Reimbursement Review

Tafasitamab (Minjuvi)

Sponsor: Incyte Biosciences Canada Corporation

Therapeutic area: Diffuse large B-cell lymphoma

What Is Relapsed or Refractory Diffuse Large B-Cell Lymphoma?

Relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) is a subtype of non-Hodgkin lymphoma, a fast-growing blood cancer that can return or stop responding to treatment. When this happens, patients may experience serious illness with limited treatment options, which may be especially challenging for those who are older or have other health concerns. In Canada, DLBCL is the most common type of non-Hodgkin lymphoma, making up about 30% to 40% of cases or about 5.6 cases per 100,000 people each year.

What Are the Treatment Goals and Current Treatment Options for Patients With r/r DLBCL?

The primary treatment goals for adults with r/r DLBCL who are ineligible for autologous stem cell transplant (ASCT) are to achieve strong and durable disease control — ideally a complete response that leads to prolonged remission and improved survival. Clinicians also emphasized minimizing treatment-related toxicity, controlling symptoms, and improving health-related quality of life (HRQoL), including meaningful gains in response, progression-free survival (PFS), overall survival (OS), and fewer disease-related symptoms.

Patients identified symptomatic improvement, quality of life, tolerability, and meaningful disease control as the most important outcomes. Clinician input aligned with these priorities and highlighted additional key outcomes, including overall response rate (complete or partial response), PFS, OS, time to next treatment, and sustained clinical benefit.

Current treatment options for adults with r/r DLBCL include salvage chemotherapy followed by ASCT for those patients who are eligible, while those who are ineligible for transplant commonly receive regimens such as polatuzumab vedotin, bendamustine, and rituximab (pola-BR); rituximab, gemcitabine, and oxaliplatin (R-GemOx); tafasitamab plus lenalidomide; or glofitamab, gemcitabine, and oxaliplatin (glofit-GemOx). Clinicians noted that chimeric antigen receptor T-cell therapy is preferred for eligible patients with early relapse or primary refractory disease, whereas bispecific antibodies such as epcoritamab and glofitamab are important alternatives in second-line and later settings, particularly for those who cannot access or tolerate cellular therapies.

What Is Minjuvi and Why Did Canada’s Drug Agency Conduct This Review?

Minjuvi (tafasitamab) is a monoclonal antibody that is administered by IV infusion. Health Canada has approved Minjuvi 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.

Canada’s Drug Agency (CDA-AMC) reviewed Minjuvi to inform a recommendation to the participating public drug programs on whether it should 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), excluding primary refractory disease, who are not eligible for ASCT and have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 2 or less. The sponsor is seeking reimbursement for this patient population. CDA-AMC previously reviewed Minjuvi for the Health Canada–approved indication and issued a recommendation not to reimburse.

How Did CDA-AMC Evaluate Minjuvi?

• CDA-AMC reviewed the clinical evidence on the beneficial and harmful effects, as well as the economic evidence, of Minjuvi in combination with lenalidomide versus other treatments used in Canada for adult patients with r/r DLBCL not otherwise specified (including DLBCL arising from low-grade lymphoma), excluding primary refractory disease, who are not eligible for ASCT and have ECOG PS scores of 2 or less. R-GemOx, pola-BR, glofit-GemOx, epcoritamab, and glofitamab were considered relevant treatments to compare with tafasitamab in combination with lenalidomide when reviewing the clinical evidence.

• CDA-AMC identified equity and ethical considerations relevant to Minjuvi in combination with lenalidomide in the treatment of adult patients with r/r DLBCL who are not eligible for ASCT.

• The review was informed by materials submitted by the sponsor, which included clinical and economic evidence.

• The review was also informed by submissions from 2 clinician groups and 1 patient group in response to the CDA-AMC call for input, and by input from the participating public drug programs on issues that may impact their ability to implement a recommendation.

• Two hematologists from Ontario and Alberta were consulted as part of the review process.

What Were the Findings?

Clinical Evidence

• CDA-AMC reviewed clinical evidence from the following:

  • One multicentre, phase II, open-label, single-arm study (the L-MIND trial) that evaluated the efficacy and safety of Minjuvi in combination with lenalidomide in adult patients with r/r DLBCL who were ineligible for ASCT was reviewed. This resubmission focuses on patients without primary refractory disease ██ █ ███, who were evaluated as a post hoc subpopulation of the L-MIND study. The full population of the L-MIND trial (N = 81) was included in the previous review.

  • Two indirect treatment comparisons (ITCs), including 1 unanchored matching-adjusted indirect comparison and 1 real-world matched analysis of Minjuvi in combination with lenalidomide versus R-GemOx, were reviewed.

  • A prospective observational cohort study (PRO-MIND) for the assessment of HRQoL, conducted in Italy, that enrolled ██ adult patients with r/r DLBCL who were ineligible for ASCT and received treatment with tafasitamab in combination with lenalidomide, was reviewed. Due to critical limitations with the study methods and the generalizability and interpretability of the results in the context of the reimbursement subpopulation in settings in Canada, CDA-AMC did not assess the study results.

• Based on evidence without a comparison with 5 years of follow-up:

  • In the L-MIND trial, of the adult patients with r/r DLBCL who were ineligible for ASCT and did not have primary refractory disease, a total of ██ ██ ██ patients had a best objective response of complete or partial response assessed by an independent review committee (IRC). The objective response rate (ORR) was █████ (95% confidence interval [CI]: █████ ██ ███████ the median PFS was ████ ██████ (95% CI, ███ ██████ ██ ████ ██████), the Kaplan-Meier estimate of PFS probability at ██ ██████ was █████ (95% CI, █████ ██ █████), the median OS was ████ ██████ (95% CI, ████ ██████ ██ ████ ██████), and the Kaplan-Meier estimate of OS event-free probability at ██ ██████ was ████ (95% CI, █████ ██ █████). Similar ORR, PFS, and OS findings were observed for investigator-assessed outcomes.

  • The median duration of response (DOR) of partial response or complete response, assessed by IRC, was ███ █████████ ████ (95% CI, ████ ██████ ██ ██), and the Kaplan-Meier estimate of DOR event-free probability at ██ ██████ was █████ (95% CI, █████ ██ █████). The median DOR (partial or complete response) assessed by an investigator was ████ ██████ (95% CI, ████ ██████ ██ ██), and the Kaplan-Meier estimate of DOR event-free probability at ██ ██████ was █████ (95% CI, █████ ██ █████).

  • No HRQoL outcome was assessed in the L-MIND trial.

  • No notable safety concerns for Minjuvi were identified during the study period. As the sample size was small, the findings were unlikely to adequately capture rare harms.

• Based on the sponsor-submitted ITCs, the effects of Minjuvi in combination with lenalidomide on ORR, PFS, OS, and DOR, compared with R-GemOx, are highly uncertain.

• There was no evidence to inform how Minjuvi in combination with lenalidomide compares with pola-BR, glofit-GemOx, epcoritamab, or glofitamab.

• Although the sponsor submitted longer-term data and a revised reimbursement request, the new evidence did not sufficiently address the previously identified gaps, including the absence of direct evidence for relevant comparators, the lack of strong indirect evidence for all relevant comparators, and the limited information on effects on HRQoL.

Economic Evidence

• Minjuvi is available as a lyophilized powder for IV infusion (200 mg). At the submitted price of $1,167.86 per 200 mg vial, the 28-day cost of Minjuvi is expected to be $29,197 per patient in the first cycle of treatment, $23,357 per patient in the second and third cycles of treatment, and $11,679 in subsequent cycles, based on the Health Canada–recommended dosage. (The cost of Minjuvi plus lenalidomide is, for cycle 1: $31,423; cycles 2 to 3: $25,583; cycles 4 to 12: $13,905; cycles 12 and beyond: $11,679.)

• Key clinical efficacy in the economic analysis (OS, PFS) of Minjuvi plus lenalidomide versus R-GemOx was derived from a sponsor-submitted ITC, with the efficacy of Minjuvi plus lenalidomide informed by the reimbursement subgroup of the L‑MIND trial, a single-arm trial. The indirect evidence submitted by the sponsor comparing Minjuvi plus lenalidomide with R‑GemOx had significant issues identified by CDA-AMC. As noted in the Clinical Review section, the unanchored matching-adjusted indirect comparison was associated with high uncertainty due to the limited number of important effect modifiers and prognostic factors considered in the sponsor-submitted ITC, and the limited overlap in covariates across the reimbursement subgroup of the L-MIND trial and the R-GemOx trial. As such, no conclusions could be drawn from the sponsor-submitted ITC, which precludes the use of the ITC to inform decision-making.

• R-GemOx was the only comparator included in the cost-utility analysis. Clinical expert input and the sponsor’s submission indicated that pola-BR, glofitamab (with or without gemcitabine and oxaliplatin), and epcoritamab were also relevant comparators for this indication. However, the sponsor did not consider it feasible to conduct ITCs for these comparators. The cost-effectiveness of Minjuvi plus lenalidomide versus these comparators is unknown.

• Based on the evidence reviewed for this submission, there is no robust evidence to suggest that Minjuvi plus lenalidomide provides greater health benefits than any of the relevant comparators. If there are no differences in health outcomes, then the total cost of Minjuvi plus lenalidomide should not exceed that of the relevant comparators for the treatment of adult patients with r/r DLBCL, excluding those with primary refractory disease, who are not eligible for ASCT, and have ECOG PS scores of 2 or less, to ensure cost-effectiveness.

• CDA-AMC estimates that the budget impact of reimbursing Minjuvi plus lenalidomide for the treatment of the requested reimbursement population will be approximately $34 million over the first 3 years of reimbursement compared to the amount currently spent on comparators, with an estimated expenditure of $57 million on Minjuvi (Minjuvi plus lenalidomide: $62 million) over this period. The actual budget impact of reimbursing Minjuvi will depend on the number of patients eligible for treatment, the market uptake of Minjuvi, and the duration of treatment.

Background

Introduction

Context for the Review

The objectives of this report are as follows:

• Review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of tafasitamab (Minjuvi), 200 mg single-use vial for IV infusion, in the treatment of patients with relapsed or refractory (r/r) diffuse large B‑cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from low-grade lymphoma), excluding primary refractory disease, who are not eligible for autologous stem cell transplant (ASCT), and have Eastern Cooperative Oncology Group Performance Status (ECOG PS) scores of 2 or less. The focus is on comparing tafasitamab to relevant comparators in clinical practice in Canada and identifying gaps in the current evidence, as outlined in Table 1.

• Review and critically appraise the economic information submitted by the sponsor, including a cost-effectiveness analysis and budget impact analysis (BIA). The focus of the Economic Review is aligned with the scope of the Clinical Review, unless otherwise stated. For most reviews, Canada’s Drug Agency (CDA-AMC) develops a base case informed by clinical expert input, the available clinical evidence, and the best interpretation of the economic evidence based on the information provided by the sponsor.

• In 2022, the sponsor filed the initial submission for tafasitamab in combination with lenalidomide (project landing page) for consideration by the pan-Canadian Oncology Drug Review Expert Review Committee (pERC). The reimbursement request was the same as the Health Canada indication; that is, 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. In 2022, pERC reviewed the initial submission and recommended that tafasitamab in combination with lenalidomide not be reimbursed by public drug programs. The sponsor requested a reconsideration. pERC acknowledged this request and deliberated on the issues identified by the sponsor in their request for reconsideration, discussed feedback from patient groups, clinical experts, and clinician groups on the initial draft recommendation, evaluated the evidence from the L-MIND trial, and issued a final recommendation to not reimburse tafasitamab in combination with lenalidomide.¹ For the current reimbursement review, the sponsor submitted a resubmission for tafasitamab in combination with lenalidomide (project landing page) with a revised reimbursement request that narrows the target population to adult patients with r/r DLBCL not otherwise specified (including DLBCL arising from low-grade lymphoma), excluding primary refractory disease, who are not eligible for ASCT and have ECOG PS scores of 2 or less.

Table 1: Information on the Application Submitted for Review and on the CDA-AMC Review

ASCT = autologous stem cell transplant; CDA-AMC = Canada's Drug Agency; DLBCL = diffuse large B-cell lymphoma; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; glofit-GemOx = glofitamab, gemcitabine, and oxaliplatin; HRQoL = health-related quality of life; NOC/c = Notice of Compliance with conditions; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; pola-BR = polatuzumab vedotin, bendamustine, and rituximab; R-GemOx = rituximab, gemcitabine, and oxaliplatin; r/r = relapsed or refractory.

^aThe focus of the Economic Review aligns with the scope of the Clinical Review, unless otherwise stated.

^bCDA-AMC has previously issued a reimbursement recommendation for this drug for the same indication or a similar indication.

Submission History for the Drug Under Review

CDA-AMC previously reviewed tafasitamab for the treatment of r/r DLBCL through the reimbursement review process and issued a recommendation not to reimburse.

Basis of Resubmission

The rationale for the 2022 pERC recommendation against reimbursement of tafasitamab plus lenalidomide for the treatment of patients with r/r DLBCL who are not eligible for ASCT is as follows:

• Although the phase II, single-arm, open-label L-MIND study (N = 81) with adults with r/r DLBCL who were ineligible for ASCT showed that treatment with tafasitamab plus lenalidomide resulted in antitumour activity, based on the observed objective response rate (ORR), it was uncertain whether the magnitude of this effect was clinically meaningful as the evidence was derived from noncomparative study descriptive analyses that lacked formal statistical testing, did not assess health-related quality of life (HRQoL), and were subject to important limitations and potential selection bias that reduced confidence in the efficacy estimates.

• The L-MIND study reported longer than expected progression-free survival (PFS) and overall survival (OS) in patients with r/r DLBCL who were ineligible for ASCT. However, it was uncertain whether these results were attributable to treatment with tafasitamab plus lenalidomide because the trial lacked a comparator and enrolled a more favourable population that included some patients with non-DLBCL histology, thus limiting the generalizability of the findings to practice in Canada.

• It was uncertain whether treatment with tafasitamab plus lenalidomide provides any relative clinical benefit because, although sponsor-submitted indirect treatment comparison (ITCs) suggested potential improvements over several regimens, methodological limitations of these analyses (including heterogeneity across studies, limited matching, unmeasured confounding, small sample sizes, and the use of comparators that are not commonly used in Canada) prevented pERC from drawing definitive conclusions.

• It was uncertain whether treatment with tafasitamab plus lenalidomide would address the needs identified as important to patients who are ineligible for ASCT, including prolonged survival and remission, better symptom control, improved quality of life, and fewer side effects, given the substantial uncertainty in the clinical efficacy results, the absence of HRQoL data, and the limited comparative safety information.

• In this resubmission the sponsor submitted additional longer-term data (follow-up of 5 years) excluding the data of patients with unconfirmed DLBCL histology, and a revised reimbursement request for tafasitamab in combination with lenalidomide for the treatment of adult patients with r/r DLBCL not otherwise specified (including DLBCL arising from low-grade lymphoma), excluding primary refractory disease, who are not eligible for ASCT and have ECOG PS scores of 2 or less.

Sources of Information

The contents of the Reimbursement Review report are informed by materials submitted by the sponsor, input received from interested parties (patient groups, clinician groups, and drug programs), and input from clinical experts consulted for this review.

Calls for patient group and clinician group input are issued for each reimbursement review. One patient group submission was received from Lymphoma Canada. Lymphoma Canada gathered information from 79 patients, including 3 patients who had experience with tafasitamab in combination with lenalidomide, through an online survey conducted between December 2025 and January 2026.

Two clinician group submissions were received from:

• the Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee (the author did not mention the number of clinicians who contributed to the submission; the information was gathered during a video conference)

• the Ad Hoc Group of Ontario Medical Oncologists and Hematology-Oncologists (AHG-OMOHO) along with Lymphoma Canada's Scientific Advisory Board (LCS), with 17 clinicians contributing to the submission.

Information gathered for this submission was based on relevant data from clinical trials and expert evidence-based review by cancer specialists in Canada with experience treating DLBCL. The full submissions received are available on the project landing page in the consolidated input document. The drug programs provide input on each drug being reviewed through the reimbursement review process by identifying issues that may impact their ability to implement a recommendation.

Input from patient and clinician groups is considered throughout the review, including in the selection of outcomes in the Clinical Review section and in the interpretation of the clinical and economic evidence. Relevant patient and clinician group input is summarized in the Disease Background, Current Management, and Unmet Needs and Existing Challenges sections.

Each review team includes at least 1 clinical expert 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. Two hematologists from Ontario and the Prairies (Alberta) with expertise in the diagnosis and management of DLBCL participated as part of the review team.

Disease Background

Non-Hodgkin lymphoma (NHL) refers to a diverse group of cancers that originate in the lymphatic system and involve abnormal lymphocyte growth. With more than 60 subtypes, NHL presents in various forms, each with unique clinical features.¹ DLBCL is the most common NHL subtype in Canada, accounting for 30% to 40% of cases or 5.6 cases per 100,000 people annually.^2,3 DLBCL is an aggressive form of B-cell lymphoma that can arise on its own or evolve from other types like follicular lymphoma.³

Clinical presentation and symptoms vary depending on the disease location and stage, but often include painless lymphadenopathy, persistent fatigue, skin rashes or itchiness, and systemic signs such as unexplained fever, night sweats, and weight loss.⁴ DLBCL staging follows the Ann Arbor system, with stages I to IV based on lymph node and extranodal involvement. Risk stratification uses the International Prognostic Index (IPI), incorporating age, ECOG PS, lactate dehydrogenase (LDH) levels, stage, and involvement of extranodal sites.⁵

DLBCL is a heterogeneous disease that differs in prognosis. Prognosis for patients with r/r DLBCL who do not receive ASCT is poor.³ While many patients respond well to first-line treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy, about 30% to 50% experience relapse or refractory disease.³ According to a published poster abstract, Gong et al.⁶ conducted a population-based study in Canada (that included patients with primary and nonprimary refractory disease) and reported 2-year and 5-year OS rates of 33% and 26%, respectively, after second-line treatment.⁶ Key predictors of outcomes include early chemoimmunotherapy failure, ECOG PS, refractory disease, number of prior lines of therapy, double- or triple-hit lymphoma, age, IPI score, Ann Arbor stage, serum LDH levels, and Deauville score.⁷ The clinical experts consulted by CDA-AMC highlighted that in the context of emerging therapies, including CD20-targeting bispecific antibodies and CD19-targeting chimeric antigen receptor (CAR) T-cell therapies, lack of CD20 or CD19 expression at relapse may be associated with poorer prognoses.⁸

Patient group input: According to Lymphoma Canada, the physical symptoms reported by survey respondents included fatigue and/or lack of energy, enlarged lymph nodes, body aches and pains, indigestion, abdominal pain or bloating, and night sweats. In addition, the patients reported the psychosocial impacts they experienced, which included stress of diagnosis, anxiety and/or worry, difficulty sleeping, inability to continue daily activities, frequency of health care appointments, and financial impacts. The patients also noted the long wait times and delays in confirming diagnosis and receiving treatment. Lymphoma Canada noted that patient- reported impacts on daily life, including the ability to travel, complete household chores, perform day-to-day activities, contribute financially, attend places of work, school, and/or volunteering, exercise, and spend time with family and friends. Out of 38 respondents, most indicated that they received 1 (42%) or 2 lines of treatment (34%), while 24% received 3 or more lines of treatment.

Current Management

Treatment Goals

Clinician input: According to the clinical experts, the most important treatment goals for adults with r/r DLBCL who are not eligible for ASCT and have good performance status are to achieve strong and lasting disease control — ideally a complete response that leads to a long remission and improved survival. In addition to prolonging life and delaying progression, the experts emphasized minimizing treatment-related side effects, controlling symptoms, and improving HRQoL. Input from the clinician group aligned with these priorities, emphasizing meaningful improvements in disease response, PFS, OS, HRQoL, and disease-related symptoms.

Patient group input: Based on the patient group input, important factors when considering a novel DLBCL treatment included longer survival (95%), longer remission (95%), better control of disease and symptoms (92%), improved quality of life based on the ability to perform daily activities (92%), and fewer side effects (76%). Further, 87% of patients indicated that it is very or extremely important to have a choice in deciding which drug to take based on known side effects and expected outcomes of treatment. A total of 81% of patients also indicated that they would be willing to tolerate side effects for a new and effective treatment if these were short-term side effects, and 70% of patients felt that there is currently a need for more therapy options for patients with DLBCL.

Regarding experience with the drug under review, Lymphoma Canada noted that 3 patients (all from Canada and all female) reported receiving treatment with tafasitamab in combination with lenalidomide for treatment of r/r DLBCL. Two of these patients received this therapy as a second-line treatment, and 1 patient received it as a third-line treatment. All patients are currently in remission, with 2 in new remission (less than 6 months) and 1 in remission for 6 months to 1 year. The side effects experienced by these 3 patients included aches and pains (n = 3), fatigue and/or lack of energy (n = 2), nausea and/or vomiting (n = 2), constipation, abdominal pain, or bloating (n = 2), hypertension (n = 2), weight loss and/or reduced appetite (n = 2), low platelet counts (n = 1), low white blood cell count (n = 1), and low red blood cell count (n = 1).

Current Treatment Options

The clinical experts indicated that for adults with r/r DLBCL, treatment choice depends on their level of fitness (i.e., age, comorbidities, performance status) and time to relapse after first-line treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (for patients with activated B-cell–like subtype). Possible systemic treatment options in the second-line setting include rituximab-gemcitabine-dexamethasone-cisplatin followed by ASCT for patients who are eligible for transplant; and rituximab, gemcitabine, and oxaliplatin (R-GemOx) or polatuzumab vedotin, bendamustine, and rituximab (pola-BR) for patients who are not eligible for ASCT. The clinical experts indicated that glofitamab, gemcitabine, and oxaliplatin (glofit-GemOx) is another treatment option for patients with r/r DLBCL. According to the clinical experts, early relapse (≤ 12 months) or primary refractory disease in eligible patients are managed with CAR T-cell therapy (e.g., axicabtagene ciloleucel and lisocabtagene maraleucel) in addition to salvage chemotherapy such as gemcitabine plus oxaliplatin or polatuzumab vedotin–based combinations. For patients who are ineligible to receive CAR T-cell therapies (due to frailty, comorbidities, and/or limited access), bispecific antibodies (e.g., epcoritamab and glofitamab) are important options in second-line and/or later settings and can often be delivered largely in outpatient settings; however, treatment with bispecific antibodies first may preclude later CAR T-cell therapy (e.g., axicabtagene ciloleucel, lisocabtagene maraleucel, or tisagenlecleucel). When cellular therapies are not feasible, commonly used regimens include pola-BR (or polatuzumab vedotin plus rituximab), R-GemOx, and tafasitamab plus lenalidomide. For some patients who experience relapse after the first year, high-dose chemotherapy followed by ASCT can still lead to durable remissions. Practical burdens include the need for bridging therapy, travel to tertiary centres, and prolonged infection risk and immunoglobulin replacement after T-cell–redirecting therapies.

Input from the clinician group was consistent with that of the clinical experts consulted for this review. AHG-OMOHO and the LCS added that, in general, patients with r/r DLBCL have limited treatment options. Salvage chemotherapy followed by ASCT has traditionally been the primary treatment for eligible with r/r DLBCL. However, not all patients are eligible for ASCT and few options exist for those who are ineligible for transplant. CAR T-cell and bispecific antibody therapies were recently introduced and have significantly improved the ability to treat patients with r/r DLBCL who previously would have received palliative regimens. The landscape for treating r/r DLBCL is rapidly evolving, with various treatment options emerging. Bispecific antibodies, such as epcoritamab and glofitamab, which target CD20 and CD3 are promising agents that could potentially be available to a broader population of patients than CAR T-cell therapy or after CAR T-cell therapy failure.

Unmet Needs and Existing Challenges

Clinician input: The clinical experts agreed that major unmet needs remain for adults with r/r DLBCL, as current treatments often fail to provide durable disease control, have substantial toxicities, and require frequent hospital or clinic visits, resulting in considerable burden for patients and caregivers. They noted that response to available therapies varies widely depending on factors such as disease biology, tumour burden, age, comorbidities, performance status, and time to relapse, which means that many patients do not achieve long-lasting remissions even with newer treatment options. Access to complex treatments (e.g., CAR T-cell or bispecific antibody therapies) also differs by region, with patients in rural or remote areas facing greater challenges in terms of travel requirements, the limited number of specialized centres, and variable availability of supportive services such as transfusions or emergency care. Social, cultural, and logistical factors, including caregiver support and acceptance of supportive care measures, further contribute to inequities. The experts indicated that the challenges affecting patients in rural or remote regions may create substantial financial and psychosocial burdens for patients and families. As a result, there is a continued need for treatments that are more effective, better tolerated, easier to access, and less burdensome for both patients and their support networks. The clinical experts also highlighted the unmet needs of patients with CD20-negative progressive disease following exposure to bispecific antibodies, CD19-negative progressive disease following CAR T-cell therapy, and secondary central nervous system (CNS) involvement and the unmet needs of patients who are ineligible for intensive chemotherapy or ASCT.

Input from the clinician group was consistent with that of the clinical experts consulted for this review, with improvement in HRQoL added as an unmet need. The clinician groups indicated that patient performance status and concomitant non-oncologic conditions affect the ability to receive aggressive chemotherapy. For example, the average number of comorbidities experienced by all patients with r/r DLBCL at the Hudson Regional Cancer Program is ██ (unpublished data). The goals of care for patients with r/r DLCBL differ based on the presence or absence of comorbidities. Patients with r/r DLBCL and comorbidities often accept the fact that the disease is incurable and express a wish to receive any form of palliative therapy directed at prolonging survival and maintaining a reasonable quality of life. However, there is an important unmet medical need for a nontoxic tolerable therapy with proven clinical activity that may palliate patients’ disease and extend their lives.

Patient group input: Based on the survey input, 11% of respondents indicated they were very dissatisfied or dissatisfied with the number of first-line treatment options available to them, while 18% gave the same rating for the number of second-line treatment options, and 4% for the number of third-line and additional treatment options, indicating higher dissatisfaction in the number of later lines. The respondents also provided information about their ability to access their DLBCL treatment, with 17% of patients indicating that this was “somewhat challenging,” 5% indicated that they lived in a community without a cancer centre, and 14% indicating that the treatment was not available at their local cancer centre. For 3% of patients, the treatment was not available in their region. The most common financial implications reported for treatment of DLBCL were travel costs (60%), absence from work (51%), and drug costs or supplementary drug costs to address side effects (36%).

Lymphoma Canada highlighted the importance of access to novel therapies and noted that increased number of treatment options allows patients, in collaboration with their health care team, to choose therapies that align with their individual goals, including quality of life and treatment tolerability. Because many patients with DLBCL experience relapse after first-line therapy, and access to second-line treatments varies across Canada, there remains a significant unmet need for additional effective and well-tolerated therapies. Survey findings highlight the ongoing physical, emotional, and financial burden experienced by patients, as well as challenges related to accessing care, particularly for those living outside major centres. This need is especially great for patients who may not be eligible for more intensive options such as transplant or who face barriers related to travel and location of residence. Patients expressed a strong desire for treatments that can provide meaningful remission, maintain quality of life, and be delivered in a manner that is accessible and sustainable in their daily lives.

Considerations for Using the Drug Under Review

The contents within this section have been informed by input from the clinical experts consulted for the purpose of this review and from clinician groups, as well as the reimbursement conditions proposed by the sponsor (refer to the Supplemental Material document, Appendix 1, Table 2, available on the project landing page). The implementation questions from the public drug programs and corresponding responses from the clinical experts consulted for this review are summarized in the Supplemental Material document, Appendix 1, Table 3. The following has been summarized by the review team.

Place in Therapy

According to the clinical experts, tafasitamab in combination with lenalidomide would be used as a chemotherapy-free, immunotherapy-based option in the second- or third-line setting for patients with r/r DLBCL who are not candidates for CAR T-cell therapy, bispecific antibodies, ASCT, or more intensive regimens (e.g., R-GemOx or pola-BR). The experts noted that the regimen’s CD19-targeted mechanism and oral component may make it suitable for older patients or patients with reduced physical capacity who cannot tolerate or access other treatments, and that its administration schedule requires fewer clinic visits than many of the available options. While tafasitamab targets a pathway distinct from that of bispecific antibodies and rituximab, the experts did not anticipate a major shift in the current treatment paradigm. The clinical experts agreed that other treatments should generally be tried before initiating tafasitamab in combination with lenalidomide, depending on patient eligibility and treatment goals. The experts noted that CAR T‑cell therapy or stem cell transplant should be used first as treatment for patients with good performance status and/or no comorbidities and who meet criteria, as these approaches are preferred in the event of early relapse despite the higher toxicity and need for treatment in tertiary centres. The clinical experts indicated that if funded, they would consider glofit-GemOx before tafasitamab plus lenalidomide in the second-line treatment setting.

AHG-OMOHO and the LCS added that to be eligible for tafasitamab in combination with lenalidomide, patients should be diagnosed with relapsed DLBCL when relapse occurs more than 6 months after completion of previous therapy. The disease should not be primary refractory disease.

Patient Population

The clinical experts indicated that patients with r/r DLBCL who are older, have comorbidities, or have reduced performance status (e.g., ECOG PS scores < 2 or Karnofsky performance status scale scores of 70%) are considered most in need of treatment. The experts indicated that r/r DLBCL disproportionately affects marginalized and equity-deserving populations because limited access to specialized centres, long travel requirements, diagnostic delays, and lack of caregiver support contribute to more advanced disease at presentation and poorer outcomes. The experts emphasized that patients in rural or underserved regions experience significant barriers, including transportation challenges, long wait times for imaging or biopsy, and unequal distribution of cancer care infrastructure, which can lead to some patients forgoing further treatment entirely. According to the clinical experts, the patients who are best suited for treatment with tafasitamab plus lenalidomide are those who experience disease relapse after 6 months, are ineligible for ASCT or CAR T-cell therapy, and have acceptable but possibly impaired performance status. The experts indicated that patients with DLBCL transformed from indolent NHL are also considered appropriate candidates for this regimen. According to the clinical experts, patients with primary refractory disease or relapse in the first 6 months after initial treatment, secondary CNS involvement, double-hit or triple-hit features, or multiple prior relapses are least suitable for treatment.

The clinical experts stated that patients suitable for tafasitamab plus lenalidomide treatment are identified through routine posttreatment follow-up, during which relapse is detected via symptoms, examination findings, or abnormal laboratory test results. The experts mentioned that diagnosis and confirmation of relapse rely on biopsy with standard immunohistochemistry and molecular testing supported by CT or PET-CT imaging. In addition, LDH levels, performance status, and comorbidity assessments (e.g., Cumulative Illness Rating Scale, 6-minute walk test, Cancer and Aging Research Group chemotherapy toxicity score) help determine whether patients can tolerate treatment. The experts indicated that access to testing is generally available in Canada, though some molecular results such as MYC gene rearrangement may be delayed.

The clinical experts indicated that the sponsor-proposed initiation conditions generally align with the needs of older patients or those with comorbidities who cannot receive aggressive therapy, but they suggested that the criteria should explicitly exclude patients with secondary CNS disease and double- or triple-hit lymphoma.

Input from the clinician group was consistent with that of the clinical experts consulted for this review.

Assessing the Response to Treatment

According to the clinical experts, in clinical practice treatment response in r/r DLBCL is evaluated using a combination of symptomatic improvement, physical examination findings, laboratory markers, and imaging (CT or PET-CT), which aligns well with outcomes used in clinical trials. The experts agreed that clinically meaningful benefit includes clear symptomatic improvement, reduction in lymphadenopathy, normalization of abnormal laboratory test parameters, or achievement of a partial or complete response assessed using imaging (preferably PET-CT or CT). The experts noted that partial and complete response, PFS, OS, and time to next treatment are meaningful outcomes that align well with clinical practice. The experts considered sustained benefit in outcomes over approximately 6 months to be clinically meaningful. The experts advised assessing monthly early in treatment, then every 2 to 3 months once stability is established, with timing of PET-CT scans adapted to take into account access and clinical judgment.

The clinical experts indicated that treatment with tafasitamab plus lenalidomide should be discontinued when there is clear evidence of disease progression on imaging (such as new or enlarging lymphomatous lesions on PET-CT scans), when patients develop severe or recurrent grade 3 to 4 toxicities despite dose modification, or when serious clinical deterioration occurs, including new organ failure, secondary CNS involvement, active severe infection, significant cognitive decline, or a marked decrease in performance status. The experts also noted that patient preference, development of a second primary malignancy, or other life-limiting conditions may justify stopping a therapy, and they emphasized that discontinuation decisions should focus on whether the patient is continuing to derive clinical benefit. The experts indicated that these factors are consistent with real-world practice and align with typical discontinuation principles used in oncology settings in Canada. The experts agreed that the sponsor’s proposed discontinuation criteria are generally appropriate and feasible to implement, though 1 expert cautioned against stopping treatment prematurely in patients who are tolerating therapy and responding, given that lenalidomide is often used long-term in other hematologic conditions.

Input from the clinician group was consistent with that of the clinical experts consulted for this review. AHG‑OMOHO and LCS highlighted that important outcomes included overall response rate (complete response, partial response, stable disease, progressive disease); OS and disease-free survival; and quality of life. Due to the palliative nature of the tafasitamab plus lenalidomide therapy, there is less need for interim restaging and posttreatment PET scans. Both clinician groups added that when deciding to discontinue treatment, disease progression and serious side effects should be considered.

Prescribing Considerations

According to the clinical experts, tafasitamab in combination with lenalidomide should be prescribed and monitored in settings with hematology expertise, ideally by hematologists or oncology teams experienced in managing DLBCL, interpreting imaging, and handling drug-specific toxicities such as infusion reactions. The experts noted that treatment is generally initiated in a specialist cancer centre (often by a hematologist) with ongoing cycles supportable by nurse practitioners, clinical associates, or general practitioner oncologists in centres where these roles exist. The experts indicated that access to this therapy may vary across regions due to provincial funding differences, uneven distribution of cancer centres, and access challenges in remote areas. The experts agreed that the sponsor’s proposed prescribing conditions align well with standard operating procedures and are feasible to implement in practice in Canada.

In its clinician group submission, the Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee noted that treatment is appropriate in an outpatient setting, managed by a physician with expertise in treating lymphoma.

According to AHG-OMOHO and the LCS, it is important to emphasize that tafasitamab plus lenalidomide can be administered in local cancer centres, and even in satellite chemotherapy suites. The latter is of particular value for patients living in remote communities. Tafasitamab plus lenalidomide can be administered by hematologists and internists trained in systemic therapy. Actual administration will be done by nursing staff at chemotherapy suites.

Clinical Review

Methods

The review team considered studies in the sponsor’s systematic review (pivotal studies and randomized controlled trials), sponsor-submitted long-term extension studies, ITCs, and studies addressing gaps in the evidence. Studies eligible for the systematic review included published and unpublished pivotal studies and phase II and III interventional studies. Relevant patients and interventions were defined by the reimbursement request and the recommended dosage in the product monograph. Patients without primary refractory disease were considered potentially important for informing the reimbursement recommendation. Relevant comparators were drugs used in clinical practice in Canada to treat the patients described in the indication under review. These comparators included R-GemOx, pola-BR, glofit-GemOx, epcoritamab, and glofitamab, as CDA-AMC has previously issued reimbursement recommendations for these regimens and/or drugs for the same or a similar indication. CAR T-cell therapy is not considered a relevant comparator because of the curative intent of the regimen. No long-term extensions of included pivotal studies or studies addressing gaps in the evidence were submitted. The ITCs submitted by the sponsor were included when they filled an identified gap in the systematic review evidence (e.g., missing comparator). The sponsor-submitted ITC included tafasitamab in combination with lenalidomide versus R-GemOx alone. The sponsor cited lack of feasibility as the reason, stating that it was not possible to conduct ITCs to assess the comparative effectiveness of tafasitamab in combination with lenalidomide versus pola-BR, glofit-GemOx, epcoritamab, or glofitamab.

The review team selected outcomes (and follow-up times) for review, taking into account the sponsor’s Summary of Clinical Evidence, clinical expert input, and patient and clinician group input. Included outcomes are those considered relevant to pERC deliberations, and they were selected in consultation with committee members. For consistency with the initial reimbursement review of tafasitamab,⁹ and per CDA-AMC resubmission policies, summarized efficacy end points and notable harms were not assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Methods for data extraction and risk of bias appraisal are provided in the Supplemental Material document, Appendix 2.

Clinical Evidence

In this report, the following sources of evidence submitted by the sponsor are reviewed and appraised:

• 1 multicentre, phase II, open-label, single-arm study (L-MIND; N = 81) included in the systematic review; the evidence for this resubmission is based on data from patients without primary refractory disease, evaluated as a post hoc subpopulation of the L-MIND study ██ █ ███

• 2 ITCs, including 1 unanchored matching-adjusted indirect comparison (MAIC) and 1 real-world matched analysis of tafasitamab in combination with lenalidomide versus R-GemOx

• a prospective observational cohort study (PRO-MIND) that evaluated HRQoL and included ██ adult patients in Italy with r/r DLBCL who were ineligible for ASCT and received treatment with tafasitamab in combination with lenalidomide.

Systematic Review

Description of Studies

Study Characteristics

Characteristics of the L-MIND trial are summarized in Table 2. Details pertaining to the study objectives, eligibility criteria, interventions and comparators, and relevant outcome measures are provided in the Supplemental Material document, Appendix 3.

The L-MIND trial was a multicentre, phase II, open-label, single-arm study that evaluated the efficacy and safety of tafasitamab in combination with lenalidomide in adult patients with r/r DLBCL who were not eligible for ASCT. Patients received IV tafasitamab (12 mg/kg) and oral lenalidomide (25 mg/day) for up to 12 cycles (28 days each), followed by tafasitamab monotherapy in patients with stable disease or better until disease progression. The total study duration was 5 years including periods of screening (up to 28 days), the treatment period (maximum 12 cycles for tafasitamab in combination with lenalidomide followed by tafasitamab monotherapy thereafter) and the survival follow-up phase. Tafasitamab monotherapy was to be administered until disease progression, unacceptable toxicity, or discontinuation for any other reason. The survival follow-up was defined as up to 5 years from cycle 1, day 1 or until withdrawal of consent or death. The study was conducted at 35 sites in 10 countries (in Europe and the US). There were no sites in Canada.

A total of 81 patients were enrolled in the L-MIND study. The current resubmission focuses on patients without primary refractory disease, who were included in a post hoc subpopulation of the L-MIND study ██ ███ The main body of this report presents data for the subpopulation from the 5-year final analysis with a data cut-off date of November 14, 2022.

Table 2: Characteristics of the L-MIND Study

ASCT = autologous stem cell transplant; CNS = central nervous system; CR = complete response; DLBCL = diffuse large B-cell lymphoma; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IRC = independent review committee; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; ULN = upper limit of normal.

^aAlso eligible were patients with disease showing evidence of histological transformation to DLBCL from an earlier diagnosis of low-grade lymphoma (e.g., an indolent pathology such as follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia) into DLBCL with a subsequent DLBCL relapse.

^bRelapsed disease was defined as the appearance of any new lesions or an increase in size by ≥ 50% of previously involved sites, according to the 2007 International Working Group response criteria,¹⁰ after the most recent systemic therapy. Refractory disease was defined as disease progression, per International Working Group response criteria, showing less than a PR to first-line treatment or disease recurrence or progression within < 6 months from the completion of first-line therapy or showing less than a PR to the most recently administered systemic therapy. Eligible patients had disease that relapsed after or was refractory to at least 1, but no more than 3 systemic regimens (with at least 1 anti-CD20 therapy).

^cThe lesion must have a greatest transverse diameter of ≥ 1.5 cm and greatest perpendicular diameter of ≥ 1.0 cm at baseline. The lesion must be positive on PET scan.

^dUnless secondary to Gilbert syndrome or documented lymphoma involvement in liver.

^ePrimary refractory DLBCL was defined as a disease progressing in the course of the first-line treatment, as per International Working Group response criteria,¹⁰ and/or showing a response of less than a PR to first-line treatment or disease recurrence or progression within < 6 months from the completion of first-line therapy.

Sources: Clinical Study Report for L-MIND 5 Year Analysis – Subpopulation¹¹ and Salles et al. (2020).¹² Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹³

Protocol amendment: In the L-MIND trial, a total of 3 protocol amendments were reported. Of these 3, amendment 2 (June 27, 2016) removed eligibility for patients with disease that had relapsed or progressed between 3 and 6 months of first-line therapy. Amendment 2 was made after the first patient was enrolled (January 18, 2016). Before protocol amendment 2, primary refractory disease was defined as relapse within 3 months of prior anti-CD20 therapy. Amendment 2 revised the definition to include less than a partial response to first-line therapy or progression within 6 months of completing first-line therapy and removed the requirement for relapse or progression to occur at least 3 months after prior CD20-containing therapy. In the L-MIND trial, 15 patients with disease that relapsed or progressed between 3 and 6 months of first-line therapy were recruited before the protocol amendment. These patients were considered to have primary refractory disease, as per National Comprehensive Cancer Network guidelines on B-cell lymphoma.¹⁴ CDA-AMC notes that the impact of amendment 2 was limited as the resubmission subpopulation excluded patients with primary refractory disease (n = 15).

Statistical Testing and Analysis Populations

To determine a suitable sample size for the full L-MIND study, it was assumed that the combination treatment could improve the ORR from a value of 20% (under lenalidomide monotherapy) to 35% (under combination therapy). The assumptions regarding the best ORR used for sample size calculation were justified based on evidence from historic trials evaluating lenalidomide monotherapy or other lenalidomide-containing regimens.^15-17 Applying an exact binomial test with a 2-sided significance level of 5% and a power of 85%, the estimated sample size was 73 patients. According to this scenario, an observed ORR of 32% would lead to a statistically significant study outcome. Assuming a dropout rate of 10%, a total sample size of about 80 patients was estimated.

Efficacy in the L-MIND study was assessed using descriptive analyses only. No formal statistical hypothesis testing was performed. For continuous variables, the number of nonmissing observations and the mean, median, standard deviation, and minimum and maximum values were presented. For categorical variables, the numbers of nonmissing and missing observations, the relevant percentage on the analysis population, and frequencies were reported. If not defined otherwise, the percentage denominator was the number of patients with nonmissing information. In the case of subcategories, the relative frequencies were calculated on the basis of the number of patients in the respective category.

Analysis populations: This review focuses on the L-MIND trial subpopulation ██ ███, which excluded patients with primary refractory disease ██ ████ without centrally confirmed DLBCL ██ ███, and who did not receive treatment ██ ███

Patient Disposition

In the L-MIND trial subpopulation (██), all patients received tafasitamab in combination with lenalidomide. Of these, █ patients █████ completed 12 cycles of combination treatment with both study drugs. A total of ██ patients ██████ discontinued tafasitamab and lenalidomide before completing 12 cycles; the most frequently reported reason for treatment discontinuation was disease relapse ██████ Among patients who completed all 12 cycles, █ patients ██████ subsequently discontinued tafasitamab; the most frequently reported reasons were disease relapse ██████ and other reasons ███████ For lenalidomide, ██ patients ███████ discontinued after completing the 12 cycles of combination treatment, with treatment completion reported as the most common reason ██████ and █ patients ██████ discontinuing due to an adverse event (AE). A total of ██ patients ██████ entered the survival follow-up phase and ██ patients ██████ withdrew from survival follow-up; the most frequently reported reason was death ███████

Details of patient disposition in the L-MIND trial subpopulation are summarized in the Supplemental Material document, Appendix 4.

Baseline Characteristics

The median age of the L-MIND reimbursement subpopulation was ████ years with a range of ███ ███. More than half of patients █████ in the L-MIND trial were older than 70 years. Most patients had ECOG PS scores of 0 or 1 █████ and had 1 █████ or 2 █████ prior lines of systemic treatment, Ann Arbor stage III or IV disease ██████ and no prior ASCT █████. Other detailed baseline characteristics are available in the Supplemental Material document, Appendix 4.

Table 3: Summary of Baseline Characteristics in the L-MIND Study Reimbursement Subpopulation

ASCT = autologous stem cell transplant; DLBCL = diffuse large B-cell lymphoma; ECOG PS = Eastern Cooperative Oncology Group Performance Status.

Sources: Clinical Study Report for L-MIND 5 Year Analysis – Subpopulation.¹¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹³

Treatment Exposure and Concomitant Medications

In the L-MIND trial reimbursement subpopulation, patients receiving tafasitamab in combination with lenalidomide had a median treatment duration of ████ █████ (range, ███ ██ █████ █████). The study had an exposure extending up to 85 cycles for tafasitamab, with a median treatment duration of ████ █████, while lenalidomide treatment alone was limited to 12 cycles and had a shorter median duration of ████ ██████

Concomitant medications were not recorded, and subsequent treatments were not reported.

Details of patients’ treatment exposure and adherence are provided in the Supplemental Material document, Appendix 4.

Critical Appraisal

Internal Validity

The L-MIND trial was a phase II, open-label, single-arm study that evaluated the efficacy and safety of tafasitamab in combination with lenalidomide in adults with r/r DLBCL who were not eligible for ASCT. For this resubmission, the sponsor narrowed the reimbursement request to adult patients with r/r DLBCL not otherwise specified (including DLBCL transformed from low-grade lymphoma), excluding primary refractory disease, who are not eligible for ASCT and have ECOG PS scores of 2 or less.

For the primary end point and several secondary end points (including PFS, OS, and duration of response [DOR]), an independent review committee [IRC] was appropriately used to reduce the risk of detection bias in assessments. The IRC was composed of independent radiology and hematology oncology specialists, and there was generally good agreement between IRC and investigator assessments of tumour response (concordance rate ranged from 76.7% to 91.3%). The study used the International Working Group criteria described by Cheson et al. (2007),¹⁰ which were appropriate for the trial period. More recent guidance, such as the Lugano 2014 criteria,¹⁸ incorporates PET-based assessment more extensively, but it is uncertain whether applying these updated criteria would have meaningfully altered the results. Although the sponsor reported high concordance between IRC and investigator assessments of overall response rate, PFS, and DOR, a substantial difference was observed in median follow-up for PFS, with shorter follow-up in the IRC assessment (49.9 months) compared with the investigator assessment (60.7 months). The sponsor confirmed that both assessments used the same data cut-off date, censoring rules, and assessment schedule, and attributed the discrepancy to inherent differences in the way progression was evaluated and how censoring occurred at the patient level. According to the sponsor, investigator assessments incorporated real-time clinical judgment, including symptoms and treatment decisions, whereas IRC assessments applied standardized retrospective criteria, which resulted in a higher proportion of censored patients in the IRC assessment (35.7% versus 44.6% for investigator assessment versus IRC assessment).¹⁹ CDA-AMC notes that these differing censoring patterns introduce uncertainty and may affect the comparability of the PFS estimates. This limitation is particularly important in a single-arm study in which PFS is a key measure of treatment effectiveness and discrepancies between assessment methods reduce confidence in the robustness of the results.

The evidence supporting this resubmission was derived entirely from this single-arm, open-label study. No direct comparative evidence was available, and therefore the relative efficacy and safety of tafasitamab plus lenalidomide compared with relevant active treatments is not established. The absence of a comparator limited the ability to attribute observed outcomes to the intervention, as results may have been influenced by patient selection, underlying prognostic factors, or the natural disease course. The open-label design also increased the potential for performance and detection bias, particularly for outcomes requiring subjective assessment. Although time-to-event outcomes were analyzed using appropriate statistical approaches, including Kaplan-Meier estimation with censoring, causal inference was limited without a comparator arm. Overall, these design limitations may contribute to uncertainty about both the magnitude of treatment benefit and the comparative effectiveness of the regimen.

Results were based on subgroup analyses in the reimbursement population that were not supported by formal statistical testing, which limited the ability to interpret whether outcomes were consistent across patient subsets. Without hypothesis-driven testing or adjustment for multiple comparisons, the findings were exploratory and may have reflected random variability rather than meaningful patterns. Moreover, the sample size was relatively small ██ █ ████ which reduced statistical precision, increased the likelihood of unstable estimates, and made the results more sensitive to outliers or chance findings. Overall, the reliance on nonprespecified, exploratory analyses in the subpopulation and the limited sample size contributed to substantial uncertainty and reduced confidence in the robustness and generalizability of these findings.

In the L-MIND trial reimbursement subpopulation, no information on concomitant medications or subsequent therapies was reported, which may have introduced uncertainty about the extent to which the observed outcomes can be attributed solely to the intervention. Although the clinical experts noted that few concomitant medications would be expected to meaningfully influence the effect of tafasitamab plus lenalidomide in patients with r/r DLBCL, CDA-AMC noted that the absence of documentation on supportive care, coadministered treatments, or postdiscontinuation therapies meant that potential influences on clinical outcomes could not be assessed. This lack of information also limited the ability to evaluate confounding, particularly in the single-arm study for which causal interpretation was already constrained by the absence of a comparator group. As a result, the specific contribution of tafasitamab plus lenalidomide to the observed outcomes remained uncertain, and the overall magnitude of the treatment effect could not be reliably established.

HRQoL was identified by patients and clinicians as an important outcome. However, no assessment of HRQoL was conducted in the L-MIND trial reimbursement subpopulation.

External Validity

Overall, the estimands, end points, and outcome measures used in the L-MIND trial subpopulation were appropriate for evaluating clinical benefit. Several of the assessed outcomes, such as ORR (partial or complete response), PFS, OS, and DOR, are commonly used in clinical practice and were considered clinically meaningful and important to clinicians and patients.

According to the clinical experts, the baseline characteristics of the subpopulation in the L-MIND trial were generally aligned with those of patients who would be considered potential candidates for tafasitamab plus lenalidomide in clinical practice, which supports the clinical relevance of the findings. The trial excluded patients with CNS involvement, and the experts confirmed that individuals with primary CNS lymphoma or secondary CNS disease would typically not be considered for this regimen due to the limited evidence and the poor prognosis associated with CNS involvement. The experts also agreed that excluding patients with double-hit or triple-hit lymphoma was appropriate, as these biologically distinct subtypes result in aggressive disease and patients with these disease subtypes are unlikely to benefit from the therapies evaluated in the L-MIND trial. However, reliance on a selected subpopulation may introduce bias because the eligibility criteria may not fully capture the heterogeneity of the broader population with r/r DLBCL who are not eligible for ASCT. For example, the experts indicated that some patients with an ECOG PS score fluctuating between 2 and 3 may still be considered for treatment with tafasitamab plus lenalidomide in practice, noting that performance status assessments are not always clear-cut and that certain patients with assessments that fall between categories may be appropriate candidates for treatment if the regimen is expected to be tolerable. In addition, the baseline characteristics show that most of the L‑MIND trial participants were white and there was limited or no representation of Alaska Native, American Indian, or Black or African American individuals [wording of original source]. Given the small sample size and restrictive eligibility criteria, these factors may limit the generalizability of the results to the diverse population of patients with r/r DLBCL who are not eligible for ASCT.

Results

The key efficacy and harms results and findings in the L-MIND trial subpopulation from the 5-year final analysis with a data cut-off date of November 14, 2022 are presented in this section. Detailed efficacy and harms results can be found in the Supplemental Material document, Appendix 4.

Efficacy

Key results include the following:

• A total of ██ ██ ██ patients had a best objective response of complete or partial response assessed by an IRC; the ORR assessed by IRC was █████ (95% confidence interval [CI], █████ ██ █████). The best objective response for patients was complete response for ██ patients ███████ and partial response for ██ patients ███████. Similar findings were observed for ORR when assessed by an investigator.

• With a median follow-up of ████ ██████, the median PFS assessed by an IRC was ████ ██████ (95% CI, ███ ██████ to ████ ██████); the Kaplan-Meier estimate of PFS probability at ██ ██████ was █████ (95% CI, █████ ██ █████). Similar findings were observed for PFS when assessed by an investigator, with a median follow-up time of ████ ██████.

• With a median follow-up of ████ ██████, the median OS was ████ ██████ (95% CI, ████ ██████ ██ ████ ██████); the Kaplan-Meier estimate of OS event-free probability at ██ ██████ was ████ (95% CI, █████ ██ █████).

• The median DOR assessed by an IRC was ███ █████████ ████ (95% CI, ████ ██████ ██ ██); the Kaplan-Meier estimate of DOR event-free probability at ██ ██████ was █████ (95% CI, █████ ██ █████). The median DOR, when assessed by an investigator, was ████ ██████ (95% CI, ████ ██████ ██ ██); the Kaplan-Meier estimate of DOR event-free probability at ██ ██████ was █████ (95% CI, █████ to █████).

• HRQoL was not assessed in the L-MIND trial.

• Results for the following supportive outcomes are provided in the Supplemental Material document, Appendix 4: investigator-assessed ORR, PFS, and DOR as well as time to progression, time to next treatment, and time to response.

Harms

Key results include the following:

• At least 1 AE was reported for ███ ██████ patients. The most common ████ ██ █████ AEs were blood and lymphatic system disorders ████████ general disorders and administration site conditions ████████ and infections and infestations ████████

  • At least 1 grade 3 or higher AE was reported for █████ ███ ██ ███ of patients. The most common ████ ██ █████ grade 3 or higher AE was blood and lymphatic system disorders ███████ including neutropenia ████████

• At least 1 serious AE was reported for █████ of patients. The most common ████ ██ █████ serious AE was neutropenia ████████

• Discontinuation due to an AE of tafasitamab in combination with lenalidomide before completion of 12 cycles occurred in █████ of patients, and discontinuation due to an AE of tafasitamab monotherapy after successful completion of study treatment (12 cycles of combination treatment) occurred in ████ of patients.

• Overall, ██████ ███████ had a fatal AE. The cause of death was COVID-19.

• The clinical experts consulted by CDA-AMC identified infection ████████ neutropenia ████████ anemia ████████ thrombocytopenia ████████ and deep vein thrombosis ██████ as AEs of special interest in the case of treatment with tafasitamab in combination with lenalidomide.

Health-Related Quality of Life

• The sponsor conducted PRO-MIND, a noninterventional, multicentre, prospective observational cohort study conducted in Italy that enrolled ██ adults with r/r DLBCL (including primary refractory disease) who were ineligible for ASCT and were treated with tafasitamab plus lenalidomide. Only patients contributed to the descriptive analysis of HRQoL at █████ ██ using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the European Organisation for Research and Treatment of Cancer – Quality of Life Questionnaire for High-Grade Non-Hodgkin’s Lymphoma, 29-item module (EORTC QLQ-NHL-HG29).²⁰

• At █████ ██, the mean EORTC QLQ-C30 global health score was ████ ██████ (standard deviation = ██) and the EORTC QLQ-NHL-HG29 symptom burden score was ████ points (standard deviation = █████).

• Detailed results from the PRO-MIND study can be found in the Supplemental Material document, Appendix 4.

Long-Term Extension Studies

No long-term extension studies were included in the review.

Indirect Evidence

Currently, no head-to-head trials have compared tafasitamab plus lenalidomide with other active treatments for adults with r/r DLBCL who are not eligible for ASCT. Available treatment options for this population include R-GemOx, pola-BR, glofitamab-GemOx, epcoritamab, and glofitamab. Indirect comparisons were therefore needed to address this evidence gap and to inform the pharmacoeconomic model.

Description of ITCs

The sponsor submitted 2 ITCs — a MAIC and a real-world matched analysis — of tafasitamab in combination with lenalidomide versus R-GemOx on efficacy outcomes in adult patients with r/r DLBCL who are not eligible for ASCT.

The primary objective of the MAIC and real-world matched analysis was to assess the comparative efficacy of tafasitamab in combination with lenalidomide versus key comparators for adult patients presenting with r/r DLBCL not otherwise specified (including DLBCL arising from low-grade lymphoma), who are not eligible for ASCT, have an ECOG PS score of 2 or less, and do not have primary refractory disease. Outcomes to support the comparisons of efficacy included OS, PFS, ORR, and DOR.

Study Selection and Review Methods

MAIC: The ITC was informed by a systematic literature review (SLR) of evidence of interventions in adult patients with r/r DLBCL who were not eligible for ASCT. Studies of interventions with tafasitamab in combination with lenalidomide, pola-BR, R-GemOx, glofit-GemOx, glofitamab, or epcoritamab were eligible. CAR T-cell therapy was not included among the interventions of interest in the sponsor-commissioned SLR because of the curative intent of the treatment. Relevant outcomes in the SLR included OS, PFS, DOR, ORR, HRQoL, and safety. Eligible study designs included randomized controlled trials and single-arm trials. Nonrandomized or supplementary evidence, such as observational studies, preclinical pharmacokinetic and/or pharmacodynamic research, protocol documents, reviews and expert opinions, and guidelines, and non-English publications were excluded.

The database search included Ovid, MEDLINE, Embase, and Cochrane Library. Clinical trial registries were also searched. The search was limited to full-text publications. Data were extracted into standardized tables by 2 independent investigators and validated by another reviewer, and discrepancies were resolved through consultation with a third investigator. Quality assessments were not conducted at this stage of the SLR. Risk of bias in the studies included in the ITC analyses was not assessed.

Real-world matched analysis: The indirect comparison used data from the RE-MIND2 trial (a retrospective observational cohort study),²¹ selecting only patients with confirmed DLBCL and nonprimary refractory disease to match the L-MIND trial reimbursement subpopulation. Tafasitamab plus lenalidomide was compared with R-GemOx on the following efficacy outcomes: OS, PFS, DOR, and ORR. Data were drawn from health records across global sites, with eligibility defined by standard clinical criteria and exclusions such as CNS involvement, prior CD19-directed therapy, or previous tafasitamab exposure. All data were extracted from existing medical records, deduplicated, and captured through electronic systems, with no additional visits or testing required.

ITC Analysis Methods

For additional information on the analysis methods of the ITC, refer to the Supplemental Material document, Appendix 6.

MAIC: An unanchored MAIC was deemed feasible for a comparison of tafasitamab in combination with lenalidomide versus R‑GemOx using L-MIND and the single-arm R-GemOx trial by Mounier et al. (2013)²² for the outcomes of OS, PFS, ORR, and DOR. Given that the L-MIND trial is a single-arm trial for which patient-level data are available and only summary level data are available for all comparator trials, including the single-arm R-GemOx trial by Mounier et al. (2013),²² only unanchored population-adjusted ITCs (e.g., MAICs) are methodologically possible. Unanchored methods rely on the assumption that all relevant prognostic factors and treatment effect modifiers are identified and adjusted for in the analysis.

The MAIC was used to compare tafasitamab plus lenalidomide with R-GemOx because the single-arm R-GemOx trial by Mounier et al. (2013)²² was the only eligible trial that reported the required outcomes. Covariates for adjustment were chosen from published MAICs of r/r DLBCL and validated by clinical experts in Canada consulted by the sponsor, who identified a list of prognostic factors and treatment effect modifiers: primary refractory status, refractoriness to last line of therapy, line of therapy, age, high-grade B-cell lymphoma (double or triple hit), double expressor, Ki67 index, cell of origin (activated B-cell–like cell or germinal centre B cell), IPI score, Ann Arbor stage, LDH levels, extranodal involvement, CNS involvement, ECOG PS, prior ASCT, and Deauville score. A logistic propensity score model was used to weight individual L-MIND trial participants so that their baseline characteristics matched those in the R-GemOx trial, with model parameters estimated using the method of moments. After weighting, covariate balance was checked to assess residual confounding. The weighted data were then used to estimate comparative outcomes using Cox models for OS and PFS assessed by an investigator, a generalized linear model for ORR assessed by an investigator, and a median ratio for DOR assessed by an investigator. Effective sample size (ESS) was calculated to assess the impact of weighting, and scenario analyses examined how adjusting for additional covariates affected results. The primary analysis contained the minimum set of covariates identified as the most important for adjustment (i.e., the top-ranked prognostic factors and treatment effect modifiers according to the clinical experts consulted by the sponsor: line of therapy, age, and cell of origin). Separate adjusted comparisons were conducted sequentially, adjusting incrementally for the remaining factors in order of importance, until the final model contained all available factors. The scenario analysis was conducted using the full L-MIND DLBCL population ███████ including patients with primary refractory disease. Sensitivity analyses were conducted using IRC-assessed outcomes and ECOG PS re-ranked as a higher-priority covariate. Safety and/or tolerability and patient-reported outcomes were not assessed due to the expected cross-trial heterogeneity in how these outcomes were measured and reported.

Real-world matched analysis: Patients included in the RE-MIND2 trial were selected to match the characteristics of the patients in the L-MIND trial. As such, several key eligibility criteria identical to those employed in the L-MIND trial were used to identify patients for the observational RE-MIND2 trial cohort.¹³ In addition, estimated propensity score–based methods were applied to balance cohorts, thus contributing to mitigation of treatment selection bias.²¹ The following 9 covariates were used for matching: age, Ann Arbor stage, refractoriness to last line of therapy, number of previous lines of therapy, history of primary refractoriness, prior ASCT, neutropenia, anemia, and elevated LDH levels.

Summary of Included Studies

MAIC: The SLR identified 12 unique trials (including the L-MIND trial) from 30 screened records. Of these, 10 trials were included in the ITC feasibility assessment; the POLARGO trial²³ was excluded because efficacy data were not yet available and the ICP-CL-00901 trial²⁴ was excluded because it was single-arm tafasitamab-lenalidomide study specific to China and not relevant to the target setting. Across the 10 included trials, outcomes of interest (i.e., OS, PFS, ORR, and DOR) were reported, though most had shorter follow-up (< 24 months) than that of the L-MIND trial. Cross-trial heterogeneity existed with respect to prior treatment, refractoriness (e.g., number of prior lines of therapy, proportion with primary refractory disease), and outcome definitions (e.g., different versions of International Working Group response criteria), and all comparator trials included patients with primary refractory disease. Because the L-MIND trial subpopulation did not include patients with primary refractory disease and only aggregate comparator data were available, adjusting for this key prognostic factor in an ITC was not feasible.

A MAIC was deemed feasible for R-GemOx using data from the R-GemOx trial by Mounier et al. (2013),²² which included a relatively small proportion (12%) of patients with primary refractory disease.

Both the L-MIND trial and the R-GemOx trial by Mounier et al. (2013)²² enrolled adult patients with r/r DLBCL who were not eligible to receive ASCT. While the R-GemOx trial by Mounier et al. (2013)²² included a relatively small proportion (12%) of patients with primary refractory disease, the L-MIND trial subpopulation ██████ excluded patients with primary refractory disease. Differences emerged in eligibility criteria: the L-MIND trial included patients with transformed lymphoma, whereas these patients were excluded from the R-GemOx trial by Mounier et al. (2013).²² In addition, different response criteria were used, depending on when the trial was conducted, and different starting points were used for the measurement of PFS and OS. Baseline characteristics showed variability across trials. Median age ranged from ████ █████ ██ ████ █████. The proportion of patients who had prior ASCT ranged from █████ ██ ██████ Additional information on homogeneity of the trials in the sponsor’s MAIC can be found in the Supplemental Material document, Appendix 6.

Real-world matched analysis: Baseline characteristics of the matched cohort were well-balanced across key demographic and clinical variables, including age, sex, ECOG PS, disease stage, prior lines of therapy, and presence of comorbidities. Matching was performed using propensity score methods to ensure comparability between the patients in the L-MIND trial and those in the observational cohort, thereby minimizing confounding and enabling a robust comparative analysis of treatment outcomes. To derive the comparison for the L-MIND trial subpopulation (with confirmed DLBCL and nonprimary refractory disease), the original matched cohort in the RE-MIND2 trial was limited to the patients of interest in the L-MIND trial. Detailed key demographic characteristics and clinical variables in the L-MIND trial subpopulation and the matched RE-MIND2 trial cohort can be found in the Supplemental Material document, Appendix 6.

Table 4: Summary of Baseline Characteristics Before and After Weighting in the MAIC

ASCT = autologous stem cell transplant; ECOG PS = Eastern Cooperative Oncology Group Performance Status; GCB = germinal centre B cell; IPI = International Prognostic Index; LDH = lactate dehydrogenase; MAIC = matching-adjusted indirect comparison; R-GemOx = rituximab, gemcitabine, and oxaliplatin.

Sources: Matching-adjusted indirect comparison technical report.²⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹³

Critical Appraisal of ITCs

Matching-Adjusted Indirect Comparison

The sponsor’s search for potentially eligible studies was reasonably comprehensive, and the methods used to select relevant studies and extract data were adequate. However, quality assessments were not completed at this stage of the SLR, and the risk of bias for the studies included in the ITC was not evaluated. Without this information, it is difficult to determine the strengths or potential limitations of the underlying evidence, which introduces uncertainty regarding the validity of the ITC estimates and lowers confidence in the overall certainty of the results. Although the sponsor conducted a feasibility assessment for ITCs of tafasitamab plus lenalidomide versus other relevant comparators (e.g., pola-BR, glofit-GemOx, epcoritamab, and glofitamab), the sponsor provided limited information to support the approach. There was also insufficient discussion of feasibility considerations and sensitivity analyses. This lack of detail limits the ability to assess whether key assumptions underlying the ITCs were appropriate, increasing the risk of bias and further reducing confidence in the robustness of the findings. Although the MAIC provided comparative efficacy estimates for tafasitamab plus lenalidomide versus R-GemOx, the lack of comparative efficacy of tafasitamab plus lenalidomide versus other comparators that are relevant to clinical practice in Canada may limit the contextual interpretation and generalizability of the findings. Considered together, these limitations may reduce the overall certainty of the evidence, and the ITC results should be interpreted with caution.

The MAIC is unanchored because the L-MIND trial and the R-GemOx trial by Mounier et al. (2013)²² did not share a common comparator. As a result, the validity of the treatment effect estimates depended entirely on whether all important effect modifiers and prognostic factors were identified and adequately balanced. The adjustment for confounders and effect modifiers included a list of prognostic factors and treatment effect modifiers identified by the clinical experts consulted by the sponsor based on published MAICs of r/r DLBCL. In the primary analysis, only a small number of available variables were adjusted for (i.e., line of therapy, age, and cell of origin). Using only these covariates may increase the likelihood of residual bias from unknown or unadjusted confounders and reduce confidence in the results. In addition, the selection and ranking of prognostic factors and treatment effect modifiers were based on ratings provided by the clinical experts consulted by the sponsor. The clinical experts consulted by CDA-AMC for this review ranked these factors slightly differently, considering CNS disease and ECOG PS to be more important. This discrepancy may raise uncertainty about whether all relevant variables were adjusted for in the analysis, although the results were consistent across scenario and sensitivity analyses, including with higher prioritization of key covariates such as ECOG PS.

There was notable cross-trial heterogeneity that may affect the certainty of the results. The R-GemOx trial²² was conducted in 2013, when treatment options, patient experience, and supportive care differed from current practice, which may limit comparability with more recent studies. In addition, key efficacy end points were defined differently across the compared studies, introducing further inconsistency in how outcomes were measured and interpreted. These cross-trial differences may reduce confidence in the ITCs and contribute to uncertainty in the estimated treatment effects.

The inclusion of patients with primary refractory disease in the R-GemOx trial by Mounier et al. (2013)²² may have introduced bias. Primary refractory disease is generally associated with poorer prognosis, according to the clinical experts. The review team noted that including these patients could bias the comparative effectiveness results against R-GemOx because the L-MIND trial subpopulation did not include patients with primary refractory disease. At the same time, a substantial proportion of patients in the R-GemOx arm did not have experience with rituximab (35%), which could lead to overestimation of treatment benefit because rituximab-containing regimens tend to show greater relative improvements in populations of patients without previous exposure to rituximab. Overall, these opposing influences on effect estimates increase uncertainty regarding the true magnitude and direction of treatment effect.

A moderate reduction in ESS in the primary analysis ██ ███ ████ suggested that substantial reweighting was required to achieve balance between the trial populations. This degree of variability in weights indicated that the matched population may no longer be fully representative of the original study sample, which may introduce concerns about the selectivity of the analytic population and the risk of residual imbalance. Moreover, the reduced ESS effectively narrowed the amount of usable information contributing to the estimates, which could lead to wider CIs and increased imprecision. Taken together, the moderate decrease in ESS raises concerns about the stability of the treatment effect estimates and reduces confidence in the certainty of the findings from this analysis.

In the MAIC, the median ratio of DOR was reported without a 95% CI because the comparator R-GemOx trial by Mounier et al. (2013)²² provided only a median estimate and did not report any measure of variability. Without uncertainty information for the comparator, the variance of the ratio cannot be derived, and the precision of the estimate cannot be assessed. The absence of a CI may limit interpretability, prevent formal inference regarding comparative effectiveness, and increase uncertainty about the stability of the estimate. As a result, the certainty of the DOR findings was reduced because the reliability and stability of the estimate cannot be evaluated.

HRQoL was identified by patients and clinicians as an important outcome. However, no indirect comparison was conducted for HRQoL.

Real-World Matched Analysis

Key differences in eligibility criteria between the L-MIND and RE-MIND2 trials may limit comparability of the study populations and introduce concerns about potential bias. Although propensity score–based methods were applied to mitigate treatment selection bias, only 9 covariates were included in the matching process. As a result, several clinically relevant factors were not balanced between the L-MIND and the RE-MIND2 trial cohorts.²¹ The real-world comparator groups therefore included patients who would have been excluded from the L-MIND trial, such as those with ECOG PS scores greater than 2, double- or triple-hit cytogenetics, elevated thromboembolic risk, significant comorbidities, or missing required laboratory parameters. Including patients with these higher-risk characteristics in the comparator cohorts, but not in the tafasitamab plus lenalidomide cohort, may create baseline prognostic imbalances that favour tafasitamab plus lenalidomide. These population differences may reduce alignment across studies, increase the potential for residual confounding despite adjustment, and decrease confidence in the certainty of the comparative effectiveness estimates.

Comparing the prospective L-MIND trial with the retrospective, real-world RE-MIND2 study may introduce substantial uncertainty because of inherent differences in data collection and response assessment procedures. In the L-MIND trial, tumour responses were evaluated using predefined response criteria, standardized assessment protocols, and scheduled imaging consistent with a controlled prospective trial. In contrast, the RE-MIND2 observational study²¹ cohorts lacked uniform assessment procedures, with variable imaging frequency, heterogeneous application of response criteria, and reliance on investigator-assessed outcomes based on routine clinical practice. These methodological differences may increase the risk of misclassification and inconsistency in tumour-based end points such as ORR, DOR, and PFS. Although the RE-MIND2 study incorporated mitigation strategies (for example, by applying a 6-month follow-up rule to reduce bias related to delayed assessments), these approaches cannot fully overcome the limitations of using retrospective real-world data. As a result, the potential for measurement bias remains high, reducing confidence in the comparability of outcomes across studies, and lowering the certainty of the comparative effectiveness estimates.

Key differences in how outcomes were defined across the L-MIND and RE-MIND2 trials make it challenging to generate reliable comparative estimates. The L-MIND trial used prespecified criteria and uniform rules for determining clinical responses and subsequent events, whereas the real-world RE-MIND2 study datasets applied definitions that were shaped by local practice patterns, documentation habits, and site-specific interpretations. As a result, events such as response, progression, or duration of benefit may not represent equivalent constructs across the data sources. These inconsistencies may lead to differential classification of outcomes, complicating interpretation of comparative findings and contributing to uncertainty about the validity of the effect estimates.

Efficacy Results of ITCs

Key results of the ITCs are provided in Table 5 and Table 6.

Overall Survival

• MAIC: The hazard ratio (HR) for OS was ████ (95% CI, ████ ██ ████) in favour of tafasitamab plus lenalidomide versus R-GemOx.

• Real-world matched analysis: Median OS was ████ ██████ (95% CI, ████ ██ ██) with tafasitamab plus lenalidomide versus ████ ██████ (95% CI, ███ ██ ████) with R-GemOx. The HR was ████ (95% CI, ██████).

Progression-Free Survival

• MAIC: The HR for PFS assessed by an investigator was ████ (95% CI, ████ ██ ████) in favour of tafasitamab plus lenalidomide versus R-GemOx.

• Real-world matched analysis: Median PFS assessed by an investigator was ████ ██████ (95% CI, ███ ██ ████) with tafasitamab plus lenalidomide versus ███ ██████ (95% CI, ███ ██ ███) with R-GemOx. The HR was ████ (95% CI, ███████).

Objective Response Rate

• MAIC: The odds ratio for ORR assessed by an investigator was ████ (95% CI, ████ ██ ████) in favour of tafasitamab plus lenalidomide versus R-GemOx.

• Real-world matched analysis: The investigator-assessed ORR was █████ (95% CI, █████ ██ █████) with tafasitamab plus lenalidomide and █████ (95% CI, █████ ██ █████) with R-GemOx.

Duration of Response

• MAIC: The median ratio for DOR assessed by an investigator, was ████ in favour of tafasitamab plus lenalidomide versus R-GemOx.

• Real-world matched analysis: Median DOR assessed by an investigator was ████ ██████ (95% CI, ████ ██ ██) with tafasitamab plus lenalidomide versus ███ ██████ (95% CI, ███ ██ ████) with R-GemOx. The HR was ████ (95% CI, ████ ██ ██████).

HRQoL and Safety

• Not assessed in the MAIC or the real-world matched analysis.

Across scenario and sensitivity analyses, including using the full L-MIND trial population ███████ substituting IRC for investigator-assessed outcomes, and reprioritizing ECOG PS, the results did not substantially differ from the base-case analyses. Detailed results of the base, scenario, and sensitivity analyses can be found in the Supplemental Material document, Appendix 6.

Table 5: Summary of MAIC Results for Tafasitamab in Combination With Lenalidomide vs. R-GemOx

CI = confidence interval; DLBCL = diffuse large B-cell lymphoma; DOR = duration of response; ESS = effective sample size; HR = hazard ratio; INV = investigator; MAIC = matching-adjusted indirect comparison; OR = odds ratio; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; R-GemOx = rituximab, gemcitabine, and oxaliplatin; vs. = versus.

^aNote that CIs, and therefore statistical significance, cannot be determined for DOR because the comparator trial of R-GemOx reported only the median value with no measure of uncertainty.

^bAdjustment factors include line of therapy, age, and cell of origin.

^cL-MIND trial outcomes were per investigator assessment for PFS, ORR, and DOR, to align with outcome reporting in the comparator R-GemOx trial by Mounier et al. (2013).²²

Sources: Matching-adjusted indirect comparison technical report.²⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹³

Table 6: Summary of Real-World Matched Analysis Results for Tafasitamab in Combination With Lenalidomide vs. R-GemOx

CI = confidence interval; ESS = effective sample size; HR = hazard ratio; NE = not estimable; R-GemOx = rituximab, gemcitabine, and oxaliplatin; vs. = versus.

^aThe medians were calculated using the Kaplan-Meier method. The CIs were calculated using the Brookmeyer and Crowley method.

^bHRs were estimated using the observational cohort as reference group in Cox proportional hazards models.

^cP values were calculated using the Wald test.

^dBased on investigator assessment.

^eThe CI was calculated using the Clopper-Pearson exact method.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹³

Studies Addressing Gaps in the Systematic Review Evidence

No studies addressing gaps in the systematic review evidence were included in the review.

Discussion

Efficacy

The L-MIND trial was a phase II, open-label, single-arm study that assessed the efficacy and safety of tafasitamab plus lenalidomide in adults with r/r DLBCL who were not eligible for ASCT. For the current resubmission, the sponsor narrowed the target population to adult patients with r/r DLBCL not otherwise specified (including DLBCL arising from low-grade lymphoma), excluding primary refractory disease, who are not eligible for ASCT and have an ECOG PS of 2 or less. The subpopulation was evaluated using outcomes that included ORR, PFS, OS, and DOR, which aligned with what patients and clinicians consider meaningful in this setting. However, the L-MIND trial did not assess HRQoL, which patients and clinicians identified HRQoL as an important outcome.

The sponsor submitted HRQoL data from the PRO-MIND study, a prospective observational cohort study conducted in Italy that enrolled ██ adult patients with r/r DLBCL who were ineligible for ASCT and who received treatment with tafasitamab in combination with lenalidomide.²⁰ The relevance of the PRO-MIND study for interpreting HRQoL was limited because of the noncomparative observational study design, the small sample size, and the uncertain generalizability to the treatment setting in Canada. As the study was conducted entirely in Italy, differences in health care systems, clinical practices, and disease management practices may reduce generalizability to the patient population in Canada. The small sample size further limits the robustness and interpretability of the HRQoL results. Consequently, it is uncertain whether evidence from the PRO-MIND study adequately addresses the evidence gap with respect to HRQoL for patients with r/r DLBCL receiving treatment in Canada.

Patients and clinicians highlighted the need for effective treatments for r/r DLBCL that control disease with manageable side effects and that maintain HRQoL. Although the observed results for ORR, PFS, OS, and DOR appeared clinically meaningful, according to the clinical experts, interpretation of the L-MIND results was substantially limited by the single-arm design. The absence of a comparator arm meant that there was no direct evidence to contextualize the magnitude or durability of response against relevant treatments used in clinical practice for patients with r/r DLBCL who are ineligible for ASCT. In addition, no formal statistical testing was conducted. The lack of measures of uncertainty around DOR reduced confidence in the reliability of the observed effects and increased the difficulty of distinguishing true treatment-related benefit from variability that might arise in a small, uncontrolled study. Overall, these limitations meant that the evidence from the L-MIND trial could not support conclusions about the comparative efficacy of tafasitamab plus lenalidomide. Any perceived treatment effect should therefore be interpreted with caution, given the inherent uncertainty associated with a single-arm trial without statistical testing or an appropriate comparator.

In the L-MIND trial subpopulation, the observed plateaus in the Kaplan-Meier curves for PFS, OS, and DOR, starting from approximately ██ ██ ██ ██████ may have been driven by substantial censoring at the data cut-off, ongoing responders who had not yet experienced an event, and very small numbers of patients remaining at risk. With few events and a shrinking risk set, the Kaplan-Meier variance increases and CIs widen, making estimates unstable and sensitive to small changes in events. Moreover, if censoring was not strictly noninformative, survival may have been overestimated. Overall, these factors may introduce imprecision and limit confidence in inferring durable benefit from the estimated treatment effect.

When interpreting the findings from the L-MIND trial subpopulation, several factors may affect generalizability to the broader population of patients with r/r DLBCL who are not eligible for ASCT and do not have primary refractory disease. The trial applied response criteria that were appropriate when the study was conducted; however, assessment guidelines have evolved since then, and more contemporary standards place greater emphasis on PET-based evaluations. It is uncertain whether using updated criteria would have meaningfully altered response assessments or shifted the interpretation of clinical benefit. The clinical experts consulted for this review indicated that the baseline characteristics of the subpopulation relevant to the reimbursement request were broadly reflective of patients who would typically be considered for treatment with tafasitamab plus lenalidomide in practice. This alignment supported the clinical relevance of the observed outcomes. Nonetheless, several eligibility restrictions limit the confidence with which the results can be applied to all patients seen in real-world settings, and some patients who might reasonably be considered for treatment with tafasitamab plus lenalidomide in practice were not represented. For example, the enrolled population lacked racial and ethnic diversity; thus, it is uncertain whether the efficacy and safety outcomes observed in the study would be consistent across the broader, more diverse population of individuals with r/r DLBCL who are not eligible for ASCT and do not have primary refractory disease.

In Canada, available treatment options for adults with r/r DLBCL who are ineligible for ASCT include R-GemOx, pola-BR, glofit-GemOx, epcoritamab, and glofitamab. CAR T-cell therapy was not considered a relevant comparator for tafasitamab plus lenalidomide because it is an intensive, 1-time treatment with curative intent that occupies a distinct clinical niche more comparable to ASCT. The clinical experts consulted by CDA-AMC agreed that tafasitamab plus lenalidomide is primarily positioned for the treatment of patients who are ineligible for ASCT or not suitable for highly intensive therapies.

R-GemOx was the only relevant comparator that the sponsor deemed feasible for conducting ITCs with tafasitamab plus lenalidomide. The sponsor submitted 2 ITCs as comparative evidence for tafasitamab plus lenalidomide versus R-GemOx: an unanchored MAIC using data from the L-MIND trial subpopulation versus an external comparator (the R-GemOx trial by Mounier et al. [2013]²²) and a retrospective real-world comparison from the RE-MIND2 trial. The unanchored MAIC was highly uncertain because not all the important effect modifiers and prognostic factors could be included in the matching, and the limited overlap in available covariates across the L-MIND trial and the R-GemOx trial by Mounier et al. (2013)²² resulted in a markedly reduced ESS, in residual bias, and in violation of the assumption of conditional constancy of absolute effects; therefore, no firm conclusions could be drawn from the unanchored MAIC. In contrast, analyses of the L-MIND trial subpopulation compared to the RE-MIND2 trial cohort suggested a benefit of tafasitamab plus lenalidomide over R-GemOx, with statistically significant improvements in OS, PFS, DOR, and ORR. However, differences in study design (prospective single-arm versus retrospective real-world studies), heterogeneity between trial and external cohorts, and differences in end point definitions limit comparability and introduce selection and measurement biases. Overall, while both ITCs sought to provide indirect comparative evidence of tafasitamab plus lenalidomide versus R-GemOx, their methodologies, included their respective populations and outcome definitions, differed in aspects that caused potential residual confounding and imprecision in estimates and lowered confidence in robustness. Therefore, there is low certainty regarding the comparative efficacy of tafasitamab plus lenalidomide versus R-GemOx for patients with r/r DLBCL who are ineligible for ASCT, and the current evidence would not support a claim of superiority. Important evidence gaps remain, notably the comparative efficacy and safety of tafasitamab plus lenalidomide versus comparators relevant to practice in Canada, that is, pola-BR, glofit-GemOx, epcoritamab, and glofitamab.

In the absence of robust comparisons with all relevant comparators, there is uncertainty regarding the relative effectiveness of tafasitamab plus lenalidomide and its exact place in the treatment landscape. The clinical experts consulted by CDA-AMC highlighted the unmet needs of patients with refractory disease, early relapse after CAR T-cell therapy, progression after bispecific antibodies, or loss of CD20 expression. Early relapse following CAR T-cell therapy may be associated with T-cell exhaustion and may result in limited response to subsequent T-cell–redirecting therapies, while loss of CD20 expression reduces the effectiveness of CD20-based treatments. In this context, tafasitamab plus lenalidomide, which has a different mechanism of action, may have a potential role, although the available evidence is limited to case reports and small studies.²⁶ The clinical experts noted that tafasitamab plus lenalidomide may function primarily as a palliative option for patients who are older or who have frailty, offering modest clinical activity and a favourable safety profile in a setting with few other treatments.

Harms

Inputs from patient and clinician groups highlighted the need for a tolerable treatment with fewer side effects. In the L-MIND trial reimbursement subpopulation, no new safety concerns for tafasitamab were identified, and the clinical experts considered the safety profile of tafasitamab plus lenalidomide to be acceptable and manageable and aligned with expectations for the regimen in routine practice. Grade 3 or higher neutropenia and infections were observed, but not in numbers greater than the clinical experts expected with other, commonly used regimens. CDA-AMC noted that the use of granulocyte colony-stimulating factor and antimicrobial prophylaxis during or after treatment in the L-MIND trial may have underestimated the incidence of neutropenia and infections. The experts also indicated that excluding patients with higher risk for thrombosis or those unwilling to take thromboprophylaxis likely lowered the observed rate of deep vein thrombosis, although prophylaxis is standard with lenalidomide treatment and the reported incidence was consistent with clinical practice. Important evidence gaps remain, as safety data were derived from a single-arm trial and no comparative safety outcomes were included in the sponsor-submitted ITC, limiting the ability to contextualize the regimen’s safety profile relative to R-GemOx and other relevant comparators.

Ethics and Equity Considerations

Available evidence and expert input suggested that there are no clearly established differences in the incidence of r/r DLBCL across population groups. However, limited data from Canada indicate that patients living in small or medium rural areas may experience poorer OS compared with those in urban regions, highlighting potential geographic inequities in outcomes.²⁷ The experts also noted that certain subgroups, such as older adults and people with immunosuppression, may experience greater treatment-related risks, which contributes to uncertainty regarding the applicability of the L-MIND trial findings to the reimbursement subpopulation, particularly given the limited representation of diverse demographic groups. CDA-AMC notes that the uncertainty regarding this lack of data on the safety and efficacy of tafasitamab in diverse population groups should be accounted for in clinical decision-making when considering treatment with tafasitamab in populations or groups not represented in the trial. The requirement for IV infusion may further exacerbate inequities, as frequent visits to infusion centres can create logistical, financial, and psychosocial burdens for older adults, individuals with limited mobility, and those living in rural or underserved areas. These burdens include transportation challenges, time away from work or caregiving, and difficulties with venous access. Although the experts did not identify ethical concerns beyond those typical in oncology care, they noted that supporting patient autonomy depends on clear communication of treatment burden, expected outcomes, and available alternatives, especially for populations underrepresented in the clinical evidence. Collectively, these considerations underscore that disparities related to geography, age, functional status, and immunosuppression may affect access, tolerance, and outcomes, and that uncertainty remains regarding the balance of benefits and harms for equity-deserving groups not adequately represented in the evidence base.

Conclusion

This resubmission of evidence from the phase II, open-label, single-arm (L-MIND) study focused on a subpopulation of ██ patients with r/r DLBCL who were ineligible for ASCT and did not have primary refractory disease. Although the clinical experts consulted by CDA-AMC noted that the observed treatment effects of tafasitamab plus lenalidomide on ORR, PFS, OS, and DOR appeared clinically meaningful, the results were based on post hoc descriptive analyses without formal hypothesis testing and with substantial uncertainty due to the single-arm design and the small sample size. Without a comparator arm and formal statistical testing, no conclusions could be drawn about the efficacy of tafasitamab plus lenalidomide. The safety profile was consistent with the product monograph and clinical expert input, but no comparative data were available. Additional data submitted on HRQoL were from a small observational study conducted in Italy that may not be generalizable to the patient population in Canada.

In the absence of direct evidence with relevant comparators, the sponsor submitted 2 ITCs comparing tafasitamab plus lenalidomide with R-GemOx, the only indirect comparison with a relevant comparator that the sponsor deemed feasible. The findings were uncertain due to methodological limitations, residual confounding, and imprecise estimates. Therefore, no firm conclusions can be drawn regarding which treatment is favoured for the assessed outcomes. In addition, the indirect evidence did not include assessments of HRQoL or harms. Important evidence gaps remain, including a lack of indirect evidence comparing tafasitamab plus lenalidomide with other comparators relevant to practice in Canada, namely pola-BR, glofit-GemOx, epcoritamab, and glofitamab.

Economic Review

Methods

The review team appraised the pharmacoeconomic evidence submitted by the sponsor on the cost-effectiveness of tafasitamab plus lenalidomide compared to that of R-GemOx for the requested reimbursement population (i.e., adult patients with r/r DLBCL not otherwise specified [including DLBCL arising from low-grade lymphoma], excluding primary refractory disease, who are not eligible for ASCT and have an ECOG PS of 2 or less), which is narrower than the Health Canada indication. The sponsor also submitted a BIA assessing the budgetary impact of reimbursing tafasitamab plus lenalidomide for the requested reimbursement population as well as for the full Health Canada indication (i.e., adult patients with r/r DLBCL who are not eligible for ASCT).

Summary of the Submitted Economic Evaluation

The sponsor submitted a cost-utility analysis to estimate the cost-effectiveness of tafasitamab plus lenalidomide from the perspective of a public health care payer in Canada over a lifetime horizon (20 years).²⁸The modelled population comprised adult patients with r/r DLBCL, excluding primary refractory disease, who are not eligible for ASCT and have ECOG PS scores of 2 or less, which is aligned with the reimbursement request, but is narrower than the Health Canada population, and was based on the subgroup of the L-MIND trial.^28,29 The sponsor’s base-case analysis included costs related to drug acquisition and administration, concomitant medication use, subsequent treatment, end-of-life care, disease management and monitoring, and AEs.²⁸

In the sponsor’s base case, tafasitamab plus lenalidomide was associated with incremental costs of $275,818 and 1.50 incremental quality-adjusted life-years (QALYs) relative to R-GemOx.²⁸ This resulted in an incremental cost-effectiveness ratio of $184,231 per QALY gained.²⁸ Of the incremental benefit compared to R-GemOx (1.50 incremental QALYs gained), approximately 67% of the benefit was predicted to be accrued after the observation period of the L-MIND trial (maximum follow-up: 5 years).^28,29 Additional information about the sponsor’s submission is summarized in the Supplemental Material document, Appendix 10.

CDA-AMC identified several key issues with the sponsor’s analysis (refer to Table 7; full details are provided in the Supplemental Material document, Appendix 11).

Table 7: Key Issues With the Sponsor’s Economic Submission

CDA-AMC = Canada’s Drug Agency; DLBCL = diffuse large B-cell lymphoma; ITC = indirect treatment comparison; LY = life-year; MAIC = matching-adjusted indirect comparison; OS = overall survival; PFS = progression-free survival; pola-BR = polatuzumab vedotin, bendamustine, and rituximab; R-GemOx = rituximab, gemcitabine, and oxaliplatin; r/r = refractory or recurrent; TTD = time-to-treatment discontinuation; vs. = versus.

Note: Full details of the issues identified by CDA-AMC are provided in the Supplemental Material document, Appendix 11.

CDA-AMC Assessment of Cost-Effectiveness

In the absence of head-to-head trials comparing tafasitamab plus lenalidomide with relevant comparators, the sponsor conducted a MAIC of the L-MIND trial reimbursement subgroup and the R-GemOx trial.²⁵ The CDA-AMC clinical review could not draw any conclusions regarding comparative efficacy and safety of tafasitamab plus lenalidomide versus R-GemOx due to the limitations of the sponsor-conducted MAIC. Clinical expert input and the sponsor’s submission indicated that pola-BR, glofitamab (with and without gemcitabine and oxaliplatin), and epcoritamab were also relevant comparators in this indication. However, the sponsor did not consider it feasible to conduct ITCs for these other comparators. As there was no robust comparative evidence available, the cost-effectiveness of tafasitamab plus lenalidomide versus all relevant comparators is unknown.

Summary of the Budget Impact

The sponsor submitted a BIA that estimated the 3-year (2027–2029) budget impact of reimbursing tafasitamab for use in the reimbursement requested population.³⁰ The sponsor assumed that the payer would be CDA-AMC–participating public drug plans and derived the size of the eligible population using an epidemiological approach.³⁰ The price of tafasitamab was aligned with the price included in the sponsor’s economic evaluation, whereas the prices of comparators were based on the publicly available list prices.³⁰ Additional information pertaining to the sponsor’s submission is provided in the Supplemental Material document, Appendix 12.

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 (Supplemental Material document, Appendix 12). CDA-AMC estimated that 2,175 patients would be eligible for tafasitamab plus lenalidomide over a 3-year period (year 1 = 547; year 2 = 779; year 3 = 849), of whom 567 would be expected to receive tafasitamab plus lenalidomide (year 1 = 83; year 2 = 186; year 3 = 298). The estimated incremental budget impact of reimbursing tafasitamab plus lenalidomide is predicted to be approximately $34 million over the first 3 years, with an expected expenditure of $57 million on tafasitamab (tafasitamab plus lenalidomide: $62 million). The actual budget impact of reimbursing tafasitamab plus lenalidomide will depend on the number of patients eligible for treatment, the market uptake of tafasitamab plus lenalidomide, and the duration of treatment.

Conclusion

Based on the CDA-AMC clinical review of the sponsor-submitted ITC, the comparative efficacy and safety of tafasitamab plus lenalidomide are highly uncertain due to several limitations, including the inclusion and balance of all important effector modifiers and prognostic factors and the limited overlap of covariates across the 2 trials. In addition, no comparative evidence was submitted for pola-BR, glofitamab (with or without gemcitabine and oxaliplatin), and epcoritamab. Given the uncertainty in the comparative clinical evidence, there is insufficient robust evidence to determine whether tafasitamab plus lenalidomide provides greater health benefit than R-GemOx or any other comparator. If there are no differences in health outcomes between tafasitamab plus lenalidomide and other relevant comparators, then the total cost of tafasitamab plus lenalidomide should not exceed that of any relevant comparator.

The budget impact of reimbursing tafasitamab plus lenalidomide to the public drug plans in the first 3 years is estimated to be approximately $34 million. The 3-year expenditure on tafasitamab plus lenalidomide (i.e., not accounting for current expenditure on comparators) is estimated to be $62 million (tafasitamab, $57 million; lenalidomide, $5 million).

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