Drugs, Health Technologies, Health Systems
Indication: For the first-line treatment of adult patients with unresectable or metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer
Sponsor: Bristol Myers Squibb Canada Co.
Final recommendation: Reimburse with conditions
Summary
What Is the Reimbursement Recommendation for Opdivo in Combination With Yervoy?
Canada’s Drug Agency (CDA-AMC) recommends that Opdivo in combination with Yervoy be reimbursed by public drug plans for the first-line treatment of adult patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer, if certain conditions are met.
Which Patients Are Eligible for Coverage?
Opdivo in combination with Yervoy should only be covered to treat adult patients with histologically confirmed, locally advanced, unresectable or metastatic colorectal cancer (mCRC) that has not previously been treated with systemic therapy for advanced disease and is not amenable to surgery and that has a known tumour MSI-H or dMMR status based on validated test(s) per local standard of practice.
What Are the Conditions for Reimbursement?
Opdivo in combination with Yervoy should only be reimbursed if prescribed by clinicians with expertise in the diagnosis and treatment of patients with mCRC and if the cost of Opdivo in combination with Yervoy is reduced.
Why Did CDA-AMC Make This Recommendation?
Evidence from a clinical trial demonstrated that in patients with unresectable or metastatic MSI-H or dMMR colorectal cancer, first-line treatment with Opdivo in combination with Yervoy resulted in a statistically significant improvement in progression-free survival (PFS) compared to chemotherapy.
Based on the CDA-AMC assessment of the health economic evidence, Opdivo in combination with Yervoy may represent good value to the health care system at the public list price. However, this finding may not hold when confidential negotiated prices are considered. A price reduction may therefore be required.
Opdivo in combination with Yervoy addresses some important patient needs, especially for those with liver metastasis, by improving PFS with manageable toxicity, reducing symptoms, and potentially enhancing patients’ health-related quality of life.
Based on public list prices, Opdivo in combination with Yervoy is estimated to reduce costs to the public drug plans by approximately $235,000 over the next 3 years. This estimate may change when confidential negotiated prices are considered.
Additional Information
What Is Unresectable or Metastatic MSI-H or dMMR Colorectal Cancer?
Colorectal cancer is described as metastatic and unresectable when the cancer has spread beyond the colon or rectum to distant organs and cannot be removed surgically due to its location, size, or involvement with other organs. Unresectable or metastatic MSI-H or dMMR colorectal cancer refers to a specific subtype of advanced colorectal cancer with mutations that result in defective DNA repair mechanisms. In 2024, colorectal cancer was the fourth most diagnosed cancer and the second leading cause of cancer-related death among people in Canada. Overall, MSI-H and/or dMMR tumours account for 15% of colorectal cancer cases.
Unmet Needs in Unresectable or Metastatic MSI-H or dMMR Colorectal Cancer
Patients with unresectable or metastatic MSI-H or dMMR colorectal cancer have a poor prognosis and poor response to standard chemotherapy.
How Much Does Opdivo With Yervoy Cost?
Treatment with Opdivo in combination with Yervoy is expected to cost approximately $21,724 in the 12-week initiation phase and $8,604 to $9,387 for each subsequent 28-day cycle.
The pCODR Expert Review Committee (pERC) recommends that nivolumab in combination with ipilimumab be reimbursed for the first-line treatment of adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer, only if the conditions listed in Table 1 are met.
One phase III, open-label, and randomized controlled trial (CheckMate-8HW, N = 303) showed that, in patients with unresectable or metastatic MSI-H or dMMR colorectal cancer, first-line treatment with nivolumab plus ipilimumab resulted in a statistically significant improvement in PFS compared to chemotherapy. After a median follow-up of 42 months, the median PFS in patients with centrally confirmed MSI-H or dMMR mCRC was 54.08 months for nivolumab plus ipilimumab compared to 5.85 months with chemotherapy (hazard ratio [HR] = 0.21; 95% confidence interval [CI], 0.14 to 0.31). Evaluations in patients with locally confirmed MSI-H or dMMR mCRC showed similar improvement in PFS. The 12-month between-group difference in PFS rates was 57.45% (95% CI, 45.41% to 69.49%), and the PFS difference was maintained at 36 months. An assessment using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework indicated with high certainty that the PFS gain was clinically meaningful. Consistent results were observed in subgroups of patients with liver metastasis (HR = 0.11; 95% CI, 0.05 to 0.25) as well as those without liver metastasis (HR = 0.28; 95% CI, 0.17 to 0.46). Based on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status (GHS), pERC noted that treatment with nivolumab plus ipilimumab may result in a clinically important improvement in patients’ health-related quality of life (HRQoL) compared with chemotherapy, although there was some uncertainty due to limitations such as the substantial attrition rate. pERC noted that overall, treatment-emergent adverse events were similar across treatment groups, and patients in the chemotherapy arm had more neutropenia and grade 3 or 4 adverse events (AEs). However, the incidence of grade 3 or 4 immune-mediated adverse events (IMAEs) was higher with nivolumab plus ipilimumab compared with chemotherapy. pERC determined that the CheckMate-8HW trial did not identify any new safety signals, and the harms profile of nivolumab plus ipilimumab was generally consistent with that previously known to be associated with nivolumab and ipilimumab, which are mostly predictable and manageable in most patients. pERC discussed evidence from a sponsor-submitted indirect treatment comparison (ITC) evaluating nivolumab plus ipilimumab versus pembrolizumab, and they concluded that the results suggest that the PFS benefit with nivolumab plus ipilimumab was at least comparable to pembrolizumab.
Patients and clinicians identified a need for new effective treatment options with a manageable toxicity profile that prolong survival, delay disease progression, improve quality of life, and alleviate symptoms. Based on the evidence reviewed, pERC concluded that nivolumab plus ipilimumab met some needs identified by patients and clinicians (especially for those with liver metastasis), by improving PFS with manageable toxicity and potentially enhancing patients’ HRQoL and reducing symptoms.
Using the sponsor-submitted price for nivolumab and ipilimumab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for nivolumab plus ipilimumab was $30,522 per quality-adjusted life-year (QALY) gained compared with chemotherapy. The ICER for pembrolizumab versus chemotherapy was higher than the ICER for nivolumab plus ipilimumab versus chemotherapy, meaning that pembrolizumab was extendedly dominated. At this ICER, nivolumab plus ipilimumab would be considered cost-effective at a $50,000 per QALY gained willingness-to-pay threshold as first-line therapy for adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer. However, due to confidential negotiated prices for all comparators in the economic analysis and uncertainty in the indirect evidence, a price reduction may still be required.
Table 1: Reimbursement Conditions and Reasons
Reimbursement condition | Reason | Implementation guidance |
|---|---|---|
Initiation | ||
1. Nivolumab in combination with ipilimumab should only be reimbursed in adult patients (≥ 18 years) who meet all the following criteria: 1.1. histologically confirmed locally advanced unresectable or metastatic colorectal cancer with no prior systemic therapy for advanced disease and not amenable to surgery 1.2. known tumour MSI-H or dMMR status based on validated tests per local standard of practice. | Evidence from the CheckMate-8HW study demonstrated that treatment with nivolumab plus ipilimumab provides clinical benefit in patients with these characteristics. | Patients with prior surgery and/or radiotherapy related to the current cancer and those who had received prior neoadjuvant and/or adjuvant chemotherapy were enrolled in the CheckMate-8HW study. |
2. The maximum duration of reimbursement is up to 12 weeks of ipilimumab and up to 2 years of nivolumab in patients without disease progression. | This condition is consistent with the dosing regimen used in the CheckMate-8HW study. | Patients who completed 2 years of nivolumab plus ipilimumab treatment with ongoing response at the time of discontinuation of therapy should be eligible for re-treatment for another year if they have progression while on surveillance. The choice of re-treatment with either nivolumab monotherapy or a combination of nivolumab and ipilimumab should be left to the discretion of the treating clinician based on prior response and toxicity. |
3. Patients must have a good performance status. | The CheckMate-8HW study only included patients with an ECOG performance status less than or equal to 1. | The clinical experts indicated that patients with an ECOG performance status of 2 (but not more than 2) may be eligible for nivolumab in combination with ipilimumab. |
4. Ineligibility criteria: Patients with the following conditions are not eligible: 4.1. an active, known, or significant autoimmune diseasea 4.2. history of interstitial lung disease or pneumonitis. | The CheckMate-8HW study excluded patients with these characteristics. | pERC noted that drug plans may adopt similar criteria to those used for pembrolizumab in the same indication when determining patient eligibility for individuals with active, known, or significant comorbidities. |
Discontinuation | ||
5. Reimbursement of treatment should be discontinued for disease progression based on immune-modified RECIST 1.1 criteria, or for unacceptable toxicity. | Criteria used for treatment discontinuation in the CheckMate-8HW study | — |
Prescribing | ||
6. Treatment with nivolumab plus ipilimumab should be prescribed by clinicians with expertise in the diagnosis and management of patients with metastatic colorectal cancer. | To ensure the appropriate patients receive treatment with nivolumab plus ipilimumab and to optimize toxicity management | — |
Pricing | ||
7. A reduction in price. | The ICER for nivolumab plus ipilimumab is $30,522 per QALY gained when compared with chemotherapy. At this ICER, no price reduction is needed to achieve an ICER of $50,000 per QALY gained compared to chemotherapy at public list prices. Pembrolizumab was subject to extended dominance (i.e., would not be considered optimal at any willingness to pay) by the comparison between nivolumab plus ipilimumab and chemotherapy. However, given confidential negotiated prices for all drugs included in the economic evaluation, the finding of extended dominance is uncertain. A price reduction may be necessary to ensure cost-effectiveness. | — |
dMMR = mismatch repair deficient; ECOG = Eastern Cooperative Oncology Group; ICER = incremental cost-effectiveness ratio; MSI-H = metastatic microsatellite instability-high; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; QALY = quality-adjusted life-year; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1.
aAccording to the CheckMate-8HW protocol amendment, participants with type 1 diabetes, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol.
Unmet need: pERC discussed input from patient and clinician groups that emphasized that metastatic MSI-H or dMMR colorectal cancer is a highly aggressive disease with poor prognosis and has limited treatment options. Approximately 30% to 40% of patients do not respond to pembrolizumab monotherapy and experience disease progression within the first 2 to 3 months of treatment. The committee noted that nivolumab plus ipilimumab provides a valuable first-line treatment option for patients with unresectable or metastatic MSI-H or dMMR colorectal cancer, especially those with liver metastases, in whom response to current therapies is notably limited.
Uncertainty about impact on survival: pERC noted the significant improvements in PFS with nivolumab plus ipilimumab over chemotherapy, which were replicated across subgroups. The committee noted that the sponsor did not submit overall survival (OS) data because they were not mature and could not be evaluated per their preplanned hierarchical approach. However, pERC considered the input from clinical experts consulted by CDA-AMC that OS data are not yet available for any of the comparisons evaluated in this study. pERC also noted that PFS is a validated surrogate for OS in chemotherapies or targeted therapies in mCRC. Therefore, the absence of OS data in this case should not change the interpretation of the significant PFS benefit of nivolumab plus ipilimumab to patients with unresectable or metastatic MSI-H or dMMR colorectal cancer, as demonstrated in the CheckMate-8HW trial.
Appropriate comparator: pERC considered the relevance of chemotherapy as a comparator in the CheckMate-8HW trial, considering the clinical experts’ input indicating that, in the absence of absolute contraindications, the current standard initial treatment for patients with dMMR colorectal cancer would be immunotherapy, such as pembrolizumab. The committee noted that, in the absence of a direct comparison to an immunotherapy indicated for MSI-H or dMMR colorectal cancer, the sponsor submitted an ITC evaluating the efficacy of nivolumab plus ipilimumab versus pembrolizumab. pERC determined that, despite certain limitations such as concerns for longer-term extrapolations and the inability to adjust for some relevant treatment effect and prognostic modifiers, the evidence from the ITC suggests that the PFS benefit of nivolumab plus ipilimumab is at least comparable to that of pembrolizumab. pERC could not draw a conclusion on comparative safety between nivolumab plus ipilimumab compared to pembrolizumab based on the sponsor-submitted ITC.
Place in therapy: pERC agreed with the clinical experts that the combination of nivolumab and ipilimumab may be preferred over pembrolizumab for fit patients who are receptive to more aggressive treatment and can tolerate the potential risks of IMAEs. However, the committee noted that, for patients who are more frail or those who cannot tolerate intensive treatments with double immunotherapy, pembrolizumab monotherapy may be a more appropriate or preferred option.
Testing procedure considerations: pERC noted that evaluating mismatch repair (MMR)/microsatellite instability (MSI) status before the initiation of nivolumab plus ipilimumab would be required. pERC acknowledged that considering MMR testing by immunohistochemistry is already standard of care and done reflexively at diagnosis, testing is not anticipated to be an implementation or access barrier.
Economic considerations: pERC noted the presence of confidential negotiated prices for nivolumab, ipilimumab, pembrolizumab, and chemotherapy. The committee also noted that while the comparative efficacy of nivolumab plus ipilimumab versus chemotherapy was available from the CheckMate-8HW trial, the comparison to pembrolizumab was likely more reflective of the clinical decision in this indicated population. Pembrolizumab was subject to extended dominance, meaning that pembrolizumab would not be considered the optimal therapy at any willingness to pay because the ICER of pembrolizumab versus chemotherapy ($31,492 per QALY gained) is higher than the ICER of nivolumab plus ipilimumab versus chemotherapy ($30,522 per QALY gained). However, the economic evaluation was conducted using publicly available list prices, rather than the negotiated drug prices that are actually paid by the drug plans. The presence of confidential negotiated prices for all comparators means that the true relationship between costs and QALYs is not known. The extended dominance relationship may not be present if these negotiated prices were used in the evaluation. Uncertainty in the comparative evidence for nivolumab plus ipilimumab versus pembrolizumab also adds uncertainty to the QALYs associated with each treatment, and thereby the relationship of extended dominance. Because of this uncertainty in costs and QALYs, a price reduction for nivolumab and ipilimumab may still be necessary to achieve cost-effectiveness versus pembrolizumab.
In Canada, colorectal cancer was the third most prevalent cancer overall in 2024. Colorectal cancer is also the fourth most commonly diagnosed cancer as well as the second leading cause of cancer-related death (11% of all cancer deaths) among residents of Canada. In 2024, the incidence was 14,100 and 11,000 cases among females and males, respectively. Presenting symptoms can be nonspecific (diarrhea, constipation, abdominal pain, rectal bleeding or pain, unexplained weight loss, unexplained iron deficiency anemia, nausea, vomiting), contributing to delays in diagnosis. Around 20% to 25% of patients with colorectal cancer present with metastasis at diagnosis, and almost 50% of patients with nonmetastatic colorectal cancer will eventually develop metastases. mCRC is largely incurable, with a 5-year OS of less than 15%. The MSI-H or dMMR subtype of colorectal cancer arises from germline or sporadic impairments of the mismatch repair system, the protein complex responsible for correcting errors during DNA replication. Overall, MSI-H and/or dMMR tumours account for 15% of colorectal cancer cases. However, the prevalence of microsatellite instability differs across disease stages. It can range from 10% in stage II and 20% in stage III to approximately 5% to 7% in stage IV. According to the clinical experts consulted by the review team, testing for MMR and MSI status is currently part of the standard of care for unresectable or mCRC, and testing is not anticipated to be a barrier to implementation.
Currently, pembrolizumab is the recommended first-line therapy in Canada that is indicated for patients with MSI-H or dMMR mCRC. Multiagent chemotherapy, along with targeted therapies against vascular endothelial growth factor and epidermal growth factor receptor are the principal first-line therapies in patients with metastatic proficient MMR/microsatellite stable colorectal cancer. These agents may be used as the first-line treatment in a limited number of patients with deficient MMR/MSI-H metastatic colorectal cancer in whom there is a severe contraindication to immunotherapy.
Nivolumab in combination with ipilimumab has been previously reviewed by CDA-AMC in the population with melanoma, malignant pleural mesothelioma, non–small cell lung cancer, advanced or metastatic renal cell carcinoma, and metastatic melanoma. The combination is also currently under review for another indication in people with unresectable or advanced hepatocellular carcinoma.
Nivolumab in combination with ipilimumab has been approved by Health Canada for the first-line treatment of adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer. Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds to PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response. Ipilimumab is a fully human monoclonal antibody to the CTLA-4 antigen. Both nivolumab and ipilimumab are available as a solution for IV injection (nivolumab: 40 mg/4 mL [10 mg/mL] and 100 mg/10 mL [10 mg/mL]; ipilimumab: 50 mg/10 mL [5 mg/mL] and 200 mg/40 mL [5 mg/mL], IV).
To make its recommendation, the committee considered the following information:
a review of 1 multinational, phase III, open-label, active-controlled randomized controlled trial (RCT) in adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer and 1 ITC
patients’ perspectives gathered by 2 patient groups: Colorectal Cancer Resource and Action Network (CCRAN) and Colorectal Cancer Canada (CCC)
input from public drug plans and cancer agencies that participate in the reimbursement review process
2 clinical specialists with expertise in diagnosing and treating patients with colorectal cancer
input from 2 clinician groups: the Ontario Health Cancer Care Ontario (OH-CCO) Gastrointestinal Cancer Drug Advisory Committee and the Canadian Gastrointestinal Oncology Evidence Network (CGOEN), in collaboration with the CCC Medical Advisory Board
a review of the pharmacoeconomic model and report submitted by the sponsor.
Two patient groups, CCRAN and CCC, provided input for this submission. CCRAN is a national, not-for-profit, patient advocacy group championing the health and well-being of people in Canada by providing support, education, and advocacy to help improve patient outcomes, longevity, and quality of life. CCRAN used a multifaceted approach to contact medical oncologists based in Canada, Europe, and the US between July 24, 2024, and February 19, 2025, to gather lived patient experience. None of the Canadian clinicians had treated patients with MSI-H colorectal cancer. In collaboration with the Canadian Cancer Survivor Network, a social media campaign was conducted from July 16, 2024, to March 15, 2025. Patients from France (n = 2), Italy (n = 2), and the US (n = 2) shared their experience with nivolumab plus ipilimumab through either telephone interviews or written input. One patient from Canada with MSI-H metastatic colorectal cancer without access to nivolumab and ipilimumab provided input. Further, responses from a previous colorectal cancer survey distributed from March 17, 2024, to April 17, 2024, comprising 77 patients with colorectal cancer or their respective caregivers, were submitted.
CCC is a not-for-profit organization for patients with colorectal cancer, dedicated to raising awareness, education, supporting patients and their caregivers, and advocating on their behalf. Patient and caregiver perspectives regarding nivolumab and ipilimumab were gathered through an online survey and semistructured interviews from August 2024 to April 2025. Of the 11 patients and 1 caregiver who responded to the online survey, 1 patient lived in Australia, 3 patients lived in Canada, 1 caregiver lived in England, and 7 patients lived in the US. Of the 4 patients who were interviewed, 3 lived in Canada and 1 lived in the US.
Both patient group survey respondents highlighted how the inability to work, exercise, and participate in social activities and/or family obligations significantly impacted quality of life. They also highlighted that the inability to plan for the future, fear of recurrence, constant worry, and fatigue resulted in significant psychological impacts. Caregiver respondents reported challenges caring for patients with colorectal cancer, including the inability to work outside, difficulty managing treatment-induced side effects, loss of income and/or financial strain, time spent on medical appointments, and medication administration. Respondents from the CCC survey indicated that symptoms such as abdominal cramps, gas, feeling bloated, abdominal pain, fatigue, and diarrhea were important to control.
Respondents to both patient group surveys indicated the following side effects from available systemic treatments: fatigue, brain fog, diarrhea, loss of appetite, hair loss, peripheral neuropathy, nausea, and low white blood cell count. In addition, the CCC survey respondents highlighted that diarrhea, hand and foot syndrome, and fatigue are the most difficult side effects to tolerate. Respondents from the CCRAN survey noted the burden of out-of-pocket expenses for additional medications required to manage treatment-induced side effects. In addition, patients who were interviewed reported that ineffective chemotherapeutics to control cancer caused poor quality of life and negatively impacted mental health. The CCC survey results noted that 30% of respondents believed that their needs were not met by currently available treatments. Five percent of patients indicated “no” and 45% indicated “somewhat” when asked whether available drug therapies were effective in controlling disease progression.
Both patient groups noted tumour shrinkage, tumour stability, reduced pain, improved breathing, and improved quality of life (e.g., improved mobility, improved sense of wellness, relief from side effects) as important outcomes with new treatments. The caregiver respondent in the CCRAN survey indicated that preventing death (i.e., survival) and stopping the spread of the illness were important treatment outcomes. The CCC survey respondents (53%) indicated a willingness to accept a treatment with significant yet tolerable side effects (i.e., nausea, anemia, neutropenia) if it offered an OS of at least 3 or 4 months.
Four patients interviewed by CCRAN who received the combination therapy achieved a durable and complete response and maintained no evidence of disease for over 5 years. Patients also noted that side effects were manageable, treatment administration was easily managed, and they were able to maintain a high quality of life. Respondents (11 of 12) from the CCC survey indicated that nivolumab plus ipilimumab controlled their cancer and its spread to other organs. Sixty-four percent of respondents indicated that they were able to continue their daily activities while undergoing treatment. Most respondents were able to complete treatment without interruptions, whereas 25% of respondents stopped treatment earlier or skipped doses due to side effects and/or complications. Anxiety and/or worry, fatigue, and side effects were noted as the most difficult AEs of receiving nivolumab plus ipilimumab. The top 5 side effects included skin itchiness, skin rash, joint stiffness, vomiting, and diarrhea. Several patients considered side effects with nivolumab plus ipilimumab as more manageable than those associated with chemotherapy. All patients interviewed experienced tumour shrinkage and/or stabilization during treatment with nivolumab plus ipilimumab and were able to return to daily activities. Patients noted that although there were considerable side effects, they resolved over time.
The clinical experts highlighted that the 3 most important goals of all therapies for metastatic MSI-H or dMMR colorectal cancer are to improve OS, improve quality of life, and reduce AEs and toxicity.
The clinical experts indicated that for patients with unresectable or metastatic MSI-H or dMMR colorectal cancer, pembrolizumab is the current funded standard first-line treatment. According to the clinical expert, a concern with the pembrolizumab monotherapy is that only approximately 40% of patients will respond to treatment, and patients with liver metastases may derive significantly less benefit. The clinical experts emphasized that nivolumab plus ipilimumab will likely replace pembrolizumab, particularly in the population of patients with liver metastases, given that the CheckMate-8HW trial showed consistent treatment benefit in this population of patients. However, the enhanced efficacy of using nivolumab plus ipilimumab comes at the expense of a higher risk of side effects and/or toxicity. Therefore, single-agent pembrolizumab will remain an important therapeutic alternative for frail and comorbid patients. The clinical experts noted that following disease progression on first-line therapy, the standard of care, second-line systemic treatment in Canada is chemotherapy (FOLFIRI or FOLFOX) in combination with bevacizumab. Following disease progression on 2 lines of therapy, the third-line treatment options become very limited in number and efficacy.
The clinical experts stated that patients with treatment-naive unresectable or metastatic MSI-H or dMMR colorectal cancer, with no contraindications to immunotherapy, reasonable performance status, and no concerns about the immunotherapy-related side effects, would be the ideal candidates for treatment with nivolumab plus ipilimumab. The clinical experts highlighted that although OS is the most important treatment outcome in this disease, PFS is considered an accepted surrogate outcome for OS in this setting. They noted that based on the statistically significant and clinically meaningful improvement in PFS reported in the CheckMate-8HW trial, OS improvement is very much expected. The clinical experts noted that patients should be assessed by a clinician after every 2 to 3 cycles of treatment, and more frequently if bothersome symptoms or side effects are occurring. Radiological assessment (e.g., CT scans) should be completed every 2 to 3 months. Tumour markers should be completed at least once every 4 weeks.
The clinical experts indicated that disease progression and/or unacceptable toxicities are the 2 main reasons to discontinue treatment with nivolumab plus ipilimumab.
The clinical experts noted that treatment with nivolumab plus ipilimumab could be safely administered in a hospital and should only be prescribed by or under the supervision of a specialist in medical oncology with expertise in managing immunotherapy-related side effects. One clinical expert further indicated that in some jurisdictions in Canada, private-pay immunotherapy is allowed to be administered in outpatient private infusion centres.
Two clinician groups, the OH-CCO Gastrointestinal Cancer Drug Advisory Committee and CGOEN, in collaboration with the CCC Medical Advisory Board, provided their input for this submission. The OH-CCO provides evidence-based clinical and health system guidance on drug-related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. The group gathered information via emails, and 5 clinicians provided their input. The CGOEN is a network of Canadian gastrointestinal oncology clinicians who contribute to the knowledge of gastrointestinal cancer and its treatments by participating in clinical trials; conducting observational research; and participating in local, provincial, and national clinical guideline development and health technology assessment. The Medical Advisory Board of CCC works alongside the patient group to ensure its activities and health information are relevant and useful for patients and caregivers. For this submission, 11 clinicians provided input based on relevant information from the CheckMate-8HW trial and evidence-based expert opinions.
Clinician groups agreed that improving survival and quality of life were important treatment goals. The OH-CCO further noted the following treatment goals: prolong PFS, delay disease progression, potentially convert some patients to surgery, reduce the severity of symptoms, and minimize AEs. The CGOEN clinician group noted that about 30% to 40% of patients do not respond to pembrolizumab and progress within the first 2 to 3 months of treatment.
Clinician groups agreed that treatment with nivolumab and ipilimumab would be the new standard first-line for patients with dMMR or MSI-H tumours. The CGOEN further mentioned that the treatment may be administered in any centre and by any specialist experienced in treating patients with mCRC using systemic therapy.
The CGOEN noted that the treatment should be limited to patients not amenable to surgical resection or with metastatic disease. They highlighted that patients would require regular clinical evaluations to assess clinical response and toxicity. They also noted routine imaging would be required at timed intervals for objective assessments and suggested that patient preference, tolerability of treatment, and quality of life be considered when assessing meaningful response to treatment. The CGOEN noted that disease progression (radiological or clinical), toxicity, clinician discretion, or patient request should be considered reasons for treatment discontinuation.
Input was obtained from the drug programs that participate in the reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a recommendation for nivolumab plus ipilimumab:
considerations for initiation of therapy
considerations for discontinuation of therapy
considerations for prescribing of therapy
generalizability of trial populations to the broader populations in the jurisdictions
care provision issues
system and economic issues
potential need for a provisional funding algorithm.
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
Drug program implementation questions | Clinical expert response |
|---|---|
Relevant comparators | |
Issues with the choice of comparator in the submitted trial Patients in the CheckMate-8HW trial were randomized to receive either nivolumab plus ipilimumab combination therapy, nivolumab monotherapy, or the investigator’s choice of chemotherapy (including FOLFOX, FOLFIRI, with or without bevacizumab or cetuximab). Pembrolizumab monotherapy is funded in most jurisdictions for this indication and would be considered the current standard of care. Other treatment options can include combination chemotherapy with or without bevacizumab, panitumumab, as well as cetuximab in some jurisdictions. | This is a comment from the drug plans to inform pERC deliberations. One of the clinical experts noted that the chosen comparators in the clinical trial were appropriate at the time of the trial design. The most appropriate modern-day comparator would be single-agent PD-1 inhibition (e.g., pembrolizumab). pERC agreed with the clinical experts. |
Considerations for initiation of therapy | |
Eligibility for re-treatment Should patients who complete 2 years of treatment and experience disease progression or recurrence off of nivolumab plus ipilimumab treatment be eligible for up to 1 year (17 cycles) of re-treatment? If yes, would this be nivolumab monotherapy or nivolumab plus ipilimumab combination therapy? | The clinical experts indicated that, consistent with all prior immunotherapy approvals, patients who completed 2 years of treatment of nivolumab plus ipilimumab treatment with ongoing response at the time of discontinuation of therapy should be eligible for re-treatment for another 1 year if they have progression while on surveillance. The choice of re-treatment with either nivolumab monotherapy or a combination of nivolumab and ipilimumab should be at the discretion of the treating clinician based on prior response/toxicity. pERC agreed with the clinical experts. |
Consistency with initiation criteria associated with other drugs reviewed by CDA-AMC in the same therapeutic space Consider alignment with existing pembrolizumab indication criteria. | This is a comment from the drug plans to inform pERC deliberations. pERC noted that, based on the attending clinician’s discretion, patients with small bowel or appendiceal adenocarcinoma would be considered eligible for treatment with nivolumab plus ipilimumab. |
Considerations for continuation or renewal of therapy | |
Consistency with renewal criteria associated with other drugs reviewed by CDA-AMC in the same therapeutic space Consider alignment with existing pembrolizumab indication criteria. | This is a comment from the drug plans to inform pERC deliberations. |
Considerations for discontinuation of therapy | |
Consistency with discontinuation criteria associated with other drugs reviewed by CDA-AMC in the same therapeutic space Consider alignment with existing pembrolizumab indication criteria. | This is a comment from the drug plans to inform pERC deliberations. |
Considerations for prescribing of therapy | |
Dosing, schedule and/or frequency, dose intensity If therapy is funded and/or implemented, most jurisdictions are likely to implement a weight-based nivolumab dosing, as used for other funded indications (i.e., nivolumab 3 mg/kg IV every 3 weeks up to a maximum of 240 mg per dose for the first 4 cycles, and then 3 mg/kg IV every 2 weeks up to a maximum of 240 mg per dose or 6 mg/kg IV every 4 weeks up to a maximum of 480 mg per dose thereafter). The ipilimumab was weight-based in the CheckMate-8HW trial as 1 mg/kg IV every 3 weeks for the first 4 cycles. | This is a comment from the drug plans to inform pERC deliberations. |
Concerns related to combination usage In the trial, if ipilimumab had to be discontinued early due to toxicity, then nivolumab can still be continued. However, if nivolumab had to be discontinued, then ipilimumab was discontinued as well. Could pERC clarify whether patients can continue monotherapy of ipilimumab if nivolumab is discontinued due to toxicity? If yes, what would be the duration for ipilimumab monotherapy treatment? | The clinical experts did not support continuing with ipilimumab as monotherapy if a patient discontinued therapy with nivolumab due to toxicity. They endorsed sticking to the approach outlined in the trial protocol (i.e., if nivolumab has to be discontinued, then ipilimumab has to be discontinued as well). pERC agreed with the clinical experts. |
Consistency with prescribing criteria associated with other drugs reviewed by CDA-AMC in the same therapeutic space Consider alignment with existing pembrolizumab indication criteria. | This is a comment from the drug plans to inform pERC deliberations. |
Generalizability | |
Populations of interest matching the indication but with insufficient data Should patients with an ECOG performance status of 2 or greater be eligible? | The clinical experts indicated that they agree with expanding the eligibility to include patients with an ECOG performance status of 2 (but not more than 2). pERC agreed with the clinical experts. Suggest using the term “patients with good performance” instead of “ECOG performance status of 2.” |
Funding algorithm | |
Request initiation of a rapid provisional funding algorithm. Note that if the final reimbursement recommendation for this drug under review is “Do not Reimburse,” the project will be suspended indefinitely. | This was a comment from the drug programs to inform pERC deliberations. |
Drug may change the place in therapy of comparator drugs | This was a comment from the drug programs to inform pERC deliberations. |
Complex therapeutic space with multiple lines of therapy, subpopulations, or competing products | This was a comment from the drug programs to inform pERC deliberations. |
Other aspects: Under what clinical circumstances would nivolumab plus ipilimumab be preferred over pembrolizumab in this setting? | The clinical experts indicated that they would rather phrase it in the algorithm such that nivolumab plus ipilimumab is the preferred standard of care among patients with MSI-H mCRC. Pembrolizumab should be considered only if the treating physician has concerns about tolerability to nivolumab plus ipilimumab because of frailty or comorbidity. pERC agreed with the clinical experts regarding nivolumab plus ipilimumab for healthy fit patients, noting that pembrolizumab monotherapy may be the appropriate or preferred option for patients who are more frail or those who cannot tolerate intensive treatments with double immunotherapy. |
Care provision issues | |
Drug preparation, storage, administration, or dispensing Preparation of both nivolumab and ipilimumab is familiar in many jurisdictions due to their use in other indications. | This was a comment from the drug programs to inform pERC deliberations. |
Companion diagnostics (e.g., access issues, timing of testing) This indication requires MMR/MSI testing; however, this testing is established in this patient population in most jurisdictions. | This was a comment from the drug programs to inform pERC deliberations. |
System and economic issues | |
Presence of confidential negotiated prices for comparators Pembrolizumab has confidential pricing in place. | This was a comment from the drug programs to inform pERC deliberations. |
CDA-AMC = Canada’s Drug Agency; ECOG = Eastern Cooperative Oncology Group; mCRC = metastatic colorectal cancer; MMR = mismatch repair; MSI = microsatellite instability; pERC = pan-Canadian Oncology Drug Review Expert Review Committee.
One pivotal trial (CheckMate-8HW) is included in this review. CheckMate-8HW is an ongoing multinational, phase III, open-label, active-controlled RCT to evaluate the efficacy and safety of nivolumab plus ipilimumab (N = 202) compared with chemotherapy (N = 101) in adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer. Key inclusion criteria included histologically confirmed recurrent or mCRC with no prior treatment history with chemotherapy and/or targeted agents for metastatic disease and not amenable to surgery; locally confirmed MSI-H or dMMR status, and ECOG performance status lower than or equal to 1. A total of 303 patients in 22 countries, including 204 (67.3%) patients from Canada, Europe, and the US, were randomized to receive treatment with nivolumab plus ipilimumab or chemotherapy (2:1 randomization). Randomization was conducted using an interactive response technology system and stratified by primary tumour location (sidedness: left versus right). The baseline demographic and disease characteristics were largely balanced between treatment groups. The median age of all patients was 63.0 years, ranging from 21 to 87 years. Most of the patients were white (86.1%), followed by Asian (10.6%), Black or African American (1.3%), or other (2.0%). About 54% of all participants were female and 46% were male. The patients with an ECOG score of 0 or 1 were 53.8% and 46.2% respectively. The primary efficacy outcome was PFS, assessed per a blinded independent central review (BICR) based on centrally confirmed MSI-H or dMMR mCRC. The secondary efficacy outcome was PFS, assessed per a BICR based on locally confirmed MSI-H or dMMR mCRC. The exploratory outcome included the HRQoL (e.g., EORTC- QLQ-C30). The harm outcomes included AEs, serious adverse events (SAEs), discontinuation from the treatment due to AEs, IMAEs, and other events of special interest. The results of PFS presented in this report are based on the data cut-off on August 28, 2024 (with a median follow-up time of 42.05 months). Results of HRQoL were based on the data cut-off on October 12, 2023 (median follow-up of 31.57 months). Safety outcomes results were based on the safety population at the data cut-off on both October 12, 2023, and August 28, 2024.
After a median follow-up of 42.05 months, a total of 53 (31.0%) PFS events were observed in the nivolumab plus ipilimumab arm and 54 (64.3%) in the chemotherapy arm. The median PFS was 54.08 months (95% CI, 54.08 to not available) in the nivolumab plus ipilimumab arm and 5.85 months (95% CI, 4.37 to 7.79 months) in the chemotherapy arm (HR = 0.21, 95% CI, 0.14 to 0.31). In the landmark time points, compared with chemotherapy, nivolumab plus ipilimumab showed a clinically meaningful higher PFS probability starting from 6 months and sustained to 36 months. Based on the GRADE assessment, nivolumab plus ipilimumab results in a clinically important increase in the probability of being progression-free at 12 months compared to chemotherapy. The PFS results for patients with MSI-H or dMMR mCRC were consistent whether the patients were centrally confirmed (primary outcome) or locally confirmed (a key secondary outcome).
The results of the predefined subgroup analysis showed a statistically significant improvement in PFS probability with nivolumab plus ipilimumab compared with chemotherapy in patients with liver metastasis (HR = 0.11; 95% CI, 0.05 to 0.25) and patients without liver metastasis (HR = 0.28; 95% CI, 0.17 to 0.46). Sensitivity analyses of PFS were consistent with the primary analysis.
Compared with chemotherapy, treatment with nivolumab plus ipilimumab demonstrated a statistically significant improvement from week 13 to week 37. The GRADE assessment suggested nivolumab plus ipilimumab may result in clinically important improvement in EORTC QLQ-C30 GHS compared with chemotherapies at week 37.
After a median follow-up of 42.05 months, the overall proportion of patients with AEs was similar in both the nivolumab plus ipilimumab arm compared with the chemotherapy arm (nivolumab plus ipilimumab versus chemotherapy: 99.0% versus 98.9%). Compared to those in the nivolumab plus ipilimumab arm, more patients on chemotherapy reported all-cause grade 3 or 4 AEs (nivolumab plus ipilimumab versus chemotherapy: 50.5% versus 67.0%), all-causality SAEs (nivolumab plus ipilimumab versus chemotherapy: 35.5% versus 42.0%), and death (nivolumab plus ipilimumab versus chemotherapy: 25.5% versus 47.7%). The proportion of patients who discontinued treatment because of AEs was similar (nivolumab plus ipilimumab versus chemotherapy: 15.0% versus 15.9%). However, it should be noted that the AEs of special interest such as all-causality grade 3 or 4 IMAEs were much higher in the nivolumab plus ipilimumab arm than in the chemotherapy arm (nivolumab plus ipilimumab versus chemotherapy: 17.0% versus 1.1%). The between-group difference was 15.9% (95% CI, not reported). The GRADE assessment suggested that nivolumab plus ipilimumab likely results in clinically important increases in grade 3 or 4 IMAEs, compared with chemotherapies. The clinical experts consulted for this review indicated that the safety profile of nivolumab and ipilimumab has been well established. The harms profile of nivolumab plus ipilimumab observed in the CheckMate-8HW trial was generally consistent with that of previously known AEs associated with nivolumab and ipilimumab. No new safety signals were identified. Overall, most AEs were predictable and clinically manageable in most patients.
The CheckMate-8HW study was a phase III, open-label RCT. Appropriate methods for randomization were reported. The outcomes assessed are clinically relevant, and statistical analyses were done using standard methods. Overall, the risk of selection bias and detection bias is considered very low for the key outcome (i.e., PFS per BICR). However, the open-label design introduces a potential bias in the subjective outcomes of HRQoL (e.g., EORTC QLQ-C30) and AEs (such as fatigue, nausea). However, the extent and direction of bias due to treatment knowledge is uncertain. In addition, the EORTC QLQ-C30 assessment may be further biased due to high attrition, particularly at a longer follow-up (e.g., at week 37).
The clinical experts highlighted that the inclusion and exclusion criteria of the CheckMate-8HW trial are standard for clinical trials, but stricter than what pertains in clinical practice. For example, they noted that patients with an ECOG performance status of more than 1 were not eligible for the trial, whereas patients with an ECOG performance status of 2 would be considered potential candidates for nivolumab plus ipilimumab in the clinical experience. However, the clinical experts considered that overall, the inclusion and exclusion criteria of the CheckMate-8HW trial are consistent with clinical practice in the setting in Canada, and its findings present no major generalizability concerns in terms of clinical practice in Canada.
For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.19 20 Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.
When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect. The target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold (minimal important difference [MID]) for a clinically important effect. In this review, the threshold (MID) assessment of between-group difference for PFS was based on published information21,22 in combination with the MID suggested by clinical experts consulted for this review. The threshold (MID) for the HRQoL (i.e., EORTC QLQ-C30 GHS) assessment of between-group difference was based on the published information,23 which was aligned with the suggestion by the clinical experts consulted for this review. The threshold (MID) for assessment of between-group difference for harms (i.e., IMAEs) was suggested by clinical experts consulted for this review.
The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:
PFS
HRQoL
safety.
Table 3 presents the GRADE summary of findings for nivolumab in combination with ipilimumab versus chemotherapy for the first-line treatment of adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer.
Table 3: Summary of Findings of Nivolumab Plus Ipilimumab Combination Therapy Versus Chemotherapy for the First-Line Treatment of Patients With Unresectable or Metastatic MSI-H or dMMR Colorectal Cancer
Outcome and follow-up | Patients (studies), N | Relative effect (95% CI) | Absolute effects (95% CI) | Certainty | What happens | ||
|---|---|---|---|---|---|---|---|
Chemotherapy | Nivolumab + ipilimumab | Difference | |||||
PFS at data cut-off on August 28, 2024 (median follow-up of 42.05 months, 95% CI, NR) | |||||||
PFS probability at 12 months, centrally confirmed | 255 (1 RCT) | NR | 216 per 1,000 | 790 per 1,000 | 575 more per 1,000 (454 to 695 per 1,000) | High | Nivolumab plus ipilimumab results in a clinically important increase in the probability of being progression-free at 12 months, compared to chemotherapy. |
PFS probability at 12 months, locally confirmed | 303 (1 RCT) | NR | 240 per 1,000 | 710 per 1,000 | 470 more per 1,000 (366 to 575 more per 1,000) | High | Nivolumab plus ipilimumab results in a clinically important increase in the probability of being progression-free at 12 months, compared to chemotherapy. |
Health-related quality of life (EORTC QLQ-C30 GHS) at data cut-off on October 12, 2023 | |||||||
EORTC QLQ-C30 GHS Total Score, locally confirmed | 303 (1 RCT) | NR | 58.4 | 72.4 (69.3, 75.5) | 14.0 (5.9, 22.1) | Lowa | Nivolumab plus ipilimumab may result in clinically important improvement in EORTC QLQ-C30 GHS, compared with chemotherapy at week 37. |
Notable harms (i.e., AESIs) at data cut-off on August 28, 2024 (median follow-up of 42.05 months, 95% CI, NR) | |||||||
All-causality grade 3 or 4 IMAEs within 100 days of last dose | |||||||
Total number of patients with grade 3 or 4 IMAEs (safety population), n (%) | 288 (1 RCT) | NR | 11 per 1,000 | 170 per 1,000 (NR) | 159 more per 1,000 (NR) | Moderateb,c,d | Nivolumab plus ipilimumab likely results in a clinically important increase in grade 3 to 4 IMAEs, compared with chemotherapies over an overall median follow-up of 42.05 months. |
AE = adverse event; AESI = adverse event of special interest; CI = confidence interval; dMMR = deficient mismatch repair; EORTC = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; IMAE = immune-mediated adverse event; MID = minimal important difference; MSI-H = microsatellite instability-high; NR = not reported; PFS = progression-free survival; RCT = randomized controlled trial.
Notes: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.
The between-group MID for PFS at 12 months was based on the publications (≥ 10%),21 22 in combination with the MID suggested by the clinical experts consulted for this review. (i.e., 10% to 20% for PFS probabilities at 12 months).
Musoro et al. reported that the between-group MID for EORTC QLQ-C30 GHS Total Score was 6 points.23 The clinical experts consulted for this review suggested between-group difference MIDs for EORTC QLQ-C30 GHS Total Score at 37 weeks is 5 to 7 points.
There is no established between-group MID for the proportion of patients with grade 3 or 4 IMAEs after an overall median follow-up of 42.05 months. The clinical experts consulted for this review suggested a MID of 5% for the odds of experiencing grade 3 or 4 IMAEs after an overall median follow-up of 42.05 months.
aRated down 2 levels for very serious study limitations for this outcome: there is risk of bias in measurement of the outcome due to open-label study design and risk of bias due to a substantial attrition rate; that is, only 119 (59%) patients in the nivolumab plus ipilimumab arm and 15 (15%) patients in the chemotherapy arm were included for the analysis at week 37.
bRated down 2 levels for very serious study limitations for this outcome: because no 95% CI for between-group difference was reported, it was rated down 2 levels for imprecision.
cRated up 1 level for a very large between-group difference.
dDespite it being an open-label study design, the evidence certainty is not rated down for the grade 3 or 4 IMAEs because the grade 3 or 4 IMAEs reported in the review are all objective, which were unlikely biased due to the open-label design.
The sponsor conducted an ITC using a matching-adjusted indirect comparison (MAIC) to estimate the relative efficacy (i.e., PFS) and network meta-analysis (NMA) for safety outcomes comparing nivolumab plus ipilimumab with pembrolizumab for the first-line treatment of MSI-H or dMMR mCRC.
Anchored MAIC: The point estimate of the time-varying HR of PFS is lower than 1 over the estimated 10-year period (HR < 1 indicates in favour of nivolumab plus ipilimumab compared with pembrolizumab). █████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ ████. The 95% CIs do not cross the null value (i.e., 1) at 12 months and 24 months, which indicates that PFS for nivolumab plus ipilimumab is favourable compared with pembrolizumab. However, starting from 36 months until 120 months, the 95% CI of HR includes the null value (i.e., 1), indicating that the estimation of the HR is uncertain.
Constant HR-based scenario NMA: █████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ █████ .
Unanchored MAIC: █████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ █████ █████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ ████.
Constant HR-based scenario NMA analysis: █████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ ████ ██ █████████ ███ ███ █████ .
In summary, all results of the ITC analysis (i.e., anchored MAIC using time-varying HR approach, unanchored MAIC using time-varying HR approach, and the scenario NMAs using constant HR approach) suggested a favourable PFS improvement in patients with nivolumab plus ipilimumab treatment compared with pembrolizumab, despite certain key limitations (e.g., not able to adjust all treatment effect modifiers and prognostic modifiers).
The evidence of the NMA was not sufficient to demonstrate the difference of grade 3 or higher AEs █████ ███ ███ ████ ██ █████████ between the 2 treatments. It should be noted that no ITC was done for the overall AEs, overall SAEs, and discontinuation due to AEs, especially for the proportion of patients with total IMAEs.
The key limitation for the MAICs was their inability to balance all (known or unknown) treatment effect modifiers due to the unavailability of published summary statistics in the KEYNOTE-177 trial. Another key limitation for the NMA was that the heterogeneity in terms of treatment effect modifiers between the 2 studies was not adjusted, which may threaten the transitivity assumption for the NMA analysis.
The sponsor submitted evidence from the CheckMate-8HW trial comparing nivolumab plus ipilimumab to nivolumab monotherapy in patients with MSI-H or dMMR mCRC receiving treatment across all lines of therapy to inform questions on the contribution of ipilimumab in addition to nivolumab. Per the CDA-AMC Procedures for Reimbursement Reviews, nivolumab monotherapy does not meet the CDA-AMC definition of relevant comparator because it is neither approved by Health Canada nor reimbursed by participating drug plans in Canada for the first-line treatment of MSI-H or dMMR mCRC. Therefore, the evidence was considered out of scope for this review.
Nivolumab is available as an IV solution at a strength of 10 mg/mL. At the submitted price of $782.22 per 4 mL, the per-cycle cost of nivolumab is expected to be $4,693 per patient for the first 4 doses and $9,387 for subsequent doses, based on the Health Canada–recommended dosage. Ipilimumab is available as an IV infusion at a strength of 5 mg/mL. At the submitted price of $5,800.00 per 10 mL, the per-cycle cost of ipilimumab is expected to be $11,600 per patient, based on the Health Canada–recommended dosage. For the first 4 doses, nivolumab is administered as a flat dose of 240 mg, and ipilimumab is assumed to be administered as a weight-based dose of 1 mg/kg IV every 3 weeks. After 4 doses, nivolumab is administered as a flat dose of 480 mg until disease progression, death, or other reasons for discontinuation up to a maximum of 2 years.
Clinical efficacy in the economic analysis for nivolumab and ipilimumab versus chemotherapy was derived from the CheckMate-8HW trial. Evidence submitted by the sponsor indicates that nivolumab plus ipilimumab is likely to improve time to progression or death compared with chemotherapy among patients with unresectable or metastatic MSI-H or dMMR colorectal cancer. For nivolumab plus ipilimumab versus pembrolizumab, clinical efficacy was informed by sponsor-submitted ITC, which suggests that nivolumab and ipilimumab may improve time to progression compared with pembrolizumab.
The results of the CDA-AMC base case suggest the following:
Nivolumab plus ipilimumab will be associated with higher costs to the health care system than chemotherapy (incremental costs = $118,050), primarily driven by the higher costs associated with drug acquisition.
Nivolumab plus ipilimumab is associated with a gain of 4.81 life-years compared to chemotherapy. When the impact on HRQoL is also considered, nivolumab plus ipilimumab may result in a gain of 3.98 QALYs compared to chemotherapy.
The ICER of nivolumab plus ipilimumab compared to chemotherapy was $30,522 per QALY gained in the CDA-AMC base case.
The incremental costs and QALYs compared to pembrolizumab are uncertain. Comparative PFS versus pembrolizumab was estimated using an unanchored MAIC, which could not control for potential treatment confounders. Although the CDA-AMC base case estimated a gain in QALYs with nivolumab plus ipilimumab compared to pembrolizumab (incremental: 1.42), more than 89% of the incremental benefit was gained in the extrapolated period (i.e., after 42.05 months). In the absence of direct comparative evidence during the trial period and a high degree of uncertainty in the long-term extrapolation from the indirect evidence, the duration of time that patients spend in the progression-free state is uncertain. Given that time in this state is a primary driver of incremental costs and incremental QALYs, the estimated ICER in the CDA-AMC base case is highly uncertain and may be overestimated. In the CDA-AMC base case, nivolumab plus ipilimumab extendedly dominates pembrolizumab.
CDA-AMC estimates that the budget impact of reimbursing nivolumab plus ipilimumab for the first-line treatment of adult patients with unresectable or metastatic MSI-H or dMMR mCRC will be a savings of approximately $235,000 over the first 3 years of reimbursement compared to the amount currently spent on pembrolizumab and chemotherapies, with an estimated expenditure of $114 million on nivolumab plus ipilimumab over this period. The actual budget impact of reimbursing nivolumab plus ipilimumab will depend on the proportion of eligible patients who receive nivolumab plus ipilimumab and if the treatments will be dosed by weight or a flat dose.
Dr. Catherine Moltzan (Chair), Dr. Kelvin Chan (Vice Chair), Dr. Phillip Blanchette, 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 Villneuve, and Danica Wasney.
Meeting date: August 13, 2025
Regrets: Five expert committee members did not attend.
Conflicts of interest: None
ISSN: 2563-6596
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