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Indication: Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, DLBCL transformed from indolent lymphoma, high grade B-cell lymphoma, primary mediastinal B-cell lymphoma or follicular lymphoma Grade 3B after two or more lines of systemic therapy and who have previously received or are unable to receive CAR-T cell therapy
We recommend that Epkinly be reimbursed by public drug plans for the treatment of adults with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL transformed from indolent lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, or follicular lymphoma grade 3B after 2 or more lines of systemic therapy and who have previously received or are unable to receive chimeric antigen receptor (CAR) T-cell therapy for a time-limited period while additional evidence is generated if certain conditions are met.
Please note that time-limited reimbursement refers to temporary reimbursement by the drug programs while additional evidence is generated and submitted for reassessment (i.e., this does not refer to the length of treatment or number of cycles administered).
Epkinly should only be covered to treat adults who have DLBCL, not otherwise specified, DLBCL transformed from indolent lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, or follicular lymphoma grade 3B that has come back or that did not respond to 2 or more previous treatments for their cancer, and who have also previously received CAR T-cell therapy, declined CAR T-cell therapy, or cannot receive CAR T-cell therapy.
Epkinly should only be reimbursed if not given in combination with other anticancer drugs. Reimbursement of Epkinly should be discontinued if a patient’s cancer grows or spreads or if the treatment is unacceptably toxic to the patient. Epkinly should only be reimbursed when prescribed by specialists with experience managing large B-cell lymphoma (LBCL), and if its cost is reduced.
A time-limited recommendation is a recommendation to publicly fund a drug or drug regimen for a certain period of time on the condition the sponsor will generate additional data that addresses uncertainty in the evidence. Health Canada requires the sponsor to complete a phase III study and confirm that Epkinly improves survival in patients with DLBCL compared to bendamustine and rituximab (BR) or rituximab, gemcitabine, and oxaliplatin (R-GemOx). Given that there is uncertainty in the magnitude of clinical benefit with Epkinly, reimbursement has recommended in a time-limited manner and is contingent on a reassessment of the comparative efficacy and cost-effectiveness when the results of the phase III study are available from the sponsor.
Non-Hodgkin lymphoma (NHL) is a type of cancer that forms in the lymphatic system. DLBCL is an aggressive type of NHL that accounts for 30% to 40% of NHL cases in Canada. DLBCL occurs when a type of white blood cell, called a B-cell, grows or divides abnormally, which causes tumours in the lymph nodes or other organs, including the spleen, liver, or bone marrow. r/r DLBCL is cancer that has come back after treatment (relapsed) or has not responded to certain treatments (refractory).
Not all patients with DLBCL respond to or are cured by first-line treatment with the combination chemotherapy treatment of rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulphate, and prednisone (R-CHOP). Approximately 30% to 50% of patients will experience disease progression or relapse within the first 2 years following R-CHOP therapy and will require additional treatments for their disease. There is also a need for accessible treatments for patients who progress after CAR T-cell therapy or for those who cannot receive CAR T-cell therapy.
Treatment with Epkinly is expected to cost approximately $14,320 in cycle 1, $26,436 in each of cycles 2 and 3, $13,218 in each of cycles 4 to 9, and $6,609 in each of cycles 10 and beyond. Costs are reported per patient.
The pCODR Expert Review Committee (pERC) recommends that epcoritamab (Epkinly) be reimbursed for the treatment of adults with r/r DLBCL not otherwise specified, DLBCL transformed from indolent lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, or follicular lymphoma grade 3B after 2 or more lines of systemic therapy and who have previously received or are unable to receive CAR T-cell therapy for a time-limited period while additional evidence is generated and only if the conditions listed in Table 1 are met.
Evidence from 1 ongoing phase I/II open-label, single-arm study (EPCORE NHL-1, which included 157 patients with r/r LBCL) suggested that treatment with epcoritamab may result in clinically meaningful improvements in median overall survival (OS) (OS = 18.5 months; 95% confidence interval [CI], 11.7 to ||||) and progression-free survival (PFS) (PFS = 4.4 months; 95% CI, 3.0 to 8.8). Additional landmark analyses of OS and PFS at 12 months |||| |||||| |||| |||||| and 18 months |||| |||||| |||| |||||| were supportive of the survival analyses. Epcoritamab was associated with a clinically meaningful complete response (CR) rate of ||||| |||| ||| |||| || ||||| and a durable response (median duration of response [DOR] = |||| ||||||; 95% CI, 9.7 to |||||). The results of the EPCORE NHL-1 study suggested no detriment in health-related quality of life (HRQoL).
Patients identified a need for additional treatments that result in longer disease remission and improved survival, disease symptom control, and improvement in HRQoL. Furthermore, patients indicated a need for easier access to new treatments that can be received closer to home and are aligned with their preferred treatment goals. Based on the evidence reviewed, pERC concluded that epcoritamab may meet some of these needs, including potentially extending disease remission and survival, as well as providing an alternative treatment that may be more tolerable for some patients in this palliative setting compared with regimens that include the use of cytotoxic chemotherapy; no definitive conclusion could be reached regarding the effects of epcoritamab on HRQoL.
Using the sponsor-submitted price for epcoritamab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) as estimated by CADTH for epcoritamab was $120,435 per quality-adjusted life-year (QALY) gained compared with salvage chemotherapy in patients who had not previously received CAR T-cell therapy. This analysis was based on the hazard ratio of |||| from the sponsor-submitted indirect treatment comparison (ITC) for epcoritamab versus rituximab-based chemoimmunotherapy (R-CIT) (costs informed by the R-GemOx regimen) but did not include a postprogression benefit for patients who received epcoritamab. At this ICER, epcoritamab is not cost-effective at a $50,000 per QALY gained willingness-to-pay threshold for patients with r/r LBCL after at least 2 prior lines of therapy. A price reduction is required for epcoritamab to be considered cost-effective at a $50,000 per QALY gained threshold.
pERC noted that Health Canada has mandated the sponsor complete the ongoing EPCORE DLBCL-1 phase III study and confirm that epcoritamab improves the OS of patients with DLBCL compared to investigator’s choice of either BR or R-GemOx. Given the considerable uncertainty in the magnitude of clinical benefit and cost-effectiveness, pERC recommends time-limited reimbursement of epcoritamab, with a reassessment of the comparative efficacy and cost-effectiveness when the results of the phase III EPCORE DLBCL-1 study are available from the sponsor. pERC noted that this approach would help facilitate equitable and timely access to promising treatments for patients while ensuring that treatments considered for public reimbursement adhere to a level of rigour that sufficiently demonstrates effectiveness, safety, and cost-effectiveness. The time-limited reimbursement strategy allows the integration of future clinical trial evidence to help shape stronger health policy and drug funding decisions where longer-term follow-up data are required. The sponsor has confirmed that the EPCORE DLBCL-1 trial results will be filed with CADTH in accordance with the timelines and requirements for a reassessment as described in the Procedures for Time-Limited Reimbursement Recommendations.
Reimbursement Conditions and Reasons.
DLBCL is the most common type of NHL, accounting for approximately 30% to 40% of all NHL cases in Canada. DLBCLs are a heterogeneous group of aggressive B-cell malignancies that differ in clinical presentation, molecular features, prognosis, and treatment options. The Canadian Cancer Society estimated that 11,400 people in Canada were diagnosed with NHL in 2022, with 3,000 dying from the disease. For patients who are not chemosensitive and who are ineligible for autologous stem cell transplant (SCT), or whose disease relapses after SCT or CAR T-cell therapy, the prognosis is poor and there is no standard treatment approach. The available options are currently limited to palliative chemotherapies, including rituximab plus gemcitabine and oxaliplatin (R-GemOx) and pola-BR, or clinical trials with novel drugs.
Epcoritamab is a humanized immunoglobulin G1-bispecific antibody that binds to a specific extracellular epitope of CD20 on B-cells and to CD3 on T-cells. The activity of epcoritamab is dependent on simultaneous engagement of CD20-expressing cells and CD3-expressing endogenous T-cells by epcoritamab that induces specific T-cell activation and T-cell–mediated killing of CD20-expressing cells.
Epcoritamab is administered via subcutaneous injection at a step-up dose of 0.16 mg/0.8 mg/48 mg according to the following schedule:
Epcoritamab was issued a Notice of Compliance with Conditions (NOC/c) by Health Canada for use in the treatment of adult patients with r/r DLBCL not otherwise specified, DLBCL transformed from indolent lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, or follicular lymphoma grade 3B after 2 or more lines of systemic therapy and who have previously received or are unable to receive CAR T-cell therapy. Health Canada issued an NOC/c for epcoritamab with the following key confirmatory requirements regarding efficacy:
To make its recommendation, the committee considered the following information:
Two patient groups, LC and LLSC, responded to CADTH’s call for patient input for the current review of epcoritamab. LC is a national Canadian registered charity that empowers the lymphoma community through education, support, advocacy, and research. LLSC is a national organization dedicated to finding a cure for blood cancers and supporting patients and their families by funding life-enhancing research and providing educational resources, services, and support.
LC gathered information for this submission via a survey that was launched from October 3 to November 20, 2023, targeting patients living with LBCL. The LC survey data included 33 respondents and a France submission that was based on a survey regarding the use of epcoritamab for diffuse LBCL conducted by Ensemble Leucémie Lymphomes Espoir (ELLyE) with 9 survey respondents, supported by results of the Lymphoma Coalition's 2022 survey that included the experience of patients with DLBCL (n = 171). LLSC conducted four 1 on 1 interviews in November 2023; 2 interviewees were patients with DLBCL and 2 were caregivers. Three interviewees resided in Canada and 1 interviewee resided in the US.
According to input from both groups, living with LBCL is associated with extreme fatigue, body aches, nausea, shortness of breath, and lack of energy, as well as stress and worry, all of which have a significant impact on day-to-day activities and patients’ quality of life.
The patient groups identified a need for additional second- and third-line treatment options, and they described having difficulties regarding the management of treatment regimens and side effects. Current available treatments have significant mental and psychological tolls on patients and their loved ones, are associated with immense financial burdens, and negatively impact their ability to work, travel long distances, and participate in daily activities. Expectations are, according to both inputs, for new treatments to be more effective and less invasive with fewer side effects. Patients are seeking to have a choice in their treatment decisions and a variety of options that offer a longer life span, longer remission, and better quality of life.
The patients indicated that epcoritamab could offer hope and relief to those with LBCL who require a third-line treatment option, and the subcutaneous route of administration could mean less time in hospitals per visit, which can improve the quality of life of patients and caregivers.
The clinical experts consulted by CADTH stated that the goal of treatment at this stage is palliative and generally includes maintaining HRQoL through relieving lymphoma-related symptoms, delaying disease progression, and balancing the toxicities of therapy. There is no standard of care in this setting, but options include chemotherapy (e.g., pola-BR or R-CIT), radiation, and potential enrolment in clinical trials. The clinical experts stated that there is an unmet need for safe and effective treatments for patients who are not eligible for curative treatment, or whose lymphoma has progressed after second-line treatment consisting of SCT or CAR T-cell therapy, as there are limited treatment options for disease control and currently available options are often associated with significant toxicity that limits their usefulness and applicability. Additionally, prognosis of LBCL relapsing after transplant and post-CAR T-cell therapy is limited, and poor bone marrow function may prevent patients from receiving or tolerating further cytotoxic therapy. The clinical experts also noted that there is a significant group of patients who may be eligible for intensive treatments but are unable to access them because of barriers related to location. Many patients are unable to travel with caregivers to specialized cellular therapy centres and choose not to have this treatment as they wish to be treated closer to home. As such, there is an additional unmet need for treatments that patients can access and receive closer to home.
After failure of first-line R-CHOP (curative intent), treatment in the second line consists of salvage rituximab-based chemotherapy and autologous SCT for patients who are transplant-eligible chemosensitive (curative intent) and third-line therapy consisting of CAR T-cell therapy (curative intent). There is no standard of care following these treatment options and patients who are transplant ineligible in the second and third line tend to receive palliative rituximab-based chemotherapy (e.g., pola-BR or R-GemOx), radiation, and/or treatments received through clinical trials. The clinical experts highlighted that there is a planned shift to use CAR T-cell therapy as second-line therapy for primary refractory or early relapsed DLBCL pending funding in Canada. The clinical experts emphasized that cytopenias are a major problem of palliative cytotoxic treatment options.
Acknowledging that the Health Canada–approved indication for epcoritamab limits use to patients “who have previously received or are unable to receive CAR T-cell therapy,” the clinical experts consulted by CADTH highlighted that epcoritamab could be a beneficial treatment option for:
The experts noted that these patients would be identified in routine practice by clinicians familiar with the treatment of patients with lymphoma who are undergoing surveillance for relapse (clinical and/or imaging). The experts could not identify a specific subgroup of patients that would demonstrate an enhanced benefit or a reduced benefit from epcoritamab treatment. The experts highlighted that repeat biopsy is not always required in cases of suspected relapsed of DLBCL but is recommended in the late relapse setting or if the patient had prior history of indolent lymphoma and it was unclear which lymphoma had relapsed.
The clinical experts stated that response to treatment would include standard assessment of lymphoma response using the Lugano criteria. Patients would undergo interim imaging every 3 months to confirm response, which would either lead to ongoing treatment or discontinuation. Patients would also be assessed for lymphoma-related symptoms at each visit; however, the clinical experts noted that these outcomes are more subjective but do factor into patients’ decisions for continuation of therapy. The experts also noted that the frequency of these assessments may vary across Canada. In terms of meaningful response to treatment, the clinical experts stated that a response of 6 months or more with improved symptoms can be considered meaningful. The experts did not consider temporary shrinking of tumours beneficial to patients and believed that a meaningful partial response (PR) or CR should have a duration of at least 6 months, otherwise epcoritamab should be discontinued. Additionally, with a current median OS of 6 months in this population, the experts considered a benefit of at least 6 months and 3 months over current standard of care to be clinically meaningful for OS and PFS, respectively.
The clinical experts suggested that treatment with epcoritamab should be discontinued upon overt disease progression or lack of response to treatment. The experts noted that adverse events (AEs) may vary, and resolution of severe AEs can still allow for resumption of therapy, so this is more variable and discontinuation should be left to physician judgment and patient request.
The clinical experts indicated that patients with r/r DLBCL are typically under the care of hematologists or oncologists who are familiar with the treatment of patients with lymphoma. They also noted that the monitoring and treatment of these patients must be conducted at tertiary centres that also have the means to monitor and treat cytokine release syndromes (CRS), which may require some initial training of site staff before implementation.
Three clinician groups, LC (3 clinicians contributed to the input), the Ontario Health Hematology Cancer Drug Advisory Committee (7 clinicians contributed to the input), and the LLSC Nurses Network (6 clinicians contributed to the input), responded to CADTH’s call for clinician group input.
According to the clinician groups, there are poor and limited treatment options for patients with r/r DLBCL. LC indicated that for patients who are eligible for aggressive curative intensive therapies, options such as autologous SCT and CAR T-cell therapy are considered. Those who have disease progression following CAR T-cell therapy or are unfit for CAR T-cell therapy for medical and/or social reasons have the greatest unmet need for treatment as they do not have another curative intent therapy readily available.
In contrast, those who are not eligible for curative autologous SCT-based or CAR T-cell therapy approaches are managed with palliative approaches such as pola-BR or the anti-CD19 antibody tafasitamab in combination with lenalidomide. CADTH notes that tafasitamab in combination with lenalidomide received a do not reimburse recommendation and is not currently reimbursement by the participating drug programs. A small percentage of patients might have pursued allogeneic SCT, but the vast majority of patients in this setting were managed with a variety of palliative chemotherapy regimens, radiation therapy, or treatments received in clinical trials. Multiple novel drugs (e.g., ibrutinib, lenalidomide, tafasitamab, selinexor) do not have Health Canada approvals or provincial funding for r/r DLBCL.
The clinician groups noted there is an unmet need for safe and effective treatments for patients who are not eligible for CAR T-cell therapy or those whose disease did not respond to second-line treatment. LC and the LLSC Nurses Network added that there are limited treatment options for disease control, and currently, available options are often associated with significant toxicity of past treatments, side effects, and both mental and physical treatment fatigue. LC stated that while autologous SCT or CAR T-cell therapy are considered effective for some patients, patients are unable to access them due to barriers based on location, and only a select number of sites are equipped to offer CAR T-cell therapy.
The most important goals of treatment for DLBCL, according to the clinician groups, are to prolong survival, delay disease progression, and improve symptoms, which in turn can improve the quality of life of patients and caregivers. The clinician groups agreed, in regard to the indication, that epcoritamab can be used in the third line or beyond if the patient was previously treated with CAR T-cell therapy or ineligible for CAR T-cell therapy. LC and the LLSC Nurses Network stated that this treatment, as an off-the-shelf product, could alleviate regional access issues, and the subcutaneous injection could possibly become a more feasible and well-favoured option than currently available treatments.
According to the clinician groups, improved survival (PFS, OS) and blood work, less presence of cancer cells in their bone marrow, and improvement in disease symptoms are outcomes used to determine whether a patient’s disease is responding to treatment. LC added that a clinically meaningful response would be PR or CR, which is typically determined using CT and or PET scans.
The clinician groups agreed that discontinuation of therapy should be considered in patients with disease progression or toxicity and that epcoritamab can be given in any inpatient and outpatient setting that has the ability to admit and monitor patients who are receiving anticancer therapy and should have expertise in managing CRS and neurotoxicity.
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
One ongoing, phase I/II, open-label, single-arm study (EPCORE NHL-1) was included in this review. The review for epcoritamab was based on the dose expansion phase of the study, which consisted of 157 patients with r/r LBCL whose disease relapsed after or failed to respond to at least 2 prior systemic treatment regimens. Patients were excluded if they had a known primary central nervous system lymphoma or known central nervous system involvement. Patients were also excluded if they received CAR T-cell therapy within 30 days or an autologous SCT within 100 days before first dose of epcoritamab. Patients with any prior allogenic hematopoietic SCT were excluded. Eligible patients received treatment with epcoritamab monotherapy at the step-up recommended doses: priming dose of 0.16 mg (cycle 1, day 1), an intermediate dose of 0.8 mg (cycle 1, day 8), and a full dose of 48 mg (cycle 1, day 15; cycle 1, day 22; and then every 4 weeks thereafter until unacceptable toxicity or disease progression). The primary end point was ORR, with secondary or exploratory end points of CR, DOR, PFS, OS, HRQoL, and safety.
The majority of patients in the LBCL intention-to-treat population had DLBCL (88.5%) with smaller subgroups that had high-grade B-cell lymphoma (5.7%), primary mediastinal B-cell lymphoma (2.5%), or follicular lymphoma grade 3B (3.2%). Patients had received 2 (29.9%), 3 (30.6%), or 4 or more prior lines of antilymphoma therapy (39.5%), and a majority had disease that was refractory to their last prior therapy (82.8%). Prior CAR T-cell therapy was reported for 38.9% of patients and 19.7% had received prior SCT.
Table 2 summarizes the results for the efficacy end points from the EPCORE NHL-1 trial using the most recent data cut-off date (April 21, 2023).
As of the data cut-off date (April 21, 2023), ||| ||||||| patients with LBCL had experienced at least 1 treatment-emergent adverse event (TEAE). A total of ||| ||||||| patients experienced grade 3 or higher TEAEs. The most frequent (at least 20% of patients) TEAEs by preferred term (PT) were CRS (80; 51.0%), pyrexia (not attributed to CRS; || |||||||), fatigue (|| |||||||||), neutropenia (|| |||||||||), nausea (|| |||||||||), anemia (|| |||||||||), and diarrhea (|| |||||||||). The most common grade 3 or 4 TEAEs (≥ 5%) by PT in patients with LBCL (N = 157) were neutropenia (|| ||||||| patients), anemia (|| ||||||| patients), decreased neutrophil count (|| |||||| patients), COVID-19 (|| |||||| patients), and thrombocytopenia (|||||| patients). Serious TEAEs were reported in ||| ||||||| of patients. The most frequent (≥ 2%) serious TEAEs by PT in patients with LBCL were CRS (|| |||||||||); COVID-19 (|| |||||| patients); COVID-19 pneumonia (|||||| patients); pleural effusion (||||||||), pneumonia (|||||| patients); and pyrexia (not attributed to CRS), sepsis, immune effector cell-associated neurotoxicity syndrome (ICANS), and febrile neutropenia (|||||| patients each). ||||| patients experienced at least 1 TEAE that led to treatment discontinuation and ||||| of patients had at least 1 TEAE that led to delayed dosing.
CRS: Eighty (51.0%) patients had at least 1 CRS event. The majority of these were grade 1 events (50 of 80 patients) and occurred most frequently after the first full dose of epcoritamab (65 of 80 patients). Grade 2 and grade 3 events occurred in 25 and 5 of 80 patients, respectively. There were no grade 4 or 5 events. The CRS symptoms resolved in || || || ||||||| patients.
Immune effector cell-associated neurotoxicity: Events of ICANS were reported in 10 patients (6.4%); 7 patients (4.5%) had grade 1 ICANS, 2 patients (1.3%) had grade 2 ICANS, and 1 patient (0.6%) had grade 5 (fatal) ICANS. ||||||| patients experienced events of ICANS that led to dose delay and in ||||||| patient this event led to treatment discontinuation.
Clinical tumour lysis syndrome: Two patients (1.3%) experienced events of clinical tumour lysis syndrome, both were grade 3 in severity. ||||||| ||||| ||| |||||||| ||||| || ||| ||||||||| |||||| ||||| ||| || ||||||| ||||||||||||.
EPCORE NHL-1 is an ongoing phase I/II, multicenter, open-label, single-arm study of epcoritamab. The EPCORE NHL-1 trial was conducted as part of a clinical trial program that includes the ongoing comparative phase III trial, EPCORE DLBCL-1. The single-arm trial was justified considering that the study was designed as an early phase I/II study where an internal comparator group is not required, as well as the severity of illness for patients at this stage (i.e., those with r/r illness following at least 2 lines of prior systemic therapy). However, the decision to conduct a single-arm study also has implications for the overall strength and interpretability of the results. As a single-arm study, there is an increased risk of bias in the estimation of treatment effects because of the potential for confounding related to natural history and prognostic factors. The potential influence of selection bias is also difficult to ascertain in a single-arm study. Additionally, time-to-event end points cannot be adequately assessed in a single-arm trial because all patients received the same treatment. As such, the effect of epcoritamab on time-to-event end points such as PFS, OS, and DOR are uninterpretable and can only be considered as exploratory and supportive.
Health Canada issued an NOC/c for epcoritamab based on promising results from EPCORE-NHL1. In absence of a comparator group in the EPCORE NHL-1, assessing the comparative clinical value of epcoritamab relies on indirect comparisons (unanchored MAICs), which rely on numerous assumptions about the comparability of treatment groups, thereby increasing the uncertainty related to the comparative efficacy. The uncertainty in the comparative efficacy of epcoritamab versus relevant comparators was acknowledged by Health Canada, which specified that the sponsor must provide phase III trial results showing that epcoritamab improves the OS of patients with DLBCL compared to investigator's choice of either BR or R-GemOx. In addition to the single-arm design, the EPCORE NHL-1study was administered in an open-label manner, whereby the investigator and the study participants were aware of their treatment status, potentially increasing the risk of detection bias and performance bias. As such, the open-label trial design limits interpretability of the subjective study outcomes such as tumour response, patient-reported outcomes such as HRQoL, and AEs. However, to mitigate the impact of this bias, PFS and ORR were assessed by both IRC and the investigator using the Lugano classification criteria for the response.
The EPCORE NHL-1 study was an international, multicenter study and the clinical experts consulted by CADTH had no concerns regarding the generalizability of the study results to the setting in Canada. The clinical experts consulted by CADTH noted that the baseline characteristics were a reasonable reflection of the patient population for whom epcoritamab could be considered an appropriate treatment in clinical practice in Canada. The proportion of patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 was relatively low (3.2%) and the clinical experts noted that this could be greater in clinical practice. The clinical experts noted that 40% of patients with prior CAR T-cell therapy exposure is a reasonable reflection of the target population in Canada (though noted this would vary across jurisdictions) and that the overall proportion of patients with SCT could be slightly lower than may be anticipated in routine practice in Canada for patients whose disease failed on 2 or more lines of systemic therapy. The treatment regimen used in the EPCORE NHL-1 trial aligns with recommendations within the Health Canada–approved product monograph for epcoritamab (i.e., priming dose of 0.16 mg; intermediate dose of 0.8 mg; and then a full dose of 48 mg thereafter). The clinical experts consulted by CADTH noted that dosing of epcoritamab and medications used for the management of AEs throughout the peri-treatment period are reflective of the regimen that would be administered in practice in Canada.
For pivotal studies and randomized controlled trials identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group. Although GRADE guidance is not available for noncomparative studies, the CADTH review team assessed pivotal single-arm trials for study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for single-arm trials started at very low certainty with no opportunity for rating up.
The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and the input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with the expert committee members: median OS, median PFS, change from baseline in HRQoL, and clinical response (CR, ORR, median DOR). For time-to-event outcomes, landmark analyses at 12 and 18 months were also of interest.
When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.
The target of the certainty of evidence assessment was the presence of a clinically important improvement in survival (OS and PFS) and HRQoL, which were considered the most important outcomes by the clinical experts consulted by CADTH, and the clinician group and patient group inputs. According to the clinical experts consulted by CADTH, clinically important thresholds for the outcomes of OS and PFS were a benefit of at least 6 months and 3 months over current standard of care for OS and PFS, respectively. Additionally, response to treatment (CR, ORR, DOR) was included in the certainty of evidence assessment based on the potential translation to long-term survival outcomes.
Summary of Findings for Epcoritamab for Patients With r/r DLBCL.
One sponsor-submitted ITC was summarized and critically appraised by CADTH. The MAICs focused on 3 patient populations: first, the overall LBCL population; second, the LBCL with no prior CAR T-cell therapy population; and third, the LBCL with no prior CAR T-cell therapy but considered eligible to receive CAR T-cell therapy population. The indirect comparisons of interest for the CADTH review were epcoritamab versus pola-BR and R-CIT. The sponsor-submitted ITC included comparisons against 3 CAR T-cell regimens: axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel. Given that the Health Canada–approved indication for epcoritamab states that the drug is only approved for use in patients “who have previously received or are unable to receive CAR-T cell therapy,” CADTH does not consider CAR T-cell therapies to be relevant comparators for the current review. This approach is consistent with applications that have been filed in the same therapeutic area. Outcomes evaluated in the MAIC included OS, PFS, ORR, and CR.
In the adjusted overall LBCL patient population, the sponsor reported that epcoritamab was associated with significant improvements in both PFS (||| |||||| ||| ||| ||||| || ||||||||| ||||||) and OS (||| |||||| ||| ||| ||||| || ||||||||| ||||||) compared to pola-BR. The sponsor also reported a significant improvement with epcoritamab versus pola-BR in both CR rate (|||||| ||| ||| ||||| || |||||| |||||||) and ORR (|||||| ||| ||| |||| || |||||||| ||||||).
Compared with pola-BR in the analysis for patients with prior CAR T-cell therapy, the sponsor reported no significant difference in PFS (||| |||||| ||| ||| ||||| || ||||||| ||||||), OS (||| |||||| ||| ||| ||||| || ||||||| ||||||), or CR rate ||||||| ||| ||| |||||| || |||||||| ||||||). The sponsor reported that epcoritamab was associated with an improvement in ORR versus pola-BR (|||||| ||| ||| |||| || |||||||| ||||||).
PFS could not be reported for the comparison with R-CIT in the LBCL with no prior CAR T-cell therapy population. Compared to chemoimmunotherapy, the sponsor reported that epcoritamab was associated with significant improvements in OS (||| |||||| ||| ||| ||||| || ||||||| ||||||); CR rate (|||||| ||| ||| ||||| || ||||||| ||||||); and ORR (|||||| ||| ||| ||||| || ||||||| ||||||).
Given the lack of direct evidence comparing epcoritamab to relevant treatments in the r/r DLBCL third-line setting, the sponsor’s decision to conduct an ITC (i.e., unanchored MAIC) was justified. There were important differences in the design of the included studies and the cohorts evaluated that limit the ability to draw strong conclusions about the efficacy of epcoritamab compared with pola-BR and R-CIT. The EPCORE NHL-1 study of epcoritamab was a phase I/II, single-arm study, whereas the GO29365 study was a comparative phase Ib/II randomized, open-label study; SCHOLAR-1 was a retrospective research study; and Liebers et al., (2021) was a real-world study. In addition, all of the comparisons involved the use of subgroup data from 1 or both of the studies included in the indirect comparison.
In addition to differences in study design, there were notable differences in the eligibility criteria of the included studies, which resulted in heterogeneity in baseline characteristics across populations. The sponsor provided a comprehensive list of likely prognostic factors and treatment-effect modifiers (identified through consultation with clinical experts). However, adjustment of all these factors could not be achieved because of differences in reporting across the various studies and a lack of access to patient-level data (other than for those enrolled in the EPCORE NHL-1 trial). It is unclear if the lack of adjustment for differences in baseline characteristics (particularly those that may be prognostic factors, such as primary refractory disease) would have an impact on the results of the MAIC. A key limitation of the sponsor-submitted MAICs, which is a limitation inherent to all unanchored MAICs, is that it assumes that all effect modifiers and prognostic factors are accounted for in the model. This assumption is largely considered impossible to meet, according to the NICE DSU Technical Guidance report on the methods for population-adjusted indirect comparisons.
Overall, CADTH conclude that there were multiple limitations of the sponsor-submitted MAICs, including differences in inclusion and exclusion criteria, heterogeneity in baseline characteristics across studies, and notable reductions in sample sizes because of matching and weighting; thus, there was significant uncertainty about the overall generalizability of the results to the population in Canada. Additionally, wide 95% CIs led to imprecision and uncertainty in the results.
CADTH notes that Haute Autorité de Santé (HAS) in France similarly concluded that no formal conclusions can be drawn from the sponsor’s MAICs, citing methodological limitations, including uncertainty regarding the quality of the data (particularly the real-world evidence), significant heterogeneity between the populations included in the different studies, and residual differences across the various treatments after weighting. However, the National Institute for Health and Care Excellence (NICE) in the UK acknowledged that, despite the uncertainty associated with the sponsor’s MAICs, epcoritamab was likely to be more effective than R-CIT based on the sponsor’s MAIC. Clinical experts consulted by NICE noted that it was plausible epcoritamab was more effective than pola-BR; however, the NICE expert committee noted that there was too much uncertainty with the indirect comparison and concluded that an assumption of equal efficacy would be more appropriate to inform the economic evaluation.
Not applicable.
Not applicable.
Summary of Economic Evaluation.
CADTH identified the following key limitations with the sponsor’s budget impact analysis: uncertainty in the proportion of patients whose disease relapses and who receive third-line treatment, uncertainty in the proportion of patients whose disease relapses after CAR T-cell therapy, inappropriate exclusion of the premedication drug costs associated with epcoritamab, and uncertainty in using R-GemOx as a proxy for all chemoimmunotherapies costs. The CADTH reanalysis updated the proportion of patients whose disease relapses and who receive third-line treatment, incorporated the premedication drug costs associated with epcoritamab, and informed the cost of chemoimmunotherapies as an average between R-GemOx and rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP). In the CADTH base case, the budget impact of reimbursing epcoritamab is $3,478,047 in year 1, $14,752,278 in year 2, and $25,799,166 in year 3. Therefore, the 3-year total budget impact is $44,029,491.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Philip Blanchette, Dr. Kelvin Chan, Dr. Matthew Cheung; Dr. Michael Crump, Dr. Jennifer Fishman, Mr. Terry Hawrysh, Dr. Yoo-Joung Ko, Dr. Christian Kollmannsberger, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik
Meeting date: April 10, 2024
Regrets: Three expert committee members did not attend.
Conflicts of interest: One expert committee member did not participate because of conflict of interest considerations.
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
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Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third-party supplier of information.
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About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Indication: Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, DLBCL transformed from indolent lymphoma, high grade B-cell lymphoma, primary mediastinal B-cell lymphoma or follicular lymphoma Grade 3B after two or more lines of systemic therapy and who have previously received or are unable to receive CAR-T cell therapy.
Sponsor: AbbVie Corporation
Final recommendation: Time-limited reimbursement
This recommendation is time-limited and contingent on a reassessment of additional evidence.
Copyright © 2024 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
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