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Indication: For the first-line treatment of adult patients with unresectable hepatocellular carcinoma who require systemic therapy
CADTH recommends that tremelimumab (Imjudo) in combination with durvalumab (Imfinzi) should be reimbursed by public drug plans for the treatment of patients with unresectable hepatocellular carcinoma (HCC) if certain conditions are met.
Imjudo in combination with Imfinzi should only be covered to treat adult patients who have confirmed liver cancer that cannot be removed by surgery, are classified as Child-Pugh score class A, and require systemic therapy. Patients should be in relatively good health (i.e., have a good performance status, as determined by a specialist).
Imjudo in combination with Imfinzi should only be reimbursed as first-line treatment and should not be given in combination with other systemic anticancer drugs. Imjudo in combination with Imfinzi should be prescribed by clinicians with expertise and experience in treating unresectable HCC. In addition, the price for Imjudo in combination with Imfinzi should be reduced.
HCC is the most common type of primary liver cancer, which occurs when tumour cells form in the tissues of the liver. HCC classically develops and grows in silent fashion, which makes it difficult to detect before the development of the later stages of the disease. The majority of liver tumours found in people at later stages are determined to be unresectable, which means the tumour cannot be removed with surgery. HCC is a severe form of liver cancer that represents approximately 72% of liver cancers in Canada. It is estimated that 3,500 new patients will be diagnosed with primary liver cancer and 1,650 Canadians will die from this disease in 2022.
Despite the currently available treatments for HCC, new treatment options are needed to delay disease recurrence or worsening, prolong patient life, and improve quality of life.
Treatment with Imjudo in combination with Imfinzi is expected to cost approximately $34,320 in the first 28-day cycle and $11,733 per 28-day cycle thereafter. This is due to the 1-time, upfront dose of Imjudo.
The CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that tremelimumab in combination with durvalumab be reimbursed for the first-line treatment of adult patients with unresectable hepatocellular carcinoma (HCC) who require systemic therapy only if the conditions listed in Table 1 are met.
Evidence from 1 phase III, randomized, open-label, sponsor-blind, multicentre, global study (HIMALAYA; N = 1,324, including 393 patients in the tremelimumab in combination with durvalumab group and 389 patients in the sorafenib group) demonstrated that treatment with tremelimumab in combination with durvalumab resulted in added clinical benefit in adult patients with unresectable hepatocellular carcinoma. The HIMALAYA study showed that treatment with tremelimumab in combination with durvalumab was associated with a statistically significant and clinically meaningful improvement in overall survival (OS) with a median OS of 16.4 months (95% CI, 14.2 to 19.6 months) in the tremelimumab in combination with durvalumab group compared to 13.8 months (95% CI, 12.3 to 16.1 months) in the sorafenib group (hazard ratio [HR] = 0.78; 96.02% CI, 0.65 to 0.93; P = 0.0035). The OS rate at 36 months was 30.7% (95% CI, 25.8% to 35.7%) in the tremelimumab in combination with durvalumab group and 20.2% (95% CI, 15.8% to 25.1%) in the sorafenib group. The HIMALAYA trial showed that objective response rate (ORR) was 20.1% in the tremelimumab in combination with durvalumab group and 5.1% in the sorafenib group (odds ratio [OR] = 4.69; 95% CI, 2.85 to 8.04). The median time to onset of response from randomization was 2.2 months (interquartile range [IQR], 1.8 to 4.0 months) in the tremelimumab in combination with durvalumab group and 3.8 months (IQR, 1.9 to 8.4 months) in the sorafenib group. The safety profile of tremelimumab in combination with durvalumab was consistent with the known safety profile of other immuno-oncology checkpoint inhibitors and was considered manageable. Tremelimumab in combination with durvalumab addresses an unmet need for patients with unresectable HCC who are at a higher risk of bleeding and are not eligible for atezolizumab in combination with bevacizumab.
Patients identified a need for effective treatments that prolong life, improve quality of life, and have manageable side effects. pERC concluded that tremelimumab in combination with durvalumab met some of the patients’ needs by offering an additional effective treatment option, improving OS, and having manageable side effects. Patients identified a need for treatments that maintain quality of life; although the frequency of treatments would be reduced compared to atezolizumab in combination with bevacizumab, no definitive conclusion could be reached regarding the effects of tremelimumab in combination with durvalumab on health-related quality of life (HRQoL) because the results were based on a large amount of missing data in both groups.
Using the sponsor-submitted price for tremelimumab and durvalumab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for tremelimumab in combination with durvalumab compared with sorafenib was $265,036 per quality-adjusted life-year (QALY) gained. At this ICER, tremelimumab in combination with durvalumab is not cost-effective at a willingness-to-pay threshold of $50,000 per QALY gained for the indicated population. A price reduction is required for tremelimumab and durvalumab to be considered cost-effective at this threshold.
Reimbursement Conditions and Reasons.
Primary liver cancer is one of the fastest-rising cancers in Canada, and it is estimated that 3,500 new patients will be diagnosed with primary liver cancer and 1,650 people living in Canada will die from this disease in 2022. According to Statistics Canada’s Short-Term Cancer Prevalence in Canada 2018 report, the estimated 5-year prevalence of liver cancer is approximately 11.3 cases per 100,000 for both sexes. HCC is a severe form of liver cancer that represents approximately 90% of primary liver cancers globally and approximately 72% of liver cancers in Canada. HCC is the third-leading cause of cancer deaths worldwide, with a 5-year survival rate of only 20% in Canada. It is most commonly diagnosed in people older than 70 years and is 3 times more common in males than females. Due to the insidious nature of the disease, the majority of patients are diagnosed with advanced disease, with a median survival following diagnosis of approximately 6 to 8 months or 25% at 1 year. The predominant risk factors for HCC include chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV), misuse of alcohol or alcoholic steatohepatitis, and nonalcoholic fatty liver disease or nonalcoholic steatohepatitis. HCC is often diagnosed using noninvasive imaging, tissue biopsy, physical examination, or blood tests.
For advanced, unresectable HCC, the goal of treatment is to extend long-term survival, delay progression, and maintain and improve the patient’s quality of life, and guidelines recommend the use of systemic targeted therapies. According to the clinical experts consulted by CADTH, systemic treatment options have improved over the past several years with the introduction of the combination of atezolizumab and bevacizumab, lenvatinib, and sorafenib as first-line systemic treatment options in Canada. The clinical experts consulted by CADTH identified a key limitation of the current first-line therapy with atezolizumab in combination with bevacizumab: patients with untreated or incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding are not candidates for this combination therapy. Therefore, upper endoscopy is indicated for patients with cirrhosis or high risk of bleeding.
The Health Canada indication for tremelimumab in combination with durvalumab is for the first-line treatment of adult patients with unresectable HCC who require systemic therapy, which generally aligns with the sponsor’s requested reimbursement criteria. Tremelimumab is a selective, fully human immunoglobulin G2 antibody that blocks cytotoxic T lymphocyte–associated protein 4 interaction with CD80 and CD86, thus enhancing T-cell activation and proliferation, resulting in increased T-cell diversity and enhanced antitumour immune activity. Durvalumab is an engineered monoclonal antibody that blocks the interaction of programmed cell death ligand-1 with its receptors PD-1 and CD80. The recommended dose of tremelimumab is 300 mg intravenously as a single priming dose in combination with durvalumab 1,500 mg IV for cycle 1 day 1, followed by durvalumab 1,500 mg IV as a single agent every 4 weeks.
To make its recommendation, the committee considered the following information:
CCRAN in collaboration with the CCSN, CLF, and GI Society, provided a collective patient input for this review. CCRAN is a national not-for-profit patient advocacy group championing the health and wellbeing of Canadians affected by colorectal cancer and those at risk of developing the disease. CCSN, CLF, and the GI Society thoughtfully collaborated with CCRAN to ensure that the perspectives of patients with advanced HCC and their caregivers are captured, represented, and well weaved in this submission. CCRAN gathered information for this review from in-depth interviews with 2 patients with HCC (both patients had experience with the currently available treatment of HCC; only 1 patient had experience with the drugs under review), a literature review, and online public forums for patient-reported outcomes.
According to the patient input received from CCRAN, HCC is the most common primary liver cancer. CCRAN noted that risk factors associated with HCC include cirrhosis, hepatitis B and C infections, and alcohol intake. Both patient interviews indicated that they had not been experiencing any symptoms at the time of HCC diagnosis. CCRAN indicated that a diagnosis and symptoms of HCC represent a substantial physiological and psychological burden for patients and their caregivers and can significantly affect their HRQoL. CCRAN pointed to various symptoms of HCC that affected their patients’ quality of life and daily activities, including sleep disorders, sexual dysfunction, ascites, gynecomastia, pruritis, fatigue, muscle cramps, and lack of appetite even after treatment. Both patient respondents highlighted that the daily activities that were most commonly affected included the ability to work, participate in activities they enjoy, and spend time with family and friends. One of the interviewed patients (age = 92 years, female, age at HCC diagnosis = 71 years) found herself cycling through the same stages of cancer grief — anger, depression, guilt, anxiety, hopelessness, and fear — which hit her hard at the time of the initial diagnosis and subsequent relapse.
CCRAN indicated that patients with HCC expect the following key outcomes to be improved from any new drug or treatment: improved quality of life, prolonged survival, manageable side effects, maintenance of functionality, ability to engage in society and be contributing members of the workforce. According to the patient input received from CCRAN, HCC is a unique carcinoma because the majority of cases will develop in patients with cirrhosis; therefore, therapeutic options will be limited due to the patient’s overall health status. CCRAN indicated that patients with early-stage HCC are preferred candidates for resection, transplant, and local ablation, whereas patients at intermediate stages may be candidates for transarterial chemoembolization, and those with advanced disease will receive systemic therapies. CCRAN noted that the current systemic treatments for HCC include atezolizumab in combination with bevacizumab, as well as lenvatinib, sorafenib, regorafenib, and cabozantinib. The limited treatment tolerability, in part due to the side effects, was highlighted by CCRAN as a major challenge to available systemic therapy for advanced HCC.
One of the interviewed patients (age = 74 years, male, age at HCC diagnosis = 68 years) had experience with treatment with the drug under review after transarterial chemoembolization, which negatively affected his quality of life. The patient respondent, who resided in Cranbrook, British Columbia, had access to tremelimumab in combination with durvalumab through a clinical trial. That patient respondent indicated that the drug under review had promising and durable treatment results, with no side effects other than an occasional skin rash. He also mentioned that tremelimumab in combination with durvalumab helped him regain functionality and livelihood, which reduced the burden on his caregivers and loved ones. CCRAN advocated for tremelimumab in combination with durvalumab to be approved for the indication under review and suggested that it will help alleviate the gaps in current HCC therapy.
All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of unresectable HCC.
The clinical experts consulted by CADTH for this review stated that the treatment goals for patients with unresectable HCC include prolonging life and delaying progression. They mentioned that treatments have improved in the past several years with the introduction of lenvatinib, which has better efficacy and lower toxicity than sorafenib, and atezolizumab in combination with bevacizumab. However, the benefits of current treatments have been incremental. Moreover, atezolizumab in combination with bevacizumab is limited to patients who have had a recent upper endoscopy and were found not to have symptomatic varices. The clinical experts noted that tremelimumab in combination with durvalumab would be indicated as first-line therapy for patients who would currently be indicated for atezolizumab and bevacizumab, and that choice of therapy would depend on clinician and patient preference. They also mentioned it may be indicated for patients who had started tyrosine kinase inhibitor therapy and had progressed or experienced severe toxicity.
The clinical experts agreed that tremelimumab in combination with durvalumab would be recommended for patients with unresectable HCC with preserved liver function (Child-Pugh A), good performance status (potentially up to Eastern Cooperative Oncology Group Performance Status [ECOG PS] of 2), and who are not indicated for local therapy, such as transarterial chemoembolization. They mentioned that patients who were on tyrosine kinase inhibitors and/or other therapies but had severe side effects leading to permanent discontinuation would also be eligible for tremelimumab in combination with durvalumab. Patients who are not candidates for other immune checkpoint inhibitors would not be candidates for tremelimumab in combination with durvalumab.
The clinical experts mentioned that, in clinical practice, imaging would be obtained every 3 months to assess response to treatment. The most important outcomes are prolonged survival, delayed progression, disease control, and maintained quality of life with low toxicity profile. The clinical experts noted that tremelimumab in combination with durvalumab should be discontinued if there is disease progression or intractable severe immune-related adverse effects. According to the clinical experts, tremelimumab in combination with durvalumab can be administered in most systemic therapy suites in which cancer patients receive chemotherapy and immunotherapy. Administration of this therapy can be supervised by most medical oncologists experienced in treating HCC.
The clinician group input was obtained from 2 clinician groups, including the CGOEN represented by 6 clinicians, and Ontario Health (Cancer Care Ontario) GI DAC represented by 5 clinicians, and from a clinician from the Alberta Health Services Cancer Care, University of Alberta.
CGOEN indicated that with modern systemic therapy, downsizing of disease has led to newer options for local regional treatments of the liver (i.e., stereotactic radiation, embolization, ablation, resection, or transplant). CGOEN highlighted that patients with HCC may have an increased bleeding risk due to the underlying liver disease and the vascular nature of the disease itself, and therapy that does not increase this risk will be key in this area. The clinician groups agreed that given a good safety profile, tremelimumab in combination with durvalumab will be another first-line HCC treatment option, especially for patients with hypertension or varices, or when upper GI endoscopy is not available. The clinician from the University of Alberta indicated that tremelimumab in combination with durvalumab may become the preferred first-line immunotherapy option for treatment of patients with unresectable HCC. CGOEN and the clinician form the University of Alberta noted that patients receiving tremelimumab in combination with durvalumab would have fewer clinic visits and less time in the clinic because they would be treated every 4 weeks and essentially with 1 drug except for the first cycle, whereas for atezolizumab in combination with bevacizumab, patients are treated every 3 weeks and with 2 drugs. The clinician groups pointed out several reasons that may lead to the discontinuation of tremelimumab in combination with durvalumab, including disease progression, unacceptable drug-related toxicities, or patient preference. The clinician groups highlighted that treatment with tremelimumab in combination with durvalumab should be provided by clinicians with expertise and experience in treating HCC. The GI DAC noted that treatment with tremelimumab in combination with durvalumab should be performed in outpatient infusion clinics, including satellite clinics.
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
HIMALAYA was a randomized, open-label, sponsor-blind, multicentre, global, phase III study to assess the efficacy and safety of tremelimumab in combination with durvalumab versus sorafenib in the treatment of patients with unresectable HCC who are not eligible for locoregional therapy and who have not received prior systemic therapy for HCC in the first-line setting. The HIMALAYA study included 2 additional treatment groups who received durvalumab monotherapy and a lower dose of tremelimumab in combination with durvalumab. The HIMALAYA study was designed to compare all 3 groups (durvalumab monotherapy and both doses of tremelimumab in combination with durvalumab) to sorafenib. The 2 additional groups (durvalumab monotherapy and a lower dose of tremelimumab in combination with durvalumab) were not relevant to this review, therefore results related to the 2 additional groups were not reported.
The primary objective was to compare OS for tremelimumab in combination with durvalumab versus sorafenib in all randomized patients. Secondary objectives included comparing OS rates (at 18, 24, and 36 months), progression-free survival (PFS), time to progression, ORR, disease control rate, and duration of response (DOR) per investigator assessment, patient-reported outcomes, and safety between both treatment groups. The study was funded by AstraZeneca Canada Inc. and included 9 study centres in Canada.
Patients were randomly assigned in a 1:1:1:1 ratio using an interactive web response system into 1 of 4 treatment groups: tremelimumab in combination with durvalumab (300 mg IV × 1 dose plus durvalumab 1,500 mg IV every 4 weeks, [n = 393]), sorafenib (400 mg orally twice daily [n = 389]), durvalumab monotherapy (not included in this review [n = 389]), and a different dosing regimen of tremelimumab in combination with durvalumab (n = 153, recruitment to group closed due to preliminary efficacy findings). Randomization was stratified according to macrovascular invasion (yes or no), etiology of liver disease (confirmed HBV vs. confirmed HCV vs. others), and ECOG performance status (0 vs 1). Tumour imaging assessments were to be performed at randomization and then every 8 weeks (± 1 week) for the first 48 weeks following randomization, and then every 12 weeks (± 1 week) thereafter until confirmed disease progression.
Patient demographic characteristics and key disease characteristics were balanced between both treatment groups. ||| |||| ||| || |||| |||||| ||| ||||||||||||| || ||||| ||| and up to 15% of the patients in both groups were 75 years or older. Most patients were male (85%), and 15% of patients were female. |||||| |||| |||| ||||| |||||| ||||| ||||| || |||||||| |||| |||||| |||||| ||| |||||||| ||| |||||||||| ||||| |||||||||. Approximately 80% of patients had BCLC score C, and 20% had BCLC score B. Half of the patients had extrahepatic spread, and a quarter of the patients had macrovascular invasion. |||| ||||||| || |||||||| ||||||||||||||| |||||||||| |||| ||||| || |||||||| ||| ||||||||| ||||||||||| ||||||||||||| ||||||||||||| ||| ||| ||||||||| ||||||||||| |||||||, and 12% in the tremelimumab in combination with durvalumab group and 10% in the sorafenib group had received prior radiotherapy.
Key efficacy results of the HIMALAYA trial for all randomized patients are summarized in Table 3. As of the final primary analysis on August 27, 2021, the data cut-off date, ||| ||||||| ||||||||| |||| ||| ||| ||||||, and median follow-up time in the tremelimumab in combination with durvalumab group was 33.2 months (95% CI, 31.7 to 34.5 months) and in the sorafenib group was 32.2 months (95% CI, 30.4 to 33.7 months). The median total treatment duration was 5.5 months (range, 0.4 to 42.7 months) in the tremelimumab in combination with durvalumab group and 4.1 months (range, 0.1 to 38.6 months) in the sorafenib group.
The efficacy analyses of OS in all randomized patients showed that patients in the tremelimumab in combination with durvalumab group had longer OS than those in the sorafenib group. The median OS was 16.4 months (95% CI, 14.2 to 19.6 months) in the tremelimumab in combination with durvalumab group compared with 13.8 months (95% CI, 12.3 to 16.1 months) in the sorafenib group, with an HR of 0.78 (96.02% CI, 0.65 to 0.93) and P value of 0.0035. The OS rate at 36 months was 30.7% (95% CI, 25.8% to 35.7%) in the tremelimumab in combination with durvalumab group and 20.2% (95% CI, 15.8% to 25.1%) in the sorafenib group. Effect estimates for all predefined subgroups were consistent with the overall OS analysis.
All secondary outcomes were based on investigator assessment according to Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1) and were not adjusted for multiplicity. Median PFS in the full analysis set was 3.8 months in the tremelimumab in combination with durvalumab group and 4.1 months in the sorafenib group, with an HR of 0.90 (95% CI, 0.77 to 1.05). ORR was 20.1% (79 patients) in the tremelimumab in combination with durvalumab group and 5.1% (20 patients) in the sorafenib group. When comparing tremelimumab in combination with durvalumab and sorafenib, the OR for ORR was 4.69 (95% CI, 2.85 to 8.04) in favour of tremelimumab in combination with durvalumab. ||||| |||| || |||||||| ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| || |||||||| |||||| || ||| ||||||||| ||||| ||| |||||||| ||||| ||||||||| |||||||| ||||| || |||||||| |||||||| |||| || ||||||| |||||||| |||| ||||| || ||||||||||| ||||||||| |||||| ||||||||| ||| ||||||||| || |||||| ||||||| || ||||| |||||| ||||| ||| |||||| || |||||||||||| |||||||||||.There were 13 patients (3.3%) in the tremelimumab in combination with durvalumab group who achieved CR, and none in the sorafenib group. Among the 79 responders in the tremelimumab in combination with durvalumab group and 20 responders in the sorafenib group, the median DOR based on investigator assessment according to RECIST 1.1 was 22.3 months (IQR, 8.5 months to not reached [NR]) and 18.4 months (IQR, 6.5 to 26 months), respectively. The percentage of patients remaining in response at 12 months based on the Kaplan-Meier technique was 65.8% in the tremelimumab in combination with durvalumab group and 63.2% in the sorafenib group. Median time to onset of response from randomization was 2.2 months (IQR, 1.8 to 4 months) in the tremelimumab in combination with durvalumab group and 3.8 months (IQR, 1.9 to 8.4 months) in the sorafenib group. The overall disease control rate (CR, PR, or stable disease) was similar between both groups with 236 patients (60.1%) in the tremelimumab in combination with durvalumab group and 236 patients (60.7%) in the sorafenib group achieving controlled disease. ||| |||||| |||| || ||||||||||| ||| ||| |||||| |||| ||| ||| || |||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||| |||||| |||| ||| ||| || |||| || ||| ||||||||| ||||||. Results from the assessment of exploratory outcomes (based on BICR assessments using modified RECIST for HCC and immune-related RECIST were not provided by the sponsor).
Results for patient-reported outcomes (assessed by the European Organization for Research and Treatment of Care Core Quality of Life questionnaire [EORTC QLQ-C30 and QLQ-HCC]) suggested similar overall health status in both study groups at baseline, with no mean change scores from baseline reaching minimal important difference (MID) (i.e., mean change ≥ 10 points) at any time point. However, |||||||||| ||||| ||| |||||||| || ||| ||| ||| || |||| || || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||| ||||||||| ||||||| ||||||||||||. Median time to deterioration scores for patients favoured tremelimumab in combination with durvalumab over sorafenib in EORTC QLQ-C30 GHS/QoL (7.5 vs. 5.7 months; HR = 0.76; 95% CI, 0.61 to 0.96), physical functioning (12.9 vs. 7.4 months; HR = 0.68; 95% CI, 0.53 to 0.87), fatigue (7.4 vs. 5.4 months; HR = 0.71; 95% CI, 0.57 to 0.89), nausea (25.0 vs. 11.0 months; HR = 0.65; 95% CI, 0.49 to 0.87), appetite loss (12.6 vs. 6.9 months; HR = 0.59; 95% CI, 0.46 to 0.75), and EORTC QLQ-HCC18 abdominal pain (16.8 vs. 8.9 months; HR = 0.61; 95% CI, 0.47 to 0.80), and abdominal swelling (20.9 vs. 11.1 months; HR = 0.74; 95% CI, 0.56 to 0.97). The improvement rate in ||||||||||||||||||||| ||| |||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| |||||||| || ||| ||||||||| |||||| |||||||| ||| ||||| |||||| || ||||||| |||| ||| |||||| ||| |||||||||| |||||||||| .
Summary of Key Results From the HIMALAYA Study (FAS With Final Data Cut-Off August 27, 2021).
A summary of harms in the HIMALAYA trial are presented in Table 4.
A total of 378 patients (97.4%) in the tremelimumab in combination with durvalumab group and 357 patients (95.5%) in the sorafenib group experienced at least 1 adverse event (AE). The most frequently reported treatment-emergent AEs in the tremelimumab in combination with durvalumab and sorafenib groups were diarrhea (26.5% vs. 44.7%, respectively), pruritis (22.9% vs. 6.4%, respectively), rash (22.4% vs. 13.6%, respectively), fatigue (17% vs. 19%, respectively), decreased appetite (17% vs. 17.9%, respectively), and palmar-plantar erythrodysesthesia syndrome (0.8% vs. 46.5%, respectively). ||||| |||| ||| |||||||| ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| |||||| ||| ||| |||||||| ||||||| || ||| ||||||||| ||||| ||| ||||||||||| || ||||| ||| |||| ||||| |. A total of 157 patients (40.5%) in the tremelimumab in combination with durvalumab group and 111 patients (29.7%) in the sorafenib group experienced at least 1 serious AE. The most frequently reported serious AEs in the tremelimumab in combination with durvalumab and sorafenib groups were diarrhea (2.3% vs. 1.6%, respectively), sepsis (2.1% vs 0, respectively), and pneumonia (1.8% vs. 2.1%, respectively). Fifty-three patients (13.7%) in the tremelimumab in combination with durvalumab group and 63 patients (16.8%) in the sorafenib group stopped treatment due to AEs.
At the final data cut-off date of August 21, 2021, in the FAS, there were 262 deaths (66.7%) in the tremelimumab in combination with durvalumab group and 293 deaths (75.3%) in the sorafenib group, |||| |||||||| |||||||||| || ||| ||||||| |||||||||||. In the safety analysis set, 30 patients (7.7%) and 27 patients (7.2%) died in the tremelimumab in combination with durvalumab group and sorafenib group, respectively.
||||||| |||||| || ||||||| |||||||| ||||||| |||||||| |||| |||||||||| || |||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| |||| ||| ||||||||| ||||| ||||||| |||| || |||| ||| |||||||| || ||| ||||||||||||||||||||||| ||||| |||| |||| |||||| || |||||||| |||||||| ||||||||||||||| || ||||| ||||| |||| || ||| |||||||||||||. All AEs of special interest were more frequently reported in the tremelimumab in combination with durvalumab group, except for diarrhea or colitis which was more frequently reported in the sorafenib group (45% vs. 28%, respectively). Immune-mediated AEs were also more frequently reported in patients in the tremelimumab in combination with durvalumab group than the sorafenib group (36% vs. 8%, respectively). There were 6 patients in the tremelimumab in combination with durvalumab group that died due to immune-mediated AEs (pneumonitis, 3 hepatic events, myocarditis, and myasthenia gravis) and no deaths in the sorafenib group. |||||||| |||||||| |||||| |||||||| || || |||||||| |||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||||||| |||||| || ||| ||||||||| |||||| .
There were 144 patients (37.1%) in the tremelimumab in combination with durvalumab group with any Hepatic Standardized MedDRA Query (SMQ) AE compared with 121 patients (32.4%) in the sorafenib group. ||| || ||| ||||||| |||||||| ||| ||| || ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||||| || ||| ||||||||| |||||. There were 44 patients (11.3%) in the tremelimumab in combination with durvalumab group with any Hemorrhage SMQ AE compared with 56 patients (15%) in the sorafenib group. ||| || ||| |||||||||| ||| ||| || ||||||| || ||| |||||||||||| || ||||||||||| |||| |||||||||| ||||| ||| ||||||| || ||| ||||||||| |||||. In the HIMALAYA trial, tremelimumab in combination with durvalumab showed no increase in liver toxicity or risk of bleeding.
Summary of Key Harms Results From the HIMALAYA Study (SAS With Final Data Cut-Off August 27, 2021).
HIMALAYA was an open-label, sponsor-blind, randomized phase III study comparing tremelimumab in combination with durvalumab and sorafenib in adult patients with unresectable HCC who required systemic therapy. The sponsor stated that an open-label, sponsor-blind design was used due to the nature of the treatment administration (IV versus oral) and the different administration schedules (every 4 weeks versus twice daily). The study used an appropriate central randomization method sufficient for concealing allocation until assignment to the intervention. Randomization appeared adequate in balancing baseline demographic and disease characteristics between the tremelimumab in combination with durvalumab group and the sorafenib group. The open-label design can result in a risk of bias in the study conduct, including the measurement of the outcomes, particularly for subjective outcomes assessed by unblinded assessor such as PFS and ORR, or self-reported such as HRQoL, and subjective harms. With the exception of subjective harms, the bias will likely favour the experimental intervention, although the extent and direction of bias are uncertain. This bias would not be introduced into the measurement of objective outcomes, such as OS, which is the primary outcome of the trial. At the first interim analysis after at least 32 weeks of follow-up, tumour response assessments were performed by BICR (which would minimize bias in the measurement of these outcomes) but, in the final analysis, tumour response assessments were performed only by investigator assessment. Results from the interim analysis were similar to results from the final analysis. In the final analysis, exploratory end points included assessment of the PFS, time to progression, ORR, disease control rate, and DOR by BICR to mitigate this bias; however, the results of these assessments were not available. The study was powered to detect a treatment difference in the primary end point of OS between treatment group, and the enrolled sample size was adequate. However, the study was not powered for individual subgroup comparisons and no multiplicity adjustments were made, rendering any conclusion uncertain. There was no multiplicity control for other outcomes which may have increased the risk of false-positive conclusions. Maintaining and improving quality of life overall was rated as an important outcome by patients, yet the interpretation of results for the HRQoL instruments (i.e., the ability to assess trends over time and to make comparisons across treatment groups) is limited by the significant decline in the number of patients available to provide an assessment over time.
According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics of the HIMALAYA study population were reflective of the Canadian population with unresectable HCC. There were a large number of screening failures in the study in which almost a third of screened patients were not randomized, most commonly due to eligibility criteria not being fulfilled. However, the eligibility criteria that were most commonly not fulfilled were clear contraindications to treatment with tremelimumab in combination with durvalumab, such as lack of adequate organ and marrow function. The clinical experts noted that, although including only patients with a Child-Pugh score of A is reasonable in clinical trials, it would be reasonable to include other patients (e.g., Child-Pugh score of B7) in clinical practice. They also noted that, although the trial excluded patients with prior systemic therapy, a large number of patients in clinical practice would have already received prior systemic therapy. It is unclear if findings from this study can be generalized to patients beyond the first-line of therapy. All patients in the trial had ECOG PS 0 or 1 as per the eligibility criteria, but the experts indicated this would not be reflective of clinical practice and that clinicians would require some flexibility in restricting treatment by performance status. The clinical experts consulted by CADTH indicated that at the time of the HIMALAYA study design, sorafenib was the only approved treatment for unresectable HCC patients who were ineligible for locoregional therapy and who had not undergone prior systemic therapy. Hence, in this study, sorafenib was considered standard of care treatment for these patients and was selected as the active comparator. According to the clinical experts and recent clinical guidelines, sorafenib is no longer the most common standard of care therapy and has been replaced by current therapies that include atezolizumab in combination with bevacizumab, and lenvatinib.
No long-term extension studies were identified by the sponsor.
Two MAICs and a published indirect treatment comparison (ITC) submitted by the sponsor were summarized and appraised for this CADTH review.
In the absence of direct comparative evidence from trials, the aim of the MAICs conducted by the sponsor was to compare the efficacy and safety of tremelimumab in combination with durvalumab against atezolizumab in combination with bevacizumab (from the IMbrave150 trial), and lenvatinib (from the REFLECT trial) in patients with unresectable HCC. MAIC was identified as the preferred option to adjust for suspected heterogeneity between trials with individual patient data for the HIMALAYA and aggregate data available from the comparator trials. Individual patient data from the HIMALAYA trial were used to match and adjust patients to those included in the comparator trials (IMbrave150 and REFLECT). All 3 trials (HIMALAYA, IMbrave150, and REFLECT) were phase III, open-label, multicentre studies. The mean duration of study follow-up was 33.2 months in HIMALAYA, 27.5 months in REFLECT, and 8.5 months in IMbrave150. The efficacy end points included OS and PFS in both MAICs, and ORR and DOR were only assessed in the MAIC comparing tremelimumab in combination with durvalumab versus atezolizumab in combination with bevacizumab. For parameters related to disease progression, the HIMALAYA and IMbrave150 trials used the RECIST 1.1, whereas the REFLECT trial used the modified RECIST. Harms related to the use of tremelimumab in combination with durvalumab were also evaluated in both MAICs, including AEs, serious AEs, and AEs leading to treatment discontinuation. Patient-reported outcomes were only reported in the MAIC comparing tremelimumab in combination with durvalumab versus atezolizumab in combination with bevacizumab.
This section will focus on the findings of the sponsor-submitted MAICs.
After restriction and reweighting, the HR was 1.09 (95% CI, 0.80 to 1.48) for OS, and |||| |||| ||| ||| || ||||| ||| |||. The OR was 1.18 (95% CI, 0.44 to 3.21) for ORR, and |||| |||| ||| |||| || ||||| ||| |||. The HR for |||| || ||||||||||||| ||||| || |||||||||||||| ||||||| || |||| ||||||| ||| |||| |||| ||| |||| || ||||), while the HR for ||| || ||||||||| |||||||| ||| |||| |||| ||| |||| || ||||||.
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After restriction and reweighting, the OR was 0.73 (95% CI, 0.44 to 1.19) for AEs of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4, |||| |||| ||| |||| || ||||| ||| ||||||| |||| ||| |||| |||| ||| |||| || ||||| ||| ||| ||||||| || ||||||||| |||||||||||||||.
||||| ||||||||||| ||| |||||||||||| ||| || ||| |||| |||| ||| |||| || ||||| ||| ||| || ||||| ||||| ||| || |||| |||| ||| |||| || ||||| ||| ||||||| |||| ||| |||| |||| ||| |||| || ||||| ||| ||| ||||||| || ||||||||| ||||||||||||||||.
Although the methodology for matching and adjustment was in line with the technical guidance, the sponsor-submitted MAICs had a number of limitations that challenge the interpretation of the internal and external validity of the findings. Overall, based on the methods detailed in the report, the systematic literature review had a comprehensive search, and the screening strategies were sufficient to minimize error and selection bias. The risk of bias of included studies was assessed per individual study; however, it may be different depending on the study outcomes (i.e., OS versus patient-reported outcomes). The clinical experts consulted by CADTH for this review mentioned several studies published over the past year providing updated efficacy and safety data from IMbrave150 and REFLECT, which were not identified in this search and therefore were not included in the ITC. As a result, MAIC analyses did not select some efficacy outcomes (i.e., PFS, ORR, DOR, patient-reported outcomes) based on the longer follow-up data, which may have influenced the results. Although the sponsor inadvertently missed including the reference of longer follow-up data for the IMbrave150 trial in the MAIC report and the clinical evidence document, OS results from the IMbrave150 trial used in the MAIC analysis (HR = 0.66; 95% CI, 0.52 to 0.85) were as reported in the Cheng et al. (2022) publication. The matching criteria were based on the inclusion and exclusion criteria for the IMbrave150 and REFLECT trials and availability of comparable data from the HIMALAYA trial; therefore, matching was not possible for all criteria that may remove an important portion of the patient population from the HIMALAYA trial. The effective sample size was reduced after matching and adjustment in both MAICs (65.7% to 78% of the original sample size in HIMALAYA). This implies that the weighted estimates are influenced by a subset of the patients from the HIMALAYA trial that may not be representative of the entire study population, which may limit the generalizability of the results. In addition, the MAIC analysis could not account for some sources of heterogeneity in trials, such as differences in observation times or definition of end points. The clinical experts noted that given the time gap, there is a possibility of systemic differences between patients in the HIMALAYA trial (from 2017 to 2019) and the REFLECT trial (from 2013 to 2016), such as treatments received before systemic therapy (i.e., locoregional treatment). Furthermore, not all trials included the same subjective and objective measurements, so the comparative efficacy and safety of relevant treatments included remain unknown. Although OS and PFS were available in all 3 trials, ORR and DOR were not assessed in the REFLECT trial. In addition, disease control rate, considered by clinical experts consulted for this review as an important outcome, was assessed only in the HIMALAYA trial. Results on patient-reported outcomes (quality of life, abdominal swelling), which was considered as an important outcome for this review, were only reported in the MAIC comparing tremelimumab in combination with durvalumab versus atezolizumab in combination with bevacizumab in patients with unresectable HCC. In both MAICs, results for some efficacy and harm estimates were imprecise (i.e., wide confidence intervals favouring either tremelimumab in combination with durvalumab or the comparators), which precluded conclusions from being drawn.
In addition to the MAICs conducted by the sponsor, a published network meta-analysis (NMA) conducted by Fulgenzi et al. (2022) was also identified. A frequentist NMA using fixed-effects models was performed to compare the efficacy and safety of first-line treatments for unresectable HCC from 2007 to 2022. Two analyses were performed: the first comparing the efficacy of atezolizumab in combination with bevacizumab versus all other first-line treatments and the second comparing all first-line treatments with placebo. Because tremelimumab in combination with durvalumab is of interest to this report, only a comparison of atezolizumab in combination with bevacizumab versus tremelimumab in combination with durvalumab was presented in this report. The results of the NMA showed that the HR for OS for atezolizumab in combination with bevacizumab compared with tremelimumab in combination with durvalumab was 0.74 (95% CI, 0.52 to 1.06). The HR for PFS for atezolizumab in combination with bevacizumab compared with tremelimumab in combination with durvalumab was 0.66 (95% CI, 0.49 to 0.87). The OR for ORR for atezolizumab in combination with bevacizumab compared with tremelimumab in combination with durvalumab was 0.60 (95% CI, 0.28 to 1.25).
The results of the published NMA are highly uncertain given the heterogeneity in the baseline characteristics of patients within the included trials, data sparseness, network structure, and differences in the duration of follow-up for efficacy outcomes. The use of fixed-effect models seems appropriate given the sparsity of data; however, no rationale was provided for the selection of the model in the published NMA. Furthermore, the evidence is imprecise in the effect estimates from the NMA due to the sparseness of data, with wide confidence intervals which, for many outcomes, included the possibility of benefit, lack of benefit, or harm for atezolizumab in combination with bevacizumab compared with tremelimumab in combination with durvalumab. Model fit was not evaluated, so it is not clear how well the model estimates treatment differences. No results on patient-reported quality of life were evaluated, which was considered an important end point for this review. In addition, there were no comparative effect estimates for the harms. Thus, these limitations must be considered when drawing conclusions on the results of the published NMA.
Summary of Economic Evaluation.
CADTH identified the following key limitations with the sponsor’s analysis: the health care payer perspective was inappropriate; the sponsor’s estimates of the NIHB population did not consider provincial coverage of oncology treatments; BCLC staging at diagnosis was inappropriately derived; some patients with BCLC stage A were inappropriately excluded; the efficacy of sorafenib was inappropriately modelled, as was the time to discontinuation of single-dose tremelimumab in combination with regular-interval durvalumab (STRIDE) and sorafenib; the proportion of patients receiving systemic therapy may have been underestimated; and the market displacement caused by STRIDE is uncertain. CADTH estimated a revised base case by assuming a drug payer perspective, adjusting the NIHB population, revising the BCLC staging distribution of HCC patients at diagnosis, incorporating patients diagnosed at BCLC stage A who initially received treatments other than liver transplant or resection, and adjusting the median OS of patients treated with sorafenib and the median time-to-treatment discontinuation of STRIDE and patients treated with sorafenib to match those of the CADTH pharmacoeconomic reanalysis. The CADTH reanalysis suggests that reimbursing the STRIDE regimen for the treatment of unresectable HCC would be associated with an incremental cost of $5,816,972 in year 1, $6,532,047 in year 2, and $6,053,880 in year 3, for a 3-year budgetary impact of $18,402,899.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Matthew Cheung; Dr. Winson Cheung, Dr. Michael Crump, Dr. Leela John, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik.
Meeting date: August 9, 2023
Regrets: 3 expert committee members did not attend.
Conflicts of interest: None
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Indication: For the first-line treatment of adult patients with unresectable hepatocellular carcinoma who require systemic therapy
Sponsor: AstraZeneca Canada Inc.
Recommendation: Reimburse with conditions
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