Drugs, Health Technologies, Health Systems
Indication: In combination with carboplatin and paclitaxel for first-line treatment of adult patients with primary advanced or recurrent mismatch repair deficient endometrial cancer who are candidates for systemic therapy followed by maintenance treatment with Imfinzi as monotherapy
Sponsor: AstraZeneca Canada Inc.
Final recommendation: Reimburse with conditions
Summary
What Is the Reimbursement Recommendation for Imfinzi?
Canada’s Drug Agency (CDA-AMC) recommends that Imfinzi in combination with carboplatin and paclitaxel be reimbursed by public drug plans for the treatment of primary advanced or recurrent mismatch repair deficient (dMMR) endometrial cancer in patients who are candidates for systemic therapy, if certain conditions are met.
Which Patients Are Eligible for Coverage?
Imfinzi in combination with carboplatin and paclitaxel should only be covered to treat adult patients with primary advanced or recurrent stage III or IV endometrial cancer whose disease has returned after initial treatment and who have not previously received systemic anticancer therapy for advanced disease or have not received prior adjuvant systemic anticancer therapy at least 6 months from the date the last dose was administered to the date of subsequent relapse. Eligible patients should have confirmed dMMR tumour status before starting treatment with Imfinzi and have a good performance status.
What Are the Conditions for Reimbursement?
Imfinzi should only be reimbursed in combination with carboplatin and paclitaxel if it is prescribed by clinicians with expertise in advanced uterine cancer, and treatment should be supervised and delivered in institutions with expertise in systemic therapy delivery. The total cost of durvalumab plus carboplatin and paclitaxel should be negotiated so that it does not exceed the total drug program cost associated with dostarlimab plus carboplatin and paclitaxel.
Why Did CDA-AMC Make This Recommendation?
Evidence from a clinical trial suggested that treatment with Imfinzi in combination with carboplatin and paclitaxel may extend life and delay cancer progression compared to carboplatin and paclitaxel alone.
Imfinzi in combination with carboplatin and paclitaxel may meet some important patient needs by providing another treatment option that prolongs life and delays disease progression; however, there was not enough evidence to show that Imfinzi would improve quality of life.
The effect of Imfinzi on survival and safety compared to dostarlimab was uncertain based on evidence from 1 indirect treatment comparison.
Based on the CDA-AMC assessment of the health economic evidence, Imfinzi does not represent good value to the health care system at the public list price. The committee determined that there is insufficient evidence to justify a greater total treatment cost for Imfinzi compared with dostarlimab plus standard of care (SOC).
Based on public list prices, Imfinzi is estimated to cost the public drug plans approximately $28 million over the next 3 years.
Additional Information
What Is Endometrial Cancer?
Endometrial cancer is a cancer of the lining of the uterus; dMMR tumours have cells that are unable to repair certain genes properly. In stage III and IV endometrial cancer, the cancer has grown and spread to the bladder, bowel, or other body parts. In Canada, it was estimated that 8,600 women would be diagnosed with uterine cancer in 2024 and 1,600 women would die of the disease.
Unmet Needs in Endometrial Cancer
There is an unmet need for treatment options that extend life, delay symptoms, maintain quality of life, and have fewer side effects.
How Much Does Imfinzi Cost?
Treatment with Imfinzi is expected to cost approximately $13,996 per 21-day cycle in the chemotherapy phase, and $11,733 per every 28-day cycle in the maintenance phase.
The pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that durvalumab be reimbursed in combination with carboplatin and paclitaxel for the first-line treatment of adult patients with primary advanced or recurrent dMMR endometrial cancer who are candidates for systemic therapy, followed by maintenance treatment with durvalumab as monotherapy only if the conditions listed in Table 1 are met.
One phase III, double-blind, placebo-controlled trial (DUO-E; N = 718) evaluated the efficacy and safety of durvalumab in combination with carboplatin and paclitaxel followed by durvalumab maintenance, compared with placebo plus carboplatin and paclitaxel followed by placebo maintenance in patients with primary advanced or recurrent endometrial cancer. A subgroup of patients in the DUO-E trial (N = 95) aligned with the indication under review: adults with primary advanced or recurrent dMMR endometrial cancer who are candidates for systemic therapy. Subgroup analyses suggested that, compared with placebo plus carboplatin and paclitaxel, durvalumab plus carboplatin and paclitaxel may improve median overall survival (OS) (███ ███████ ███ ████ ██████; hazard ratio [HR] = 0.34; 95% confidence interval [CI], 0.13 to 0.79), and median progression-free survival (PFS) (not reached versus 7.0 months; HR = 0.42; 95% CI, 0.22 to 0.80). However, the magnitude of the results was uncertain due to the immaturity of the data, small sample size, and imprecision in the estimates (wide CIs). Additional analyses of OS at the 12-month (█████ ███ █████) and 18-month (█████ ███ █████) landmarks were supportive of the potential survival advantage demonstrated by durvalumab plus carboplatin and paclitaxel in this subgroup. The sponsor-submitted indirect evidence comparing durvalumab plus carboplatin and paclitaxel to dostarlimab plus carboplatin and paclitaxel suggested that there was insufficient evidence to detect a difference between the 2 treatments; however, significant limitations impacted the validity and certainty of the results, which precluded pERC from drawing conclusions on the comparative efficacy and safety of durvalumab versus dostarlimab. pERC also considered the safety profile of durvalumab plus carboplatin and paclitaxel to be manageable with no unexpected toxicities.
Patients identified a need for new effective and accessible treatment options that prolong survival, delay the onset of symptoms, maintain quality of life, and have fewer side effects. pERC concluded that durvalumab plus carboplatin and paclitaxel may meet some patients’ needs because it offers a new treatment that may delay disease progression and improve survival compared to carboplatin plus paclitaxel. Based on exploratory analyses, the addition of durvalumab to carboplatin and paclitaxel did not suggest a detriment in health-related quality of life (HRQoL) from baseline to week 18 and week 42; however, results for HRQoL were inconclusive due to high attrition rates.
Using the sponsor-submitted price for durvalumab and publicly listed prices for all other drug costs, durvalumab plus carboplatin and paclitaxel was more costly and less effective than dostarlimab plus carboplatin and paclitaxel in adult patients with primary advanced or recurrent dMMR endometrial cancer who are candidates for systemic therapy. Given that the indirect evidence did not support a difference in outcomes between these 2 treatments, there is insufficient evidence to justify a price premium for durvalumab.
Table 1: Reimbursement Conditions and Reasons
Reimbursement condition | Reason | Implementation guidance |
|---|---|---|
Initiation | ||
1. Treatment with durvalumab plus carboplatin and paclitaxel should be reimbursed in adult patients (aged 18 years or older) with primary advanced or recurrent dMMR endometrial cancer who meet at least 1 of the following criteria: 1.1. Newly diagnosed stage III or IV endometrial cancer 1.2. Have a first recurrence and have not previously received systemic anticancer therapy for advanced disease 1.3. Have received prior adjuvant systemic anticancer therapy at least 6 months from the date of last dose administered to the date of subsequent relapse. | Evidence from the dMMR subgroup from the DUO-E trial suggested that treatment with durvalumab plus carboplatin and paclitaxel resulted in a clinical benefit in patients with these characteristics. | MMR status must be determined before starting treatment with durvalumab. |
2. Patients should have good performance status. | Patients with an ECOG performance status of 0 or 1 were included in the DUO-E trial. | Treating patients with an ECOG performance status of 2 may be at the discretion of the treating clinician. |
3. Patients must not have any of the following: 3.1. Relapse within 6 months of completing adjuvant systemic anticancer therapy 3.2. Prior therapy with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 drug for advanced disease 3.3. Uncontrolled CNS metastases. | There is no evidence to support the benefit of durvalumab plus carboplatin and paclitaxel in patients with these characteristics because they were excluded from the DUO-E trial. | — |
Discontinuation | ||
4. Treatment should be discontinued upon the occurrence of any of the following: 4.1. Objective disease progression 4.2. Unacceptable toxicity. | Patients in the DUO-E trial discontinued treatment upon progression or unacceptable toxicity consistent with clinical practice. | — |
Prescribing | ||
5. Durvalumab (plus carboplatin and paclitaxel, as applicable) should be prescribed by clinicians with expertise in advanced uterine cancer; treatment should be supervised and delivered in institutions with expertise in systemic therapy delivery. | This will ensure that treatment is prescribed only for appropriate patients and adverse effects are managed in an optimized and timely manner. | — |
6. Durvalumab plus carboplatin and paclitaxel should only be reimbursed when started in combination. | In the DUO-E trial, durvalumab was initiated in combination with carboplatin and paclitaxel. | — |
Pricing | ||
7. The total cost of durvalumab plus carboplatin and paclitaxel should be negotiated so that it does not exceed the total drug program cost associated with dostarlimab plus carboplatin and paclitaxel for the treatment of adult patients with primary advanced or recurrent dMMR endometrial cancer who are candidates for systemic therapy. | The findings of the indirect evidence suggested a similar clinical benefit in OS and PFS when comparing durvalumab plus carboplatin and paclitaxel to dostarlimab plus carboplatin and paclitaxel. In the economic evaluation, durvalumab plus chemotherapy was more costly and less effective (i.e., produced fewer QALYs) than dostarlimab plus chemotherapy (i.e., durvalumab was dominated). Patients treated with durvalumab will continue to receive it until disease progression or unacceptable toxicity. Patients treated with dostarlimab will discontinue treatment after 3 years. Consequently, identical drug pricing for durvalumab and dostarlimab will result in increased drug spending in patients who remain progression-free for longer than 3 years. | — |
CNS = central nervous system; dMMR = mismatch repair deficient; ECOG = Eastern Cooperative Oncology Group; MMR = mismatch repair; OS = overall survival; QALY = quality-adjusted life-year.
Unmet need: pERC discussed the input from patient and clinician groups as well as the clinical experts, all of whom consider prolonged survival to be the most important outcome that new treatments for advanced or recurrent endometrial cancer should address, given the poor prognosis and high proportion of patients who do not respond to current first-line treatments. pERC agreed that there is an unmet need for effective and safe therapeutic options in the requested population and noted that the addition of durvalumab to carboplatin and paclitaxel may address these needs relative to carboplatin and paclitaxel alone. However, pERC was unable to ascertain whether durvalumab plus carboplatin and paclitaxel met the unmet needs identified, versus dostarlimab plus carboplatin and paclitaxel, due to a lack of direct comparative evidence and limitations associated with the submitted indirect evidence. The clinical experts also emphasized that there is no evidence to choose one immune checkpoint inhibitor (ICI) over another.
Certainty of evidence: pERC discussed that the focus of the pivotal evidence submitted for this review consisted of a prespecified subgroup of patients with dMMR status from 1 phase III randomized controlled trial (RCT) (DUO-E); however, the analysis was not preplanned, and the sample sizes were small. As such, the committee only considered the results supportive of the overall effect of durvalumab. pERC also discussed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment for durvalumab plus carboplatin and paclitaxel compared to carboplatin and paclitaxel alone, in which the certainty of evidence was rated as low or very low for all outcomes primarily due to the use of the subgroup and the immaturity of the results (median PFS and OS for the durvalumab group were not reached; and 51.0% versus 32.6% and █████ versus █████ of patients in SOC and durvalumab plus carboplatin and paclitaxel arms experienced PFS or OS events, respectively). Despite the nature of the analyses, pERC acknowledged that the results from the dMMR subgroup in the DUO-E trial were considered compelling, as noted by the clinical experts, and were supportive of a potential survival advantage for durvalumab plus carboplatin and paclitaxel over SOC.
Indirect evidence: pERC discussed the indirect evidence submitted for this review, which consisted of matching-adjusted indirect comparisons (MAICs) comparing durvalumab to dostarlimab, which is the most relevant comparator in the Canadian clinical setting. The results of the MAICs suggested that there was ██ ██████████ ██ ███ ███████ ███ █ █████████ ████████ █████ ██ ████████ ████ ███████ █████████ ███ ████ ████ ███ ████ ██ ███████ however, the results were uncertain given the reduced sample size and the wide 95% CI. pERC also noted that the evidence on OS and harms was based on an unweighted indirect comparison and was, therefore, considered exploratory, though it was generally consistent with the analysis for PFS. Overall, pERC emphasized the limitations of the MAIC analyses, highlighting the clinical and methodological heterogeneity between the DUO-E and RUBY Part 1 trials, including differences in patient populations before and after the matching procedure, differences in follow-up and treatment duration, as well as the quality of evidence across studies with respect to data immaturity, the use of subgroups, and analysis methods within the trials, which precluded pERC from drawing conclusions on the comparative efficacy of durvalumab.
Testing procedure considerations: pERC noted that MMR testing is currently performed as the SOC for patients with endometrial cancer in Canada and acknowledged that evaluating MMR status before the initiation of durvalumab would be required. pERC also noted that, considering this is already SOC, MMR testing is not anticipated to be an implementation or access barrier.
Price condition: There is insufficient evidence to support a price premium for durvalumab plus carboplatin and paclitaxel over dostarlimab plus carboplatin and paclitaxel, and the economic evaluation suggests that durvalumab is dominated by dostarlimab in this setting. However, given the uncertainty associated with the indirect treatment evidence and the overall finding of similar OS and PFS, and given that durvalumab is associated with higher overall treatment costs, reimbursing durvalumab may provide value to the health care system if the impact on drug plan budgets is similar for these 2 regimens.
Endometrial cancer is a type of uterine cancer originating in the lining of the uterus and is the most common gynecological malignancy, accounting for approximately 95% of uterine cancers. The symptoms of advanced stage (stage III or IV) and recurrent (return following primary treatment) disease are variable but include abnormal vaginal bleeding, pelvic or back pain, the presence of a palpable mass in the lower abdomen, and unintentional weight loss. Patients often experience additional issues like sexual dysfunction, anxiety, depression, and the long-term effects of chemotherapy, all of which further reduce HRQoL. In Canada, the overall 5-year net survival for uterine cancer is 82%, with stage-specific survival rates of 30% for stage III and 15% for stage IV. Endometrial cancer is categorized into microsatellite instability–high (MSI-H), microsatellite instability–low (MSI-L), and microsatellite stable based on MSI testing, and into proficient mismatch repair (pMMR) or dMMR based on mismatch repair (MMR) status. According to the clinical experts consulted by the review team, MMR testing, assessed by immunohistochemistry, is currently performed as the SOC for patients with endometrial cancer in Canada.
Durvalumab has been approved by Health Canada 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 is a fully human, high-affinity, immunoglobulin G1 kappa monoclonal antibody. It is available as an IV infusion, and the dosage recommended in the product monograph is 1,120 mg in combination with carboplatin and paclitaxel every 3 weeks (21 days) for 6 cycles, followed by maintenance with 1,500 mg every 4 weeks as monotherapy until disease progression or unacceptable toxicity.
To make its recommendation, the committee considered the following information:
A review of 1 RCT in patients with newly diagnosed advanced or recurrent endometrial cancer and 1 indirect treatment comparison consisting of 2 MAICs
Patients’ perspectives gathered by 1 patient group, the Colorectal Cancer Resource & Action Network (CCRAN) in collaboration with the Canadian Cancer Survivor Network and HPV Global Action
Input from public drug plans that participate in the reimbursement review process
Two clinical specialists with expertise in diagnosing and treating patients with newly diagnosed advanced or recurrent dMMR endometrial cancer
Input from 2 clinician groups, the Ontario Health (Cancer Care Ontario) Gynecologic Cancer Drug Advisory Committee and the Gynecologic Oncology Society of Canada
A review of the pharmacoeconomic model and report submitted by the sponsor.
One patient group, the 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 the CCRAN to 12 Canadian clinicians in September, 2024, and 17 US-based clinician investigators involved in the DUO-E clinical trial in October, 2024, as well as 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 microsatellite stable endometrial cancer who participated in the DUO-E trial. Also, data from a previous 2023 survey, which resulted in 4 online patient experiences and 6 responses, was used for this input. In the survey, 2 patients reported not having endometrial cancer.
The patient group input highlighted that patients with endometrial cancer face significant inequities, including research underfunding, rising incidence rates particularly among postmenopausal women, and increasing mortality rates despite advancements in oncology. According to the patient group input, a diagnosis of endometrial cancer is profoundly distressing, bringing 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 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 endometrial cancer patients ranked “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 and minimal side effects, whereas a third patient receiving durvalumab treatment in Australia highlighted the positive impact of targeted therapies on their quality of life.
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 respond to the current first-line treatment paradigm; for context, they noted that in general approximately 40% of patients are expected not to respond to chemotherapy, and the duration of response to chemotherapy alone is often very short. The addition of an ICI improves the overall treatment response rate but has the most significant improvement in the duration of response. The unmet needs in patients with dMMR endometrial cancer include better identification of nonresponders, determining the therapy they might respond to, and determining the ideal duration of maintenance treatment in patients who do respond to therapy.
The experts indicated that durvalumab would be an additional first-line option alongside dostarlimab as an ICI option to 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 in which multiple approved options are available, any of them could be offered. If a patient did not respond to ICI therapy, the clinical experts noted it was unlikely they would trial the drug class again; however, if patients had a recurrence more than 12 months after therapy and had responded previously, then re-treatment might be considered.
The clinical experts noted that the DUO-E trial results did not identify specific molecular subtypes of patients (beyond dMMR) that may 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 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.
Two inputs from Ontario Health’s Gynecologic Cancer Drug Advisory Committee (7 clinicians contributed to the input) and 1 from the Gynecologic Oncology Society of Canada (1 clinician contributed to the input) were provided for this review. The Ontario Health input was gathered through conference calls and emails, whereas the Gynecologic Oncology Society of Canada 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, though compassionate access to dostarlimab in combination with chemotherapy is available.
The clinician groups agreed with the experts that the primary treatment goals are to prolong survival, delay disease progression, control symptoms, improve HRQoL, and, when possible, cure the disease. The clinician input also agreed with the experts in that chemotherapy fails to provide a durable response in patients with dMMR endometrial cancer. Both clinician groups aligned with the experts and noted 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 Gynecologic Oncology Society of Canada 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 Gynecologic Oncology Society of Canada 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 are best prescribed by specialist physicians experienced in systemic therapy.
The clinical experts consulted for the review provided advice on the potential implementation issues raised by the drug programs.
Table 2: Responses to Questions From the Drug Programs
Implementation issues | Response |
|---|---|
Relevant comparators | |
The DUO-E trial compared treatment arms (durvalumab with carboplatin + paclitaxel, then maintenance durvalumab and durvalumab with carboplatin + paclitaxel, then maintenance with durvalumab and olaparib) to 6 cycles of carboplatin and paclitaxel chemotherapy. In Canada, carboplatin + paclitaxel is the current standard. At the time of this review, dostarlimab in combination with carboplatin + paclitaxel (for patients with dMMR tumours) has completed pCPA negotiations and is currently at the jurisdictional level to approve funding. Dostarlimab is under review to expand use beyond dMMR to all patients. Pembrolizumab is also under review for the first-line treatment of primary advanced or recurrent endometrial cancer regardless of the MMR status. | This is a comment from the drug programs to inform pERC deliberations. |
In the DUO-E trial, durvalumab maintenance continued until progression or toxicity. Dostarlimab is continued for a maximum of 3 years in this indication. Pembrolizumab is continued for a maximum of 2 years. | This is a comment from the drug programs to inform pERC deliberations. |
Considerations for initiation of therapy | |
MMR testing is not reflexive in all jurisdictions for endometrial carcinoma. Is there a standard definition of dMMR to help define treatment for eligible patients? | The clinical experts noted that MMR testing is reflexive in a majority of care settings, and the standard definition most use would be based on immunohistochemistry. pERC acknowledged and agreed with the clinical experts’ response. |
Can durvalumab be administered with alternate chemotherapy if a patient cannot receive or tolerate carboplatin and/or paclitaxel? | The experts indicated that patients could receive alternate chemotherapy such as single-drug carboplatin, paclitaxel, or another single platinum drug. pERC acknowledged and agreed with the clinical experts’ response. pERC noted that there was insufficient evidence to support combining durvalumab with other chemotherapy regimens other than those used in the DUO-E trial (i.e., carboplatin and paclitaxel). pERC noted that combining durvalumab with other chemotherapy regimens would be outside of the Health Canada indication. |
Patients who received previous systemic therapy were eligible only if previous treatment was in the adjuvant setting and there was ≥ 12 months between the last dose and subsequent relapse. Should patients be eligible for treatment if there was less than 12 months between the last dose of adjuvant therapy and subsequent relapse? | The experts indicated that there is no data for this setting, but they speculated that patients with dMMR endometrial cancer who have a rapid recurrence after platinum-based therapy would probably be treated with immunotherapy. pERC agreed with the clinical experts’ response. |
In the DUO-E trial, patients had to complete a minimum of 4 cycles before being eligible for the maintenance phase. If patients must discontinue carboplatin-paclitaxel before the fourth cycle, should they be considered for maintenance treatment? | The clinical experts indicated that the reason for the discontinuation would be a factor in decision-making, and that it would be a clinical decision. However, patients with dMMR status would likely proceed with maintenance treatment in this scenario. pERC agreed with the clinical experts’ response, noting that if patients do not complete the chemotherapy phase due to toxicity, they could receive maintenance durvalumab if there was no evidence of progression during the chemotherapy phase. |
In the DUO-E trial, treatment was continued until disease progression or unacceptable toxicity. If a patient stopped treatment for a reason other than progression or unacceptable toxicity and then wanted to resume at the time of progression, would they be eligible? If yes, which components of the regimen? | The clinical experts indicated that the reason for stopping treatment initially would be a factor in the decision-making. In this scenario, however, they noted that disease progression or toxicity are the main reasons they do not rechallenge with the same therapy. As such, they likely would resume treatment at the time of progression, though the components of the regimen would depend on when in the treatment the stoppage occurred. For example, the experts noted that if a patient stopped treatment after 1 week, they would likely be considered to be untreated and resume treatment at the beginning. However, if they stopped treatment after 5 cycles, then they could be considered to have received the whole chemotherapy regimen and could be evaluated for maintenance therapy. pERC agreed with the clinical experts’ response. |
If recommended for reimbursement, would it be appropriate to consider aligning the initiation criteria of the drug under review with the initiation criteria for dostarlimab and pembrolizumab in endometrial cancer? | pERC and the clinical experts noted that, in the absence of direct comparative evidence, they consider these treatments to be somewhat equivalent, and therefore, the initiation criteria could be aligned with dostarlimab and pembrolizumab in the same care setting. |
Considerations for continuation or renewal of therapy | |
If there is progression during a “drug holiday,” can treatment be resumed? According to what time frame? | The experts indicated that the reason for the drug holiday would be an important factor in the decision-making for this situation, and this would likely be a patient-specific clinical decision. Examples of factors they would take into consideration included the reason for the holiday, how much treatment the patient had received before the holiday, and after which interval their disease recurred. For example, if a longer interval had elapsed, then the experts would be more likely to consider re-treatment, while a shorter interval may imply a lack of benefit. pERC acknowledged and agreed with the clinical experts’ response. |
Considerations for prescribing of therapy | |
Most jurisdictions use weight-based dosing up to a cap for durvalumab: 15 mg/kg to 20 mg/kg (up to a maximum of 1,500 mg) every 3 weeks in combination with chemotherapy, then 20 mg/kg (up to a maximum of 1,500 mg) every 4 weeks. | This is a comment from the drug plans to inform pERC deliberations. |
Generalizability | |
The exclusion criteria for the DUO-E study excluded patients with ECOG > 1 and patients with sarcomas. Should either of these groups of patients be considered for treatment? | The clinical experts indicated they would likely treat patients with an ECOG status of 2, but there is no data on pure sarcomas, and they would not consider them for this treatment. pERC agreed with the clinical experts’ response. |
Should patients who are currently receiving first-line chemotherapy be eligible to add durvalumab? | pERC and the experts indicated that, should durvalumab become available and the patients otherwise meet the eligibility criteria, they would add durvalumab to their chemotherapy regimen, provided there is no disease progression. |
Should patients currently receiving dostarlimab in combination with chemotherapy be eligible to switch to durvalumab? Should patients currently receiving dostarlimab maintenance be eligible to switch to durvalumab? | The clinical experts indicated that they would not generally switch 1 ICI for another unless data were to become available to support a switch or if there were a contract change in their care centre. In general, if a patient’s disease failed to respond to ICI treatment, they also would not rechallenge with another drug from that treatment class. A treatment change may be considered from durvalumab to a more convenient treatment schedule (every 6 weeks in the maintenance setting — dostarlimab or pembrolizumab), which may improve patient QoL and reduce resource use at the treating centre. pERC agreed with the clinical experts’ response, highlighting that this would only be the case if there was no evidence of disease progression. |
Funding algorithm | |
Durvalumab may change the place in therapy of comparator drugs and may change the place in therapy of drugs reimbursed in subsequent lines. Under what circumstances would durvalumab be chosen over dostarlimab or pembrolizumab if reimbursed in the same line of therapy? | The experts indicated that if all 3 treatments were available, they did not think there would be a compelling reason to use one ICI over another, other than the potential convenience of 6 weekly infusions from agents such as dostarlimab or pembrolizumab. pERC agreed with the clinical experts’ response. |
System and economic issues | |
Confidential prices exist for other treatment options. | These are comments from the drug plans to inform pERC deliberations. |
PAG would like to inform pERC that there is concern about the budget impact of durvalumab in the first-line treatment of all patients with endometrial cancer compared to chemotherapy alone and other ICIs. Dostarlimab continues for up to 3 years, pembrolizumab continues for up to 2 years, and durvalumab would continue until progression or unacceptable toxicity with no maximum cut-off. There is no comparative data to determine whether durvalumab provides a significant advantage over dostarlimab or pembrolizumab. | |
dMMR = mismatch repair deficient; ECOG = Eastern Cooperative Oncology Group; ICI = immune checkpoint inhibitor; MMR = mismatch repair; PAG = provincial advisory committee; pCPA = pan-Canadian Pharmaceutical Alliance; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; QoL = quality of life.
DUO-E is an ongoing phase III, randomized, multicentre, double-blind, placebo-controlled RCT of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or maintenance durvalumab in combination with olaparib in patients with newly diagnosed advanced or recurrent endometrial cancer compared to SOC alone (paclitaxel and carboplatin). Enrolment for the DUO-E trial ended in March 2022; however, treatment and follow-up are still ongoing. In total, 718 patients were randomized 1:1:1 to either SOC (arm A; N = 241), durvalumab plus SOC (arm B; N = 239), or durvalumab plus olaparib plus SOC (arm C; N = 238). Arm A received a chemotherapy phase 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 IV durvalumab placebo IV every 4 weeks plus olaparib placebo tablets twice daily. Arms B and C received the same platinum-based chemotherapy as the SOC arm plus durvalumab for 6 cycles, then arm B received maintenance phase therapy consisting of durvalumab plus olaparib placebo tablets twice daily, whereas arm C received both durvalumab and olaparib. The primary end point of the DUO-E study was PFS, with secondary end points consisting of OS, objective response rate, duration of response, time to discontinuation or death, 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 patients included in arm B of the DUO-E study).
In the dMMR subgroup, there were a total of 25 (51.0%) events in the SOC arm (N = 49 patients) and 15 (32.6%) events in the SOC plus durvalumab arm (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 ███ months (95%, ███ ██ ████), whereas the median PFS was not calculable 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 progression-free was █████ (95% CI, ████ ██ █████) at 6 months; █████ (95% CI, ████ ██ █████) at 12 months; and █████ (95% CI, █████ ██ █████) at 18 months.
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, ███ ██████████), whereas 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.
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) (95% CI) for response was ████ █████ ██ █████ in favour of durvalumab.
In the dMMR subgroup, ███████ patients out of the ██ with a response subsequently progressed or died in the SOC arm. The median duration of response (measured from the onset of response) was ████ months. In the SOC plus durvalumab arm ███████ patients out of the ██ with a response subsequently progressed or died; the median duration of response was not calculable. The difference between study arms for the proportion of patients remaining in response was █████ (95% CI, █████ ██ █████) at 6 months, █████ (95% CI, █████ ██ █████) at 12 months, and █████ (95% CI, █████ ██ █████) at 18 months.
In the dMMR subgroup, 37 (75.5%) patients in the SOC arm and 22 (47.8%) patients 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).
The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) — Core 30 (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, ████ ██ █████).
The EORTC QLQ — Endometrial Cancer Module (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, █████ ██ █████).
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, █████ ██ ████).
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 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).
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 (██ 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.
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.
Immune-mediated AEs (exact conditions not specified) and infusion reactions were identified as AEs of special interest by the clinical experts. 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, and █████ 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 adverse event of special interest for durvalumab. 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.
DUO-E is an ongoing phase III trial assessing the efficacy and safety of durvalumab plus SOC compared to 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 who discontinued treatment in the SOC arm 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 for efficacy outcomes were not provided separately for the chemotherapy and maintenance phases; thus, the impact of the chemotherapy phase versus the maintenance phase individually on response to treatment remains unknown. Due to the design of the DUO-E trial, it included patients with endometrial cancer with both dMMR and pMMR status. However, given the Health Canada indication and reimbursement request, the focus of this review was 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 a type I error, which is particularly important given that the sample sizes in each study arm were small. Results from the DUO-E trial were from an interim analysis, and the P value cut-off for the interim analysis 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 intent-to-treat population, the median PFS and OS were not estimable for the dMMR subgroup in the respective analyses. In the intent-to-treat population, this analysis was based on an information fraction of █████, whereas 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 HRQoL end points, baseline estimates and the estimates at weeks 18 and 42 have a substantial amount of missing data. The end points were analyzed by a mixed model for repeated measures model, which assumes that the missing data are missing at random; however, given the nature of the disease and 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 they are systematically different from patients who are included in the analysis, and 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 and, therefore, the reasons for study failure and the distribution of screening failures between study arms are 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 throughout 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 Eastern Cooperative Oncology Group status greater than 1 were not included in the trial, and 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-, 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 there is a proportion of patients with dMMR cancer who do not respond to current ICI therapy, the reason for which is not always clear. Therefore, it is possible that the same nonresponder population may also exist for patients treated with durvalumab.
For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.
Following the GRADE approach, evidence from RCTs started as having high certainty and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.
When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; 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 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 who were progression-free 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 3: Summary of Findings for Durvalumab in Combination With Carboplatin and Paclitaxel Versus Placebo in Combination With Carboplatin and Paclitaxel for Patients With Primary Advanced or Recurrent dMMR Endometrial Cancer
Outcome and follow-up | Patients (studies), N | Absolute effects (95% CI) | Certainty | What happens | ||
|---|---|---|---|---|---|---|
SOC | SOC + durvalumab | Difference | ||||
Survival outcomes | ||||||
Progression-free survivala | ||||||
Proportion of patients who are progression-free at 12 months Median follow-up: ██ ███ ███ ██████ | | 95 (1 RCT) | ███ ███ ████ █████ ██ ███ ███ █████ | ███ ███ ████ █████ ██ ███ ███ █████ | ███ ███ ████ ████ ██ ███ ███ ████ | Lowd,e | Durvalumab in combination with carboplatin and paclitaxel, followed by durvalumab monotherapy, may result in an increase in the proportion of patients who are progression-free at 12 months when compared to carboplatin and paclitaxel. |
Proportion of patients who are progression-free at 18 months Median follow-up: ██ ███ ███ ██████ | | 95 (1 RCT) | ███ ███ ████ ████ ██ ███ ███ █████ | ███ ███ ████ ████ ██ ███ ███ █████ | ███ ███ ████ ████ ██ ███ ███ ████ | Lowd,e | Durvalumab in combination with carboplatin and paclitaxel, followed by durvalumab monotherapy, may result in an increase in the proportion of patients who are progression-free at 18 months when compared to carboplatin and paclitaxel. |
Overall survivala | ||||||
Proportion of patients who are alive at 12 months Median follow-up: ██ ███ ████ ██████ | | 95 (1 RCT) | ███ ███ ████ ████ ██ ███ ███ █████ | ███ ███ ████ ████ ██ ███ ███ █████ | ███ ███ ████ ███ ██ ███ ███ ████ | Lowf,g | Durvalumab in combination with carboplatin and paclitaxel, followed by durvalumab monotherapy, may result in an increase in the proportion of patients who are alive at 12 months when compared to carboplatin and paclitaxel. |
Proportion of patients who are alive at 18 months Median follow-up: ██ ███ ████ ██████ | | 95 (1 RCT) | ███ ███ ████ ████ ██ ███ ███ █████ | ███ ███ ████ ████ ██ ███ ███ █████ | ███ ███ ████ ███ ██ ███ ███ ████ | Lowf,g | Durvalumab in combination with carboplatin and paclitaxel, followed by durvalumab monotherapy, may result in an increase in the proportion of patients who are alive at 18 months when compared to carboplatin and paclitaxel. |
Health-related quality of lifea | ||||||
EORTC QLQ-C30 Global Health Status Score (100 [best] to 0 [worst])c | ||||||
Change from baseline, points |Follow-up: ██ █████ | 95 (1 RCT) | ██████ ████████ ██ ██████ | ████████ ██ ███ ██ ██████ | ████████ █ ████ ██ █████ | Very lowh,i | The evidence is very uncertain about the effect of durvalumab in combination with carboplatin and paclitaxel followed by durvalumab monotherapy on the change in EORTC QLQ-C30 Global Health Status score from baseline to 18 weeks, when compared with carboplatin and paclitaxel. |
Change from baseline, points Follow-up: ██ █████ | 95 (1 RCT) | ████████ █ █████ ██ ██████ | ████████ █ ██ ██ ██████ | ████████ █ ██ ██ ██████ | Lowi | Durvalumab in combination with carboplatin and paclitaxel, followed by durvalumab monotherapy, may result in an increase in EORTC QLQ-C30 Global Health Status score from baseline to 42 weeks when compared with carboplatin and paclitaxel. |
EORTC QLQ-EN24 Pain in Back and Pelvis Score (100 [best] to 0 [worst])c | ||||||
Change from baseline, points Follow-up: ██ █████ | 95 (1 RCT) | ████████ █ █ █ █ ██ ██████ | ████████ █ █ ██ ██ ██████ | ████████ █ ██ ██ ██████ | Very lowh,i | The evidence is very uncertain about the effect of durvalumab in combination with carboplatin and paclitaxel followed by durvalumab monotherapy on the change in EORTC QLQ-C30 Global Health Status score from baseline to 18 weeks, when compared with carboplatin and paclitaxel. |
Change from baseline, points Follow-up: ██ █████ | 95 (1 RCT) | ████████ █ █ █ ██ ██ ███ | ████████ █ █ ██ █████ | ████████ ██ █ ██ ██ | Very lowh,i | The evidence is very uncertain about the effect of durvalumab in combination with carboplatin and paclitaxel followed by durvalumab monotherapy on the change in EORTC QLQ-C30 Global Health Status score from baseline to 42 weeks, when compared with carboplatin and paclitaxel. |
EORTC QLQ-EN24 Urological Symptoms Score (100 [best] to 0 [worst])c | ||||||
Change from baseline, points Follow-up: ██ █████ | 95 (1 RCT) | ████████ █ █ █ ██ ████ | ████████ █ █ ██ ██ ███ | ████████ █ █ █ ██ ████ | Very lowh,i | The evidence is very uncertain about the effect of durvalumab in combination with carboplatin and paclitaxel followed by durvalumab monotherapy on the change in EORTC QLQ-C30 Global Health Status score from baseline to 18 weeks, when compared with carboplatin and paclitaxel. |
Change from baseline, points Follow-up: ██ █████ | 95 (1 RCT) | ████████ █ █ █ ██ █ █████ | ████████ █ █ █ ██ ███ | ████████ █ █ █ ██ ██ | Very lowh,i | The evidence is very uncertain about the effect of durvalumab in combination with carboplatin and paclitaxel followed by durvalumab monotherapy on the change in EORTC QLQ-C30 Global Health Status score from baseline to 42 weeks, when compared with carboplatin and paclitaxel. |
Harms | ||||||
Proportion of patients with immune-mediated adverse events Follow-up: ██ | 95 (1 RCT) | ███ ███ ████ ████ ██ ███ | ███ ███ ████ ████ █ | ██ | Lowj | Durvalumab in combination with carboplatin and paclitaxel, followed by durvalumab monotherapy, may result in an increase in the proportion of patients with immune-mediated adverse events when compared with carboplatin and paclitaxel. |
Proportion of patients with infusion reactions Follow-up: ██ | 95 (1 RCT) | ███ ███ ████ ████ ██ ███ | ██ ███ ████ ████ ██ ███ | ██ | Very lowj | The evidence is very uncertain about the effect of durvalumab in combination with carboplatin and paclitaxel followed by durvalumab monotherapy on the proportion of patients with infusion reactions when compared with carboplatin and paclitaxel. |
CAR-PAC = carboplatin and paclitaxel; CI = confidence interval; dMMR = mismatch repair deficient; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire — Core 30; EORTC QLQ-EN24 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire — Endometrial Cancer Module; NR = not reported; RCT = randomized controlled trial; SOC = standard of care (carboplatin + paclitaxel for 6 cycles).
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 + CAR-PAC versus placebo + CAR-PAC.
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. Median progression-free survival was not reached at the time of data cut-off, and the study did not meet the primary end point in the dMMR subgroup at the time of data cut-off. This implies that the progression-free survival 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 progression-free survival events in each arm was 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. Median overall survival was not reached at the time of data cut-off, and the study did not meet the secondary end point in the dMMR subgroup at the time of data cut-off. This implies that the overall survival 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 overall survival events at 12 months and 18 months in each arm was 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 number of patient data was missing at the time points, and based on the study design, it is likely that the missing data are informative.
IRated down 1 level for serious imprecision. Based on a non-null target certainty assessment, the confidence interval for the estimate contains the possibility of reduced HRQoL as well as improved health-related quality of life.
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.
Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence and additional information provided by the sponsor.
The submission did not contain any long-term extension studies.
The DUO-E trial included SOC chemotherapy (carboplatin plus 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 MAICs.
A systematic literature review (SLR) was conducted with a focus on systemic anticancer treatments, which excluded all other therapies. The patient population of interest was those newly diagnosed with stage III/IV disease or recurrent disease who were either not previously treated with 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.
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 less than 1 favouring SOC plus durvalumab. For safety end points, ORs were calculated for SOC plus durvalumab versus SOC plus dostarlimab, with ORs 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.
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: DUO-E and RUBY Part 1. Differences were noted in the median duration of follow-up as well as in the molecular characteristics of patients; 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 include patients with MSI-H pMMR endometrial cancer), and the main analysis in the RUBY Part 1 trial included 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 (4.1% in DUO-E after weighting, and 8.5% in RUBY Part 1), and the proportion of patients who were aged 65 and older (52.1% in DUO-E after weighting, and 49.2% in RUBY Part 1).
███ ███████ ███ ███ ████ ███ ████████, weighted MAIC suggested there was insufficient evidence to detect a difference between durvalumab plus SOC and dostarlimab plus SOC (adjusted HR = ████ ████ ███ ████ ██ ██████ effective sample size = ████). 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 = ████ ████ ███ ████ ██ ████]).
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, 0███ ████ ███ ████ ██ █████).
The procedures as described for screening and 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. The submission did not provide results of the quality assessment; therefore, the risk of bias in the studies is not known. However, because the DUO-E and RUBY 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 trial and a subgroup from the DUO-E trial were used (dMMR and/or MSI-H patients). In the case of the DUO-E trial, this resulted in the inclusion of some pMMR patients with MSI-H status 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 trial was longer than the DUO-E trial (twice as long 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 effective sample size was approximately ███ smaller (N = ████) than the number of patients before matching (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 effective sample size. The analyses undertaken for OS and harms were unweighted, anchored MAICs that did not employ the propensity score measurement process to reweight the results and were 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/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 to 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 undermine the validity of the results for OS and harms.
The submission did not contain any studies addressing gaps in the evidence from the systematic review.
Table 4: Summary of Economic Evaluation
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis PSM |
Target populations | Adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient. |
Treatments | CAR-PAC plus durvalumab |
Dose regimen | 1,120 mg durvalumab in combination with platinum-based chemotherapy every 21 days for 4 to 6 cycles, followed by maintenance with 1,500 mg every 4 weeks as monotherapy |
Submitted price | Durvalumab (50 mg/mL): $938.67 per 2.4 mL vial; $3,911.11 per 10 mL vial. |
Submitted treatment cost | Chemotherapy phase: $13,996 every 21 days (durvalumab = $8,671; carboplatin = $1,195; paclitaxel = $4,040) Maintenance phase: $11,733 every 28 days |
Comparators | CAR-PAC alone CAR-PAC plus dostarlimab |
Perspective | Canadian publicly funded health care payer |
Outcomes | QALYs, LYs |
Time horizon | Lifetime (37.4 years) |
Key data sources | DUO-E trial, sponsor-submitted ITC |
Submitted results | CAR-PAC plus durvalumab was dominated by CAR-PAC plus dostarlimab: CAR-PAC plus durvalumab is more costly by $231,661 and results in a 0.61 loss of incremental QALYs |
Key limitations |
|
CDA-AMC reanalysis results |
|
CAR-PAC = carboplatin and paclitaxel; CDA-AMC = Canada’s Drug Agency; ITC = indirect treatment comparison; LY = life years; OS = overall survival; PFS = progression-free survival; PSM = partitioned survival model; QALY = quality-adjusted life-year; RDI = relative dose intensity.
CDA-AMC identified the following key limitations from the sponsor’s analysis: uncertainty in the proportion initiating subsequent therapy. No reanalysis was performed. CDA-AMC conducted 3 scenario analyses to assess the impact of changes to subsequent therapy assumptions. The first scenario explored how initiating subsequent therapy for 70% of patients in the durvalumab and dostarlimab arms and 80% in the carboplatin and paclitaxel arm would affect the total budget impact. The second scenario examined the effect of increasing the subsequent market share for doxorubicin to 30%. The third scenario assessed the impact of a 47% price reduction in the value of durvalumab on the budget impact. In the submitted base case, the budget impact of reimbursing durvalumab with carboplatin and paclitaxel among dMMR patients was estimated to be $5,782,905 in Year 1, $10,330,546 in Year 2, and $11,916,217 in Year 3. The 3-year net-budget impact was estimated to be $28,029,667. The CDA-AMC scenario analyses demonstrated that an increase in the proportion of patients initiating subsequent treatment and a reduction in the unit price of durvalumab resulted in a decreased budget impact.
Dr. Catherine Moltzan (Chair), Dr. Philip Blanchette, Dr. Kelvin Chan, Dr. Matthew Cheung, Dr. Michael Crump, Annette Cyr, Dr. Jennifer Fishman, Dr. Jason Hart, Terry Hawrysh, Dr. Yoo-Joung Ko, Dr. Aly-Khan Lalani, Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Pierre Villeneuve, and Danica Wasney.
Meeting date: March 4, 2025
Regrets: Five expert committee members did not attend.
Conflicts of interest: None
ISSN: 2563-6596
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