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Indication: For the treatment of patients with Waldenström macroglobulinemia
CADTH recommends that Brukinsa be reimbursed by public drug plans for the treatment of adult patients with relapsed or refractory Waldenström macroglobulinemia (WM), if certain conditions are met.
Brukinsa should only be covered to treat patients with relapsed or refractory WM who have received at least 1 prior line of therapy, meet at least 1 criterion for treatment according to International Workshop on WM (IWWM) consensus panel criteria, and have good performance status. Patients eligible for reimbursement of Brukinsa should not have disease transformation, which is WM that has transformed into another type of cancer, or received prior treatment with a drug of the same class (i.e., a Bruton tyrosine kinase [BTK] inhibitor) unless such therapy was stopped because the drug was not tolerated and the disease had not progressed.
Brukinsa should only be reimbursed if prescribed by a clinician with expertise and experience in the treatment of WM and monitoring of therapy and if it does not cost more than other treatments for WM.
WM is a cancer which grows mainly in the bone marrow, causing low levels of red blood cells leading to weakness and fatigue, and low numbers of white blood cells making it hard for the body to fight infection. WM is a rare disease with 1 in 200,000 people diagnosed each year in Canada.
All patients with WM eventually relapse and need additional treatment. There are few treatment options for patients who relapse after initial treatment, such as chemotherapy.
Treatment with Brukinsa is expected to cost approximately $99,324 per patient per year.
The CADTH pCODR Expert Review Committee (pERC) recommends that zanubrutinib be reimbursed for the treatment of patients with relapsed or refractory (R/R) Waldenström macroglobulinemia (WM) only if the conditions listed in Table 1 are met.
pERC reviewed evidence from a randomized cohort of the ASPEN trial (164 patients with R/R WM) that evaluated zanubrutinib against ibrutinib, a treatment comparator that is currently used in Canadian practice accessed through compassionate programs or private insurance, but is not publicly funded in any jurisdiction. The ASPEN trial was originally designed and powered as a noninferiority trial; however, a protocol amendment revised the design to a superiority trial and noninferiority of zanubrutinib was evaluated in a post hoc analysis. At the primary analysis, the ASPEN trial demonstrated no statistically significant difference (P = 0.116) in complete response (CR) or very good partial response (VGPR) rate by International Workshop on WM (IWWM-6) response criteria between the zanubrutinib (28.9%; 95% CI, 19.5% to 39.9%) and ibrutinib (19.8%; 95% CI, 11.7% to 30.1%) treatment arms in patients with R/R WM. The post hoc analysis indicated zanubrutinib was noninferior to ibrutinib for VGPR/CR. Although the post hoc data are supportive of the primary analysis results, they are limited by the exploratory nature of the analysis. Data on longer-term outcomes including duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were assessed in the trial but were considered immature at the time of the primary analysis. The trial data suggested no difference between zanubrutinib and ibrutinib in measures of health-related quality of life (HRQoL) and a similar incidence of adverse events (AEs) albeit different safety profiles were observed. Compared to ibrutinib, zanubrutinib was associated with a lower incidence of atrial fibrillation (2.0% versus 14.3%) and major bleeding (5.9% versus 9.2%). The sponsor submitted an indirect treatment comparison (ITC) of zanubrutinib to relevant comparators in Canada but there were significant limitations of the analysis, and no conclusions could be drawn on comparative efficacy with respect to PFS and OS, and HRQoL and safety outcomes were not assessed.
Given the rarity of WM, pERC acknowledged there should be greater allowance for uncertainty in the evidence. pERC considered there is a significant unmet need for more treatment options in WM, most notably for patients with R/R WM for whom there is presently no clear standard of care regimen and retreatment with chemoimmunotherapy is of limited efficacy. Within this context, ibrutinib (obtained through compassionate access) has become a de facto standard of treatment in Canada for patients in the R/R setting, as patients and clinicians recognize the added clinical value of a targeted and oral therapy that is well tolerated in this patient population. Input from patient groups indicated that patients need additional treatment options that provide longer remission and survival and improved quality of life with fewer side effects. Given the totality of the evidence, pERC concluded that zanubrutinib met some of the needs identified by patients as it provides an additional treatment option for oral administration with the potential for fewer side effects and no apparent deterioration in quality of life.
Using the sponsor-submitted price for zanubrutinib and publicly listed prices for all other drug costs, zanubrutinib was more costly compared with funded comparators. There was no reliable evidence to quantify any additional benefit provided by zanubrutinib in R/R and treatment-naive patients with WM relative to funded comparators. As such, zanubrutinib should be no more costly than the least costly alternative that is funded for patients in this setting. Given that zanubrutinib is given until disease progression rather than for a fixed period, this would require price reductions of more than 93% to ensure cost parity over the patient’s lifetime.
Reimbursement Conditions and Reasons.
Issues that may impact the drug plan’s ability to implement a recommendation as identified by pERC and the drug plans are summarized in Table 2.
Implementation Guidance From pERC.
Zanubrutinib (Brukinsa) is a second-generation small molecule inhibitor of BTK and has a Health Canada indication for the treatment of adult patients with WM. Zanubrutinib is supplied in 80 mg oral capsules and the recommended total daily oral dose is 320 mg that may be taken as either 320 mg (four 80 mg capsules) once daily or 160 mg (two 80 mg capsules) twice daily. Treatment with zanubrutinib should continue until disease progression or unacceptable toxicity.
To make their recommendation, pERC considered the following information:
The information in this section is a summary of the input provided by the patient and clinician groups who responded to CADTH’s call for input, and from clinical experts consulted by CADTH for the purpose of this review. As well, issues identified by the provincial drug plans that may impact their ability to implement a recommendation are summarized.
Four patient groups provided input for the review of zanubrutinib in WM: The CanCertainty Coalition, LC in collaboration with the CORD, and the WMFC. The CanCertainty Coalition data collection were sourced through literature, Canadian prescription drug insurance coverage, population demographics, and previously conducted surveys. The CanCertainty data collection and submission were completed exclusively using CanCertainty resources and personnel and contract personnel. LC, CORD, and WMFC conducted an anonymous online survey for patients with WM between February 28, 2021, and May 10, 2021, in patients registered through their respective databases and through social media outlets.
Symptoms of WM that most impacted patients’ HRQoL at diagnosis included fatigue (66%), night sweats (28%), neuropathy (24%), weight loss and loss of appetite (20%), and easy bruising and bleeding (20%). A total of 81% of respondents experienced at least 1 psychological and social impact of a WM diagnosis including stress and anxiety (66%), difficulty sleeping (30%), impact on daily activities (28%), memory loss and concentration problems (19%), and depression (19%). In terms of treatment, 17% of patient respondents were receiving front-line treatment, 41% were in remission following a previous line of treatment, and 6% relapsed following previous treatment and were waiting to begin treatment. The most common treatments patient had received included chemotherapy monotherapy (55%), monoclonal antibodies (63%), and BTK inhibitors (36%). The most common side effects experienced by patients during treatment for WM included fatigue (72%), neutropenia (47%), nausea (39%), anemia (37%), peripheral neuropathy (37%), thrombocytopenia (30%), rash and itch (26%), back and joint pain (23%), mouth sores (22%), diarrhea (20%), headache (19%), and hair loss (17%). Patients noted that fatigue was particularly difficult to handle. Having a choice of treatment and having enough treatment options were considered particularly important to patients. Access to an effective oral therapy was also considered important to address access issues for patients who are unable to access treatment locally. Further, the inequity of funded access to oral therapies across Canada was also emphasized. In terms of outcomes, patients rated longer survival (75%), longer remission (76%), better HRQoL (70%), and fewer side effects (57%) as the most important outcomes of treatment.
The clinical experts consulted by CADTH indicated that zanubrutinib would be used in the R/R setting after failure of standard chemoimmunotherapy as they expect it to be more efficacious, leading to more prolonged remission, and less toxic than a repeated round of chemoimmunotherapy. The clinical experts indicated that they would generally not consider zanubrutinib in the front-line treatment setting. All patients should be offered chemoimmunotherapy first line unless truly unfit for anything other than rituximab therapy or even oral chlorambucil. These patients have a defined treatment interval and can enjoy a prolonged remission after chemoimmunotherapy (with or without rituximab), and as such, reserving zanubrutinib in later lines does not result in reduced survival. Zanubrutinib should only be offered to patients who have failed at least 1 line of therapy. The clinical experts consulted by CADTH also indicated that patients with asymptomatic disease should not be treated with zanubrutinib unless there is concern about impending hyperviscosity syndrome. Patients who are at high risk for bleeding complications (e.g., those who cannot tolerate antiplatelet or anticoagulation equivalent) would also be least suitable for treatment with zanubrutinib.
One clinical expert commented that WM is truly an orphan disease, a rare group of patients with unique clinical manifestations that do not respond as well to chemoimmunotherapy as other indolent lymphomas (e.g., follicular lymphoma), with few and generally ineffective treatment options at relapse and little or no availability of new therapies through clinical trials. Consequently, having access to BTK inhibitors is imperative for this group of patients.
A joint clinician input was received from 2 registered clinicians on behalf of the Ontario Health-Cancer Care Ontario Hematology Cancer Drug Advisory Committee for the review of zanubrutinib for the treatment of WM.
The clinicians stated that most patients demonstrate a good response to front-line BR and remain free of relapse for a few years. Contrary to the clinical experts consulted by CADTH, the clinician group advised that zanubrutinib may be used in the first-line setting or after relapse of the disease given there is currently no evidence to suggest the specific sequencing of treatment with zanubrutinib. However, it is patients with relapsed disease that have a significant unmet need for additional treatment options, including BTK inhibitors. The clinicians indicated that patients best suited to this treatment are those with symptomatic R/R WM.
Input from the drug plans identified factors pertaining to relevant comparators, considerations for initiation and discontinuation of therapy, generalizability, care provision issues, and system and economic considerations. pERC weighed evidence from the ASPEN trial and other clinical considerations, including input from clinical experts consulted by CADTH, to provide responses which are presented in Table 3.
Responses to Questions from the Drug Programs.
The ASPEN study is an ongoing phase III, randomized, open-label, multicenter study, designed to compare the efficacy and safety of zanubrutinib and ibrutinib in patients with WM who required therapy. Between January 2017 and July 2018, 164 R/R and 37 unfit treatment-naive patients with WM were recruited into cohort 1 (patients with MYD88 mutation) who were randomized 1:1 to receive either ibrutinib (420 mg once a day) or zanubrutinib (160 mg twice a day) in 28-day cycles. Cohort 2 was a non-randomized, no-comparator arm which included 28 patients (wild-type or unknown MYD88 mutation status) including 23 R/R and 5 unfit treatment-naive patients who all received zanubrutinib (160 mg twice a day). The primary efficacy end point was the proportion of patients in each arm of cohort 1 achieving either CR or VGPR, as determined by an Independent Review Committee (IRC) using an adaptation of the response criteria updated at the IWWM-6. Other end points included DOR, PFS, improvement in cancer-related symptoms, OS, HRQoL, and medical resource utilization.
The most common indications (> 20%) for therapy initiation in cohort 1 were fatigue (57.2%), anemia (43.8%), B symptoms (30.3%), hyperviscosity (26.9%), and peripheral neuropathy (22.4%). The median age of all patients was 70.0 years. The majority of patients were male (66.7%), and white (91.0%). In cohort 2, the median age was 72 years; 50% of patients were male and 96.4% were white. The most common indications for therapy initiation were fatigue (60.7%), B symptoms (35.7%), anemia (32.1%), hyperviscosity (21.4%), and peripheral neuropathy (10.7%).
The median follow-up time in cohort 1 was 19.4 months. The IRC-assessed CR/VGPR rate in the ibrutinib and zanubrutinib arms was 19.2% (95% CI, 12.0%, 28.3%) and 28.4% (95% CI, 19.9%, 38.2%), respectively. In R/R patients, the IRC-assessed CR/VGPR rate was 19.8% (95% CI, 11.7%, 30.1%) in the ibrutinib arm and 28.9% (95% CI, 19.5%, 39.9%) in the zanubrutinib arm (P = 0.116). In unfit treatment-naive patients, the IRC-assessed CR/VGPR rate was 16.7% (95% CI, 3.6%, 41.4%) in the ibrutinib arm and 26.3% (95% CI, 9.1%, 51.2%) in the zanubrutinib arm.
Nine patients in the ibrutinib arm and 6 patients in the zanubrutinib arm started non-protocol anti-cancer therapy. The median time to initiation of non-protocol anti-cancer therapy were 6.44 months in the ibrutinib treatment arm and 6.83 months in the zanubrutinib treatment arm. The median PFS had not been reached in either treatment arm. The event-free rates at 12 months for patients in the ibrutinib and zanubrutinib treatment arms were 87.2% (95% CI, 78.6%, 92.5%) versus 89.7% (95% CI, 81.7%, 94.3%), respectively, and 83.8% (95% CI, 74.5%, 89.9%) versus 85.0% (95% CI, 75.2%, 91.2%) at 18 months. The median OS was not reached in either treatment arm. At the data cut-off date (August 31, 2019), 8 deaths occurred in the ibrutinib arm, and 6 deaths occurred in the zanubrutinib arm. The event-free rates for patients in the ibrutinib versus zanubrutinib treatment arms were 93.9% (95% CI, 86.8%, 97.2%) versus 97.0% (95% CI, 90.9%, 99.0%) at 12 months.
HRQoL which was an exploratory end point and on average increased numerically during the trial observation period in both treatment arms. The least square (LS) mean (standard error [SE]) for EORC QLQ-C30 change in global health status/QoL score was 69.0 (2.3) in the ibrutinib arm and 68.3 (2.2) in the zanubrutinib arm (difference [95% CI], −0.69 [-4.95 to 3.57]). The mean (SD) change in EQ-5D-5L score from baseline was 9.0 (17.90) in the ibrutinib arm and 13.7 (14.66) in the zanubrutinib arm (at cycle 13 day 1).
The median follow-up time in cohort 2 was 17.8 months. The IRC-assessed CR/VGPR rate was 26.9% (95% CI, 11.6%, 47.8%). In cohort 2, no patients achieved CR. Three patients (1 unfit treatment-native and 2 R/R) started non-protocol anti-cancer therapy with a median time to initiation of 3.61 months.
In cohort 1, nearly all patients (97 [99.0%] of ibrutinib-treated, and 98 [97.0%] of zanubrutinib-treated patients) had at least 1 AE; grade of at least or greater than 3 AEs were reported in 62 (63.3%) and 59 (58.4%) of patients in the ibrutinib and zanubrutinib treatment arms, respectively. SAEs were reported in 40 (40.8%) and 40 (39.6%) patients in the ibrutinib and zanubrutinib treatment arms, respectively. The most common SAE in the ibrutinib treatment arm was pneumonia (9 [9.2%] patients), followed by pyrexia and sepsis (each 3 [3.1%] patients). The most common SAEs in the zanubrutinib treatment arm were febrile neutropenia, influenza, and neutropenia (each 3 [3.0%] patients). Nine (9.2%) patients in the ibrutinib arm, and 4 (4.0%) patients in the zanubrutinib treatment arm had AEs leading to study treatment discontinuation. A total of 7 (7.1%) patients in the ibrutinib treatment arm and 6 (5.9%) patients in the zanubrutinib treatment arm had died at the time of the data cut-off date; 5 (5.1%) patients in the ibrutinib arm and 1 (1.0%) patient in the zanubrutinib arm died within 30 days of the last dose of study drug.
Notable AEs included neutropenia, hemorrhage (minor and major bleeding), cardiovascular events, and second primary malignancy. In cohort 1, neutropenia was reported in 12 (12.2%) patients in the ibrutinib and 25 (24.8%) patients in the zanubrutinib arm. However, the higher incidence of neutropenia among zanubrutinib-treated patients did not translate to an increased occurrence of infections in the zanubrutinib arm. Fifty-eight (59.2%) patients in the ibrutinib arm and 49 (48.5%) in the zanubrutinib arm had hemorrhage (including minor bleeds involving mucous membranes and skin). Major hemorrhage was observed in 9 (9.2%) patients in the ibrutinib arm and 6 (5.9%) patients in the zanubrutinib arm. Atrial fibrillation and flutter was reported in 14 (14.3%) of patients in the ibrutinib arm and 2 (2.0%) patients in the zanubrutinib treatment arm. Second primary malignancy was reported in 11 (11.2%) patients in ibrutinib arm and 12 (11.9%) patients in the zanubrutinib arm.
The ASPEN trial was an open-label study. Therefore, important sources of bias from lack of blinding of patients and investigators to study treatments exist; patient’s knowledge of their treatment may have affected some safety end points, and different supportive care may have been offered to patients in the 2 treatment arms. The primary end point and key secondary end points were appropriate and adequately described. Data were immature for time to event outcomes and median PFS and OS were not reached in either treatment arm. Given that the ASPEN trial is ongoing, future analyses may be more informative with respect to time to event outcomes. In addition to PFS and OS, time to next treatment was identified in the systematic review protocol as an important efficacy outcome, but this was an exploratory outcome which limits interpretation of results. Some other important outcomes including OS and HRQoL were also exploratory outcomes in the trial. Of note, the only outcome defined in the statistical testing hierarchy, CR/VGPR rate in the R/R patient population of cohort 1, did not reach statistical significance.
Ibrutinib is not the most relevant comparator for zanubrutinib in Canadian clinical practice. The most relevant public-funded comparators for WM in Canadian jurisdictions include rituximab-based chemotherapy for treatment-naive patients and relapsed disease. Therefore, relevance to the current clinical setting is limited and the question of comparative efficacy and safety of zanubrutinib to current standard of care in Canada cannot be answered. The inclusion criteria for the ASPEN study were generally reasonable based on the intended patient population. However, the exclusion of patients with central nervous system (CNS) involvement in the ASPEN trial, although justified at the time the trial was designed due to a lack of disease management guidelines, was not considered appropriate as these patients (i.e., patients with Bing Neel disease) may benefit from early BTK inhibitor treatment. The definition of treatment naive used in the trial was patients who were unsuitable for chemoimmunotherapy based on age or comorbidities. This definition does not align with the standard definition of treatment-naive in oncology practice, which is a patient with no prior anti-cancer therapy. Therefore, the trial evidence regarding the efficacy and safety of zanubrutinib compared to ibrutinib in truly treatment-naive patients is insufficient to guide treatment decisions in this patient population in clinical practice.
The sponsor-submitted ITC that was used to inform the pharmacoeconomic model, was appraised and summarized. A matching-adjusted indirect comparison (MAIC) was conducted based on a systematic literature review that compared the individual patient data of zanubrutinib arm of the ASPEN trial to match the populations of relevant trial reports for chemotherapy regimens in adult patients with treatment-naive, or R/R WM. The analysis was informed by a systematic literature review that identified 33 trials, mainly retrospective that were subsequently excluded from the ITC. In total, 3 trials were included in the MAIC that included mixed, R/R, and treatment-naive WM patients, respectively. The interventions included zanubrutinib, BR, and DRC; however, DRC was used in the treatment-naive population, and BR in the R/R population. Three sets of pairwise MAICs were conducted; 2 pairwise comparisons matched the overall zanubrutinib population (N = 102) to the BR (N = 71) and DRC (N = 72) populations separately. A subgroup analysis was conducted matching zanubrutinib patients with R/R disease to the BR population. No MAIC was conducted specifically comparing the unfit treatment-naive subpopulation in ASPEN given the small sample size of unfit treatment-naive patient population in the zanubrutinib arm of the ASPEN trial (n = 19). Several of the preidentified variables including ECOG performance status, Beta2-microglobulin concentration, and MYD88/CXCR4 mutation status, were not accounted for during weighting due to the limitations of available data. In the MAIC comparing zanubrutinib to BR, the variables included in the weighting process included age, prior lines of therapy, IgM concentration, IPSS WM score, and presence of extramedullary disease. In the MAIC comparing zanubrutinib to DRC, the variables included in weighting were age, platelet count, hemoglobin count, and presence of extramedullary disease.
Results of the MAIC comparing zanubrutinib to BR after weighting suggest that zanubrutinib is favoured over BR, as well as in the R/R subgroup for PFS and OS, however the results lacked precision, showing wide 95% CIs. Zanubrutinib was associated with significantly longer PFS (HR: 0.37 [95% CI, 0.15 to 0.91]) after weighting compared to BR. Compared to DRC, zanubrutinib was associated with significantly longer PFS 0.35 [95% CI, 0.14 to 0.86]) after weighting. The hazard ratio for OS comparing zanubrutinib to BR indicated a statistically significantly longer OS in the overall population after weighting (HR: 0.29 [95% CI, 0.10 to 0.85]). |||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||
No indirect evidence was available for comparative safety or impact on HRQoL of zanubrutinib to relevant chemotherapy regimens.
The ITC was informed by an appropriately conducted systematic review of the literature, highlighting the relevant population, and outcomes of interest for this review. Screening was conducted based on standard methods, with studies selected independently in duplicate, according to pre-specific criteria. No formal quality assessment of the included studies was conducted which is an important limitation. The sponsor’s submitted MAIC, assumes that all effect modifiers and prognostic factors are accounted for in the model. A comprehensive list of prognostic factors and treatment-effect modifiers identified through appropriate channels was included in the report and based on discussions with the clinical experts consulted by CADTH, were considered relevant; however, some of these factors; including ECOG performance status, B2 microglobulin, and MYD88/CXCR4 mutation status were not accounted for in the calculation of weight. This may result in bias as not all prognostic factors and effect modifiers that were originally identified were accounted for in the weights. Additionally, there were discrepancies between the cutoffs of identified variables, and those available for weighting, potentially further biasing the results. In terms of external validity, the studies selected for indirect comparison included treatment with DRC in the treatment-naive population, and BR in the R/R population. In discussion with the clinical experts consulted by CADTH, the comparison to DRC in the treatment-naive, first-line population was considered irrelevant as it does not reflect clinical practice in Canada. No studies were identified in the SLR reporting results for BR in the treatment-naive population, which is the standard of care in Canada, and were thus not included in the analysis for treatment-naive patients. Moreover, no studies were included in the treatment-naive population for patients whom chemoimmunotherapy was considered unsuitable.
Summary of Economic Evaluation.
Based on the CADTH base case, the budget impact of the reimbursement of zanubrutinib for the treatment of WM is expected to be $3,075,366 in year 1, $5,673,159 in year 2, $8,665,803 in year 3, with a 3-year budget impact of $17,414,328. CADTH estimated the budget impact in the first-line setting to be $4,435,153 and $12,979,175 in the second-line setting over 3 years. This was more than twice as large as the sponsor’s estimated 3-year budget impact of $5,125,851 ($1,510,557 in the first-line setting and $3,615,293 in the second-line setting).
Dr. Maureen Trudeau (Chair), Dr. Catherine Moltzan, 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. Christopher Longo, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik.
Meeting date: October 13, 2021
Regrets: Two expert committee members did not attend.
Conflicts of interest: None.
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Indication: For the treatment of patients with Waldenström macroglobulinemia
Sponsor: BeiGene Canada ULC
Final recommendation: Reimburse with conditions
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