Reimbursement Review

Venetoclax (Venclexta)

Sponsor: AbbVie Corporation

Therapeutic area: Mantle cell lymphoma (MCL)

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

MCL = mantle cell lymphoma; NOC = Notice of Compliance.

Source: Draft product monograph for venetoclax.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²

Introduction

Mantle cell lymphoma (MCL) is a frequently aggressive subtype of B-cell non-Hodgkin lymphoma (NHL), accounting for approximately 5% to 7% of NHL cases.^3,4 In Canada, NHL is estimated to account for 11,700 new cases in 2024,⁵ with a 5-year prevalence of 32,915 cases in 2018.⁶ MCL, although representing a small subset of NHL cases, remains a significant clinical challenge due to its aggressive nature. Nearly all patients with MCL require systemic therapy, and the vast majority eventually experience relapsed or refractory disease.^7,8 MCL primarily affects older adults, with an average age of diagnosis between 60 and 70 years, and occurs 4 times more frequently in men.^3,9 The disease follows a progressive course, often involving the lymph nodes, bone marrow, spleen, and gastrointestinal tract.¹⁰ Patients typically present with symptoms such as painless lymphadenopathy, fatigue, night sweats, fever, or weight loss, which can significantly impact their health-related quality of life (HRQoL). MCL has an unfavourable prognosis, with a varying median overall survival of 2 to 10 years.^2,10-15 Diagnosis of MCL requires a comprehensive clinical evaluation, including a detailed patient history, physical examination, and specialized diagnostic testing. Diagnostic tests for MCL, including immunohistochemistry (IHC), molecular assays, and genetic testing, are widely available in Canada and are routinely used in clinical practice.²

According to the clinical experts consulted by the CDA-AMC review team, MCL is noncurable with most therapies, and the goal of first-line treatment is to achieve remission, delay progression, and improve survival. The choice of first-line chemoimmunotherapy (CIT) is determined based on patient age, fitness, comorbidities, and institutional preferences. Younger patients (aged up to approximately 65) who are medically fit and have not received prior treatment for MCL are typically treated with intensive rituximab-based CIT (e.g., rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin], vincristine sulfate [oncovin], and prednisone [R-CHOP] and rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP]; bendamustine-rituximab and cytarabine-rituximab; bendamustine-rituximab) followed by autologous stem cell transplant (ASCT) and rituximab maintenance therapy for responding patients.¹⁶ Older or medically unfit patients with treatment-naive MCL are typically treated with lower-intensity CIT (e.g., bendamustine-rituximab), followed by rituximab maintenance therapy.¹⁷ Most patients with MCL are not cured by first-line treatments and eventually experience disease progression and require second-line treatments.¹⁸ For these patients with relapsed or refractory MCL, ibrutinib, a first-generation covalent Bruton’s tyrosine kinase inhibitor (BTKi), is a standard second-line treatment in Canada.⁸ Zanubrutinib and acalabrutinib, second-generation BTKis, have been approved by Health Canada for relapsed or refractory MCL;^19,20 however, neither of them are currently publicly funded in Canada. Furthermore, most patients with MCL are not cured by second-line treatment with ibrutinib and are treated with third-line treatment, according to the clinical experts consulted by the CDA-AMC review team. Chimeric antigen receptor (CAR) T-cell therapy with brexucabtagene autoleucel is the third-line standard of care in Canada for patients with relapsed or refractory MCL who have been treated with 2 or more lines of prior systemic therapy, including a BTKi.²¹

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of venetoclax, 10 mg, 50 mg, and 100 mg tablets, taken orally, in the treatment of adult patients with relapsed or refractory MCL.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to our call for input and from clinical expert(s) consulted by for the purpose of this review.

Patient Input

CDA-AMC received 1 patient group input for this review from Lymphoma Canada. Lymphoma Canada collected patient input through an online anonymous survey between January and March 2025, gathering 82 responses from patients with MCL, with 5 patients who had received venetoclax plus ibrutinib (3 from Canada). Most of all survey respondents were living in Canada (74%), aged between 65 to 74 years (36%), with diagnoses 3 to 5 years ago (27%), or 9 to 10 years ago or more (24%).

The survey respondents reported significant impacts of MCL on their quality of life, with 28% reporting fatigue and 15% experiencing neutropenia. Patients also reported psychological challenges (with 72% experiencing stress, 70% anxiety, and 64% fear of progression) as well as mental health challenges (with 74% reporting fear of relapse and 38% having difficulty sleeping). Aspects of daily life were impacted, such as the ability to travel (38%), work (28%), and engage in social activities (20%), with many patients highlighting the challenges of managing a compromised immune system, isolation, and physical limitations due to treatment side effects.

Regarding current treatments for MCL, most respondents received 1 (56%) line of treatment. In second line or beyond, 29% of the respondents received stem cell transplants and 15% received BTKis. While 78% were satisfied with first-line treatments, satisfaction dropped for second-line (27%) and third-line (13%) options, indicating a need for more alternatives. Side effects such as fatigue, nausea, and joint pain were common and severely impacted patients’ quality of life. Patients expressed their desire to have more treatment options, especially for second- and third-line therapies.

Patients with MCL surveyed by Lymphoma Canada highlighted key outcomes of new treatments, including longer disease remission and survival, and better quality of life and symptom control. A majority (91%) were willing to tolerate mild, short-term side effects for better options, and 76% valued having treatment choices based on side effects and outcomes.

Five patients in the survey received a combination of venetoclax and ibrutinib in the second-line setting, with 1 patient newly in remission, 3 patients in remission for 1 to 2 years, and 1 patient experiencing a relapse after treatment. Reported side effects included diarrhea (3 patients), neutropenia (2 patients), fatigue (2 patients), joint pain (1 patient), and constipation (1 patient). Psychological impacts included anxiety (3 patients) and fear of progression (2 patients).

Clinician Input

Input From Clinical Experts Consulted for This Review

The clinical experts consulted by the CDA-AMC review team noted that the goal of first-line treatment for MCL is to achieve remission, delay progression, and improve survival. Treatments for patients with relapsed or refractory MCL are usually not curative, and most patients eventually experience disease progression. The clinical experts noted that ibrutinib was a standard second-line treatment for patients with MCL that has relapsed or is refractory to first-line treatments, but most patients with a response to ibrutinib eventually experience progression. Therefore, there is an unmet need for treatments with long-lasting benefits that are well tolerated for patients with relapsed or refractory MCL in the second-line treatment setting.

All clinical experts agreed that venetoclax plus ibrutinib should become a standard second-line treatment for patients with relapsed or refractory MCL and also noted that ibrutinib and venetoclax may change the current treatment paradigm, replacing ibrutinib monotherapy as the standard second-line treatment for most patients with relapsed or refractory MCL. The clinical experts consulted by the CDA-AMC review team noted that ibrutinib monotherapy could remain an alternative second-line treatment option for some patients.

The clinical experts noted that patients who are best suited for venetoclax plus ibrutinib are those with relapsed or refractory MCL who have received at least 1 prior line of therapy. The clinical experts indicated that venetoclax plus ibrutinib may not be suitable for patients whose disease is refractory to BTKis or BCL2 inhibitors. Other patients unsuited for this therapy include those who are unable or unwilling to perform bloodwork for TLS monitoring; those with serious active infections, severe liver dysfunction, or inability to swallow or absorb oral medications; those who require ongoing treatment with moderate or strong CYP3A inhibitors or inducers; and those with relative contraindications to ibrutinib (e.g., uncontrolled cardiovascular disease).

Assessing response to venetoclax plus ibrutinib generally includes a radiographic assessment after 2 to 3 months of treatment, but assessment may vary between physicians and institutions. Patients with circulating lymphoma cells and/or bone marrow involvement may have a complete blood count with or without bone marrow sampling as part of response assessment. For patients who demonstrate a response to venetoclax plus ibrutinib, treatment is continued for up to 2 years followed by ibrutinib monotherapy until disease progression or unacceptable intolerance. Subsequent imaging depends on the depth of initial response and the discretion of the treating physician.

According to the clinical experts, venetoclax should be given for a fixed-duration course of up to 2 years, while ibrutinib should be continued indefinitely. Either drug may be discontinued earlier for patients who experience disease progression or develop refractory disease or for those who experience unacceptable toxicities. The clinical experts noted that, although drugs are normally discontinued due to disease progression, in real-world practice, they may be continued while planning for the next line of therapy. The clinical experts noted that, when 1 drug is discontinued due to intolerance, it does not necessarily mean the other drug should also be discontinued at the same time, given that ibrutinib and venetoclax have different side effect profiles. The decision to discontinue either or both drugs should be made by the treating physician.

According to the clinical experts consulted by the CDA-AMC review team, venetoclax plus ibrutinib should be prescribed by a hematologist or oncologist who is familiar with the management of MCL and has knowledge regarding the safety, efficacy, and monitoring requirements of each drug, particularly regarding risk of tumour lysis syndrome (TLS) with venetoclax and cardiovascular toxicities of ibrutinib. Venetoclax plus ibrutinib (including the ramp-up phase of venetoclax) can be administered in the outpatient setting at tertiary care and community hospitals in urban and rural locations.

Clinician Group Input

CDA-AMC received input from 2 clinician groups, the Ontario Health Cancer Care Ontario (OH-CCO) Hematology Cancer Drug Advisory Committee (Hem DAC) and Lymphoma Canada Physician Group. OH-CCO Hem DAC provided input via a teleconference involving 7 clinicians. Lymphoma Canada Physician Group reviewed clinical trials, provincial guidelines, and a review on relapsed or refractory MCL by 5 experts.

According to the clinician groups, the goal of therapy for patients with MCL is long-term progression-free survival (PFS) and overall survival (OS), resolution of lymphoma-related symptoms, and improvement in quality of life. The clinician groups noted that treatment for patients with relapsed or refractory MCL includes BTKis (ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib), CIT, and bortezomib-based options. The groups highlighted that, while BTKis are standard second-line therapy, their effectiveness declines, and relapse after BTKi remains a major unmet need. Both clinician groups highlighted significant treatment gaps for relapsed or refractory MCL, as no curative therapies exist. Current treatments offer limited survival benefits, with poor outcomes after BTKi failure (average survival is under 6 months). The Lymphoma Canada Physician Group noted that, while CAR T-cell therapy is now funded in Canada, access remains restricted to specialized centres and selected patients. Most patients with MCL that relapses do not qualify, leaving palliative options as the only alternative. There is a critical need for novel, well-tolerated treatment combinations to improve survival, delay disease progression, and enhance quality of life for the majority of patients.

The clinician groups noted that venetoclax plus ibrutinib is suitable as a second-line treatment option for relapsed or refractory MCL. According to the clinician groups, suitable candidates include patients eligible for BTKi treatment, particularly those who do not have BTKi-refractory disease. They further noted that, as a fully oral therapy, the combination of venetoclax and ibrutinib is suited for outpatient care and accessible in both community and academic settings. It should be prescribed by a hematologist managing MCL.

Drug Program Input

Input was obtained from the drug programs that participate in the reimbursement review process. The following were identified as key factors that could affect the implementation of a recommendation for venetoclax.

• Relevant comparators

• Consideration for prescribing of therapy

• Generalizability

• Funding algorithm

• Care provision issues

• System and economic issues.

Clinical Evidence

Systematic Review

Description of Studies

One study (SYMPATICO) was identified from the sponsor-submitted systematic literature review. The SYMPATICO trial consisted of an open-label safety run-in phase, a double-blind randomized phase, and an open-label treatment-naive cohort. The primary focus for this review is the randomized phase of SYMPATICO, which was a phase III, multicentre, double-blind randomized controlled trial (RCT) investigating the efficacy and safety of venetoclax plus ibrutinib in patients with MCL who have received at least 1, but no more than 5, prior treatment regimens for MCL, including at least 1 prior rituximab- or anti-CD20–containing regimen. A total of 267 patients (including ██ patients in Canada) were randomized to the venetoclax plus ibrutinib group (n = 134) or the placebo plus ibrutinib group (n = 133). The primary objective of the randomized phase of SYMPATICO was to assess the efficacy of venetoclax plus ibrutinib relative to placebo plus ibrutinib, as measured by PFS per investigator assessment. Secondary end points included OS and harms. HRQoL outcomes such as Functional Assessment of Cancer Therapy — Lymphoma (FACT-Lym) total score and the lymphoma-specific subscale of FACT-Lym were also reported.

Patients in the intention-to-treat (ITT) population of the randomized phase of SYMPATICO had a median age of 68 years (range, ██ ██ ██). There were more male patients than female patients (79.0% versus 21.0%). Most patients were white (86.5%), followed by Asian (1.9%), and Black or African American (0.7%). Approximately 59.6%, 23.6%, and 16.9% of the ITT population had received 1, 2, or 3 or more lines of therapies before receiving venetoclax plus ibrutinib, respectively.

Efficacy Results

The data cut-off date was May 22, 2023 (database lock date: July 5, 2023). The median time on study was █████ ██████ (range, ███ to ████) for the venetoclax plus ibrutinib group and █████ months (range, ███ to ████) for the placebo plus ibrutinib group.

Overall Survival

In the interim analysis of OS, the proportion of the ITT population who had OS events was 51.5% in the venetoclax plus ibrutinib group versus 56.4% in the placebo plus ibrutinib group. The median OS was 44.9 months (95% confidence interval [CI], 31.9 months to not estimable [NE]) in the venetoclax plus ibrutinib group versus 38.6 months (95% CI, 25.2 to 53.4 months) in the placebo plus ibrutinib group. The hazard ratio (HR) for death was 0.854 (95% CI, 0.615 to 1.186). At 12 months, the probability of being alive was ████% (95% CI, ████ to ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ to ████) for the placebo plus ibrutinib group (between-group difference = ████%; 95% CI, █████ ██ ███). At 24 months, the probability of being alive was 65.9% (95% CI, 57.2% to 73.3%) for the venetoclax plus ibrutinib group and 61.4% (95% CI, 52.5% to 69.1%) for the placebo plus ibrutinib group (between-group difference = 4.5%; 95% CI, −7.0% to 16.2%). At 36 months, the probability of being alive was ████% (95% CI, ████ to ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ to ████) for the placebo plus ibrutinib group (between-group difference = ███%; 95% CI, ████ to ████). At 48 months, the probability of being alive was ████% (95% CI, ████ to ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ to ████) for the placebo plus ibrutinib group (between-group difference = ███%; 95% CI, –███ to ████). At 60 months, the probability of being alive was ████% (95% CI, ████ to ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ to ████) for the placebo plus ibrutinib group (between-group difference = ███%; 95% CI, █████ to ████).

PFS Per Investigator Assessment

The proportion of the ITT population who had PFS events was 54.5% in the venetoclax plus ibrutinib group and 70.7% in the placebo plus ibrutinib group. The median PFS per investigator assessment was 31.9 months (95% CI, 22.8 to 47.0 months) in the venetoclax plus ibrutinib group versus 22.1 months (95% CI, 16.5 to 29.5 months) in the placebo plus ibrutinib group. The HR for PFS per investigator assessment was 0.645 (95% CI, 0.474 to 0.878). At 12 months, the probability of being progression-free was ████% (95% CI, ████ to ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ to ████) for the placebo plus ibrutinib group (between-group difference = ████%; 95% CI, ████ to ████). At 24 months, the probability of being progression-free was 56.8% (95% CI, 47.7% to 64.9%) for the venetoclax plus ibrutinib group and 45.4% (95% CI, 36.5% to 53.8%) for the placebo plus ibrutinib group (between-group difference = 11.4%; 95% CI, −0.8% to 23.7%). At 36 months, the probability of being progression-free was ████% (95% CI, ████ to ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ to ████) for the placebo plus ibrutinib group (between-group difference = ████; 95% CI, ███ to ████). At 48 months, the probability of being progression-free was ████% (95% CI, ████ to ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ to ████) for the placebo plus ibrutinib group (between-group difference = ████%; 95% CI, ███ to ████). At 60 months, the probability of being progression-free was ████% (95% CI, ████ to ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ to ████) for the placebo plus ibrutinib group (between-group difference = ████%; 95% CI, ███ to ████).

The overall concordance for the PFS events was ████% for the venetoclax plus ibrutinib group and ████% for the placebo plus ibrutinib group.

FACT-Lym Total Score

The FACT-Lym total score ranges between 0 and 168, with a higher score indicating a better HRQoL.

The difference in change from baseline FACT-Lym total score between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group was ████ points (95% CI, █████ to ███) at ██ ██████ and ███ ██████ (95% CI, █████ to ████) at ██ ██████.

Lymphoma-Specific Subscale of FACT-Lym

The lymphoma-specific subscale of FACT-Lym ranges between 0 and 60, with a higher score indicating a better HRQoL.

The difference in change from baseline for the lymphoma-specific subscale of FACT-Lym score between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group was ████ ██████ (95% CI, ████ to ███) at ██ ██████ and ████ points (95% CI, ████ to ███) at ██ ██████.

Harms Results

The proportion of patients who had treatment-emergent adverse events (TEAEs) of grade 3 or higher was 83.6% in the venetoclax plus ibrutinib group versus 75.8% in the placebo plus ibrutinib group. The most common TEAEs of grade 3 or higher included neutropenia (31.3% in the venetoclax plus ibrutinib group versus 10.6% in the placebo plus ibrutinib group), pneumonia (12.7% in the venetoclax plus ibrutinib group versus 10.6% in the placebo plus ibrutinib group), thrombocytopenia (12.7% in the venetoclax plus ibrutinib group versus 7.6% in the placebo plus ibrutinib group), and worsening of MCL (6.7% in the venetoclax plus ibrutinib group versus 12.1% in the placebo plus ibrutinib group).

The proportion of patients who had treatment-emergent serious adverse events (TESAEs) was 60.4% in the venetoclax plus ibrutinib group versus 59.8% in the placebo plus ibrutinib group. The most common TESAE was pneumonia (12.7% in the venetoclax plus ibrutinib group versus 10.6% in the placebo plus ibrutinib group), followed by worsening of MCL (6.7% in the venetoclax plus ibrutinib group versus 12.9% in the placebo plus ibrutinib group).

Venetoclax or placebo were discontinued due to TEAEs in 22.4% of the patients in the venetoclax plus ibrutinib group versus 28.8% in the placebo plus ibrutinib group. Ibrutinib was discontinued due to TEAEs in 29.1% of the patients in the venetoclax plus ibrutinib group versus 31.1% in the placebo plus ibrutinib group. The proportion of patients with any adverse event (AE) with outcome of death was 16.4% in the venetoclax plus ibrutinib group versus 13.6% in the placebo plus ibrutinib group. The most common reason was worsening of MCL (3.0% in the venetoclax plus ibrutinib group versus 7.6% in the placebo plus ibrutinib group).

Treatment-emergent major hemorrhage, which included serious or grade 3 or higher hemorrhage and central nervous system (CNS) hemorrhage of any grade, occurred in ████ of the patients in the venetoclax plus ibrutinib group versus ████ in the placebo plus ibrutinib group. Atrial fibrillation of any grade occurred in 10.4% of the patients in the venetoclax plus ibrutinib group versus 10.6% in the placebo plus ibrutinib group. The percentage of patients who had cardiac arrhythmias (excluding atrial fibrillation) of any grade was █████ in the venetoclax plus ibrutinib group versus █████ in the placebo plus ibrutinib group. The percentage of patients who had TLS of any grade was 5.2% in the venetoclax plus ibrutinib group versus 2.3% in the placebo plus ibrutinib group. There were 4 deaths possibly due to cardiac-related causes in the venetoclax plus ibrutinib group and 2 deaths in the placebo plus ibrutinib group.

Critical Appraisal

Internal Validity

In the randomized phase of SYMPATICO, only results from the interim OS analysis were available for this review, which was considered immature, as the upper bound of the 95% CI of the median OS in the venetoclax plus ibrutinib group was NE. As a result, uncertainty remains in the interim OS evidence, which may be addressed by the final OS analysis. ██ █████ ██ ███ ██████████████ ████████ ██ ███████ ██ ████████████ ███ ███████ █████████ ████ █████ ██ ██ ████ ██ ██████ ██████████ ██ █████ █████ ████ ███ ███████ ██ █████ ███ ███ ██████ ██ ███████████ Two sets of censoring rules were used in estimating PFS: the global censoring rules for the primary analysis and the FDA censoring rules for 1 of the sensitivity analyses. In the global censoring rules, patients without progression or death were censored, while, in the FDA censoring rules, 2 additional censoring scenarios were added to the global censoring rules, i.e., patients without progressive disease or death, with subsequent anticancer therapy, or with 2 or more missed visits before the PFS event were censored. There was a large difference in median PFS in the venetoclax plus ibrutinib group (approximately a 10-month increase) but not in the placebo plus ibrutinib group (no change) between the primary PFS analysis (i.e., per the global censoring rules) and the PFS sensitivity analysis per the FDA censoring rules, as noted by the review team and other.²³ This indicated that the patients in the venetoclax plus ibrutinib group who were censored by the additional 2 scenarios of the FDA rules were not equally likely to experience disease progression, compared to those who were not censored. Specifically, the additionally censored patients in the venetoclax plus ibrutinib group were at a higher risk, which would have violated the noninformative censoring assumption of the Kaplan-Meier (KM) method, skewed the KM curve, and resulted in an overestimation of median PFS in the analysis with the FDA censoring rules.^23,24 Moreover, as Lesan et al. pointed out,²³ the possibility of overestimation in the PFS primary analysis using the global censoring rules could not be ruled out because, for example, in the primary PFS analysis, patients who missed visits were not censored. Given that these patients could be at a higher risk of disease progression (as suggested by the sensitivity analysis using the FDA censoring rules), not counting these patients as having a PFS event may have overestimated median PFS. There was a risk of unblinding in patients or investigators due to a higher occurrence of digestive AEs in the venetoclax plus ibrutinib group compared to the placebo plus ibrutinib group and a higher percentage of patients in the venetoclax plus ibrutinib group who were treated for these digestive AEs. If patients became unblinded, there was a risk of bias in the assessment of HRQoL outcomes. There was also a risk of missing outcome data for HRQoL outcomes. For instance, around half of the ITT population was missing when assessing the FACT-Lym total score and the lymphoma-specific subscale of FACT-Lym at 24 months. There was no description of how the missing data were handled for the HRQoL outcomes. Therefore, it is uncertain how the missing HRQoL data impacted the results observed.

External Validity

The eligibility criteria of the randomized phase of SYMPATICO were in general aligned with the selection criteria in the Canadian setting when identifying eligible patients with MCL in the relapsed and refractory setting, according to the clinical experts consulted by the review team. However, the clinical experts noted that some patients who might benefit from venetoclax plus ibrutinib were not included in the randomized phase of SYMPATICO, including selected patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) greater than 2; patients who have previously been exposed, but whose disease is not refractory, to venetoclax or ibrutinib; patients without at least 1 site of disease of 2.0 cm (e.g., leukemic MCL), and patients with CNS lymphoma, which is rare. Nonetheless, results from the randomized phase of SYMPATICO were still likely to be generalizable to these patients.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^25,26

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. If this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The reference points for the certainty of evidence assessment for OS and PFS per investigator assessment were set according to the presence of an important effect based on thresholds agreed upon by clinical experts consulted by the review team for this review. The reference points for the certainty of evidence assessment for the FACT-Lym total score, the lymphoma-specific subscale of FACT-Lym, and harms events were set according to the presence of any non-null effect.

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:

• Survival outcomes (OS, PFS per investigator assessment)

• HRQoL outcomes (FACT-Lym total score, lymphoma-specific subscale of FACT-Lym)

• Harms (TESAEs).

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for venetoclax plus ibrutinib versus placebo plus ibrutinib for patients with MCL who have received at least 1, but no more than 5, prior treatment regimens.

Table 2: Summary of Findings for Venetoclax Plus Ibrutinib Versus Placebo Plus Ibrutinib for Patients With MCL Who Have Received at Least 1, But No More Than 5, Prior Treatment Regimens

CI = confidence interval; FACT-Lym = Functional Assessment of Cancer Therapy — Lymphoma; MCL = mantle cell lymphoma; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; TESAE = treatment-emergent serious adverse event.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 2 levels for very serious imprecision. According to the clinical experts consulted by the CDA-AMC review team, a 5% difference (50 per 1,000) between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group in the probability of being alive could be considered clinically important (i.e., minimal important difference [MID]). The point estimate suggested little to no difference, while the upper and lower bounds of the 95% CI crossed the MID and the null (i.e., 0), respectively.

^bRated down 1 level for serious imprecision. According to the clinical experts consulted by the CDA-AMC review team, a 7% (70 per 1,000) difference between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group in the probability of being progression-free could be considered clinically important (i.e., MID). The point estimate suggested benefits, while the upper bound of the 95% CI crossed the MID.

^cCertainty of evidence was not rated down as there were no serious concerns in risk of bias, indirectness, inconsistency, and imprecision.

^dRated down 2 levels for serious risk of bias. Although the randomized phase of SYMPATICO adopted a double-blind study design, there was a risk of unblinding due to the high between-group imbalance in the occurrence of some adverse events such as diarrhea (64.9% versus 34.1%) and nausea (31.3% versus 16.7%). Moreover, there was a risk of bias due to data missing from a high percentage of patients. Rated down 2 levels for very serious imprecision given that the 95% CIs of the mean difference crossed the null threshold of 0.

^eRated down 2 levels for imprecision. The 95% CI crossed the null, suggesting both benefit and harm.

Source: SYMPATICO Clinical Study Report²⁷ and sponsor response to CDA-AMC request for additional information.^22,28

Long-Term Extension Studies

No long-term extension studies were identified for this review.

Indirect Comparisons

No indirect evidence was identified for this review.

Studies Addressing Gaps in the Evidence from the Systematic Review

No studies addressing gaps in the pivotal and RCT evidence were identified for this review.

Conclusions

The randomized phase of the SYMPATICO trial, a phase III, double-blind RCT, assessed the efficacy and safety of venetoclax plus ibrutinib relative to placebo plus ibrutinib in patients with MCL who have received at least 1, but no more than 5, prior treatment regimens for MCL. The interim analysis of OS, based on OS data that were immature at the time of analysis, indicated that venetoclax plus ibrutinib may result in little to no difference in the probability of being alive at 48 or 60 months, compared to placebo plus ibrutinib. The certainty of the interim OS evidence was low, which may be addressed in the final OS analysis. Added clinical benefit was observed with venetoclax plus ibrutinib in the trial’s designated primary efficacy outcome — PFS per investigator assessment. Venetoclax plus ibrutinib, compared to placebo plus ibrutinib, likely results in a clinically meaningful improvement in the probability of being progression-free at 36 and 60 months, based on moderate- to high-certainty evidence. However, the possibility of overestimation in the PFS benefits could not be ruled out due to the informative censoring observed in the PFS sensitivity analysis, whereby patients censored might have been at a higher risk of having disease progression. Venetoclax plus ibrutinib appears to be overall safe, and the safety profile of venetoclax plus ibrutinib is consistent with the known harms for the individual components of the regimen.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of venetoclax, 10 mg, 50 mg, and 100 mg tablets, taken orally, in the treatment of adult patients with relapsed or refractory MCL.

Disease Background

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

MCL is a frequently aggressive subtype of B-cell NHL, accounting for approximately 5% to 7% of NHL cases.^3,4 It primarily affects older adults, with an average age of diagnosis between 60 and 70 years, and occurs 4 times more frequently in men.^3,9 The disease follows a progressive course, often involving the lymph nodes, bone marrow, spleen, and gastrointestinal tract.¹⁰ Patients typically present with symptoms such as painless lymphadenopathy, fatigue, night sweats, fever, or weight loss, which can significantly impact their HRQoL. MCL has an unfavourable prognosis, with a varying median OS of 2 to 10 years.^{2,10-15,29-31}

In Canada, NHL is estimated to account for 11,700 new cases in 2024,⁵ with a 5-year prevalence of 32,915 cases in 2018.⁶ MCL represents a small subset of these cases, yet it remains a significant clinical challenge due to its frequently aggressive nature. Nearly all patients with MCL require systemic therapy, and the majority eventually experience relapsed or refractory disease.^7,8

Diagnosis of MCL requires a comprehensive clinical evaluation, including a detailed patient history, physical examination, and specialized diagnostic testing. A biopsy of an affected lymph node or bone marrow sample is essential for confirming the presence of MCL.³² Histopathological examination typically reveals a monomorphic proliferation of small to medium lymphoid cells with irregular nuclear contours.³³ The disease is definitively diagnosed through IHC, detecting cyclin D1 overexpression in 98% of cases, or by identifying the t(11;14)(q13;32) translocation through molecular or cytogenetic methods.³³

Accurate classification of MCL is crucial for treatment planning. The 2022 International Consensus Classification and WHO classifications divide MCL into indolent and aggressive forms.^34,35 Classical MCL is the more common, aggressive subtype, whereas leukemic non-nodal MCL follows a more indolent course. Prognostic risk stratification includes assessment of the following: blastoid or pleomorphic morphology, increased Ki-67 nuclear protein (e.g., > 30% to 50%), and the Mantle Cell Lymphoma International Prognostic Index-combined.³⁶ Additionally, genetic testing, including fluorescence in situ hybridization (FISH) or next-generation sequencing, may be conducted to assess high-risk mutations such as TP53 deletions or mutations, which are present in approximately 11% of patients with MCL and are associated with poor outcomes.^17,37-40 Diagnostic tests for MCL, including IHC and FISH, are widely available in Canada and are routinely used in clinical practice.² Molecular testing is not widely available in the standard-of-care setting.

Standards of Therapy

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

According to the clinical experts consulted by the CDA-AMC review team, MCL is not curable with most therapies, and the goal of first-line treatment is to achieve remission, delay progression, and improve survival. The choice of first-line CIT is based on patient age, fitness, comorbidities, and institutional preferences. Younger patients (aged up to approximately 65) and medically fit patients with treatment-naive MCL are typically treated with intensive rituximab-based CIT (e.g., R-CHOP and R-DHAP, bendamustine-rituximab and cytarabine-rituximab, bendamustine-rituximab), followed by ASCT and maintenance therapy with rituximab for responding patients.¹⁶ Older or medically unfit patients with treatment-naive MCL are typically treated with lower-intensity CIT (e.g., bendamustine-rituximab) followed by rituximab maintenance.¹⁷

Most patients with MCL are not cured by first-line treatments, eventually experience disease progression, and require second-line treatments.¹⁸ For these patients with relapsed or refractory MCL, ibrutinib, a first-generation covalent BTKi, is a standard second-line treatment in Canada.⁸ Zanubrutinib and acalabrutinib, second-generation BTKis, have been approved by Health Canada for relapsed or refractory MCL.^19,20 However, neither of them are currently publicly funded in Canada. According to the clinical experts consulted by the CDA-AMC review team, zanubrutinib and acalabrutinib may be available through special access programs in Canada. A small number of patients with relapsed or refractory MCL who are ineligible for BTKi due to existing cardiovascular risk may receive CIT or other nonfunded therapies.⁸

Furthermore, most patients with MCL are not cured by second-line treatment with ibrutinib and will receive third-line treatment, according to the clinical experts consulted by the CDA-AMC review team. CAR T-cell therapy with brexucabtagene autoleucel is the third-line standard of care in Canada for medically fit patients with relapsed or refractory MCL and who have been treated with 2 or more lines of prior systemic therapy, including a BTKi.²¹ According to the clinical experts consulted by the CDA-AMC review team, for patients unsuitable for CAR T-cell therapy (e.g., older or patients with comorbidities), alternative options include noncovalent BTKis such as pirtobrutinib, which is not yet funded in Canada but may be available through compassionate access programs; bortezomib- or lenalidomide-based therapies, which are not universally funded in Canada; CIT; venetoclax, which may be available through compassionate access programs; investigational treatments through clinical trials; or palliative or best supportive care. Allogeneic hematopoietic cell transplant is also an option for younger, medically fit patients.

Drug Under Review

Key characteristics of venetoclax are summarized in Table 3 with other treatments available for MCL in adult patients. Venetoclax has not been previously reviewed by CDA-AMC for MCL.

Venetoclax exerts its antitumour effects by selectively inhibiting BCL2, a protein that prevents apoptosis in malignant cells.¹ BCL2 overexpression is a key driver of chemotherapy resistance in many hematologic cancers, including MCL, making it a critical therapeutic target. By binding to BCL2 and disrupting its interaction with proapoptotic proteins, venetoclax restores apoptotic signalling, leading to cell death.¹

Venetoclax was approved by Health Canada on July 31, 2025, for use in combination with ibrutinib for adult patients with relapsed or refractory MCL. Venetoclax is an oral BCL2 inhibitor available in 10 mg, 50 mg, and 100 mg film-coated tablets.¹ The dosing regimen begins with a starting dose of 20 mg once daily for 7 days, followed by a weekly ramp-up schedule over 5 weeks to a recommended daily dose of 400 mg, i.e., 20 mg (2 × 10 mg) in week 1, 50 mg (1 × 50 mg) in week 2, 100 mg (1 × 100 mg) in week 3, 200 mg (2 × 100 mg) in week 4, and 400 mg (4 × 100 mg) in week 5.¹ This gradual dose escalation helps reduce tumour burden and mitigate the risk of TLS.¹ When used for MCL, venetoclax is initiated on day 1 alongside ibrutinib 560 mg once daily.¹ After the 5-week ramp-up phase, venetoclax is continued at 400 mg daily with ibrutinib for an additional 23 months, followed by ibrutinib monotherapy until disease progression or unacceptable toxicity.¹

Sensitivity to venetoclax is enhanced when combined with agents targeting complementary survival pathways, such as BTKis.^41-45 BTKi, given as a single drug, is the current standard option for patients with relapsed or refractory MCL.² Ibrutinib, the only BTKi currently reimbursed for relapsed or refractory MCL across CDA-AMC-participating drug plans, is used as the primary comparator in the pharmacoeconomic analysis.²

Table 3: Key Characteristics of Venetoclax Plus Ibrutinib and Ibrutinib Alone

BTK = Bruton’s tyrosine kinase; BTKi = Bruton’s tyrosine kinase inhibitor; MCL = mantle cell lymphoma; NA = not applicable; TLS = tumour lysis syndrome.

^aHealth Canada–approved indication.

Source: Product monograph for Imbruvica⁴⁶ and draft product monograph for Venclexta.¹

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

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

CDA-AMC received 1 patient group input for this review from Lymphoma Canada, a national charity dedicated to empowering patients and the lymphoma community through education, support, advocacy, and research, while collaborating with stakeholders to improve early detection, treatments, and outcomes for patients with lymphoma. Lymphoma Canada collected patient input through an anonymous online survey between January and March 2025, gathering 82 responses from patients with MCL, with 5 patients who had received combination therapy of venetoclax and ibrutinib. Three of these patients were from Canada. The majority of all survey respondents lived in Canada (74%), were aged between 65 to 74 years (36%), and had received diagnoses 3 to 5 years ago (27%), or 9 to 10 years ago or more (24%).

The survey respondents reported significant impacts of MCL on their quality of life, with common symptoms at diagnosis including fatigue (33%), enlarged lymph nodes (27%), and abdominal issues (22%). Psychosocial challenges were prevalent, with 72% experiencing stress, 70% anxiety, and 64% fear of progression. Approximately 28% of respondents reported fatigue, and 15% reported neutropenia as major concerns. Mental health challenges such as fear of relapse (74%) and difficulty sleeping (38%) were also significant. Aspects of daily life were impacted, such as the ability to travel (38%), work (28%), and engage in social activities (20%), with many patients highlighting the challenges of managing a compromised immune system, isolation, and physical limitations due to treatment side effects.

Regarding current treatments for MCL, 64% of patients required immediate treatment upon diagnosis, while 36% were placed on “watch and wait.” Most patients received 1 (56%) or more than 3 (22%) lines of treatment, with common first-line therapies including:

• bendamustine-rituximab (35%)

• R-CHOP (25%)

• R-DHAP or a combination of carmustine or lomustine, etoposide, cytarabine, and melphalan (BEAM) (12%).

In second-line therapy or beyond, 29% received stem cell transplants and 15% received BTKis. While 78% were satisfied with first-line treatments, satisfaction dropped for second-line (27%) and third-line (13%) options, indicating a need for more alternatives. Side effects such as fatigue, nausea, and joint pain were common and severely impacted patients’ quality of life. Difficulties accessing treatments were reported by 10% of patients, with reasons including financial burdens such as travel and drug costs. These difficulties led to patient frustration over treatment availability and the financial implications of their care. Patients expressed a desire for more treatment options, especially for second- and third-line therapies.

Patients with MCL surveyed by Lymphoma Canada highlighted key outcomes of new treatments, including longer disease remission, survival, quality of life, and symptom control. A majority (91%) were willing to tolerate mild, short-term side effects for better options, and 76% valued having treatment choices based on side effects and outcomes. More than half considered the mode of administration (e.g., oral versus IV) important for their treatment. Most patients (87%) believed more therapy options were needed, emphasizing the importance of targeted therapies and improved treatment experiences.

Five patients responding to the survey had received the combination of venetoclax and ibrutinib in the second-line setting, with 1 newly in remission, 3 in remission for 1 to 2 years, and 1 experiencing relapse after treatment. Reported side effects included diarrhea (3 patients), neutropenia (2 patients), fatigue (2 patients), joint pain (1 patient), and constipation (1 patient). Psychological impacts included anxiety (3 patients) and fear of progression (2 patients). Three patients rated the therapy as very good, while 2 rated it satisfactory, but all 5 would recommend it to other patients with MCL. One patient emphasized the benefits of receiving oral treatment, avoiding hospitalization, and experiencing fewer side effects compared to traditional chemotherapy.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 3 clinical specialists with expertise in the diagnosis and management of MCL.

Unmet Needs

The clinical experts noted that the goal of first-line treatment for MCL is to achieve remission, delay progression, and improve survival. Treatments for patients with relapsed or refractory MCL are rarely curative, and most patients eventually experience disease progression.

The clinical experts noted that ibrutinib is a standard second-line treatment for patients with MCL that has relapsed or is refractory to first-line treatments. It is also the most commonly used, publicly funded second-line treatment for patients with MCL in Canada. The clinical experts indicated that, in most patients who are responding to ibrutinib, MCL will progress eventually, and there are few effective and well-tolerated third-line treatments available in Canada. Also, ibrutinib, although well tolerated by many patients, has potential cardiovascular and other toxicities that make it unsuitable for some patients or that can result in premature treatment discontinuation. Therefore, there is an unmet need for treatments that are more effective, have long-lasting benefits, and are well tolerated for patients with relapsed or refractory MCL in the second-line treatment setting.

Place in Therapy

All clinical experts agreed that venetoclax plus ibrutinib should become a standard second-line treatment for patients with relapsed or refractory MCL and that ibrutinib and venetoclax may change the current treatment paradigm, replacing ibrutinib monotherapy as the standard second-line treatment for most patients with relapsed or refractory MCL. The clinical experts indicated that ibrutinib monotherapy could remain an alternative treatment option in the second-line treatment setting for some patients, e.g., those who have significant renal dysfunction, those who have difficulty coming to hospital for the ramp-up dosing schedule of venetoclax, or those who choose not to receive venetoclax plus ibrutinib combination therapy.

Patient Population

The clinical experts noted that patients who are best suited for venetoclax plus ibrutinib are those who have relapsed or refractory MCL and have received at least 1 prior line of therapy. These patients would be identified by their treating hematologist or oncologist, and no diagnostic test is required. They noted that patients with CNS lymphoma, which is rare, might benefit from venetoclax plus ibrutinib in the real-world setting, given the ability of these drugs to penetrate the blood-brain barrier.

The clinical experts noted that patients with disease refractory to BTKis or BCL2 inhibitors may not be suitable for venetoclax plus ibrutinib. They also noted that there is an increase in the use of BTKis in the first-line treatment setting via compassionate access programs in Canada, although they are not currently funded as first-line therapy in Canada. According to the clinical experts, patients previously exposed to a BTKi or BCL2 inhibitor were excluded from the enrolment in the pivotal SYMPATICO trial. However, in real-world practice, it would be reasonable to re-treat a patient with venetoclax plus ibrutinib if they have achieved a reasonably durable remission (e.g., lasting > 6 to 12 months off treatment) and did not experience disease progression while on therapy.

The clinical experts noted that patients may not be suitable candidates for venetoclax plus ibrutinib in some rare occasions, such as patients who are unable or unwilling to perform bloodwork for TLS monitoring; patients with serious active infections, severe liver dysfunction, or inability to swallow or absorb oral medications; patients require ongoing treatment with moderate or strong CYP3A inhibitors or inducers; and patients with relative contraindications to ibrutinib (e.g., uncontrolled cardiovascular disease).

Assessing the Response Treatment

The clinical experts stated that assessing response to venetoclax plus ibrutinib, which may vary between physicians and institutions, generally includes a radiographic assessment (e.g., PET or CT) after 2 to 3 months of treatment. They noted that patients with circulating lymphoma cells and/or bone marrow involvement may have a complete blood count with or without bone marrow sampling as part of response assessment. Patients who demonstrate a response to venetoclax plus ibrutinib would continue for up to 2 years of treatment with venetoclax plus ibrutinib, followed by ibrutinib monotherapy until disease progression or unacceptable intolerance. Subsequent imaging would depend on the depth of initial response and the discretion of the treating physician.

Discontinuing Treatment

The clinical experts indicated that venetoclax should be given for a fixed-duration course of up to 2 years, while ibrutinib should be continued indefinitely. Either drug may be discontinued earlier for patients who experience disease progression or develop refractory disease while on treatment or for those who experience unacceptable toxicities. The clinical experts consulted by the CDA-AMC review team noted that, although drugs are normally discontinued due to disease progression, in real-world practice, they may be continued while planning for the next line of therapy. They further stated that, when 1 drug is discontinued due to intolerance, it does not necessarily mean the other drug should also be discontinued at the same time, because ibrutinib and venetoclax have different side effect profiles. The decision to discontinue either or both drugs should be made by the treating physician.

Prescribing Considerations

According to the clinical experts, venetoclax plus ibrutinib should be prescribed by a hematologist or oncologist who is familiar with the management of MCL and has knowledge regarding the safety, efficacy, and monitoring requirements of each drug, particularly regarding the TLS risk of venetoclax and cardiovascular toxicities of ibrutinib. They noted that TLS monitoring required during the venetoclax ramp-up may briefly require hospitalization, but most hematologists in Canada are well equipped at managing this. The clinical experts indicated that venetoclax plus ibrutinib (including the ramp-up phase of venetoclax) can be administered in the outpatient setting at tertiary care and community hospitals in urban and rural locations.

Clinician Group Input

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

CDA-AMC received input from 2 clinician groups, OH-CCO Hem DAC and Lymphoma Canada Physician Group. OH-CCO’s Drug Advisory Committees support the Provincial Drug Reimbursement Programs and the Systemic Treatment Program through timely, evidence-based recommendations on drug-related issues. Lymphoma Canada Physician Group is a national organization dedicated to research, education, and raising awareness. OH-CCO Hem DAC provided input via teleconference among 7 clinicians. Lymphoma Canada Physician Group reviewed clinical trials, provincial guidelines, and a review on relapsed or refractory MCL by 5 experts.

According to the clinician groups, the goal of therapy for patients with MCL is long-term PFS and OS, resolution of lymphoma-related symptoms, and improvement in quality of life. The clinician groups noted that treatment for patients relapsed or refractory MCL includes BTKis (ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib), CIT, and bortezomib-based options. Brexucabtagene autoleucel is available as a third-line therapy. First-line treatment depends on patient characteristics and typically involves CIT, often followed by high-dose therapy and ASCT. The groups highlighted that, while BTKis are standard second-line therapy, their effectiveness declines, and relapse after BTKi remains a major unmet need.

Both groups highlighted significant treatment gaps for relapsed or refractory MCL, as no curative therapies exist. Current treatments offer limited survival benefits, with poor outcomes after BTKi failure (average survival is under 6 months). The Lymphoma Canada Physician Group noted that, while CAR T-cell therapy is now funded in Canada, access remains restricted to specialized centres and selected patients. Most patients with MCL that relapses do not qualify for CAR T-cell therapy, leaving palliative options as the only alternative. There is a critical need for novel, well-tolerated treatment combinations to improve survival, delay disease progression, and enhance quality of life for the majority of patients.

The clinician groups noted that the combination of venetoclax and ibrutinib is suitable as a second-line treatment option for relapsed or refractory MCL, as the pivotal trial results showed its benefit in improving PFS and delaying the need for third-line CAR T-cell therapy. According to the clinician groups, suitable candidates include patients eligible for BTKi treatment, particularly those who do not have BTKi-refractory disease. Regular assessments, including imaging and clinical evaluations, are required to monitor response. Discontinuation is recommended in cases of disease progression or severe toxicity, after dose reductions or substitution of ibrutinib with zanubrutinib are tried.

The clinician groups noted that, as a fully oral therapy, the combination of venetoclax and ibrutinib is suited for outpatient care and accessible in both community and academic settings. It should be prescribed by a hematologist managing MCL. The groups highlighted that additional laboratory monitoring for venetoclax-related risk of TLS is necessary. Also, cardiac evaluation may be needed due to ibrutinib’s risks.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by for this review are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

BTKi = Bruton’s tyrosine kinase inhibitor; CDA-AMC = Canada’s Drug Agency; ECOG PS = Eastern Cooperative Oncology Group performance status; MCL = mantle cell lymphoma; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; TLS = tumour lysis syndrome.

Clinical Evidence

The objective of this clinical review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of venetoclax, 10 mg, 50 mg, and 100 mg tablets, taken orally, in the treatment of adult patients with relapsed or refractory MCL. The focus will be placed on comparing venetoclax to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of venetoclax is presented in 1 section with our critical appraisal of the evidence at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. Our assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The sponsor did not submit any long-term extension studies, indirect evidence from the sponsor, or additional studies to address important gaps in the systematic review evidence.

Included Studies

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

• One phase III, RCT (SYMPATICO) identified in the systematic review.

Systematic Review

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

Description of Studies

One study (SYMPATICO) was identified from the sponsor-submitted systematic literature review. The SYMPATICO trial consisted of an open-label safety run-in phase, a double-blind randomized phase, and an open-label treatment-naive cohort. Of note, according to the sponsor, the primary focus for this review is the randomized phase of SYMPATICO. All information presented in the review is therefore for the double-blind randomized phase, unless otherwise stated.

The characteristics of the randomized phase of SYMPATICO are summarized in Table 5. The randomized phase of SYMPATICO is a phase III, multicentre, double-blind RCT, investigating the efficacy and safety of venetoclax plus ibrutinib in patients with MCL who have received at least 1, but no more than 5, prior treatment regimens for MCL, including at least 1 prior rituximab- or anti-CD20–containing regimen. A total of 267 patients (including ██ patients in Canada) were randomized, using an interactive response technology system, to the venetoclax plus ibrutinib group (n = 134) and the placebo plus ibrutinib group (n = 133). The randomization was stratified by the number of prior lines of therapy, ECOG PS, and TLS risk category. Patients, investigators, and the sponsor’s study team members remained blinded to the treatment assignment. The primary objective of the randomized phase of SYMPATICO was to assess the efficacy of venetoclax plus ibrutinib, compared to placebo plus ibrutinib, in patients with relapsed or refractory MCL, as measured by PFS. Secondary end points included OS, complete response (CR) rate, overall response rate (ORR), measurable residual disease (MRD)–negative remission rate, and harms.

Table 5: Details of Studies Included in the Systematic Review

AE = adverse event; BTKi = Bruton’s tyrosine kinase inhibitor; CNS = central nervous system; CR = complete response; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group performance status; FACT-Lym = Functional Assessment of Cancer Therapy — Lymphoma; MCL = mantle cell lymphoma; MRD = measurable residual disease; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; TTNT = time to next treatment.

Source: SYMPATICO Clinical Study Report²⁷ and SYMPATICO Clinical Study Protocol Amendment 4.⁵³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²

Populations

Inclusion and Exclusion Criteria

The randomized phase of SYMPATICO included adult patients (≥ 18 years) with pathologically confirmed MCL who had received 1 to 5 prior therapies for MCL (including at least 1 prior rituximab- anti-CD20–containing regimen), failed to achieve at least partial response (PR), with or documented disease progression after the most recent treatment regimen, and had an ECOG PS of 0 to 2. Patients with a history or current evidence of CNS lymphoma or who had received anticancer therapy, including chemotherapy, radiotherapy, small-molecule, and investigational agents 21 days before the start of intervention were excluded.

Interventions

Venetoclax Plus Ibrutinib

Venetoclax was taken orally according to the 5-week ramp-up dosing schedule (i.e., week 1: 20 mg once daily; week 2: 50 mg once daily; week 3: 100 mg once daily; week 4: 200 mg once daily; week 5: 400 mg once daily). After completing the ramp-up phase, patients continued on venetoclax at a dosage of 400 mg once daily for an additional 23 months (a total duration of combination treatment for 24 months).

Ibrutinib was given at a dosage of 560 mg once daily, starting from day 1 until disease progression or unacceptable toxicity.

Placebo Plus Ibrutinib

Patients received placebo once daily for 24 months, matched to the dosing schedule (including the 5-week ramp-up) for venetoclax in the venetoclax plus ibrutinib group.

Ibrutinib 560 mg once daily was taken in combination with placebo for the 24-month period, with ibrutinib 560 mg once daily given as a single drug continued beyond 24 months until disease progression or unacceptable toxicity.

Outcomes

A list of efficacy end points assessed in this clinical review report is provided in Table 6, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review according to the clinical expert(s) consulted for this review and input from patient and clinician groups and public drug plans. Using the same considerations, we selected end points that were considered to be most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Selected harms outcomes considered important for informing expert committee deliberations were also assessed using GRADE.

Table 6: Outcomes Summarized From the Randomized Phase of SYMPATICO

FACT-Lym = Functional Assessment of Cancer Therapy — Lymphoma; OS = overall survival; PFS = progression-free survival.

^aOnly the interim analysis of OS was available and assessed by the CDA-AMC review team.

^bStatistical testing was adjusted for multiple comparisons (e.g., hierarchical testing).

Source: SYMPATICO Statistical Analysis Plan version 2,⁵⁴ SYMPATICO Clinical Study Protocol Amendment 4,⁵³ and sponsor response to CDA-AMC request for additional information.²²

Descriptions of efficacy and safety outcomes presented in the randomized phase of SYMPATICO and appraised in the clinical review are as follows:^53,54

Efficacy Outcomes

Overall Survival

OS was defined as the time from the date of randomization until death due to any cause. Patients without an OS event were censored at the date last known alive.

PFS Per Investigator Assessment

PFS was defined as time from the date of randomization to the date of the first documentation of progressive disease or the date of death due to any cause, whichever occurred first, regardless of study drug discontinuation or use of subsequent anticancer treatment. Of note, posttreatment stem cell transplant, CAR T-cell therapy, and other cellular therapies were not considered subsequent anticancer treatment for patients responding to treatment (CR or PR). Lugano Classification Criteria were used to determine disease progression.⁵⁵ If patients did not have a baseline disease assessment or any adequate postbaseline disease assessment, they were censored at the date of randomization.

Health-Related Quality of Life

The summary of measurement properties of FACT-Lym is shown in Table 7.

Table 7: Summary of Outcome Measures and Their Measurement Properties

ECOG PS = Eastern Cooperative Oncology Group performance status; FACT-G = Functional Assessment of Cancer Therapy — General; FACT-Lym = Functional Assessment of Cancer Therapy — Lymphoma; HRQoL = health-related quality of life; MCL = mantle cell lymphoma; MID = minimal important difference; NHL = non-Hodgkin lymphoma; SF-36 = Short Form (36) Health Survey.

Harms Outcomes

The harms outcomes assessed in the review report included AEs, TESAEs, withdrawals due to AEs, mortality, and notable harms. Harms events were coded in accordance with the Medical Dictionary for Regulatory Activities 24.1. Severity of harms events were rated by the investigator according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.03. The treatment-emergent period was defined as the period from the date of the first dose of study treatment up to 30 days after the date of the last dose of study treatment or the day before initiation of subsequent anticancer treatment, whichever came first. TEAEs were events that occurred or worsened during the treatment-emergent period or that were related to the study treatment.

Statistical Analysis

Sample Size and Power Calculation

In the randomization phase of SYMPATICO, sample size was powered based on the primary end point of PFS. Approximately 260 patients were planned to be randomized at a 1:1 ratio to the venetoclax plus ibrutinib group and the placebo plus ibrutinib group. The calculations were based on the following assumptions:

• The target HR was 0.61, which corresponds to an improvement of 9 months in median PFS from 14 months to 23 months for the venetoclax plus ibrutinib group, compared to the placebo plus ibrutinib group.

• A total of 134 PFS events would provide approximately 80% power at a 1-sided significance level of 0.025 for the study. No interim analysis was planned for PFS.

• Assuming an enrolment rate of approximately 10 to 11 patients per month, enrolment was projected to be completed approximately 21 months after the enrolment of the first patient. The actual length of the study and the time to the primary analysis were dependent on the actual enrolment rate and the number of events.

Sample size and power calculation for the interim and final OS analyses were as follows:

• The target HR was 0.65, which corresponds to an improvement of about 16 months in median OS from 30 months to 46.2 months for the venetoclax plus ibrutinib group, compared to the placebo plus ibrutinib group.

• A total of 155 OS events would provide about 76% power at a 1-sided significance level of 0.025, adjusting for 1 interim analysis based on group sequential design with Lan-DeMets spending function with O’Brien-Fleming boundary.

• It was anticipated that 112 and 155 OS events would be observed at the interim analysis (at about 40 months, corresponding to the timing of the primary PFS analysis) and at the final analysis (at about 57 months), respectively.

• The calculation for OS was based on a log-rank test.

To address the impact of COVID-19 on the effect size (HR), the researchers planned to conduct the primary analysis after 150 PFS events occurred during the randomization phase. At the time of the database lock date (July 5, 2023), the actual number of investigator-assessed PFS events was ███.

At the time of the primary PFS analysis, an interim analysis for OS was performed, with a prespecified 2-sided alpha of 0.001. To maintain a 2-sided overall significance level of 0.05 for OS, the significance level of the OS final analysis has been adjusted for the OS interim analysis based on Haybittle-Peto boundary (i.e., 2-sided alpha of 0.001). The final OS analysis is planned after the last patient has been followed for at least 5 years or approximately 170 OS events are observed, whichever occurs first. ██ ███ ██████████████ ████████ ██ ███████ ██ █████ ███ ███████ ███ ███████ █████████ ████ █████ ██ ██ ████ ██ ██████ ██████████ ██ █████ █████ ████ ███ ███████ ██ █████ ███ ███ ██████ ██ ███████████

Statistical Testing

Details of the statistical analysis of efficacy end points in the randomization phase of SYMPATICO are presented in Table 8.

In the primary analysis of the primary end point (i.e., PFS per investigator assessment), hierarchical testing and censoring rules for PFS followed the global rules (i.e., patients were censored at the last nonprogressive disease assessment [i.e., CR, PR, and stable disease]). The 1-sided type I family-wise error rate was controlled at 0.025 by a closed testing procedure for testing PFS and some secondary end points, including CR rate per investigator assessment, time to next treatment (TTNT), OS, and ORR per investigator assessment. These secondary end points were tested when PFS reached statistical significance (1-sided 0.025) and were ranked and tested at a 1-sided statistical significance of 0.025 sequentially in the following hierarchical order: CR rate per investigator assessment, TTNT, OS, and ORR per investigator assessment. To maintain a 2-sided overall significance level of 0.05 for OS, the significance boundary of the OS interim analysis was 2-sided alpha of 0.001 based on the Haybittle-Peto boundary.

Of note, in 1 of the sensitivity analyses of PFS, the FDA rules were followed for hierarchical testing and censoring. Based on the FDA rules, the hierarchical order for secondary end points was CR rate per investigator assessment, OS, TTNT, and ORR per investigator assessment. In addition to the global censoring rule, 2 additional censoring rules were adopted for the FDA censoring rules, in which patients were censored when subsequent anticancer therapy was used before or without a PFS event or when 2 or more consecutive response assessments were missing before a PFS event.

For FACT-Lym total score and the lymphoma-specific subscale of FACT-Lym score, summary statistics were provided, and no statistical model or adjustment factors were considered.²⁸

Table 8: Statistical Analysis of Efficacy End Points in the Randomized Phase of SYMPATICO

CI = confidence interval; HR = hazard ratio; IRC = independent review committee; KM = Kaplan-Meier; OS = overall survival; PFS = progression-free survival; TLS = tumour lysis syndrome

Source: SYMPATICO Statistical Analysis Plan version 2⁵⁴ and SYMPATICO Clinical Study Protocol Amendment 4.⁵³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²

Analysis Populations

The analysis populations in the randomized phase of SYMPATICO are summarized in Table 9.

Table 9: Analysis Populations of the Randomized Phase of SYMPATICO

ITT = intention-to-treat.

Source: SYMPATICO Clinical Study Report,²⁷ SYMPATICO Clinical Study Protocol Amendment 4.⁵³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²

Protocol Amendments and Deviations

In total, there were 7 versions of the study protocols for the randomized phase of SYMPATICO, including the initial protocol (protocol date: December 16, 2016) and 6 amendments, including Amendment 0.1, Amendment 1, Amendment 2, Amendment 2.1, Amendment 3, and Amendment 4. In Amendment 1 (November 17, 2017), trial inclusion criteria were modified, adding that a prior rituximab- or anti-CD20–containing regimen was required and that patients with ECOG PS of 2 were eligible. An interim analysis for OS at the time of the primary analysis for PFS at 134 events was added in Amendment 3 (March 25, 2021).

In the randomized phase of SYMPATICO, protocol deviations included inclusion or exclusion criteria violations, receipt of wrong treatment or incorrect dose of study drug, development of withdrawal criteria without being withdrawn, and use of prohibited concomitant medications. In total, ██ protocol deviations occurred during the randomized phase of SYMPATICO, of which the most common reason was ███ █████████ ████ ███████ ███ ██████████ ██ ███████ (██ ██████), followed by ███████████ ████████ █████████ █████████ ██████ ██ ████████ ██ ███████.

Results

Patient Disposition

The disposition of patients in the randomized phase of SYMPATICO is summarized in Table 10. In the venetoclax plus ibrutinib group, venetoclax was discontinued due to AEs in 12.7% of the patients, and ibrutinib was discontinued due to AEs in 14.9% of the patients. In the placebo plus ibrutinib group, placebo was discontinued due to AEs in 15.0% of the patients, and ibrutinib was discontinued due to AEs in 13.5% of the patients.

Table 10: Summary of Patient Disposition in the Randomized Phase of SYMPATICO (ITT Population)

ITT = intention-to-treat; NA = not applicable.

| ███ ███████ ███ ███ ███████ █████ ██████████

Source: SYMPATICO Clinical Study Report.²⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²

Baseline Characteristics

The baseline characteristics outlined in Table 11 are limited to those that are most relevant to this review or were believed to affect the outcomes or interpretation of the study results. Patients in the ITT population of the randomized phase of SYMPATICO had a median age of 68 years (range, ██ ██ ██). There were more male patients than female patients (79.0% versus 21.0%). Most of patients were white (86.5%), followed by Asian (1.9%), and Black or African American (0.7%). Approximately ████% of the ITT population had Ann Arbor stage IV disease, and 28.8% had a TP53 mutation. Approximately 59.6%, 23.6%, and 16.9% of the ITT population had received 1, 2, or 3 or more lines of therapies before receiving venetoclax plus ibrutinib, respectively.

Some differences in baseline characteristics were identified between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group, including proportion of patients with high-risk simplified MCL International Prognostic Index scores (38.1% versus 30.8%), patients with bulky disease greater than or equal to 5 cm (46.3% versus 39.8%), lymphoma involvement in bone marrow biopsy (46% versus 41%), and patients with splenomegaly (31.3% versus 24.8%).

Table 11: Summary of Baseline Characteristics in the Randomized Phase of SYMPATICO (ITT Population)

CLL = chronic lymphocytic leukemia; ECOG PS = Eastern Cooperative Oncology Group performance status; ITT = intention-to-treat; MCL = mantle cell lymphoma; MIPI = Mantle Cell Lymphoma International Prognostic Index; SD = standard deviation.

^aWording used in original study.

^bPatients with bulky disease are patients with any lesion (nodal or extranodal) with any axis (short or long) ≥ 5 cm at screening or baseline.

^cCentral laboratory testing was used as the primary source of data; a local laboratory was used only when central laboratory data were not available.

Source: SYMPATICO Clinical Study Report.²⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²

Exposure to Study Treatments

A summary of patient disposition in the randomized phase of SYMPATICO is presented in Table 12. The median overall treatment duration was 22.2 months (range, ███ to ████) in the venetoclax plus ibrutinib group and 17.7 months (range, ███ to ████) in the placebo plus ibrutinib group. SYMPATICO measured treatment compliance as relative dose intensity, which was similar between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group. The proportion of patients with dose reduction due to an AE for ibrutinib was 25.4% in the venetoclax plus ibrutinib group and 16.7% in the placebo plus ibrutinib group. The proportion of patients with dose reduction due to an AE was 23.1% for venetoclax in the venetoclax plus ibrutinib group and 11.4% for placebo in the placebo plus ibrutinib group.

Table 12: Summary of Patient Exposure in the Randomized Phase of SYMPATICO (Safety Population)

AE = adverse event; SD = standard deviation.

^aTreatment duration in months was calculated as (last dose date of study drug − first dose date of study drug + 1) / 30.4375.

^bRelative dose intensity was calculated as (actual dose intensity / planned dose intensity) × 100. Planned dose intensity was ███ ██████ for ibrutinib and █████ mg per day for venetoclax or placebo.

Source: SYMPATICO Clinical Study Report.²⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²

Prior Anticancer Therapy

Details about prior anticancer therapy in the randomized phase of SYMPATICO are shown in Table 13.

Concomitant Medications

Details about concomitant medications in the randomized phase of SYMPATICO, which consisted of any medication taken on or after first dose date and up to last dose date of study drug, are shown in Table 14.

Table 13: Prior Anticancer Therapies in the Randomized Phase of SYMPATICO (ITT Population)

HDAC = histone deacetylases; hyper CVAD = chemotherapy regimen including cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine; ITT = intention to treat; SD = standard deviation.

Source: SYMPATICO Clinical Study Report.²⁷

Table 14: Concomitant Medications (≥ 30% of Patients in Either Arm) During Study Treatment in the Randomized Phase of SYMPATICO (Safety Population)

Source: SYMPATICO Clinical Study Report.²⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²

Subsequent Anticancer Therapies

The summary of subsequent anticancer therapies in the randomized phase of SYMPATICO is shown in Table 15. Thirty-nine patients (29.1%) in the venetoclax plus ibrutinib group and 54 patients (40.9%) in the placebo plus ibrutinib group received subsequent antineoplastic agents. The most common antineoplastic agents (> 5 patients) in the venetoclax plus ibrutinib group were rituximab (20.9%), bendamustine (11.9%), cytarabine (9.0%), cyclophosphamide (6.0%), bortezomib (5.2), doxorubicin (5.2%), and ibrutinib (5.2%). The most common antineoplastic agents (> 5 patients) in the placebo plus ibrutinib group were rituximab (29.5%), bendamustine (22.0%), cytarabine (14.4%), venetoclax (11.4%), ibrutinib (9.1%), and cyclophosphamide (6.1%).

Table 15: Summary of Subsequent Anticancer Therapies in the Randomized Phase of SYMPATICO (Safety Population)

Source: SYMPATICO Clinical Study Report.²⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²

Efficacy

Key efficacy results from the randomized phase of SYMPATICO are presented in Table 16. The data cut-off date was May 22, 2023 (database lock date: July 5, 2023). The median time on study was █████ ██████ (range, ███ to ████) for the venetoclax plus ibrutinib group and █████ months (range, ███ to ████) for the placebo plus ibrutinib group.

Table 16: Summary of Key Efficacy Results in the Randomized Phase of SYMPATICO (ITT Population)

CI = confidence interval; FACT-Lym = Functional Assessment of Cancer Therapy — Lymphoma; HR = hazard ratio; IRC = independent review committee; ITT = intention-to-treat; NE = not estimable; NR = not reported; OS = overall survival; PFS = progression-free survival; SD = standard deviation.

+Indicates censored observation.

^aEstimated by KM method.

^bHR is estimated using stratified Cox regression model with treatment as the only covariate.

^cP value was from a stratified log-rank test.

^dP value has been adjusted for multiple testing.

^eIn the primary analysis of PFS, the global censoring rules (i.e., patients without progression or death were censored at last visit) were applied. In the sensitivity analyses, the FDA censoring rules were adopted for PFS per investigator assessment. On top of the global censoring rule, 2 additional censoring rules were included in the FDA censoring rules: patients were censored when subsequent anticancer therapy was used before or without a PFS event or when 2 or more consecutive response assessments were missing before a PFS event.

Source: SYMPATICO Clinical Study Report.²⁷ Sponsor response to CDA-AMC request for additional information.^22,28

Overall Survival

In the interim analysis of OS, the proportion of patients in the ITT population who had OS events was 51.5% in the venetoclax plus ibrutinib group versus 56.4% in the placebo plus ibrutinib group. The median OS was 44.9 months (95% CI, 31.9 months to NE) in the venetoclax plus ibrutinib group versus 38.6 months (95% CI, 25.2 to 53.4 months) in the placebo plus ibrutinib group. The HR for death was 0.854 (95% CI, 0.615 to 1.186). At 12 months, the probability of being alive was ████% (95% CI, ████ ██ ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ ██ ████) for the placebo plus ibrutinib group (between-group difference = ████%; 95% CI, █████ ██ ███). At 24 months, the probability of being alive was 65.9% (95% CI, 57.2% to 73.3%) for the venetoclax plus ibrutinib group and 61.4% (95% CI, 52.5% to 69.1%) for the placebo plus ibrutinib group (between-group difference = 4.5%; 95% CI, ████ ██ ████). At 36 months, the probability of being alive was ████% (95% CI, ████ ██ ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ ██ ████) for the placebo plus ibrutinib group (between-group difference = ███%; 95% CI, ████ ██ ████). At 48 months, the probability of being alive was ████% (95% CI, ████ ██ ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ ██ ████) for the placebo plus ibrutinib group (between-group difference = ███%; 95% CI, ████ ██ ████). At 60 months, the probability of being alive was ████% (95% CI, ████ ██ ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ ██ ████) for the placebo plus ibrutinib group (between-group difference = ███%; 95% CI, █████ ██ ████). The KM plot for OS at the interim analysis is presented in Figure 1.

Figure 1: KM Curves for OS in the Randomized Phase of SYMPATICO (ITT Population, Interim Analysis)

CI = confidence interval; HR = hazard ratio; ITT = intention-to-treat; KM = Kaplan-Meier; OS = overall survival.

+ Indicates censored observation.

* Stratified test or model was based on 2 randomization stratification factors: number of prior lines of therapy (1 to 2 versus ≥ 3) and TLS category (low-risk versus increased risk) at randomization.

Source: SYMPATICO Clinical Study Report.²⁷

PFS per Investigator Assessment

In the primary analysis of PFS, the proportion of patients in the ITT population who had PFS events was 54.5% in the venetoclax plus ibrutinib group versus 70.7% in the placebo plus ibrutinib group. The median PFS per investigator assessment was 31.9 months (95% CI, 22.8 to 47.0 months) in the venetoclax plus ibrutinib group versus 22.1 months (95% CI, 16.5 to 29.5 months) in the placebo plus ibrutinib group. The HR for progression per investigator assessment was 0.645 (95% CI, 0.474 to 0.878). At ██ ██████, the probability of being progression-free was ████% (95% CI, ████ ██ ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ ██ ████) for the placebo plus ibrutinib group (between-group difference = ████%; 95% CI, ████ ██ ████). At 24 months, the probability of being progression-free was 56.8% (95% CI, 47.7 to 64.9) for the venetoclax plus ibrutinib group and 45.4% (95% CI, 36.5% to 53.8%) for the placebo plus ibrutinib group (between-group difference = 11.4%; 95% CI, −0.8% to 23.7%). At ██ ██████, the probability of being progression-free was ████% (95% CI, ████ ██ ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ ██ ████) for the placebo plus ibrutinib group (between-group difference = ████; 95% CI, ███ ██ ████). At ██ ██████, the probability of being progression-free was ████% (95% CI, ████ ██ ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ ██ ████) for the placebo plus ibrutinib group (between-group difference = ████%; 95% CI, ███ ██ ████). At ██ ██████, the probability of being progression-free was ████% (95% CI, ████ ██ ████) for the venetoclax plus ibrutinib group and ████% (95% CI, ████ ██ ████) for the placebo plus ibrutinib group (between-group difference = ████%; 95% CI, ███ ██ ████). The KM plot for PFS per investigator assessment is shown in Figure 2.

Figure 2: KM Curves for PFS per Investigator Assessment in the Randomized Phase of SYMPATICO (ITT Population)

CI = confidence interval; HR = hazard ratio; ITT = intention-to-treat; KM = Kaplan-Meier; PFS = progression-free survival.

+ Indicates censored observation.

* Stratified test or model was based on 2 randomization stratification factors: number of prior lines of therapy (1 to 2 versus ≥ 3) and TLS category (low-risk versus increased risk) at randomization.

Source: SYMPATICO Clinical Study Report.²⁷

One of the sensitivity analyses examined PFS per independent review committee (IRC) assessment in the ITT population using the same censoring rule (i.e., global censoring rules) as the primary analysis did. In this sensitivity analysis, the proportion of patients in the ITT population who had PFS events was ████% in the venetoclax plus ibrutinib group versus ████% in the placebo plus ibrutinib group. The median PFS per IRC assessment was 31.8 months (95% CI, 20.9 to 47.0 months) in the venetoclax plus ibrutinib group versus 20.9 months (95% CI, 16.3 to 25.2 months) in the placebo plus ibrutinib group. The HR for PFS per IRC assessment was 0.669 (95% CI, 0.492 to 0.911). The difference in the probability of being progression-free between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group was ███% (95% CI, ████ ██ ████) at 12 months, ████% (95% CI, ███ ██ ████) at 24 months, ████% (95% CI, ███ ██ ████) at 36 months, ████% (95% CI, ███ ██ ████) at 48 months, and ██ (95% CI, ██ ██ ██) at 60 months. Information on the concordance in progressive disease between the primary PFS analysis (i.e., PFS per investigator assessment using global censoring rules) versus the sensitivity analysis (i.e., PFS per IRC assessment using global censoring rules) is shown in Table 17. The overall concordance for the PFS events was ████% for the venetoclax plus ibrutinib group and ████% for the placebo plus ibrutinib group.

In the primary analysis of PFS, the global censoring rules were applied. In the sensitivity analysis where the FDA censoring rules were adopted, the proportion of patients in the ITT population who had PFS events was ████% in the venetoclax plus ibrutinib group versus ████% in the placebo plus ibrutinib group. The median PFS per investigator assessment was 42.6 months (95% CI, 27.3 months to NE) in the venetoclax plus ibrutinib group versus 22.1 months (95% CI, 16.5 to 29.5 months) in the placebo plus ibrutinib group. The HR for PFS per investigator assessment was 0.603 (95% CI, 0.436 to 0.833).

FACT-Lym Total Score

The FACT-Lym total score ranges between 0 and 168, with a higher score indicating a better HRQoL.

The difference in change from baseline FACT-Lym total score between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group was ████ ██████ (95% CI, █████ ██ ███) at ██ ██████ and ███ ██████ (95% CI, █████ ██ ████) at ██ ██████.

Table 17: Concordance in Progressive Disease per Investigator Assessment Versus per IRC Assessment (ITT Population)

CR = complete response; IRC = independent review committee; ITT = intention-to-treat; PR = partial response.

Notes: The percentage for overall concordance was based on the number of patients in the ITT population as the denominator. Other percentages were based the number of patients with progressive disease by investigator and number of patients with nonprogressive disease by investigator as the denominators.

^aIncluding patients who had progressive disease by both investigator and IRC and patients who had nonprogressive disease by both investigator and IRC.

Source: SYMPATICO Clinical Study Report.²⁷

Lymphoma-Specific Subscale of FACT-Lym

The lymphoma-specific subscale of FACT-Lym ranges between 0 and 60, with a higher score indicating a better HRQoL.

The difference in change from baseline lymphoma-specific subscale of FACT-Lym score between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group was ████ ██████ (95% CI, ████ ██ ███) at ██ ██████ and ████ ██████ (95% CI, ████ ██ ███) at ██ ██████.

Harms

Harms data from the randomized phase of SYMPATICO are presented in Table 18.

TEAEs

All patients in the venetoclax plus ibrutinib group and 98.5% of the patients in the placebo plus ibrutinib group had at least 1 TEAE of any grade. The most common TEAEs included diarrhea (64.9% in the venetoclax plus ibrutinib group versus 34.1% in the placebo plus ibrutinib group), neutropenia (34.3% in the venetoclax plus ibrutinib group versus 14.4% in the placebo plus ibrutinib group), nausea (31.3% in the venetoclax plus ibrutinib group versus 16.7% in the placebo plus ibrutinib group), fatigue (29.1% in the venetoclax plus ibrutinib group versus 27.1% in the placebo plus ibrutinib group), anemia (22.4% in the venetoclax plus ibrutinib group versus 12.1% in the placebo plus ibrutinib group), pyrexia (20.9% in the venetoclax plus ibrutinib group versus 19.7% in the placebo plus ibrutinib group), and cough (20.1% in the venetoclax plus ibrutinib group versus 27.3% in the placebo plus ibrutinib group).

The proportion of patients who had TEAEs of grade 3 or higher was 83.6% in the venetoclax plus ibrutinib group versus 75.8% in the placebo plus ibrutinib group. The most common TEAEs of grade 3 or higher included neutropenia (31.3% in the venetoclax plus ibrutinib group versus 10.6% in the placebo plus ibrutinib group), pneumonia (12.7% in the venetoclax plus ibrutinib group versus 10.6% in the placebo plus ibrutinib group), thrombocytopenia (12.7% in the venetoclax plus ibrutinib group versus 7.6% in the placebo plus ibrutinib group), and worsening of MCL (6.7% in the venetoclax plus ibrutinib group versus 12.1% in the placebo plus ibrutinib group).

TESAEs

The proportion of patients who had TESAEs was 60.4% in the venetoclax plus ibrutinib group versus 59.8% in the placebo plus ibrutinib group. The most common TESAE was pneumonia (12.7% in the venetoclax plus ibrutinib group versus 10.6% in the placebo plus ibrutinib group), followed by worsening of MCL (6.7% in the venetoclax plus ibrutinib group versus 12.9% in the placebo plus ibrutinib group).

Treatment Discontinuation Due to TEAEs

Discontinuation of venetoclax or placebo due to TEAEs occurred in 22.4% of the patients in the venetoclax plus ibrutinib group versus 28.8% in the placebo plus ibrutinib group.

Discontinuation of ibrutinib due to TEAEs occurred in 29.1% of the patients in the venetoclax plus ibrutinib group versus 31.1% in the placebo plus ibrutinib group.

Mortality

The proportion of patients with any AE with outcome of death was 16.4% in the venetoclax plus ibrutinib group versus 13.6% in the placebo plus ibrutinib group. The most common reason was worsening of MCL (3.0% in the venetoclax plus ibrutinib group versus 13.6% in the placebo plus ibrutinib group).

Notable Harms

Treatment-emergent major hemorrhage, which included serious or grade ≥ 3 hemorrhage and CNS hemorrhage of any grade, occurred in ███% of the patients in the venetoclax plus ibrutinib group versus ███% in the placebo plus ibrutinib group. Atrial fibrillation of any grade occurred in 10.4% of the patients in the venetoclax plus ibrutinib group versus 10.6% in the placebo plus ibrutinib group. The percentage of patients who had cardiac arrhythmias (excluding atrial fibrillation) of any grade was ████% in the venetoclax plus ibrutinib group versus ████% in the placebo plus ibrutinib group. The percentage of patients who had TLS of any grade was 5.2% in the venetoclax plus ibrutinib group versus 2.3% in the placebo plus ibrutinib group. There were 4 deaths possibly due to cardiac-related causes in the venetoclax plus ibrutinib group and 2 deaths in the placebo plus ibrutinib group.

Table 18: Summary of Harms Results in the Randomized Phase of SYMPATICO (Safety Population)

AE = adverse event; MCL = mantle cell lymphoma; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event.

^aMCL was recorded as an AE if it was worsening of MCL that did not meet Cheson criteria for progressive disease.

Source: SYMPATICO Clinical Study Report.²⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²

Critical Appraisal

Internal Validity

The randomized phase of the SYMPATICO study was a phase III, double-blind RCT. An interactive response technology system, which was used to generate the randomization list and code, assigned patients to the venetoclax plus ibrutinib group or the placebo plus ibrutinib group. A stratified randomization procedure based on the number of prior lines of therapy (1 to 2 versus 3), ECOG PS (0 versus 1 to 2), and TLS risk category (low versus increased risk) were also carried out. While the distribution of most baseline characteristics was similar between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group, some between-group imbalances were observed, such as the proportion of patients with high-risk simplified MCL International Prognostic Index scores (38.1% versus 30.8%), patients with bulky disease 5 cm or greater (46.3% versus 39.8%), lymphoma involvement in bone marrow biopsy (46% versus 41%), patients with splenomegaly (31.3% versus 24.8%), and history of prior autologous transplant (28.4% versus 37.6%). The clinical experts consulted by the CDA-AMC review team noted no major concerns about these imbalances in terms of biasing the treatment effect estimates. The CDA-AMC review team determined that the risk of selection bias associated with inadequate randomization was overall low.

It was noted that the trial inclusion criteria were modified in Study Protocol Amendment 1, which added that a prior rituximab- or anti-CD20–containing regimen was required and that patients with ECOG PS of 2 were eligible. The amendment was made in 2017 which was before patients were enrolled and randomized in 2018, leading to no major concern. The clinical experts consulted by the CDA-AMC review team noted that many of the concomitant medications reported in the randomized phase of SYMPATICO were used to manage side effects caused by venetoclax or ibrutinib and these concomitant medications were unlikely to impact the assessment of survival outcomes (i.e., OS, PFS). A higher proportion of patients in the placebo plus ibrutinib group, compared to the venetoclax plus ibrutinib group, received subsequent anticancer therapy (40.9% versus 29.1%). The clinical experts consulted by the CDA-AMC review team determined that this imbalance in subsequent anticancer therapy was unlikely to cause biased results.

PFS and OS were reported in SYMPATICO as survival outcomes. The clinical experts consulted by the CDA-AMC review team acknowledged OS as the most clinically important outcome for patients with MCL. Yet only results from the interim OS analysis were available for this review. The 1-sided type I family-wise error rate was controlled at 0.025 by a closed testing procedure for testing PFS and some secondary end points, including OS. To maintain a 2-sided overall significance level of 0.05 for OS, the significance boundary of the OS interim analysis was 2-sided alpha of 0.001, based on the Haybittle-Peto boundary, which was considered by the review team as appropriate. Nonetheless, the interim OS data were immature, and the upper bound of the 95% CI of the median OS in the venetoclax plus ibrutinib group was NE. As a result, uncertainty remains in the interim OS evidence, which may be addressed by the final OS analysis. ██ █████ ██ ███ ██████████████ ████████ ██ ███████ ██ █████ ███ ███████ ███ ███████ █████████ ████ █████ ██ ██ ████ ██ ██████ ██████████ ██ █████ █████ ████ ███ ███████ ██ █████ ███ ███ ██████ ██ ███████████

PFS per investigator assessment was the primary efficacy end point in the randomized phase of SYMPATICO. The clinical experts consulted by the CDA-AMC review team noted that the selection of PFS as primary efficacy end point was necessary and informative. MCL is noncurable, especially in the relapsed or refractory setting, and PFS could provide information on the relative treatment effects on disease control and stabilization. Two sets of censoring rules were used in estimating PFS: the global censoring rules for the primary analysis and the FDA censoring rules for 1 of the sensitivity analyses. In the global censoring rules, patients without progression or death were censored, while, in the FDA censoring rules, 2 additional censoring scenarios were added to the global censoring rules, i.e., patients with subsequent anticancer therapy, or with 2 or more missed visits before the PFS event, were censored. The CDA-AMC review team noticed that, compared to the median PFS in the venetoclax plus ibrutinib group from the primary analysis, there was a marked increase in the median PFS from the sensitivity analysis using FDA censoring rules (approximately a 10-month increase from 31.9 months to 42.6 months). However, no change was observed in the median PFS in the placebo plus ibrutinib group between the analyses (with the same median PFS of 22.1 months). The large difference in median PFS in the venetoclax plus ibrutinib group but not in the placebo plus ibrutinib group between these 2 analyses, as noted by the review team and others,²³ indicated that the patients in the venetoclax plus ibrutinib group who were censored by the additional 2 scenarios of the FDA rules were not equally likely to experience disease progression, compared to those who were not censored. Specifically, the additionally censored patients in the venetoclax plus ibrutinib group were at a higher risk, which would have violated the noninformative censoring assumption of the KM method, skewed the KM curve, and resulted in an overestimation of median PFS in the analysis with the FDA censoring rules.^23,24 Moreover, as Lesan et al. pointed out,²³ the possibility of overestimation in the PFS primary analysis using the global censoring rules could not be ruled out because, for example, in the primary PFS analysis, patients who missed visits were not censored. Given that these patients were possibly at a higher risk of disease progression (as suggested by the sensitivity analysis using the FDA censoring rules), not counting these patients as having a PFS event may have overestimated median PFS.

Patients, trial investigators, and representatives of the study sponsor were blinded to treatment assignment in the randomized phase of SYMPATICO, which overall minimized the risk of bias associated with patient performance or outcome assessment. However, there was a risk of unblinding in patients or investigators because there was a higher occurrence of digestive AEs in the venetoclax plus ibrutinib group compared to that in the placebo plus ibrutinib group (i.e., diarrhea [64.9% versus 34.1%], nausea [31.3% versus 16.7%], and vomiting [18.7% versus 11.4%]) and because a higher percentage of patients in the venetoclax plus ibrutinib group were treated for these AEs (e.g., ████% of the patients in the venetoclax plus ibrutinib group versus ███% of the patients in the placebo plus ibrutinib group were treated with ██████████ ███ ████████). The CDA-AMC review team determined that the risk of bias due to unblinding affecting survival outcomes (e.g., PFS, OS) was minimal. First, disease progression was evaluated using the Lugano Classification Criteria⁵⁵ by both the investigator and the IRC. Second, the overall concordance for the PFS events was ████% for the venetoclax plus ibrutinib group and ████% for the placebo plus ibrutinib group, suggesting good agreement between the ways of assessing the primary outcome.

The potential bias due to the risk of unblinding in reporting or assessing HRQoL outcomes could not be ruled out. In addition to the unblinding risk, there was also a risk of missing data for HRQoL outcomes. For instance, only ██ ███ ██ ███ ████████ in the venetoclax plus ibrutinib group and ██ ██ ███ ████████ in the placebo plus ibrutinib group contributed to the FACT-Lym total score and the lymphoma-specific subscale of FACT-Lym at 24 months; ██████ ████ of the ITT population was missing. There was no description of how the missing data for the HRQoL outcomes were handled, and therefore the direction and magnitude of the bias due to missing outcome data remained unknown.

External Validity

The eligibility criteria of the randomized phase of SYMPATICO were in general aligned with the criteria in the Canadian setting for selecting eligible patients with MCL in the relapsed and refractory setting, according to the clinical experts consulted by the review team. However, the clinical experts noted that some patients who might benefit from venetoclax plus ibrutinib were not included in the randomized phase of SYMPATICO, including selected patients with an ECOG PC greater than 2; patients who have previously been exposed, but whose disease is not refractory, to venetoclax or ibrutinib; patients without at least 1 site of disease 2.0 cm (e.g., leukemic MCL), and patients with CNS lymphoma, which is rare. Nonetheless, results from the randomized phase of SYMPATICO were still likely to be generalizable to these patients.

Concerning the prior therapies received, the randomized phase of SYMPATICO required eligible patients to have at least 1 rituximab- or anti-CD20–containing regimen, while the Health Canada indication and the reimbursement request proposed by the sponsor do not. The clinical experts noted that all first-line therapies that are currently funded for patients with MCL in Canada contain an anti-CD20 drug. Almost all patients would receive a rituximab- or anti-CD20–containing regimen in the first-line setting, unless they have a reason not to (e.g., a patient is intolerant to rituximab). As a result, the clinical experts noted no concerns generalizing the results from the randomized phase of SYMPATICO to the indicated population.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

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:^25,26

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — that is, the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — that is, the true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — that is, the true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect. If this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The reference points for the certainty of evidence assessment for OS and PFS per investigator assessment were set according to the presence of an important effect based on thresholds agreed upon by clinical experts consulted by the review team for this review. The reference points for the certainty of evidence assessment for the FACT-Lym total score, the lymphoma-specific subscale of FACT-Lym, and harms events were set according to the presence of any non-null effect.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for venetoclax plus ibrutinib versus placebo plus ibrutinib for patients with MCL who have received at least 1, but no more than 5, prior treatment regimens.

Long-Term Extension Studies

No long-term extension studies were identified for this review.

Indirect Evidence

No indirect evidence was identified for this review.

Studies Addressing Gaps in the Systematic Review Evidence

No studies addressing gaps in the pivotal and RCT evidence were identified for this review.

Discussion

Summary of Available Evidence

The randomized phase of the SYMPATICO study was submitted by the sponsor in the systematic review of this clinical report. The randomized phase of SYMPATICO is a phase III, multicentre, double-blind RCT, investigating the efficacy and safety of venetoclax plus ibrutinib in patients with MCL who have received at least 1, but no more than 5, prior treatment regimens for MCL including at least 1 prior rituximab- or anti-CD20–containing regimen. A total of 267 patients (including ██ patients in Canada) were randomized to the venetoclax plus ibrutinib group (n = 134) and the placebo plus ibrutinib group (n = 133). The primary objective of the randomized phase of SYMPATICO was to assess the efficacy of venetoclax plus ibrutinib relative to placebo plus ibrutinib as measured by PFS per investigator assessment. Secondary end points included OS and harms. HRQoL outcomes, such as FACT-Lym total score and lymphoma-specific subscale of FACT-Lym, were also reported. Patients in the ITT population of the randomized phase of SYMPATICO had a median age of 68 years (range, ██ ██ ██). There were more male patients than female patients (79.0% versus 21.0%). Most of patients were white (86.5%), followed by Asian (1.9%) and Black or African American (0.7%). Approximately 59.6%, 23.6%, and 16.9% of the ITT population had received 1, 2, or 3 or more lines of therapies before receiving venetoclax plus ibrutinib, respectively.

Interpretation of Results

Efficacy

Survival (i.e., OS, PFS) and HRQoL outcomes (i.e., FACT-Lym, lymphoma-specific subscale of FACT-Lym) were reported in the randomized phase of the SYMPATICO study. These efficacy end points were selected based on the input from patients and clinician groups as well as the input from the clinical experts consulted by the CDA-AMC review team. These efficacy outcomes aligned with patients’ expectation of important outcomes which included prolonging life, achieving longer disease remission, controlling disease symptoms, and improving quality of life.

The evidence regarding OS reviewed in the clinical report was based on the interim analysis, and data were immature at the time of this analysis. Overall, there remains a gap in the evidence regarding OS, which may be addressed by the final analysis. The interim OS analysis showed a between-group difference of ███% (95% CI, ████ ██ ████) in the probability of being alive at ██ ██████ and ███% (95% CI, █████ ██ ████) in the probability of being alive at ██ ██████. Based on the assessment of certainty of evidence using the GRADE approach, venetoclax plus ibrutinib may result in little to no difference in the probability of being alive at 48 or 60 months, compared to venetoclax plus ibrutinib, based on low-certainty evidence. The main reason for the low certainty in OS results was the imprecision identified in the point estimates and the 95% CIs of the between-group difference in the probability of being alive. A 5% difference (50 per 1,000) between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group was considered clinically important (i.e., MID) by the clinical experts consulted by the review team. The point estimate of the between-group difference in the probability of being alive at ██ ██████ (i.e., ███%) and ██ ██████ (i.e., ███%) did not reach the MID of 5%, suggesting little to no clinically meaningful difference. Moreover, the upper and lower bounds of the 95% CIs of the probability of being alive at ██ ██████ (i.e., ████% to ████%) and ██ ██████ (i.e., █████% to ████%) crossed both the null (i.e., between-group difference = 0) and the MID (i.e., 5%), respectively, indicating a high level of uncertainty around the point estimates.

While acknowledging OS as the most clinically relevant efficacy end point for patients with MCL, the clinical experts consulted by the CDA-AMC review team also considered PFS as a necessary and informative efficacy end point due to the noncurable nature of MCL, especially in the relapsed or refractory setting. The difference in the probability of being progression-free between the venetoclax plus ibrutinib group and the placebo plus ibrutinib group was ████% (95% CI, ███ ██ ████) at ██ ████ and ████% (95% CI, ███ ██ ████) at ██ ██████. Both point estimates at ██ ███ ██ ██████ exceeded the MID (i.e., 7%) suggested by the clinical experts consulted by the CDA-AMC review team, while the lower bound of the 95% CI of the probability of being progression-free at ██ ██████ excluded the MID. Based on the GRADE approach, venetoclax plus ibrutinib likely results in a clinically meaningful benefit in PFS at ██ ███ ██ ██████, compared to placebo plus ibrutinib, based on moderate- to high-certainty evidence. However, it should be noted that there was a risk of overestimation of median PFS due to the possibility of informative censoring, as discussed previously in the Internal Validity section.²³

No between-group difference in HRQoL outcomes, including FACT-Lym and the lymphoma-specific subscale of FACT-Lym, was observed at 24 and 60 months. Both the CDA-AMC review team and the clinical experts consulted by the review team agreed that the HRQoL findings were difficult to interpret, mainly due to missing data. ██████ ████ of the ITT population were missing data for these outcomes at 24 months, and ████ ██ ███ ████████ ██ ███) were missing data at 60 months. It remains unclear how the missing data would affect the HRQoL assessment.

Harms

In the randomized phase of the SYMPATICO study, the proportion of patients who had TEAEs of grade 3 or higher was greater in the venetoclax plus ibrutinib group than in the placebo plus ibrutinib group (83.6% versus 75.8%). In addition, 22.4% of the patients in the venetoclax plus ibrutinib group and 28.8% in the placebo plus ibrutinib group discontinued venetoclax or placebo due to TEAEs, and 29.1% in the venetoclax plus ibrutinib group and 31.1% in the placebo plus ibrutinib group discontinued ibrutinib due to TEAEs. AEs led to death in 16.4% of the patients in the venetoclax plus ibrutinib group and 13.6% in the placebo plus ibrutinib group.

TLS, cardiac deaths, and sudden deaths were noted by the clinical experts consulted by the CDA-AMC review team as important notable harms. Although a higher percentage of patients in the venetoclax plus ibrutinib group had TLS compared with the placebo plus ibrutinib group (5.2% versus 2.3%), the clinical experts consulted were not concerned and considered the mainly laboratory TLS events manageable. Only 1 patient in the venetoclax plus ibrutinib group had a cardiac death and 1 had a sudden death, while no patients died due to these reasons in the placebo plus ibrutinib group. According to the clinical experts, it was uncertain whether venetoclax plus ibrutinib would cause more cardiac deaths or sudden deaths than placebo plus ibrutinib due to the small number of events and the fact that such events are more likely attributable to ibrutinib than to venetoclax.

The CDA-AMC review team noted that worsening of MCL (those cases that did not meet Cheson criteria for progressive disease) was recorded as an AE. When excluding the patients who had worsening of MCL, the proportion of patients who had harms events became generally higher in the venetoclax plus ibrutinib group than that in the placebo plus ibrutinib group: 76.9% versus 63.7% for TEAEs of grade 3 or higher, 18.5% versus 19% for discontinuation of venetoclax or placebo due to TEAEs, 25.4% versus 19.7% for discontinuation of ibrutinib due to TEAEs, and 13.4% versus 6% for deaths. According to the clinical experts consulted by the CDA-AMC review team, compared to placebo plus ibrutinib, adding venetoclax to ibrutinib is expected to increase the risk of AEs. Regardless of whether worsening of MCL was included, the clinical experts consulted by the CDA-AMC review team determined that the safety profile of venetoclax plus ibrutinib is overall manageable and consistent with the known toxicities of the individual components of the regimen. The clinical experts consulted by the CDA-AMC review team noted that many hematologists in Canada are experienced at managing the adverse effects of both drugs, and that this regimen is better tolerated than other therapies used in relapsed MCL, such as CAR T-cell therapy or allogeneic stem cell transplant.

Conclusion

The randomized phase of the SYMPATICO trial, a phase III, double-blind RCT, assessed the efficacy and safety of venetoclax plus ibrutinib relative to placebo plus ibrutinib in patients with MCL who have received at least 1, but no more than 5, prior treatment regimens for MCL. The interim analysis of OS, based on OS data that were immature at the time of analysis, indicated that venetoclax plus ibrutinib may result in little to no difference in the probability of being alive at 48 or 60 months, compared to placebo plus ibrutinib. The certainty of the interim OS evidence was low, and this low certainty may be addressed in the final OS analysis. Added clinical benefit was observed with venetoclax plus ibrutinib in the trial’s designated primary efficacy outcome — PFS per investigator assessment. Venetoclax plus ibrutinib, compared to placebo plus ibrutinib, likely results in a clinically meaningful improvement in the probability of being progression-free at 36 and 60 months based on moderate- to high-certainty evidence. However, the possibility of overestimation in the PFS benefits could not be ruled out due to the informative censoring observed in the PFS sensitivity analysis. Patients censored might have been at a higher risk of having disease progression. Venetoclax plus ibrutinib appears to be overall safe, and the safety profile of venetoclax plus ibrutinib is consistent with the known harms for the individual components of the regimen.

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44.Li Y, Bouchlaka MN, Wolff J, et al. FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma. Oncogene. 2016;35(48):6223-6234. doi:10.1038/onc.2016.155 PubMed

45.Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-16. doi:10.1056/NEJMoa1306220 PubMed

46.Janssen Inc. Imbruvica (ibrutinib): tablets, 140 mg, 280 mg, 420 mg, 560 mg, oral; ibrutinib capsules; capsules, 140 mg, oral; ibrutinib oral suspension; suspension, 70 mg/ml, oral [product monograph]. 2023. Accessed by sponsor, no date provided. https://pdf.hres.ca/dpd_pm/00071920.PDF#page=2.09

47.Canada’s Drug Agency. CADTH reimbursement recommendation: Zanubrutinib (Brukinsa) 2022. Accessed by sponsor, no date provided. https://www.cda-amc.ca/zanubrutinib-0

48.Canada’s Drug Agency. pCODR Expert Review Committee (pERC) final recommendation. Ibrutinib (Imbruvica) Accessed by sponsor, no date provided. https://www.cda-amc.ca/imbruvica-mantle-cell-lymphoma-relapsedrefractory

49.Wang M, Ramchandren R, Chen R, et al. Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. J Hematol Oncol. 2021;14(1):179. doi:10.1186/s13045-021-01188-x PubMed

50.Wang M, Jurczak W, Trneny M, et al. Ibrutinib plus venetoclax in relapsed or refractory mantle cell lymphoma (SYMPATICO): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2025;26(2):200-213. doi:10.1016/S1470-2045(24)00682-X PubMed

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Pharmacoeconomic Review

Abbreviations

Economic Review

The objective of the economic review is to review and critically appraise the pharmacoeconomic evidence submitted by the sponsor on the cost-effectiveness and budget impact of venetoclax in combination with ibrutinib compared to ibrutinib alone for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.

Table 1: Submitted for Review

AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; MCL = mantle cell lymphoma; NOC = Notice of Compliance.

Key Messages

• Venetoclax is supplied as 10 mg, 50 mg, and 100 mg tablets. At the submitted unit price (refer to Table 1), the cost of venetoclax is $1,834 per patient in the first 28-day cycle (subsequent cycles: $7,930), based on the Health Canada–recommended dosage. When used in combination with ibrutinib, the total cost is $13,016 per patient in the first 28-day cycle and $19,111 in subsequent cycles. The total recommended duration of venetoclax is 24 months.

• Clinical efficacy data used in the economic analysis were derived from the randomized phase of the SYMPATICO trial, which compared venetoclax plus ibrutinib to placebo plus ibrutinib.^1,2 Evidence from the SYMPATICO trial suggests that venetoclax plus ibrutinib likely results in a clinically meaningful improvement in the probability of being progression-free at 60 months compared to ibrutinib alone, with little to no difference in survival at 60 months.

• The results of the Canada’s Drug Agency (CDA-AMC) base case suggest:

  • Venetoclax plus ibrutinib is predicted to be associated with higher costs to the health care system than ibrutinib alone (incremental costs = $172,576), primarily driven by increased acquisition costs associated with venetoclax.

  • Venetoclax plus ibrutinib is predicted to be associated with an incremental gain of 0.51 life-years (LYs) compared to ibrutinib alone and may result in a gain of 0.48 quality-adjusted life-years (QALYs) compared to ibrutinib alone.

  • The incremental cost-effectiveness ratio (ICER) of venetoclax plus ibrutinib versus ibrutinib alone was $360,148 per QALY gained in the CDA-AMC base case. The estimated ICER was highly sensitive to the predicted overall survival (OS) benefit, and more than 85% of the incremental benefit was gained in the extrapolated period (i.e., after 60 months). In the absence of long-term data, these projected benefits are highly uncertain and may be overestimated. Additional price reductions may therefore be required.

• CDA-AMC estimates that the budget impact of reimbursing venetoclax for use in combination with ibrutinib for relapsed or refractory MCL will be approximately $43 million over the first 3 years of reimbursement compared to the amount currently spent on ibrutinib alone. The expenditure on venetoclax over this period is predicted to be approximately $40 million. The actual budget impact of reimbursing venetoclax will depend on the number of eligible patients, market uptake, and the use of other treatments.

Summary of the Submitted Economic Evaluation

The sponsor submitted a cost-utility analysis (CUA) to assess the cost-effectiveness of venetoclax in combination with ibrutinib from the perspective of a public health care payer in Canada, using a lifetime time horizon (33 years). The modelled population included adult patients with MCL who had received at least 1 prior therapy.³ This population aligns with the Health Canada indication and reimbursement request, as well as the patient population enrolled in the SYMPATICO trial.^1,2

In the sponsor’s base-case analysis, costs considered included drug acquisition (based on the submitted price for venetoclax and public list prices for comparators), health-state resource use, management of tumour lysis syndrome, subsequent treatment, and adverse events (AEs). Compared with ibrutinib alone, venetoclax plus ibrutinib was associated with an incremental cost of $173,713 and a gain of 0.90 QALYs, resulting in an ICER of $192,741 per QALY gained. Of the incremental benefit, 87% of the incremental LYs and 85% of the incremental QALYs were predicted to be accrued after the duration of the SYMPATICO trial. Further details on the sponsor’s submission are provided in Appendix 3.

CDA-AMC identified several key issues with the sponsor’s analysis (refer to Table 2; full details are provided in Appendix 4).

Table 2: Key Issues With the Sponsor’s Economic Submission

CDA-AMC = Canada’s Drug Agency; HRQoL = health-related quality of life; LY = life-year; MCL = mantle cell lymphoma; OS = overall survival; QALY = quality-adjusted life-year; vs. = versus.

Note: Full details of the issues identified by CDA-AMC are provided in Appendix 3.

^aIn addition, acalabrutinib and zanubrutinib may be received by some patients as second-line treatment (e.g., via compassionate access programs). Acalabrutinib is approved by Health Canada for treatment of patients with MCL who have received at least 1 prior therapy; however, it has not been submitted to CDA-AMC for this indication. Zanubrutinib received a recommendation of do not reimburse for the treatment of MCL in patients who have received at least 1 prior therapy from CDA-AMC in 2022.

CDA-AMC Assessment of Cost-Effectiveness

The CDA-AMC base case was derived by making changes to model parameter values and assumptions (refer to Table 6), in consultation with clinical experts. Detailed information about the base case is provided in Appendix 4.

Impact on Health Care Costs

Venetoclax plus ibrutinib is expected to be associated with additional health care costs compared to ibrutinib alone (incremental costs = $172,576). This increase in health care spending results from drug acquisition costs associated with venetoclax (refer to Figure 1).

Figure 1: Impact of Venetoclax Plus Ibrutinib vs. Ibrutinib Alone on Health Care Costs

IBR = ibrutinib; TLS = tumour lysis syndrome; VEN = venetoclax; vs. = versus.

Impact on Health

Relative to ibrutinib alone, venetoclax plus ibrutinib is predicted to increase the amount of time a patient remains progression-free by approximately 1.38 years, with an incremental gain of 0.51 LYs, compared to ibrutinib alone. Considering the impact of treatment on both quality and length of life, venetoclax plus ibrutinib is predicted to result in 0.48 QALYs per patient compared to ibrutinib alone (refer to Figure 2 and Table 7). Approximately 85% of the predicted incremental QALYs were accrued on the basis of extrapolation.

Figure 2: Impact of Venetoclax Plus Ibrutinib vs. Ibrutinib Alone on Patient Health

IBR = ibrutinib; QALY = quality-adjusted life-year; VEN = venetoclax; vs. = versus.

Overall Results

The results of the CDA-AMC base case suggest an ICER of $360,148 per QALY gained for venetoclax plus ibrutinib compared to ibrutinib alone (refer to Table 3). Additional details on the CDA-AMC base case are available in Appendix 4.

Table 3: Summary of CDA-AMC Economic Evaluation Results

CDA-AMC = Canada’s Drug Agency; ICER = incremental cost-effectiveness ratio; LY = life-year; QALY = quality-adjusted life-year; vs. = versus.

Note: Publicly available list prices were used for comparators.

Uncertainty and Sensitivity

Uncertainty was explored in the scenario analyses outlined in Table 2, which included adopting an alternative extrapolation model for OS and assuming 100% relative dose intensity (RDI) (refer to Table 10, Appendix 4). Based on the results of these analyses, the ICER for venetoclax plus ibrutinib may range from $228,921 to $409,769 per QALY gained compared with ibrutinib alone.

Summary of the Budget Impact

The sponsor submitted a budget impact analysis (BIA) to estimate the 3-year (2026 to 2029) budget impact of reimbursing venetoclax for use in combination with ibrutinib in adult patients with MCL that have received at least 1 prior therapy.³ The sponsor assumed that the payers would be CDA-AMC–participating public drug plans and derived the size of the eligible population using an epidemiologic approach.⁵ The price of venetoclax was aligned with the price included in the sponsor’s economic evaluation, while the prices of comparators were based on the publicly available list prices.^1,6-8 Additional information pertaining to the sponsor’s submission is provided in Appendix 5.

CDA-AMC identified a number of issues with the sponsor’s estimated budget impact and made changes to model parameters and assumptions in consultation with clinical experts to derive the CDA-AMC base case (Table 13). CDA-AMC estimated that 1,216 patients would be eligible for treatment with venetoclax plus ibrutinib over a 3-year period (year 1 = 396; year 2 = 405; year 3 = 415), of whom 449 are expected to receive venetoclax plus ibrutinib (year 1 = 79; year 2 = 162; year 3 = 207). The estimated incremental budget impact of reimbursing venetoclax plus ibrutinib is expected to be approximately $43 million over the first 3 years, with an expected expenditure of $40 million on venetoclax (refer to Table 14). The actual budget impact will depend on the number of eligible patients, the uptake of venetoclax plus ibrutinib, and confidentially negotiated prices of venetoclax and ibrutinib.

Conclusion

Based on the CDA-AMC base case, venetoclax in combination with ibrutinib would be considered cost-effective at the submitted price if the public health care system was willing to pay at least $360,148 for each additional QALY gained. If the public health care system is not willing to pay that amount, a price reduction should be considered (refer to Figure 3; full details of the impact of price reductions on cost-effectiveness are presented in Table 9). In the absence of long-term data, these projected benefits are highly uncertain and may be overestimated. Additional price reductions may therefore be required.

The budget impact of reimbursing venetoclax for use in combination with ibrutinib to the public drug plans in the first 3 years is estimated to be approximately $43 million. The 3-year expenditure on venetoclax (i.e., not accounting for current expenditure on comparators) is estimated to be $40 million. The estimated budget impact will depend on the number of eligible patients, the uptake of venetoclax plus ibrutinib, and confidentially negotiated prices of venetoclax and ibrutinib.

Figure 3: Summary of the CDA-AMC Economic Analysis and Price Reduction

CDA-AMC = Canada’s Drug Agency; IBR = ibrutinib; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; VEN = venetoclax.

Note: Expenditure includes only the drug cost of venetoclax. The term dominant indicates that a drug costs less and provides more QALYs than the comparator.

References

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Appendix 1: Cost Comparison Table

Please note that this appendix has not been copy-edited.

The comparators presented in the following table have been deemed to be appropriate based on feedback from clinical experts and CDA-AMC–participating public drug plans. Comparators may be recommended (appropriate) practice or actual practice. Existing Product Listing Agreements are not reflected in the table, and, as a result, the table may not represent the actual costs to public drug plans

Table 4: Cost Comparison for Relapsed or Refractory MCL