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Indication: In combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma not otherwise specified, including diffuse large B-cell lymphoma arising from low grade lymphoma, who are not eligible for autologous stem cell transplant
CADTH recommends that Minjuvi, in combination with lenalidomide, not be reimbursed by public drug plans for the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, who are not eligible for autologous stem cell transplant (ASCT).
DLBCL is a cancer of the lymphatic system that develops when the body makes abnormal B lymphocytes. DLBCL is a fast-growing type of non-Hodgkin lymphoma (NHL). If DLBCL comes back after or does not respond to first-line chemotherapy treatment, it is considered R/R. It was estimated that 11,100 people in Canada would be diagnosed with NHL and 2,900 people in Canada would die from NHL in 2021. DLBCL is the most common subtype of NHL, constituting 30% to 40% of cases in Canada. Approximately 30% to 50% of patients in Canada experience R/R disease after treatment with standard first-line chemotherapy.
Patients with R/R DLBCL have limited treatment options, 1 of which is ASCT. However, not all patients are eligible for ASCT. Prognosis of patients with R/R DLBCL remains poor, particularly for those who are not eligible for ASCT. Furthermore, not every patient’s disease responds to currently available treatments for R/R DLBCL and remission duration is often short.
Treatment with Minjuvi is expected to cost between $11,679 and $31,422 per patient per 28-day cycle.
The CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that tafasitamab not be reimbursed in combination with lenalidomide for the treatment of adult patients with R/R DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, who are not eligible for ASCT.
One phase II, single-arm, open-label study (L-MIND; N = 81) evaluated the efficacy and safety of tafasitamab in combination with lenalidomide (i.e., tafasitamab plus lenalidomide) in adult patients with DLBCL who had relapsed after or were refractory to 1 to 3 previous systemic regimens and who were not candidates for ASCT. Although 57.5% (95% confidence interval [CI], 45.9% to 68.5%) of patients from the L-MIND study showed an objective response, there was a high degree of uncertainty regarding the magnitude of clinical benefit directly attributable to tafasitamab plus lenalidomide due to the nonrandomized, noncomparative, open-label study design and the small sample size. Further, due to the absence of a comparator arm, the potential clinical benefit of tafasitamab plus lenalidomide compared to other relevant treatment comparators was unknown. HRQoL was also not assessed in the L-MIND study. The sponsor submitted 3 indirect treatment comparisons (ITCs) that compared patients in the L-MIND study to patients treated with other therapies. However, given the methodological limitations of the analyses (i.e., heterogeneity, matching based on a limited number of variables, and small sample sizes), pERC was unable to determine the comparative efficacy of tafasitamab plus lenalidomide relative to other therapies. There was limited comparative data on harms; thus, no conclusions could be drawn regarding the relative safety of tafasitamab plus lenalidomide compared to other therapies.
Patients expressed a need for treatments that prolong survival and remission, control disease symptoms, improve HRQoL, and have fewer side effects compared to current therapies. While recognizing the need for additional effective treatment options for this vulnerable patient population, pERC was uncertain whether tafasitamab plus lenalidomide meets these important therapeutic needs given the limitations associated with the evidence reviewed.
NHL is a cancer of the immune system that encompasses more than 60 types of cancers affecting the lymphocytes. In 2021, it was estimated that 11,100 people in Canada would be diagnosed with NHL and 2,900 people in Canada would die from NHL that year. DLBCL is the most common subtype of NHL, constituting 30& to 40% of cases in Canada. DLBCL represents a heterogeneous group of aggressive B-cell malignancies. Some types of indolent B-cell lymphomas can transform into DLBCL (e.g., follicular lymphoma). Although the curability rate of DLBCL is high, approximately 30% to 50% of patients in Canada experience R/R disease after treatment with standard first-line chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or a similar regimen.
Patients with R/R DLBCL have limited treatment options, which range from supportive care to conventional salvage therapy and ASCT. Eligibility for this salvage approach depends on PS, age, and comorbidities, and eligibility for ASCT is also dependent on the response to salvage chemotherapy. The prognosis of patients with DLBCL who have relapsed and do not undergo high-dose therapy and ASCT is poor. Even for those patients who respond to salvage chemotherapy and undergo ASCT, 50% are likely to relapse following ASCT. In patients with R/R DLBCL who are not eligible for intensive therapies, there is no standard treatment approach. There are numerous chemotherapy options, but response rates are generally low and remission duration is short. pola-BR is an option for people in Canada in this setting, if funded, according to the clinical experts consulted by CADTH.
Tafasitamab has been approved by Health Canada in combination with lenalidomide for the treatment of adult patients with R/R DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, who are not eligible for ASCT. Tafasitamab is a monoclonal antibody. It is available as an IV infusion and the dosage recommended in the product monograph is 12 mg/kg body weight. There is currently no Health Canada–approved indication for lenalidomide monotherapy in lymphoma.
To make its recommendation, the committee considered the following information:
After the draft recommendation for tafasitamab was issued in April 2022, the sponsor filed a request for reconsideration. In the meeting to discuss the sponsor’s request for reconsideration, the committee considered the following information:
One patient advocacy group provided input on tafasitamab for the treatment of DLBCL in adult patients; LC conducted 4 anonymous online surveys. Overall, 150 patients with DLBCL responded to the surveys, of which 2 (1%) indicated they had received tafasitamab therapy. Commonly reported symptoms affecting patients’ HRQoL at diagnosis included fatigue or lack of energy, enlarged lymph nodes, drenching night sweats, unexplained weight loss, loss of appetite, flu-like symptoms, and persistent cough. Patients also described mental and emotional problems associated with their disease and treatment that negatively impacted their quality of life. Patients rated longer survival and remission than with current therapies and controlling disease symptoms as the most important outcomes for a new therapy. Better HRQoL and fewer side effects compared to current therapies were also important considerations.
The clinical experts reported that the goal of treatment in patients with R/R DLBCL who are not eligible for intensive therapies (i.e., ASCT and/or CAR T-cell therapy) is to control symptoms with minimal toxicity to improve HRQoL, delay disease progression, and prolong life. The clinical experts noted that ASCT and CAR T-cell therapy both have toxicity and feasibility issues that limit broad application. Of the available options for patients who are not eligible for intensive therapies, or relapse after these therapies, there is no standard of care treatment and there is no treatment that is curative (i.e., patients are treated with palliative intent). Per the clinical experts, most currently used treatment options have short durations of response.
The clinical experts indicated that tafasitamab plus lenalidomide would be an option at relapse for second-line therapy in patients who are not eligible for intensive therapy. Tafasitamab plus lenalidomide treatment could also be used in the third-line or later setting for patients who relapse after ASCT.
The clinical experts indicated that patients who would most likely benefit from tafasitamab plus lenalidomide are those with relapsed DLBCL, including those with underlying indolent lymphomas. The clinical experts thought that tafasitamab plus lenalidomide may be considered in patients who are not eligible for ASCT or CAR T-cell therapy, or who decline either of these treatments. The clinical experts indicated that it is not possible to identify patients who are most likely to respond to tafasitamab plus lenalidomide before treatment because there is no data on which patient or tumour characteristics are optimal for this treatment compared to other options. The clinical experts noted that patients with primary refractory DLBCL would be least suitable for treatment with tafasitamab plus lenalidomide and that patients who cannot come in for frequent IV infusions would not be suitable for this treatment.
The clinical experts consulted by CADTH reported that standard of care for assessing treatment response would be imaging with CT or PET scans every 3 to 4 months (or sooner if there is a change in the patient’s clinical status), with a clinical exam and bloodwork drawn before each treatment. The clinical experts indicated that a clinically meaningful response to treatment would include improvement in survival as well as DOR, which would usually correlate with an improvement in symptom burden. Per the clinical experts, meaningful response would include complete response (CR), partial response (PR), or stable disease with a tolerable toxicity profile.
The clinical experts noted that any disease progression should be an indication for treatment discontinuation, and indicated that recurrent infections, serious infection due to B-cell depletion, and hypogammaglobulinemia may also be considerations for discontinuation.
Clinician input on the review of tafasitamab for the treatment of adult patients with R/R DLBCL was received from 2 groups: the OH-CCO Hematology Cancer Drug Advisory Committee and a group of 4 clinicians whose submission was coordinated by LC. The clinician groups agreed that tafasitamab plus lenalidomide would be recommended in patients with DLBCL who do not respond to or relapse after first-line therapies. There were differing opinions on which patients are unsuitable for tafasitamab. The clinicians from OH-CCO shared that patients with DLBCL who have progressed on CAR T-cell therapies would be least suitable for this therapy, while the LC-coordinated group maintained that there are no specific parameters that deem a patient to be unsuitable for this therapy.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for tafasitamab:
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
One single-arm, multicentre, open-label, phase II study (L-MIND, N = 81) of tafasitamab plus lenalidomide in adult patients with DLBCL who had relapsed after or were refractory to 1 to 3 previous systemic regimens (with at least 1 anti-CD20 therapy), and who were not candidates for HDC and subsequent ASCT, was reviewed. The primary objective of the L-MIND study was to determine the activity of tafasitamab plus lenalidomide in terms of ORR (CR plus PR) in adult patients with R/R DLBCL. Patients received IV tafasitamab (12 mg/kg) and oral lenalidomide (25 mg per day) for up to 12 cycles (28 days each), followed by tafasitamab monotherapy in patients with stable disease or better until disease progression. The primary end point was ORR by independent review committee (IRC). Other efficacy outcomes assessed included ORR by investigator assessment, OS, PFS, time to progression (TTP), event-free survival (EFS), complete response rate (CRR), DOR, time to response (TTR), and time to next treatment (TTNT). Harms outcomes were also examined. HRQoL outcomes were not assessed.
In the L-MIND study, the mean age of patients was 69.3 years. Most patients were White (88.9%), had Ann Arbor stage III or IV disease (75.3%), and did not have a prior ASCT (88.9%). Overall, 54.3% of the enrolled patients were male, 55.6% had an ECOG PS of 1, 50.6% had an International Prognostic Index score of 3 to 5, and 46.9% had disease of germinal centre B-cell like cell origin by immunohistochemistry. Mean time since first DLBCL diagnosis was 39.6 months (standard deviation [SD] = 34.8). All (100%) patients had experience with 1 or more prior anti-cancer medications; 50.6% of patients had received 2 or more prior therapy lines, and 44.4% were refractory to their most recent previous therapy. The most common reasons for ASCT ineligibility were older age (46.3%) and being chemo-refractory (22.5%).
Three analyses were conducted based on 3 data cut-off dates. The primary analysis had a data cut-off date of November 30, 2018. Two additional interim analyses, which were not prespecified in the study protocol, were conducted with data cut-off dates of November 30, 2019, and October 30, 2020. A final analysis is planned with the final data cut-off at study completion (anticipated for November 2022).
At the primary analysis, median OS was not reached (NR) (95% CI, 18.3 to NR) with a median follow-up time of 19.6 (95% CI, 15.3 to 21.9) months. As of the most recent analysis, the median OS was 33.5 months (95% CI, 18.3 to NR) with a median follow-up time of 42.7 (95% CI, 38.0 to 47.2) months.
At the primary analysis, median PFS by IRC was 11.6 months (95% CI, 5.7 to NR) with a median follow-up time of 17.6 (95% CI, 14.1 to 21.2) months. As of the most recent analysis, median PFS by IRC was 11.6 months (95% CI, 6.3 to 45.7) with a median follow-up time of 33.9 ||||| |||||||||||| months.
At the primary analysis, median TTP was 16.2 months (95% CI, 7.4 to NR). TTP results were not reported in the subsequent interim analyses.
At the primary analysis, median EFS was 8.7 (95% CI, 5.3 to 21.0) months with a median follow-up time of 19.7 (95% CI, 14.3 to 22.0) months. EFS results were not reported in the subsequent interim analyses.
ORR by IRC was the primary end point in the L-MIND trial. At the primary analysis, the ORR by IRC was 60.0% (95% CI, 48.4 to 70.8). The best objective response for patients was CR for 34 out of 80 (42.5%) patients and PR for 14 out of 80 (17.5%) patients. As of the most recent interim analysis, ORR by IRC was 57.5% (95% CI, 45.9 to 68.5) and 32 (40.0%) patients had CR and 14 (17.5%) patients had PR.
At the primary analysis, median DOR by IRC was 21.7 (95% CI, 21.7 to NR) months. Median DOR by IRC in patients with PR was 4.4 months (95% CI, 2.0 to 9.1) and NR (95% CI, 21.7 to NR) in patients with CR. As of the most recent interim analysis, median DOR by IRC was 43.9 (95% CI, 26.1 to NR) months. Median DOR by IRC in patients with PR was 5.6 (95% CI, 2.2 to NR) months compared to NR (95% CI, 43.9 to NR) in patients with CR.
At the primary analysis, median TTR (CR or PR) based on IRC evaluation was 2.0 months (range = 1.7 to 16.8 months). At the second analysis, median TTR based on IRC evaluation was 2.0 months (range = 1.7 to 16.8). TTR results were not reported at the most recent interim analysis.
At the primary analysis, median TTNT was 15.4 (95% CI, 7.6 to NR) months. At the second analysis, median TTNT was |||||||| ||||||||||| months. TTNT results were not reported in the most recent interim analysis.
HRQoL was not assessed in the L-MIND trial.
Harms data from the L-MIND study safety analysis set (N = 81) as of the most recent analysis (October 30, 2020, data cut-off) are summarized in the following. As of both the primary analysis and most recent analysis, the median duration of exposure to the study treatment (tafasitamab plus lenalidomide) was 9.2 months.
All 81 (100%) patients enrolled in the L-MIND trial experienced 1 or more treatment-emergent adverse event (AE). The most common AEs were neutropenia (n = 41; 50.6%), anemia (n= 37; 37.0%), diarrhea (n = 29; 35.8%), thrombocytopenia (n = 25; 30.9%), and cough (n = 22; 27.2%).
Overall, 53.1% of patients enrolled in the L-MIND study experienced 1 or more serious adverse event (SAE). The most common SAEs were pneumonia (n = 7; 8.6%), febrile neutropenia (n = 5; 6.2%), and pulmonary embolism (n = 3; 3.7%). Other SAEs reported in more than 1 patient included bronchitis, lower respiratory tract infection, atrial fibrillation, and congestive heart failure (n = 2; 2.5% each).
Overall, 20 (24.7%) patients permanently discontinued treatment with 1 or both study drugs due to AEs: ||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||| and 10 (12.3%) discontinued both study drugs. The only AE that led to permanent discontinuation of the study drug in more than 1 patient was neutropenia (n = 3; 3.7%).
In total, 42 (51.9%) patients enrolled in the L-MIND trial had died as of the October 30, 2020, data cut-off date. |||||||||||||||||||||||||||||||||||||||||||| |||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Overall, || ||| of patients enrolled in the L-MIND trial experienced an infection. The most common types of infections were urinary tract infections (17%) and respiratory tract infections of all grades, including pneumonia and bronchitis (53.1%).
Regarding myelosuppression, 50.6% (n = 41) of patients experienced neutropenia, 37.0% (n = 30) experienced anemia, 30.9% (n = 25) experienced thrombocytopenia, 14.8% (n = 12) experienced leukopenia, 12.3% (n = 10) experienced febrile neutropenia, and 7.4% (n = 6) experienced lymphopenia.
One (1.2%) patient developed worsening progressive multifocal leukoencephalopathy. ||||||||| |||||||| experienced hepatitis B virus reactivation. Five (6.2%) patients experienced an infusion-related reaction. No patients experienced grade 3 or higher tumour lysis syndrome or cytokine release syndrome; tumour lysis syndrome or cytokine release syndrome events of any grade were not reported.
Three sponsor-submitted ITCs were included in this review: 2 retrospective observational studies (RE-MIND and RE-MIND2) that were used as external cohorts for indirect comparison with patients enrolled in the L-MIND study, using estimated propensity score–based nearest neighbour 1:1 matching methodology, and 1 ITC that used unanchored matching-adjusted indirect comparisons (MAICs). These ITCs were used to inform the pharmacoeconomic models.
RE-MIND was designed to characterize the effectiveness of lenalidomide monotherapy in the treatment of patients with R/R DLBCL not eligible for HDC followed by ASCT by comparing a matched cohort with the efficacy outcomes observed for tafasitamab plus lenalidomide therapy in the L-MIND trial. The primary end point was ORR. Other end points assessed included OS, CRR, DOR, PFS, TTNT, and EFS. Data from the L-MIND study used in RE-MIND were from the November 30, 2018, data cut-off (primary analysis).
RE-MIND2 was designed to characterize the effectiveness of systemically administered therapies in the treatment of patients with R/R DLBCL (second line, third line, and fourth line) by generating a real-world, synthetic control group for comparison with the L-MIND trial. Eligible systemic therapies for comparison included regimens administered in routine clinical care according to the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines for patients with R/R DLBCL who were not eligible for ASCT. This study included the following treatment cohorts: systemic therapies pooled, BR, R-GemOx, CAR T-cell therapy, and pola-BR. The primary end point was OS. Other end points assessed included ORR, CRR, DOR, PFS, |||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||. Data from the L-MIND study used in RE-MIND2 were from the |||||||||||||||||||||||||| The prespecified main analysis was conducted for systemic therapies pooled, BR, and R-GemOx. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Unanchored MAICs of tafasitamab plus lenalidomide in the L-MIND study versus comparator therapies using prospective studies were conducted. In total, 5 prospective studies reporting data for lenalidomide monotherapy, pola-BR, BR, and R-GemOx were selected for the MAICs against tafasitamab plus lenalidomide. End points assessed included OS, PFS, DOR, ORR, and CRR. Data were used from the L-MIND study analysis with the October 30, 2020, data cut-off.
In RE-MIND, ORR was 67.1% (95% CI, 55.4 to 77.5) in the tafasitamab plus lenalidomide cohort compared to 34.2% (95% CI, 23.7 to 46.0) in the lenalidomide monotherapy cohort (odds ratio = 3.885; 95% CI, 1.900 to 8.142; P < 0.0001). Median OS was NR (95% CI, 15.5 to NR) in the tafasitamab plus lenalidomide cohort and 9.4 (95% CI, 5.1 to 20.0) months in the lenalidomide monotherapy cohort (hazard ratio [HR] = 0.499; 95% CI, 0.317 to 0.785; P = 0.0026). Median PFS was 12.1 (95% CI, 5.9 to NR) months in the tafasitamab plus lenalidomide cohort and 4.0 (95% CI, 3.1 to 7.4) months in the lenalidomide monotherapy cohort (HR = 0.463; 95% CI, 0.307 to 0.698; P = 0.0002). Median DOR was 20.5 (95% CI, 12.3 to NR) months in the tafasitamab plus lenalidomide cohort and 6.6 (95% CI, 4.1 to 17.2) months in the lenalidomide monotherapy cohort ||||||||||.
In RE-MIND2, patients in the tafasitamab plus lenalidomide cohort showed an improvement in OS compared to the cohorts of systemic therapies pooled (HR = 0.553; 95% CI, 0.358 to 0.855; P = 0.0076), BR (HR = 0.418; 95% CI, 0.272 to 0.644; P < 0.0001), and R-GemOx (HR = 0.467; 95% CI, 0.305 to 0.714; P = 0.0004). An improvement was also observed for PFS in the tafasitamab plus lenalidomide cohort compared with the cohorts of systemic therapies pooled (HR = 0.424; 95% CI, 0.278 to 0.647; P < 0.0001), BR (HR = 0.527; 95% CI, 0.344 to 0.809; P = 0.0033), and R-GemOx (HR = 0.433; 95% CI, 0.288 to 0.653; P < 0.0001). The ORR was higher in the tafasitamab plus lenalidomide cohort compared to the cohorts of systemic therapies pooled (|||||||||||||||||||||||||| | P = 0.0323) and R-GemOx (||||||||||||||||||||||||||| P = 0.0076). There was no difference in ORR in the tafasitamab plus lenalidomide cohort compared to the BR cohort (||||||||||||||||||||||||||| P = 0.1810).
In the MAICs, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. For the comparisons of tafasitamab plus lenalidomide to pola-BR, no differences were observed for OS, PFS by IRC, ORR, and CRR. Overall, the results of some of the comparisons to BR favoured tafasitamab plus lenalidomide, whereas others indicated no difference. Lastly, in the MAIC of tafasitamab plus lenalidomide versus R-GemOx, results indicated no difference between tafasitamab plus lenalidomide and R-GemOx for all outcomes assessed.
In RE-MIND2, 8 patients (14.5%, 14.5%, and 15.1% in the analysis sets for comparison to systemic therapies pooled, BR, and R-GemOx, respectively) discontinued due to AEs in the tafasitamab plus lenalidomide cohort. In the cohorts of systemic therapies pooled, BR, and R-GemOx, 5 (6.8%), 2 (2.8%), and 4 (5.4%) patients, respectively, had AEs leading to permanent discontinuation of treatment. The types of AEs leading to treatment discontinuation were not reported. The median duration of exposure in the tafasitamab plus lenalidomide cohort was longer (approximately 10 months) compared to the cohorts of systemic therapies pooled (2.4 months), BR (3.2 months), and R-GemOx (2.9 months). Harm outcomes were not reported in RE-MIND or the MAICs.
The RE-MIND and RE-MIND2 studies implemented multiple measures to minimize bias; however, important sources of heterogeneity between the L-MIND trial cohort and observational cohorts could not be accounted for with the methods used. Although the eligibility criteria for enrolment in RE-MIND and RE-MIND2 were based on the eligibility criteria used in the L-MIND study, differences related to the RE-MIND and RE-MIND2 studies being retrospective studies were noted. Comparison of data from a prospective, interventional trial to retrospective, observational studies using real-world data may be problematic as a number of notable differences in data collection, outcomes, and assessments were identified (e.g., tumour assessment frequency, imaging modalities, and criteria used to assess response). Most importantly, there is the impact of potential remaining unmeasured confounding factors that were not accounted for in the matching. The RE-MIND and RE-MIND2 studies used 9 covariates for matching in their main analyses (age, Ann Arbor stage, refractoriness to last therapy line, number of previous lines of therapy, history of primary refractoriness, prior ASCT, neutropenia, anemia, and elevated lactate dehydrogenase). Other known confounders were not accounted for in the matching (e.g., ECOG PS, International Prognostic Index score, cell of origin, comorbidities) in the main analyses. As a result of these limitations, there is a substantial risk of bias in the RE-MIND and RE-MIND2 study results.
There are also limitations to the external validity of the RE-MIND and RE-MIND2 studies. Lenalidomide monotherapy is not used as a treatment for R/R DLBCL in Canada, according to the clinical experts. RE-MIND2 included relevant comparators, but the clinical experts consulted by CADTH also indicated that R-GemOx and BR are not commonly used to treat patients with R/R DLBCL in Canada. They indicated that pola-BR would be the most relevant comparator, although it is not yet funded. The clinical experts noted that the relevance of CAR T-cell therapy as a comparator for tafasitamab plus lenalidomide in patients who are not eligible for ASCT was debatable. The clinical experts considered CAR T-cell therapy to be an intensive therapy and thus more comparable to ASCT. They also indicated that they would not consider using tafasitamab plus lenalidomide in patients who were eligible for CAR T-cell therapy. There are also concerns of whether the systemic therapies pooled cohort adequately reflects current contemporary practice and therapies in Canada.
Although the methods used to conduct the unanchored MAICs followed technical guidance, the analyses have limitations that impact the internal and external validity. Most importantly, not all known effect modifiers and prognostic factors identified by the authors could be adjusted for in the analyses due to the availability of data. The quality of most of the comparator studies was low. Furthermore, multiple sources of heterogeneity (e.g., study design, eligibility criteria, study end point definitions, timing of tumour assessments) were identified that could not be accounted for in the analyses conducted. Given these issues, there is substantial concern for risk of bias in the MAIC results. There are also limitations to the external validity of some of the comparators (i.e., lenalidomide monotherapy, BR, and R-GemOx) as previously described. In addition, results may only be generalizable to patients similar to those enrolled in the comparator studies, which may not be representative of patients typically seen in Canadian practice.
Summary of Economic Evaluation.
CADTH identified the following key limitations with the sponsor’s analysis: the model lacked transparency, an updated incidence of NHL was available, the proportions of patients with DLBCL who received first-line therapy were underestimated, subsequent therapies were not modelled appropriately, CAR T-cell therapies are unlikely to be displaced, the market uptake of tafasitamab plus lenalidomide may be overestimated, the relative duration of therapy is uncertain, and the relative administration costs are uncertain.
CADTH reanalysis included updating comparator costs, updating the number of new NHL cases in the base year, increasing the proportion of patients with NHL who have DLBCL, increasing the proportion of patients with DLBCL who receive a first-line therapy, removing CAR T-cells as direct comparators, and reducing the market uptake of tafasitamab plus lenalidomide and its displacement of pola-BR. Under these alterations, CADTH reanalyses reported that the reimbursement of tafasitamab plus lenalidomide for adults with R/R DLBCL who are not eligible for ASCT would be associated with a budgetary increase of $14,411,397 in year 1, $43,026,427 in year 2, and $75,935,998 in year 3, for a 3-year total incremental cost of $133,373,822. CADTH was unable to address uncertainties around subsequent therapies, relative duration of therapy, or relative administration costs.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Matthew Cheung; Dr. Winson Cheung, Dr. Michael Crump, Dr. Leela John, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Christopher Longo, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik.
Initial meeting date: April 13, 2022
Regrets: One expert committee member did not attend.
Conflicts of interest: None.
Reconsideration meeting date: September 13, 2022
Regrets: Three expert committee members did not attend.
Conflicts of interest: None.
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Indication: In combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma not otherwise specified, including diffuse large B-cell lymphoma arising from low grade lymphoma, who are not eligible for autologous stem cell transplant.
Sponsor: Incyte Biosciences Canada Corporation
Final recommendation: Do not reimburse
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