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Indication: Ibrutinib, with or without rituximab, for the treatment of adult patients with previously treated refractory or relapsed Waldenström’s macroglobulinemia
CADTH recommends that Imbruvica, with or without rituximab, should be reimbursed by public drug plans for the treatment of adult patients with previously treated relapsed or refractory Waldenström’s macroglobulinemia (WM) if certain conditions are met.
Imbruvica should only be covered to treat adult patients who have WM and have received at least 1 prior line of therapy, have good performance status, and who meet at least 1 criterion for treating WM according to the latest International Workshop on WM criteria.
Imbruvica should not be reimbursed for patients who have received prior treatment with a Bruton tyrosine kinase inhibitor and whose disease responded poorly or for patients with disease transformation. Imbruvica should only be prescribed by hematologists or oncologists with experience in treating patients with WM, and the cost of Imbruvica should be negotiated to provide cost savings for drug programs relative to zanubrutinib.
WM is a rare, slow-growing type of non-Hodgkin lymphoma that originates from malignant B cells. It leads to high levels of a circulating antibody, immunoglobulin M, which can cause symptoms such as fatigue, fever, weight loss, and vision problems. In Canada, the prevalence of this disease is approximately 4 cases per million persons per year.
Patients with WM whose disease relapses or does not respond to initial treatments are in need of more therapeutic options that are better tolerated with favourable toxicity profiles compared to current therapies. New treatments should provide better survival and survival without progression with improvement in hemoglobin levels, which are closely linked to improvements in quality of life.
Treatment with Imbruvica is expected to cost approximately $8,386 per patient per 28-day cycle.
The CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that ibrutinib, with or without rituximab, be reimbursed for the treatment of adult patients with previously treated relapsed or refractory Waldenström’s macroglobulinemia (WM), only if the conditions listed in Table 1 are met.
Evidence from 1 phase III, double-blind, randomized controlled trial (RCT) (iNNOVATE) demonstrated that treatment with ibrutinib-rituximab, when compared with placebo-rituximab, resulted in added clinical benefit in terms of progression-free survival (PFS) for patients with relapsed or refractory (r/r) WM. In patients with r/r WM, the median PFS was not reached (i.e., had not yet been determined) in the ibrutinib-rituximab arm of the study, whereas it was 14.8 months in the placebo-rituximab arm (95% CI, 5.6 to 25.8 months). The PFS rate for patients in the ibrutinib-rituximab arm ranged from 79.5% (95% CI, 63.2% to 89.2%) at 30 months to 67.5% (95% CI, 49.6% to 80.2%) at 54 months, whereas for patients treated with placebo-rituximab, the PFS rate ranged from 29.1% (95% CI, 15.5% to 44%) at 30 months to 19.9% (95% CI, 8.7% to 34.4%) at 54 months. The PFS hazard ratio (HR) was 0.22 (95% CI, 0.11 to 0.43; log rank test P < 0.001). In the single-arm iNNOVATE substudy, which had 31 patients who failed to achieve a response to rituximab and were treated with ibrutinib monotherapy, the median PFS was 39 months (95% CI, 25 months to not estimable [NE]) and the PFS rate ranged from 81% at 18 months (95% CI, 62% to 91%) to 40% (95% CI, 22% to 57%) at 5 years. The body of evidence on the effects of ibrutinib-rituximab on overall survival (OS) was very uncertain due to study limitations and imprecision. One RCT (ASPEN) that compared ibrutinib to zanubrutinib, demonstrated that effect estimates between the 2 drugs were similar with no evidence of meaningful differences for OS, PFS, duration of complete response (CR) or very good partial response (VGPR) as well as duration of response (DOR). More cases of atrial fibrillation were observed with ibrutinib, whereas neutropenia was reported more commonly with zanubrutinib.
pERC recognized the need for more treatment options for patients with r/r WM, notably for treatments that are better tolerated with favourable toxicity profiles compared with current chemoimmunotherapy and Bruton tyrosine kinase (BTK) inhibitor monotherapies. pERC concluded that ibrutinib met some of the needs identified by patients, including survival without progression and improvement in hemoglobin levels, which are closely linked to improvements in health-related quality of life among patients with WM.
At the sponsor-submitted price for ibrutinib and the publicly listed price for zanubrutinib, ibrutinib was more costly than zanubrutinib. Although ibrutinib is considered similarly effective in comparison with zanubrutinib, the available evidence suggests ibrutinib has a less favourable safety profile. As such, ibrutinib should result in cost savings to the CADTH-participating drug programs in comparison with zanubrutinib.
Reimbursement Conditions and Reasons.
Non-Hodgkin lymphomas are a group of more than 60 types of cancers originating from cells of the lymphatic system (i.e., B cells, T cells, and natural killer cells). WM is a low-grade, slow-growing cancer, also considered a subtype of lymphoplasmacytic lymphoma that develops from malignant B cells. Typical characteristics of WM include the overproduction of monoclonal immunoglobulin (IgM) antibody due to changes in the B cells during maturation and the infiltration of lymphoplasmacytic cells bone marrow by malignant cells, leading to cytopenia. Clinical manifestations of the disease include hyperviscosity, cytopenias, lymphadenopathy, organomegaly, hemolytic anemia, peripheral neuropathy, and cryoglobulinemia.
WM comprises approximately 1% of all hematologic malignancies. The incidence in Canada is estimated at 4 cases per 1,000,000 persons. Approximately 150 new diagnoses of WM are reported yearly in Canada, with an overall prevalence estimated at 1,500 cases. The median age at diagnosis is 72 years.
Ibrutinib is an oral, first-in-class, BTK inhibitor that specifically targets PCI-45227. It was approved by Health Canada on March 31, 2016, as follows: “Imbruvica (ibrutinib) for the treatment of adult patients with Waldenström’s macroglobulinemia (WM).” Later, on February 11, 2019, Ibrutinib received approval from Health Canada for the indication: “In combination with rituximab for the treatment of adult patients with WM.” The requested listing criteria for ibrutinib are for a subpopulation of the Health Canada indication and the clinical trial populations. Specifically, ibrutinib for the treatment of adult patients with previously treated r/r WM.
Ibrutinib is available as oral capsules, and the dosage recommended in the product monograph is three 140 mg capsules once daily (420 mg) until disease progression or no longer tolerated. If applicable, rituximab is administered as an IV dose of 375 mg/m2.
To make its recommendation, the committee considered the following information:
Two patient groups provided input for this submission: the WMFC and LC. Their activities include funding WM research and providing patient support services through education, support, advocacy, and research.
Input from the LC group was gathered from an anonymous online survey, The LC group collaborated with the WMFC to promote access to the survey for members within Canada. Of the 291 participants that contributed to the survey, 101 identified as Canadians. The majority of the respondents (43%) were between 65 and 74 years, and 57% identified as males. Most respondents reported that they had been diagnosed with WM for more than 9 years. Forty-nine respondents had experience with ibrutinib, and 12 respondents had experience with ibrutinib-rituximab (including 4 Canadians). Respondents described how WM had impacted their quality of life at diagnosis, expressing that fatigue, anemia, and night sweats were the most common symptoms, with stress and anxiety as common psychosocial impacts. Their current day-to-day quality of life was also affected. Some respondents expressed concerns about contracting infections, such as COVID-19, and treatment duration with current therapies.
The most important outcomes highlighted by respondents in surveys were the control of disease and symptoms, longer periods of remission, improvement in quality of life, longer survival, and fewer side effects. Most respondents expressed the importance of having a choice in treatment. A majority of respondents (71%) indicated that they were willing to tolerate treatment side effects provided these were short term. Many respondents shared that treatment was initiated following diagnosis, and almost half (48%) reported going through a period of “watch and wait.” In total, 34% (n = 82) of respondents reportedly received at least 1 line of therapy, 47% (n = 114) had received 2 or more lines, and 18% (n = 43) were currently not on any treatment. Most respondents (68%) expressed they were pleased with their current treatment options. Respondents expressed that the most difficult adverse events (AEs) to tolerate were fatigue, brain fog, neuropathy, and nausea. Ninety-six respondents from Canada provided input on WM treatments in the survey, of which 71% indicated they had little or no difficulty accessing their current or most recent treatment, 78% indicated they had local access to treatment, 25% indicated they needed to pay out-of-pocket for travel costs. Overall, 66% of respondents who had received at least 1 therapy expressed they were satisfied or very satisfied with the treatment and 38% of respondents expressed satisfaction with treatments for r/r WM.
Overall, 61 respondents indicated they had received ibrutinib in the r/r setting, of which 49 had received ibrutinib as monotherapy and 12 as a combination with rituximab. The majority of the respondents reported they had received a WM diagnosis within the past 3 to 5 years and had access to ibrutinib via a compassionate access program or public or government program. Of the respondents who indicated that ibrutinib had controlled symptoms, half reported fatigue, 42% reported anemia, and 32% indicated night sweats. The WMFC mentioned that zanubrutinib, another BTK inhibitor, is approved and currently funded across 4 jurisdictions in Canada. They noted that both therapies were considered equally effective for WM but have different toxicity profiles, which may be play a role in treatment selection.
Two clinical specialists with expertise in the diagnosis and management of WM provided input to this submission. Both agreed that treatment goals of any therapy for patients with WM include lengthening remissions, stopping progression, improving quality of life, and reducing symptom burden while balancing least possible toxicity.
Until recently, BTK therapy in Canada for patients who are either r/r or treatment naive was only available via access programs or private insurance. Zanubrutinib has been recently approved and is funded in most provinces. Although generally well tolerated, there are patients who stop zanubrutinib due to side effects; in this situation, there is a need for an alternate BTK inhibitor for patients who fail an initial treatment for relapsed WM. Even if zanubrutinib is preferred due to its safety profile (particularly with respect to risk of atrial fibrillation and bleeding due to platelet inhibition), ibrutinib can have a role among patients who are intolerant to zanubrutinib and a place in therapy as another available option for patients with WM.
The clinical experts noted that it is unclear how much the addition of rituximab to BTK inhibitors would benefit current treatment paradigms. Experts also added that there are no specific patient criteria that would identify who would preferentially be best for ibrutinib. The clinical specialists acknowledged that there are very little data on the success of switching from zanubrutinib to ibrutinib for intolerance; hence, this may be an infrequent situation if both drugs are funded. Both experts would work under the assumption of using similar criteria as zanubrutinib in most cases.
According to clinical experts, response to treatment is assessed clinically based on blood counts and chemistry tests. Successful therapy for WM is expected to lead to improvements in cytopenias and reduction in IgM monoclonal protein. The clinical experts noted ibrutinib can be continued until evidence of disease progression or intolerable AEs, although dose reduction could be considered because lower doses can maintain efficacy with a more favourable side effect profile. Failure of efficacy is typically noted through new progressive cytopenias (anemia most commonly) and increases in IgM monoclonal protein. Clinicians felt that comparative data of BTK inhibitor monotherapy versus BTK inhibitor plus rituximab is needed to consider funding of rituximab in this combination in Canada.
Experts noted that WM is a rare condition and should generally be managed by hematologists or oncologists with experience in treating lymphoproliferative disorders. Prescribing of BTK inhibitors would generally be within the scope of hematologist and medical oncologist training in Canada. Typically, WM and BTK inhibitor therapy is delivered on an outpatient basis; however, patients with WM may require hospitalization in tertiary care centres due to complications of disease or treatment.
Input from 1 clinician group, OH-CCO Hematology Cancer Drug Advisory Committee, was summarized for this submission. The OH-CCO’s Cancer Drug Advisory Committees provide timely evidence-based clinical and health system guidance on drug-related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. Information from this group was gathered via videoconferencing.
The OH-CCO Hematology Cancer Drug Advisory Committee highlighted the following important goals for patients with WM: reducing paraprotein levels, reducing symptoms, improving blood counts, and improving quality of life. The group highlighted that zanubrutinib is available for patients with WM in the r/r setting and is accessed via employee assistance programs. Other treatments highlighted included chemotherapy (e.g., bendamustine or cyclophosphamide-vincristine-prednisone [CVP]) in combination with rituximab or bortezomib. The group expressed that current BTK inhibitors (e.g., zanubrutinib) do not address treatment gaps for patients with WM; thus, they were uncertain whether the addition of rituximab to a BTK inhibitor will be beneficial compared to a BTK inhibitor alone. The group highlighted that the addition of ibrutinib alone or ibrutinib with rituximab may be a beneficial alternative for patients with WM in the second-line setting or beyond and added that ibrutinib may be an appropriate alternative for patients who are intolerant to zanubrutinib. The group indicated that the patients least suited for this treatment will be those for whom BTK inhibitors are contraindicated and/or those with a history of severe reactions to rituximab. The group indicated that response to treatment is assessed by evaluating IgM and paraprotein levels, blood counts, and symptom burden. According to the group, factors such as significant intolerance to treatment (bleeding, atrial fibrillation), disease progression, or lack of response will be considered when deciding treatment discontinuation. The group noted that ibrutinib will be best administered in an outpatient setting.
Input from the drug plans identified factors pertaining to relevant comparators, considerations for initiation and discontinuation of therapy, generalizability, care provision issues, and system and economic considerations. pERC weighed evidence from the body of evidence and input from the clinical experts consulted by CADTH, which provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
Clinical evidence for this submission included 1 pivotal study identified in the sponsor’s systematic review that included patients with r/r WM treated with ibrutinib-rituximab versus rituximab-placebo, the iNNOVATE study (N = 150 for overall population, 82 for the r/r population). This study incorporated a substudy with single-arm data of patients previously treated with rituximab who received monotherapy with ibrutinib.
PFS is a critical outcome considered important by clinical experts, patient groups, and other stakeholders for decision-making and deliberations. It was also the primary end point in the iNNOVATE study, in which the median PFS was not reached for patients with r/r WM in the ibrutinib-rituximab arm of the study, while it reached 14.8 months in the placebo-rituximab arm (95% CI, 5.6 to 25.8 months). The PFS rate for patients in the ibrutinib-rituximab arm ranged from 79.5% (95% CI, 63.2% to 89.2%) at 30 months to 67.5% (95% CI, 49.6% to 80.2%) at 54 months; for patients treated with placebo-rituximab, the PFS rate ranged from 29.1% (95% CI, 15.5% to 44%) at 30 months to 19.9% (95% CI, 8.7% to 34.4%) at 54 months. The PFS HR for this comparison in this r/r WM population was 0.22 (95% CI, 0.11 to 0.43; log rank test P < 0.001). In the iNNOVATE substudy of 31 patients treated with ibrutinib monotherapy, the median PFS was 39 months (95% CI, 25 months to NE) and the PFS rate ranged from 81% at 18 months (95% CI, 62% to 91%) to 40% (95% CI, 22% to 57%) at 5 years.
OS was also of critical interest for clinical experts and from other stakeholders’ perspective. For the r/r WM population in the iNNOVATE study, the median OS was not reported across time points for any of the arms of the study. In the single-arm substudy of those treated with ibrutinib monotherapy the OS rate reached 94% (95% CI, 77% to 98%) at 18 months and 73% (95% CI, 54% to 86%) at 5 years.
DOR was defined as the duration from the date of initial documentation of response (i.e., partial response or better) to the date of first documented evidence of progressive disease or death for responders. In the r/r WM population, 31 patients and 9 patients responded in the ibrutinib-rituximab and placebo-rituximab arms, respectively. Events of progressive disease or death occurred in 5 (16.1%) patients in the ibrutinib-rituximab group and 5 (55.6%) patients in the placebo-rituximab arm. The median DOR was not reached in the ibrutinib-rituximab arm (95% CI, 55.8 months to NE), whereas it was 23.5 months (95% CI, 9.2 months to NE) in the placebo-rituximab arm. At 30 months, 96.6% of patients (95% CI, 77.9% to 99.5%) in the ibrutinib-rituximab arm and 37.5% (95% CI, 8.7% to 67.4%) in the placebo-rituximab arm continued their response. At the 54-month landmark, the DOR rate was 82.6% for the ibrutinib-rituximab arm. No patient had a DOR greater than 48 months observed; therefore, DOR was NE in the placebo-rituximab arm.
For the r/r WM population, TTNT was reported in a Kaplan-Meier curve as subgroup analysis by prior treatment history with no specific data; at week 54, 84% of patients in the ibrutinib-rituximab arm and 21% in the placebo-rituximab arm had not received subsequent therapy. TTNT was also reported for the single-arm substudy with 31 patients, but only 10 patients (32.3%) received subsequent treatment. In this group, the median for TTNT was not reached. At the 60-month landmark estimate, 64.6% had not received subsequent treatment.
Improvements in hemoglobin levels was defined as the proportion of patients with sustained hemoglobin improvement for more than 56 days. In the r/r WM population, baseline hemoglobin levels were 10.9 g/dL in the ibrutinib-rituximab arm and 10.3 g/dL in the placebo-rituximab arm. At follow-up, 29 of 41 patients (70.7%) had sustained hemoglobin improvement in the ibrutinib-rituximab arm, whereas 12 patients (29%) had sustained improvement in the placebo-rituximab arm. This represents an absolute difference of 41.5% (95% CI, 19.3% to 60.5%; P = 0.003).
For the r/r WM population, changes in IgM levels were reported only in the iNNOVATE substudy (31 patients with ibrutinib monotherapy). At baseline, mean IgM levels were 39.2 g/L. The maximum median decrease was 36.6 g/L (95% CI, 74.8 g/L to 4.5 less g/L) in this single-arm study.
All 75 patients in each arm of the iNNOVATE study presented at least 1 AE (including 30 of 31 in the ibrutinib monotherapy arm of the iNNOVATE substudy). The most common AEs of any grade in the ibrutinib-rituximab and placebo-rituximab arms were infusion-related reaction (43% and 59%), anemia (24% and 28%), and diarrhea (31% and 15%). Some AEs more commonly reported in the ibrutinib-rituximab arm compared with the placebo-rituximab arm included hypertension (25% vs. 5%), diarrhea (31% vs. 15%), nausea (23% vs. 12%), dyspepsia (17% vs. 1%), peripheral edema (23% vs. 12%), and arthralgia (27% vs. 12%).
SAEs in the iNNOVATE study were more common in the ibrutinib-rituximab arm compared with the placebo-rituximab arm (40 patients [53%] vs. 25 patients [33%]). These included pneumonia (11% vs. 3%) and atrial fibrillation (11% vs. 1%). In the ibrutinib monotherapy arm (substudy), 16 patients presented with at least 1 SAE (52%). In the iNNOVATE study, 1 patient died due to an AE in the ibrutinib-rituximab arm, and 3 patients died in the placebo-rituximab arm. Cause of patient deaths included pneumonia, Bing-Neel syndrome, and intracranial hemorrhage. No deaths were reported in the iNNOVATE substudy.
Among the significant concerns identified by the clinical experts consulted by CADTH and other stakeholders were issues such as atrial fibrillation, serious respiratory infections, major hemorrhage, and cytopenias. All these AEs were evaluated in the general population of the iNNOVATE study and substudy.
In this case, the proportion of patients with atrial fibrillation was higher in the ibrutinib-rituximab arm (14 patients [19%]) compared with the placebo-rituximab arm (2 patients [3%]) but none in the substudy of ibrutinib monotherapy arm. Similarly, serious respiratory infections occurred in 4 patients (5%) in the ibrutinib-rituximab arm, in no patients in the placebo-rituximab arm, and in 1 patient in the substudy population. Major hemorrhage occurred slightly more frequently in the ibrutinib-rituximab arm (5 patients [7%]) than in the placebo arm (3 patients [4%]). Of the cytopenias evaluated, the ibrutinib-rituximab arm had more cases of neutropenia compared with the placebo-rituximab arm (16% vs. 9%) but did not have more cases of anemia (24% vs. 28%) or thrombocytopenia (7% vs. 11%).
Overall, the iNNOVATE trial comparing ibrutinib-rituximab to placebo-rituximab was deemed to have low risk of bias. The iNNOVATE study presents no concerns in the randomization process with a properly generated randomization list and concealment of allocation of patients to each arm of the study. No substantial baseline imbalances were detected to suggest an issue with the randomization process. The use of a placebo and blinding of patients and outcome assessors ameliorate concerns of risk of bias due to deviations from the intended interventions. An intention-to-treat analysis was performed to assess the effects of assignment to the intervention. Although patients were allowed to cross over to receive ibrutinib after disease progression, patients were analyzed in the arm to which they were initially randomized. Data regarding primary outcomes were available for almost all randomly assigned participants, minimizing the potential for bias from incomplete outcome data. There were some discrepancies on the number of censored patients in the outcome of PFS, with more patients being censored in the ibrutinib-rituximab arm, maybe related to fewer patients available to analyze in the placebo-rituximab arm as the study advanced. Despite this difference, sensitivity analyses based on censoring at the last adequate response assessment before documented progression or death showed similar results to the base case of PFS.
In terms of external validity, according to clinical experts consulted by CADTH, the patients included in the iNNOVATE study had overall baseline characteristics and prognostic factors similar to those encountered in the Canadian clinical landscape. However, a concern from the experts was the lack of a relatable direct comparison commonly used in practice (e.g., ibrutinib monotherapy or zanubrutinib monotherapy). In terms of applicability, although the iNNOVATE trial is a well conducted study, the results would only be applicable to a relatively small proportion of patients in Canada because the direct comparison provided is only against rituximab, and currently other BTK inhibitors (zanubrutinib) are available and preferred over rituximab monotherapy. The generalizability of these findings is uncertain according to clinical experts, but unlikely to have differences in real-life practice.
The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) assessments included an evaluation of the main outcomes considered important by clinicians, patient groups, and stakeholders. The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: PFS, OS, DOR, TTNT, hematological improvement, and harms. The comparison evaluated in the GRADE assessment was that of ibrutinib-rituximab against rituximab-placebo. Table 3 presents the GRADE summary of findings for this comparison.
Overall, there was moderate certainty for the outcome of PFS due to imprecision. The threshold of clinical importance for benefit or harm was set at 10 more (or fewer) patients per 1,000 on the event rate for PFS. This was obtained by iterative discussions with the clinical experts and the CADTH team. Despite observing an effect estimate beyond this threshold, the team decided to rate down 1 level due to concerns on the sample size (N = 82) in the study.
OS was very uncertain due to 1 single-arm study providing descriptive data for survival, which was rated down 3 levels for risk of bias, and 1 level due to indirectness because the population included in the study (previously treated with rituximab) was different than the population in the summary of findings table (patients with r/r WM with or without previous rituximab use). There is another row with indirect evidence obtained from the overall population (patients with r/r WM who have not been previously treated) for the PICO (population, intervention, comparison, outcome) question, hence it was rated down 1 level for indirectness and 2 levels for imprecision.
DOR was also imprecise due to the small number of observations available (i.e., only those patients who responded).
For TTNT, low certainty evidence was included from the iNNOVATE study r/r WM population (rated down 2 levels for imprecision and no thresholds to judge it, hence using only the null).
Sustained hemoglobin improvement was deemed as moderate certainty, rated down only for imprecision due to the sample size, while acknowledging input from the clinical experts that results with such a large effect size are credible, well above a threshold of 100 per 1,000 patients as the clinically important benefit — or harm if on either side. IgM were not deemed appropriate for evaluation with thresholds because no precise estimates could be obtained.
As with IgM levels, no precise estimates were obtained from AEs, SAEs, and other harms, hence the null and clinical assessment were used to judge the precision of the possible differences observed in a narrative way. Hence, except for AEs, all harms were deemed of moderate certainty.
Summary of Findings for Ibrutinib-Rituximab for Patients With Relapsed or Remitting Waldenström’s Macroglobulinemia.
To estimate the relative efficacy of the interventions for treatment of patients with WM (first line or r/r), a systematic review of the literature was conducted to identify if data were available to inform the indirect treatment comparison (ITC) section (date of the last search update: March 23, 2021). The identified evidence for treatments of WM was limited by the availability of only a few RCTs and by methodological flaws within the included studies, including small sample sizes and lack of blinding. Specific methods of ITC and adjusted comparisons depended on the type of data available, and included propensity score matching (PSM), matching adjusted indirect comparison, inverse probability of treatment weighting (IPTW) analyses, and an adjusted Cox proportional hazard model.
Despite attempts to compare ibrutinib to other interventions relevant to this submission, there were no direct feasible comparisons using these bodies of evidence. The network of evidence was not appropriate to create loops to use in a network meta-analysis. The only feasible way was using the bodies of evidence from databases and chart reviews (real-world evidence) of patients with WM using physician’s choice (PC) regimens compared to ibrutinib-rituximab or rituximab using data from the iNNOVATE study and single-arm substudy or to compare ibrutinib monotherapy to ibrutinib-rituximab. Authors still were able to present assessments for these comparisons (by using matching adjusted indirect comparison, PSM, IPTW, and naive assessments), although only the ibrutinib-rituximab versus PC was a comparison applicable to this review report, albeit with important limitations to obtain credible effect estimates.
The only possible adjusted comparison was the 1 comparing PC versus ibrutinib-rituximab, in which the authors used data from the iNNOVATE study arm with patients treated with ibrutinib-rituximab and compared it to data from patients in the chart review. Despite trying to use PSM and IPTW, the small sample size and imbalances made it challenging to obtain effect estimates.
Ibrutinib-rituximab versus ibrutinib monotherapy was a relevant comparison for this CADTH submission; however, no comparison was possible other than a naive comparison of the iNNOVATE ibrutinib-rituximab arm versus the single-arm PCYC-118E study with ibrutinib monotherapy. The HR obtained was 1.25 (95% CI, 0.63 to 2.48). The comparisons of PC versus rituximab and PC versus ibrutinib-rituximab are described but the former is not relevant for the submission and the latter was not possible to analyze.
No harms were assessed in the ITCs or adjusted analyses submitted by the sponsor.
All effect estimates from comparisons assessed in the ITCs or adjusted analyses remain very uncertain due to the limitations of the data. These include imbalances in patients’ characteristics and the nature of the observational data, generating the possibility of confounding and risk of bias due to selection of patients, or deviations from the intended interventions. All these limitations are connected to the unfeasibility of conducting any direct or indirect comparisons. Furthermore, the low number of patients and events produced very imprecise effect estimates in those situations in which HRs could be obtained.
The results of these ITCs or adjusted analyses also have limited applicability and generalizability in the current clinical practice in Canada because 1 of the main comparators currently used (zanubrutinib) was not included in the ITCs or adjusted analyses. Furthermore, according to clinical experts consulted by CADTH, the comparison of ibrutinib monotherapy versus zanubrutinib would provide more pertinent data to the Canadian practice because both are gaining more attention in the treatment of patients with r/r WM compared with the combination of ibrutinib-rituximab or rituximab monotherapy.
Two studies are included in this section. The single-arm PCYC-118E study (with a long-term assessment update) evaluated ibrutinib monotherapy in 63 patients who had a clinicopathological diagnosis of WM, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and had received 1 or more prior treatments.
The ASPEN study (N = 201 for the total population) evaluated ibrutinib against zanubrutinib in patients with r/r WM (N = 164) after 1 prior line of therapy or treatment-naive WM unsuitable for standard immunochemotherapy. ASPEN was a randomized, open-label, multicentre, phase III trial that compared the efficacy and safety of ibrutinib and zanubrutinib in patients with WM who required treatment based on the consensus criteria from IWWM-7. Patients were assigned 1:1 to receive ibrutinib at an approved dose of 420 mg, once daily or to receive zanubrutinib, 160 mg, twice daily. The primary rationale was to demonstrate the superiority of zanubrutinib versus ibrutinib, measured by the proportion of patients achieving a CR or VGPR, assessed by an independent review committee. Secondary end points included major response rate (MRR) assessed by independent review committee, DOR (time from initial qualifying response until progression or death), PFS (time from randomization until progression or death), reductions in bone marrow and extramedullary tumour burden, and harms. OS and changes in quality of life were exploratory end points. The study consisted of an initial screening phase, a treatment phase, and a follow-up phase. The study was conducted across 60 centres in 12 countries.
In the PCYC-1118E study at a median follow-up of 14.8 months, the median OS was not reached at the data cut-off (February 28, 2014). In total, 95.2% of patients were alive at the study cut-off. At the landmark of 18 months, the estimated survival rate was 92.7% (95% CI, 76.6% to 97.9%). The 5-year OS rate for all patients was 87% in the long-term evaluation. The median PFS was also not reached at the median follow-up (i.e., time on study) of 14.8 months. The 18-month landmark estimate of PFS per the independent review committee evaluation was 79.5% (95% CI, 65.8% to 88.2%). The 5-year PFS rate reported for all patients was 54% (95% CI, 39% to 67%). Sustained improvement in hemoglobin was observed in 37 of 63 (58.7%) patients in the all-treated population.
In the ASPEN study, when assessing PFS, the median PFS was not reached in either treatment arm in all cohorts (i.e., r/r or overall population). In the r/r WM population, the event-free rates at 18 months were 81.7% (95% CI, 71.1% to 88.8%) versus 85.9% (95% CI, 73.7% to 92.7%) in the ibrutinib and zanubrutinib arms, respectively. In the overall population, after a median follow-up of 18 and 18.5 months, 15 (15%) patients and 16 (16%) patients in the ibrutinib and zanubrutinib arms respectively progressed or died. For OS, the median OS was not reached in either treatment arm of r/r or the overall population. There were 8 deaths reported in the ibrutinib arm (all in the r/r population) and 6 deaths in the zanubrutinib arm (3 in the r/r population). The event-free rates for patients in the ibrutinib and zanubrutinib treatment arms at 12 months were 93.9% (95% CI, 86.8% to 97.2%) and 97.0% (95% CI, 90.9% to 99.0%), respectively. At 18 months, event-free rates were 92.8% (95% CI, 85.5% to 96.5%) and 97.0% (95% CI, 90.9% to 99.0%), in the ibrutinib and zanubrutinib arms, respectively. When assessing DOR, the median duration of CR or VGPR and MRR was not reached in the overall population or in patients with r/r WM in either treatment arm who had achieved a response to study treatment. Four events occurred in patients with VGPR or CR in the ibrutinib arm, and 1 event occurred in patients with VGPR or CR in the zanubrutinib arm. Among patients who achieved a major response, 9 events occurred in the ibrutinib arm, and 6 events occurred in the zanubrutinib arm. The event-free rates at 12 months and 18 months for patients in the ibrutinib arm who achieved a major response were 87.9% (95% CI, 77.0% to 93.8%) and 87.9% (95% CI, 77.0% to 93.8%), respectively. Median TTNT was not reached. Data showed that 9 patients in the ibrutinib arm and 6 patients in the zanubrutinib arm had begun non-protocol anticancer therapy. The median time to initiation of non-protocol anticancer therapy was 6.44 months in the ibrutinib treatment arm and 6.83 months in the zanubrutinib treatment arm.
From the ASPEN study, the most common AEs in the ibrutinib arm (overall population) were diarrhea (31.6%), upper respiratory tract infection (28.6%), and contusion and muscle spasms (both 23.5%). In the zanubrutinib arm, the most common AEs were neutropenia (24.8%), upper respiratory tract infection (23.8%), and diarrhea (20.8%).
SAEs were reported in 40 patients (40.8%) in the ibrutinib treatment arm and in 40 patients (39.6%) in the zanubrutinib treatment arms. The most common SAE in the ibrutinib treatment arm was pneumonia (9 patients [9.2%]) followed by pyrexia and sepsis (each reported by 3 patients [3.1%]). The most common SAEs in the zanubrutinib treatment arm were febrile neutropenia, influenza, and neutropenia (each reported by 3 patients [3.0%]). In total, 7 patients (7.1%) in the ibrutinib treatment arm and 6 patients (5.9%) in the zanubrutinib treatment arm died during the study. Deaths due to AEs occurred in 2 patients treated with ibrutinib and 1 patient treated with zanubrutinib.
When assessing harms of special interest, neutropenia was reported in 12 patients (13%) in the ibrutinib arm and 25 patients (29%) in the zanubrutinib arm. Hemorrhage (including minor and major bleeding) was reported in 58 patients (59.2%) in the ibrutinib arm and 49 patients (48.5%) in the zanubrutinib arm. Cardiovascular events included atrial fibrillation or flutter and were reported in 14 patients (14.3%) in the ibrutinib arm and 2 patients (2.0%) in the zanubrutinib treatment arm.
The open-label, nonrandomized design with no concurrent comparator is a key limitation of the PCYC-1118E study; hence, any treatment effects observed will be very uncertain for estimating causal effects and should be interpreted with caution.
The ASPEN trial was a randomized, phase III, open-label design. Randomization was stratified based on relevant prognostic factors, which included CXCR4(WHIM) mutational status and prior lines of therapy. Appropriate methods of randomization and treatment allocation were implemented, which reduced the potential for selection bias. The study was generally well balanced with respect to patient baseline demographics and disease characteristics, suggesting that randomization was successful. The open-label design may have introduced bias for subjective outcomes, such as the reporting of AEs and health-related quality of life outcomes, although these were not of concern according to clinical experts consulted by CADTH.
The primary end point and key secondary end points were appropriate and adequately described. Data were immature for time-to-event outcomes, and median PFS and OS were not reached in either treatment arm. There were no methods or techniques outlined to account for missing data, and no methods were described for imputing data. The absence of appropriate methods to account for missing data may have introduced bias in the assessment of efficacy outcomes. The direction of bias is unclear. Sensitivity analyses were conducted for the primary outcome, although it was unclear whether there were major differences between the primary and the sensitivity analyses. There were no credible subgroup effects observed. Subgroup analyses were predefined, and the results presented were consistent with the primary analyses.
Summary of Economic Evaluation.
CADTH identified the following key limitations with the sponsor’s budget impact analysis: incident patients with WM were not incorporated into the patient population and market share estimates were not reflective of Canadian clinical practice. The CADTH reanalysis updated the market share for ibrutinib monotherapy to reflect an uptake of 20%, 15%, and 10% in year 1, year 2, and year 3, respectively, along with the market shares of zanubrutinib, bendamustine-rituximab with or without rituximab maintenance, dexamethasone-rituximab-cyclophosphamide with or without rituximab maintenance, and “other” therapies. In the CADTH base case, the budget impact of reimbursing ibrutinib is expected to be $150,012 in year 1, $263,921 in year 2, and $340,806 in year 3. Therefore, the 3-year total budget impact is $754,739.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Philip Blanchette, Dr. Kelvin Chan, Dr. Matthew Cheung; Dr. Michael Crump, Dr. Jennifer Fishman, Mr. Terry Hawrysh, Dr. Yoo-Joung Ko, Dr. Christian Kollmannsberger, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik.
Meeting date: November 8, 2023
Regrets: Two members did not attend.
Conflicts of interest: None
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Indication: Ibrutinib, with or without rituximab, for the treatment of adult patients with previously treated refractory or relapsed Waldenström’s macroglobulinemia
Sponsor: Janssen Inc.
Final recommendation: Reimburse with conditions
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