOC) and arm B (SOC plus durvalumab) was isolated to align the trial population with the Health Canada indication. Details of the patient disposition for this subgroup are summarized in Table 14. Of the 718 patients included in the ITT population, 143 had dMMR status: 49 were randomized to the SOC arm, 46 were randomized to the durvalumab plus SOC arm, and 48 were randomized to the durvalumab plus olaparib and SOC arm. Data related to the durvalumab plus olaparib and SOC arm in the dMMR population, and all data from all patients in the pMMR population, were omitted from this review, given that these data are not relevant to the reimbursement request or the Health Canada indication.

At the time of data cut-off, all patients had discontinued carboplatin and paclitaxel, per the protocol. The most common reason for discontinuing carboplatin and paclitaxel was reaching the maximum number of chemotherapy cycles. In the dMMR subgroup, the proportion of patients discontinuing durvalumab was numerically greater in the SOC arm relative to the SOC arm. The most common reason for the discontinuation of durvalumab (or its placebo) was objective disease progression (█████ ██ █████). A numerically higher proportion of patients in the dMMR subgroup receiving SOC (██████) discontinued the study relative to the durvalumab plus SOC arm (█████). A numerically higher proportion of patients in the dMMR subgroup receiving durvalumab (█████) reported starting the maintenance phase relative to patients receiving SOC (█████).

Table 14: Summary of Patient Disposition From the DUO-E Study — dMMR Subgroup

dMMR = mismatch repair deficient; FAS = full analysis set; NR = not reported; OS = overall survival; SAS = safety analysis set; SOC = standard of care.

^aAny of the following treatments: durvalumab or its placebo, olaparib or its placebo, carboplatin or substitute, or paclitaxel or substitute. The submission did not specify substitutes.

^bPercentages were calculated from the number of patients who received the treatment.

^cRepresents patients’ disposition status at time of discontinuation from study. Some patients subsequently had vital status information collected from publicly available resources (when it was possible to do so under applicable local laws) for the purpose of the OS analysis, as detailed in the DUO-E protocol.⁶⁷

^dComprises the patients who continued treatment with durvalumab or its placebo after the end of chemotherapy treatment; however, because they did not initiate treatment with olaparib or its placebo, they were not included in the maintenance phase.

^eAll randomized patients who received any amount of study treatment (durvalumab or its placebo or olaparib or its placebo).

Source: Details included in the table are from the sponsor’s summary of clinical evidence.²²

Baseline Characteristics

The baseline characteristics of the dMMR population outlined in Table 15 are limited to those that are most relevant to this review or that were felt to affect the outcomes or interpretation of the study results. The demographic characteristics were broadly balanced between study arms; the mean age of patients was roughly ██ years and approximately half of the patients in each study arm were older than 65 years. The study arms were approximately evenly split between patients with newly diagnosed versus recurrent cancer (████% in the SOC arm and ████% in the SOC plus durvalumab arm had a recurrence of earlier cancer). There were no details of additional molecular classifications within the dMMR subgroup (e.g., p53 mutations).

The majority of patients had metastatic disease (████% in the SOC arm, ████% in the SOC plus durvalumab arm) and the majority of tumours were endometroid (83.7% in the SOC arm and 71.7% in the SOC plus durvalumab arm). Patients with recurrent disease in the SOC plus durvalumab arm had a numerically longer mean time since initial diagnosis (█████ weeks; SD = ██████) relative to the SOC arm (█████ weeks; SD = ██████). There was a numeric difference in the proportion of patients who had locally advanced disease between study arms (███% in the SOC arm, ████% in the SOC plus durvalumab arm). There were also notable differences in the proportion of patients with a history of debulking surgery (████% in the SOC arm, ████% in the SOC plus durvalumab arm), the proportion of patients with a grade G2 tumour (████% in the SOC arm, ████% in the SOC plus durvalumab arm), and in the proportion of patients with an ECOG status of 0 (59.2% in the SOC arm, 50.0% in the SOC plus durvalumab arm) or 1 (40.8% in the SOC arm, 50.0% in the SOC plus durvalumab arm).

The baseline characteristics of the ITT population can be found in Appendix 1.

Table 15: Summary of Baseline Characteristics From the DUO-E Study — dMMR Subgroup

dMMR = mismatch repair deficient; ECOG = Eastern Cooperative Oncology Group; FFPE = formalin-fixed paraffin-embedded; FIGO = International Federation of Gynecology and Obstetrics; G = grade; IVRS = interactive voice response system; MMR = mismatch repair; pMMR = mismatch repair proficient; SD = standard deviation; SOC = standard of care (carboplatin + paclitaxel); vs. = versus.

^aPatients with recurrent disease only.

^bPathology-related disease characteristics were collected at the time of primary diagnosis of disease under investigation.

^cMMR status (proficient vs. deficient) was per central laboratory result using the FDA-cleared Class II Ventana MMR immunohistochemistry panel (based on evaluation of tumour cells from an FFPE tumour tissue sample) and disease status (recurrent vs. newly diagnosed) was as collected on the electronic case report form. Note: 2 patients with “unknown” MMR status (per central laboratory) were randomized as having dMMR cancer per the IVRS based on local testing. Two additional patients were mis-stratified in the IVRS: 1 patient with dMMR cancer (per central laboratory) was randomized in the IVRS as having pMMR, and 1 patient with pMMR cancer (per central laboratory) was randomized in the IVRS as having dMMR.

^dAny metastatic site of disease.

^ePatient had only locally advanced sites of disease.

Source: Details included in the table are from the sponsor’s summary of clinical evidence.²²

Exposure to Study Treatments

The exposure to study treatments for the study arms and subgroups relevant to the reimbursement request are presented in Table 16. Of note, patients in the SOC plus durvalumab arm had a numerically longer actual exposure to treatment in the study (mean = █████ weeks; SD = █████) relative to the SOC arm (mean = █████ weeks; SD = █████). A total of ██ patients in the SOC arm and ██ patients in the SOC plus durvalumab arm received maintenance therapy. The majority of infusions in both treatment arms were reported as taking place in the maintenance phase. In the SOC arm, the mean number of infusions was █████ infusions (SD = ████; range, ██ ██) in the overall study and ████ infusions (SD = ████; range, █ to ██) in the maintenance phase. In the SOC plus durvalumab arm, the mean number of infusions was █████ infusions (SD = ████; range, █ to ██) in the overall study and █████ infusions (SD = ████; range, █ to ██) in the maintenance phase.

Table 16: Summary of Patient Exposure From the DUO-E Study — dMMR Subgroup

dMMR = mismatch repair deficient; SD = standard deviation; SOC = standard of care (carboplatin + paclitaxel).

^aIntended exposure (weeks) = ([earliest of: last dose date when dose was > 0 mg plus C days, date of death, or date of data cut-off] minus [the first dose date plus 1 day]) divided by 7, where C is equal to the scheduled number of days between doses minus 1. Note: C = 20 if the last dose date falls in the chemotherapy phase; C = 27 if the last dose date falls in the maintenance phase.

^bActual exposure (weeks) = intended exposure minus total duration of dose delays in days. Total duration of dose delays in days = (date of the dose minus date of the previous dose minus D days) divided by 7. Note: D = 21 if it happens during the chemotherapy phase; D = 28 if it happens during the maintenance phase.

Source: Details included in the table are from the sponsor’s summary of clinical evidence²² and additional information provided by the sponsor.⁶⁸

Results on the proportion of patients receiving the prespecified rescue medications were not available. Results for the most common permitted concomitant medications and the number of patients reporting the use of prohibited medications for the ITT population are presented in Appendix 1; concomitant medications specific to the dMMR subgroup were not provided in the submission.

For patients who discontinued the study drug, details on the therapy they received after discontinuation is presented in Table 17. Of note, patients who discontinued the study drug received immunotherapy, chemotherapy, hormonal therapy, or targeted therapy.

Table 17: Postdiscontinuation Disease-Related Anticancer Therapy — dMMR Subgroup

dMMR = mismatch repair deficient; SOC = standard of care (carboplatin + paclitaxel).

Source: Details included in the table are from additional information provided by the sponsor.²³

Efficacy

Survival Outcomes

Detailed results of the survival analysis to date (final analysis for PFS, IA for OS) at the data cut-off (April 12, 2023) are presented in Table 18.

Progression-Free Survival

In the dMMR subgroup, there were a total of 25 PFS-related events (51.0%; N = 49 patients) in the SOC arm and 15 events (32.6%; N = 46 patients) in the SOC plus durvalumab arm. There were ██████ censored deaths in the SOC arm and ██████ in the SOC plus durvalumab arm. The median PFS in the SOC arm was 7.0 months (95% CI, 6.7 to 14.8), while the median PFS was not calculable in the SOC plus durvalumab arm (HR, 0.42; 95% CI, 0.22 to 0.80 in favour of durvalumab). The risk difference between study arms for the proportion of patients whose cancer had not progressed was ████% (95% CI, ████ ██ ████) at 6 months; ████% (95% CI, ████ █████) at 12 months; and ████% (95% CI, █████ ██ ████) at 18 months.

Overall Survival

In the dMMR subgroup, there were a total of ██ ███████ deaths in the SOC arm and ███████ deaths in the SOC plus durvalumab arm. The median OS in the SOC arm was ████ months (95% CI, ███ ██████████), while the median OS was ███ ██████████ in the SOC plus durvalumab arm (HR, ████; 95% CI, ████ ██ ████, in favour of durvalumab). The risk difference between study arms for the proportion of patients who were alive was ████% (95% CI, █████ ██ █████) at 6 months; ████% (95% CI, ████ ██ ████) at 12 months; and ████% (95% CI, ████ ██ █████) at 18 months.

Objective Response Rate

In the dMMR subgroup, a total of ██ ███████ patients had a response out of ██ patients with measurable disease at baseline in the SOC arm, and ██ ███████ patients had a response out of ██ patients with measurable disease at baseline in the SOC plus durvalumab arm. The OR for response was ████ ████ ███ ████ ██ ████ in favour of durvalumab.

Duration of Response

In the dMMR subgroup in the SOC arm, ███████ patients out of the ██ patients who experienced a response subsequently died or experienced disease progression. The median DOR (measured from the onset of response) was ████ months. Out of the ██ patients in the SOC plus durvalumab arm who experienced a response, ████████ patients subsequently died or experienced disease progression; the median DOR was not calculable. The difference between study arms for the proportion of patients who continued to experience a response was █████ (95% CI, █████ ██ █████) at 6 months, █████ (95% CI, █████ ██ █████) at 12 months, and █████ (95% CI, ████% to ████%) at 18 months.

Time to Treatment Discontinuation or Death

In the dMMR subgroup, 37 patients (75.5%) in the SOC arm and 22 patients (47.8%) in the SOC plus durvalumab arm had an event of treatment discontinuation or death (HR = 0.47; 95% CI, 0.27 to 0.79 in favour of durvalumab).

Table 18: Summary of Survival Analysis Results From the DUO-E Study — dMMR Subgroup

CI = confidence interval; CR = complete response; dMMR = mismatch repair deficient; DOR = duration of response; HR = hazard ratio; ITT = intention to treat; NR = not reported; OR = odds ratio; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumours; SOC = standard of care (carboplatin + paclitaxel); TDT = time to study treatment discontinuation or death; vs. = versus.

^aA multiple-testing procedure was applied to the analysis of PFS and OS for the ITT population; however, this procedure was not applied to the analysis of the data from the dMMR subgroup.

^bThe HR and CI were estimated from an unstratified Cox proportional hazards model. An HR of less than 1 favoured the treatment arm of interest over the reference arm.

^cIncludes patients with unknown survival status and patients who were lost to follow-up.

^dCalculated as the time from the first confirmed CR or PR until either the date of progression or the date of censoring for PFS.

^eAny patient not known to have died and not known to have discontinued all investigational treatments was censored at the last recorded date on which the patient was known to be alive.

Source: Details included in the table are from the sponsor’s summary of clinical evidence and additional information provided by the sponsor.²³

HRQoL Outcomes

Details of the HRQoL results are presented in Table 19.

EORTC QLQ-C30 Global Health Score

In the dMMR subgroup, the mean baseline score was █████ points (SD = █████) in the SOC arm and █████ points (SD = █████) in the SOC plus durvalumab arm. At week 18 (corresponding to the sixth cycle of the chemotherapy phase), the mean change in score from baseline was ██████ points (SD = █████) in the SOC arm (N = ██) and █████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was █████ points (95% CI, ██████ to ████). At week 42 (corresponding to the sixth month of the maintenance phase), the mean change in scores from baseline was ██████ points (SD = █████) in the SOC arm (N = ██) and ████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was █████ points (95% CI, ████ to █████).

EORTC QLQ-EN24 Pain in Back and Pelvis Score

In the dMMR subgroup, the mean baseline score was █████ points (SD = █████) in the SOC arm and █████ points (SD = █████) in the SOC plus durvalumab arm. At week 18, the mean change in score from baseline was ████ points (SD = █████) in the SOC arm (N = ██), and ████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was ████ points (95% CI, █████ to █████). At week 42, the mean change in scores from baseline was █████ points (SD = █████) in the SOC arm (N = ██), and ████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was ████ points (95% CI, █████ to █████).

EORTC QLQ-EN24 Urological Symptoms Score

In the dMMR subgroup, the mean baseline score was █████ points (SD = █████) in the SOC arm and █████ points (SD = █████) in the SOC plus durvalumab arm. At week 18, the mean change in score from baseline was ████ points (SD = █████) in the SOC arm (N = ██) and −████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was ████ points (95% CI, █████ to █████). At week 42, the mean change in scores from baseline was ████ points (SD = █████) in the SOC arm (N = ██) and ████ points (SD = █████) in the SOC plus durvalumab arm (N = ██). The absolute mean difference between study arms was ████ points (95% CI, █████ to ████).

Table 19: Summary of HRQoL Results From the DUO-E Study — dMMR Subgroup

CI = confidence interval; dMMR = mismatch repair deficient; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-EN24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Endometrial Cancer Module; HRQoL = health-related quality of life; SD = standard deviation; SOC = standard of care (carboplatin + paclitaxel or substitutes).

^aCorresponds to cycle 6 of the chemotherapy phase.

^bAfter the chemotherapy phase, the assessment of outcomes shifted from every 3 weeks to every 4 weeks; week 42 corresponds to the sixth month of the maintenance phase.

Sources: Details contained in the table are from the sponsor’s summary of clinical evidence²² and additional information provided by the sponsor.⁶⁹

Harms

Results for harms from both the chemotherapy and maintenance phases (overall phase) and maintenance phase alone of the DUO-E trial, specifically in the dMMR subgroup, are summarized subsequently and in Table 20. Harms data for the entire ITT population of the DUO-E trial are presented in the Appendix.

Adverse Events

In the dMMR subgroup, all patients in each study arm experienced an AE during the DUO-E trial. A total of ████% of patients in the SOC arm and ████% of patients in the SOC plus durvalumab arm experienced an AE with a maximum grade of 3 or 4. The most common AEs were nausea (████% of patients in the SOC plus durvalumab arm, ████% of patients in the SOC arm), alopecia (████% in the SOC plus durvalumab arm, ████% in the SOC arm), arthralgia (████% in the SOC plus durvalumab arm, ████% in the SOC arm), and anemia (████% in the SOC plus durvalumab arm, ████% in the SOC arm).

There were differences between study arms in the proportion of patients with several AEs. Of note, a numerically higher proportion of patients in the SOC plus durvalumab arm reported nausea (████% versus ████% in the SOC arm), alopecia (████% versus ████% in the SOC arm), alopecia (████% versus ████% in the SOC arm), arthralgia (████% versus ████% in the SOC arm), hypomagnesemia (████% versus ████% in the SOC arm), cough (████% versus 15.2% in the SOC arm), peripheral neuropathy (████% versus ████% in the SOC arm), dyspnea (████% versus ███% in the SOC arm), and injury, poisoning or procedural complications (████% versus ████%). A numerically higher proportion of patients in the SOC arm reported anemia (████% versus ████% in the SOC plus durvalumab arm), fatigue (████% versus ████% in the SOC plus durvalumab arm), peripheral sensory neuropathy (████% versus ████% in the SOC plus durvalumab arm), decreased appetite (████% versus ████% in the SOC plus durvalumab arm), neutrophil count decreased (████% versus ████% in the SOC plus durvalumab arm), and neutropenia (████% versus ████% in the SOC plus durvalumab arm).

Serious Adverse Events

In the dMMR subgroup, a total of ████% of patients in the SOC arm and ████% in the SOC plus durvalumab arm experienced an SAE during the DUO-E trial. The most common SAEs were as follows: gastrointestinal disorders (████% in the SOC plus durvalumab arm consisting of ███████ reports of fecaloma, ███████ report each of abdominal hernia, colitis, intestinal obstruction and nausea, and ███% in the SOC arm consisting of ███████ report each of diarrhea, nausea, and vomiting), blood and lymphatic system disorders (████% in the SOC arm consisting of ███████ reports of anemia, ███████ reports of febrile neutropenia, and ███████ reports of neutropenia, and ███% in the SOC plus durvalumab arm consisting of 1 report of autoimmune hemolytic anemia), infections and infestations (███% in the SOC arm consisting of ███████ report each of COVID-19, neutropenic sepsis, urinary tract infection and urosepsis, and ███% in the SOC plus durvalumab arm consisting of ███████ report each of appendicitis, gastroenteritis, and sepsis), and renal and urinary disorders (███% in the SOC arm consisting of ███████ report each of acute kidney injury, renal failure, ureteric obstruction and urinary bladder hemorrhage, and ███████% in the SOC plus durvalumab arm).

Withdrawals Due to Adverse Events

In the dMMR subgroup. a total of ████% of patients experienced AEs leading to the withdrawal of durvalumab in the SOC plus durvalumab arm, and ████% reported this in the SOC arm. In the SOC plus durvalumab arm, the reasons for discontinuation were anemia, interstitial lung disease, maculopapular rash, symmetric drug-related intertriginous and flexural exanthema, fatigue, and procedural pain (each reported in ██ patient) In the SOC arm, the reasons for discontinuation of durvalumab placebo were anemia (2 patients), cerebrovascular accident, tinnitus, and asthenia (each reported in ██ patient). A total of ██% of patients in the SOC plus durvalumab arm and ██% of patients in the SOC arm experienced an AE leading to discontinuation of SOC.

Mortality

In the dMMR subgroup, a total of ██ patients (██%) died in the SOC arm and ███ patients (██%) died in the SOC plus durvalumab arm. The submission did not provide details on the specific causes of death in patients in the dMMR subgroup.

Notable Harms

Immune-mediated AEs (exact conditions not specified) and infusion reactions were identified by the clinical experts consulted for this review as AESIs. In the dMMR subgroup, ██% of patients experienced an immune-mediated AE in the SOC plus durvalumab arm and ██% experienced this in the SOC arm. A total of ███% of patients experienced infusion reactions in the SOC plus durvalumab arm versus ██% of patients in the SOC arm.

A total of ██% of patients in the SOC plus durvalumab arm and ███% of patients in the SOC arm experienced 1 of the AESIs that had been identified by the clinical experts for this review. The most common AEs in both arms were diarrhea (██% in the SOC plus durvalumab arm, ██% in the SOC arm) and rash (███% in the SOC plus durvalumab arm, ██% in the SOC arm). Hypothyroidism (██% of patients) was the next most common reason in the SOC plus durvalumab arm, and hyperthyroidism (██% of patients) the next most common reason in the SOC arm.

Table 20: Summary of Harms Results From the DUO-E Study — dMMR Subgroup

AE = adverse event; dMMR = mismatch repair deficient; ECOG = Eastern Cooperative Oncology Group; NR = not reported; SAE = serious adverse event; SOC = standard of care.

^aPatients with multiple AEs in the same category were counted only once for that preferred term. Patients with AEs in more than 1 category were counted once in each of these categories.

^bPatients with multiple AEs leading to discontinuation of any study treatment or SOC were counted once for each system organ class.

^cDeath not due to disease progression.

Sources: Details included in the table are from the sponsor’s summary of clinical evidence²² and additional information provided by the sponsor.²³

Critical Appraisal

Internal Validity

The DUO-E trial is an ongoing phase III trial assessing the efficacy and safety of durvalumab plus SOC compared with SOC alone in the treatment of primary advanced or recurrent endometrial cancer. Included in the submission was an IA containing results up to the data cut-off on April 13, 2023. The randomization, allocation concealment, and laboratory assessments were at low risk of bias because randomization was stratified and conducted centrally using an IVRS or interactive web response system, and placebo descriptions were provided. Likewise, the outcome ascertainment methods were at low risk of bias because the time-to-event outcomes were assessed by investigator; although BICR results were not available for the subgroups to compare, the impact is likely minimal. Blinding was likewise continued for the duration of the study; therefore, the impact on subjective outcomes (i.e., the HRQoL measures) was likely minimal. However, there were numerically higher numbers of patients in the SOC arm who discontinued treatment relative to the SOC plus durvalumab arm, which suggests the possibility that patients may have become unblinded to their treatment arm and discontinued treatment more readily than those in the SOC plus durvalumab arm. As part of the study design, patients with no evidence of progressive disease during the 6-cycle chemotherapy phase were eligible to proceed to the maintenance phase. Results separating the efficacy outcomes in the chemotherapy and maintenance phases were not provided; thus, the impact of the chemotherapy phase versus the maintenance phase individually on response to treatment remains unknown.

There are several limitations to note regarding the study design and the statistical model. First, the design of the DUO-E study comprised 3 study arms that contained patients with either dMMR and pMMR endometrial cancer. However, given the Health Canada indication and reimbursement request, the focus of this review is based on a subgroup of patients with dMMR endometrial cancer. Therefore, all results focusing on the dMMR subgroup can only be considered exploratory and supportive of the overall effect of durvalumab. Furthermore, the subgroup was not controlled for multiple comparisons and there is an increased risk of type I error, which is particularly important, given that the sample sizes in each study arm were small. Second, the study protocol was amended numerous times after patient enrolment started and, although the level of potential impact of these protocol changes was considered low based on the feedback from the clinical experts, the potential for bias due to these changes is unknown.

Results from the DUO-E trial were from an IA, and the P value cut-off for the IA of the subgroups themselves is not known; this carries an increased risk of overestimating the true effect. While the primary end point was reached for the ITT population, the median PFS and OS were not estimable for the dMMR subgroup in the respective analyses. In the ITT population, this analysis was based on an information fraction of 61.0% while, in the dMMR subgroup, only ████% of PFS events had occurred, suggesting the data were immature, particularly for OS. Lastly, the analysis for PFS, OS, and TDT in the subgroup was undertaken using an unstratified Cox proportional hazards model; an unstratified logistic regression model was used for ORR. While randomization was stratified on MMR status, disease status, and region, which are known effect modifiers described in the submission, these were not accounted for in the time-to-event analysis and might have impacted PFS, OS, ORR, and TDT outcome estimates. As such, there is increased uncertainty in the PFS and OS results, and it is therefore unclear how confidently the long-term results associated with durvalumab can be predicted.

There are additional limitations specific to the HRQoL measures reported in the DUO-E study. HRQoL end points were secondary in the DUO-E trial and the results were not adjusted for multiplicity; thus, there is an increased risk of type I error. In addition, the baseline estimates and the estimates at weeks 18 and 42 have a substantial amount of missing data (N = ██ patients in the SOC arm and ██ patients in the SOC plus durvalumab arm contributed data at 18 weeks; ██ patients in the SOC arm and ██ patients in the SOC plus durvalumab arm contributed data at 42 weeks). The end points were analyzed using a mixed model for repeated measures, which assumes that the missing data are missing at random; however, given the nature of the disease and design of the trial, the missing patient data are likely missing due to reasons related to the interventions; therefore, the missing-at-random assumption is not appropriate. The nature of the disease also means that, because patients are censored at disease progression or death, among other reasons, it is likely that these patients are systematically different from the patients included in the analysis; thus, there is also a likelihood of bias in the results. Furthermore, missing answers in the surveys were ignored and this imparts an additional risk of bias because the completeness of the survey responses was not reported. Lastly, there were no validation studies or MIDs identified specific to endometrial cancer; therefore, a direct assessment of the clinical meaningfulness of the HRQoL results was not possible.

External Validity

Per the clinical experts, the inclusion and exclusion criteria were broadly representative of patients who would be candidates for durvalumab. However, the results of patient screening were not available for the dMMR subgroup; therefore, the reasons for study failure and the distribution of screening failures between study arms is not known, so it is unclear whether there are systematic differences between the patients who passed screening and those who did not. Similarly, the exact causes of death in participants who died during the study were not reported, and it is therefore not known whether there are systematic differences between the patients who died and those who did not.

The clinical experts noted that, for the dMMR subgroup, the numeric differences in baseline patient characteristics that occurred would not be of great clinical importance, apart from the fact that the definition of “locally advanced disease” versus “metastatic disease” was not provided in the submission, and further noted that classifications within these disease categories may vary between clinicians. They also noted that patients with an ECOG status greater than 1 were not included in the trial; however, these patients would likely be considered for treatment with durvalumab in clinical practice. Apart from this, the study did not assess whether other molecular subtypes (e.g., POLE mutated, HER expression, p53 mutated) would have an impact on the results observed. The clinical experts noted that additional molecular classifications are usually undertaken in clinical practice and that a proportion of patients with dMMR cancer do not experience a response to current ICI therapy, the reason for which is not always clear. Therefore, it is possible the same nonresponder population may also exist for patients treated with durvalumab.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the 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:^20,21

• 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 refer 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; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty-of-evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. For the PFS and OS outcomes, the target of the assessment was the presence or absence of an important effect based on thresholds provided by the clinical experts. For the HRQoL outcomes, the target of the assessment was the presence or absence of any effect based on a null threshold.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for durvalumab plus carboplatin and paclitaxel followed by durvalumab maintenance therapy versus carboplatin and paclitaxel alone in patients with recurrent endometrial cancer that is dMMR.

Long-Term Extension Studies

The submission did not contain any long-term extension studies.

Indirect Evidence

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

Objectives for the Summary of Indirect Evidence

The DUO-E trial included SOC chemotherapy (carboplatin and paclitaxel) but did not include a comparison with dostarlimab, a relevant first-line comparator for patients with dMMR endometrial cancer, and information from indirect comparisons were included in the pharmacoeconomic model. Therefore, a review of the indirect evidence was undertaken.

Description of Indirect Comparisons

The body of indirect evidence consisted of 2 sponsor-submitted MAICs. Details of the study selection criteria and methods are presented in Table 21.

Indirect Treatment Comparison Design

Objectives

The objective of the MAIC was to assess the comparative efficacy and safety of durvalumab plus chemotherapy followed by maintenance durvalumab monotherapy, relative to dostarlimab plus chemotherapy, followed by maintenance dostarlimab in patients with dMMR and/or MSI-H advanced endometrial cancer.

Table 21: Study Selection Criteria and Methods for the SLR Informing the MAIC

AUC = area under the curve; dMMR = mismatch repair deficient; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30; EORTC QLQ-EN24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Endometrial Cancer Module; FACT-G = Functional Assessment of Cancer Therapy–General; HRQoL = health-related quality of life; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; MMR = mismatch repair; mTOR = mammalian target of rapamycin; OS = overall survival; PARP = poly(adenosine diphosphate ribose) polymerase; PFS = progression-free survival; PFS2 = progression-free survival from time from randomization to the earliest progression event; pMMR = mismatch repair proficient; RCT = randomized controlled trial; ROBINS-I = Risk of Bias in Non-randomised Studies of Interventions; SF-36 = Short Form (36) Health Survey; SF-6D = Short Form 6 Dimensions; SLR = systematic literature review; SOC = standard of care; VAS = visual analogue scale.

Source: Details included in the table are from the sponsor’s summary of clinical evidence.²²

Study Selection Methods

Details of the methods used for study selection are in Table 21. In summary, an SLR was conducted focusing on systemic anticancer treatments and excluded all other therapies. The patient population of interest comprised those newly diagnosed with stage III or IV disease or recurrent disease who were either naive to first-line therapy or had been treated with 1 prior line of chemotherapy. The submission did not provide details on the date when the SLR was conducted, the range of publication dates that was used in the search terms, or the search terms used.

MAIC Analysis Methods

Details of the analysis methods for the MAIC are presented in Table 22. Briefly, an anchored MAIC was performed using a frequentist approach and Bucher methodology. The treatment effects for the 2 efficacy outcomes, PFS and OS, were reported as an HR and associated 95% CI for SOC plus durvalumab versus SOC plus dostarlimab, with an HR of less than 1 favouring SOC plus durvalumab. For safety end points, ORs were calculated for SOC plus durvalumab versus SOC plus dostarlimab, with ORs of less than 1 favouring SOC plus durvalumab. ORs were estimated from AE frequency data and the number of patients included in the safety analysis sets.

Table 22: MAIC Analysis Methods

MAIC = matching-adjusted indirect comparison; NICE DSU = National Institute for Health and Care Excellence Decision Support Unit; OS = overall survival; PFS = progression-free survival; SOC = standard of care.

Source: Details included in the table are from the sponsor’s summary of clinical evidence²² and the MAIC technical report.⁷¹

Results of MAIC

Summary of Included Studies

The submission did not provide a PRISMA diagram of results from the SLR but reported that the SLR identified 2 phase III double-blind, placebo-controlled RCTs relevant to the indirect treatment comparison: the DUO-E and RUBY Part 1 studies. A summary of key study characteristics is in Table 23. Briefly, differences were noted in the median duration of follow-up as well as the molecular characteristics of patients; the primary analysis for the MAICs used data from the post hoc subgroup of the DUO-E study, which contained only patients with dMMR and/or MSI-H cancer (and therefore could contain patients with MSI-H pMMR endometrial cancer), and the main analysis in the RUBY Part 1 study enrolled patients who had either dMMR or MSI-H tumours.

Table 23: Summary of Key Study Characteristics for the DUO-E and RUBY Part 1 Trials

AUC = area under the curve; BICR = blinded independent central review; dMMR = mismatch repair deficient; ECOG = Eastern Cooperative Oncology Group; FIGO = International Federation of Gynecology and Obstetrics; MAIC = matching-adjusted indirect comparison; MMR = mismatch repair; MSI-H = microsatellite instability-high; OS = overall survival; PFS = progression-free survival; q.3.w. = every 3 weeks; vs. = versus.

Source: Details included in the table are from the sponsor’s summary of clinical evidence²² and MAIC technical report.⁷¹

Results

The base case of the MAIC for PFS matched on the following variables: region (Asia versus rest of world) and disease status. The summary of select baseline characteristics before and after matching is in Table 24. Of note, after the matching procedure, minor differences remained in the proportion of patients who were Black or African American (███% in the DUO-E trial after weighting and 8.5% in the RUBY Part 1 study), and the proportion of patients who were aged 65 years or older (████% in the DUO-E trial after weighting and 49.2% in the RUBY Part 1 study).

Table 24: Summary of Baseline Characteristics Before and After Matching — DUO-E and RUBY Part 1 Studies

ECOG = Eastern Cooperative Oncology Group; MAIC = matching-adjusted indirect comparison.

Sources: Details included in the table are from the sponsor’s summary of clinical evidence²² and MAIC technical report.⁷¹

Detailed MAIC results for the efficacy end points are presented in Table 25. Briefly, the results for PFS from the anchored, weighted MAIC and the results of OS using the anchored, unweighted MAIC suggested there was insufficient evidence to detect a difference between durvalumab plus SOC and dostarlimab plus SOC. The harms results from the anchored, unweighted MAIC also suggested there was insufficient evidence to detect a difference between durvalumab plus SOC and dostarlimab plus SOC for AEs leading to discontinuation and any SAEs. However, durvalumab plus SOC was favoured over dostarlimab plus SOC for grade 3 or greater AEs.

Critical Appraisal of MAIC

The body of indirect evidence consisted of 2 MAIC analyses informed by an SLR. The procedures as described for screening, data extraction, and the quality assessment steps used were considered generally accepted methods. However, the date on which the SLR was undertaken was not provided, and it is not known whether the most recent publications on any relevant comparators would have been captured in the search. In addition, the search terms were not provided in the submission and there was no description of the numbers of papers retrieved, screened, or extracted. As such, the results from the SLR, including the steps leading to the selection of the comparator study, are not known. Lastly, while the number of reviewers and steps for the assessment of study quality were conducted using generally accepted methods, the submission did not provide the results of the quality assessment; therefore, the risk of bias in the studies is not known. Because both the DUO-E and RUBY Part 1 studies were phase III trials, the risk of bias may be lower; however, the results of the MAIC analyses was based on subgroups from these trials, so the potential for bias remains.

Table 25: MAIC Results