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Indication: For the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma
CADTH recommends that Breyanzi should be reimbursed by public drug plans for the treatment of patients with large B-cell lymphoma (LBCL) if certain conditions are met.
Breyanzi should only be covered to treat patients who have LBCL and have received at least 2 previous treatments that have not worked or have stopped working, as determined by a specialist.
Breyanzi should only be reimbursed if patients have not already been treated with a chimeric antigen receptor (CAR) T-cell therapy and are in relatively good health to tolerate the treatment if it is prescribed and administered by specialists and trained personnel in dedicated centres and the cost of Breyanzi is reduced.
Evidence from a clinical trial demonstrated that Breyanzi was associated with clinically meaningful response to treatment and could potentially prolong survival.
Breyanzi would provide an effective alternative option with a potentially different side effect profile for patients with LBCL who need CAR T-cell therapy.
Based on CADTH’s assessment of the health economic evidence, Breyanzi does not represent good value to the health care system at the public list price. The CADTH pCODR Expert Review Committee determined that there is not enough evidence to justify a greater cost for Breyanzi compared with other available CAR T-cell therapies (Kymriah or Yescarta).
Based on public list prices, Breyanzi is estimated to cost the public drug plans approximately $6.8 million over the next 3 years. However, the actual budget impact is uncertain.
LBCL is the most common type of non-Hodgkin lymphoma. A lymphoma, which affects types of white blood cells called lymphocytes, grows primarily in the lymph nodes but it can spread into organs or tissues such as bones, brain, or intestines. It is estimated that 11,400 people living in Canada will be diagnosed with non-Hodgkin lymphoma each year and 3,000 will die.
Patients with LBCL can be treated with surgery, chemotherapy, radiation, immunotherapy, and stem cell transplant; however, not all patients benefit from available treatments. Some patients may also need further therapy with fewer choices of therapies available to them and have a shorter life expectancy.
Treatment with Breyanzi is expected to have a 1-time cost of $501,900 per patient. Additional costs associated with pre- and post-infusion management (i.e., leukapheresis, bridging therapy, conditioning chemotherapy) and administration will also apply.
The CADTH pCODR Expert Review Committee (pERC) recommends that lisocabtagene maraleucel (liso-cel) be reimbursed for the for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma, only if the conditions listed in Table 1 are met.
One multi-centre, open-label, phase I, single-arm clinical study (TRANSCEND) showed that liso-cel was associated with potential benefits in survival outcomes: median overall survival [OS] was 14.0 months (95% confidence interval [CI], 11.1 to 21.1; median follow-up = 18.8 months) and median progression-free survival [PFS] was 4.8 months (95% CI, 4.3 to 7.3; median follow-up of |||| months) in the intention-to-treat population. For the primary analysis set (PAS) of patients with DLBCL, response to treatment was objective response rate [ORR]) of 74.4% (95% CI, 66.2% to 81.6%; P < 0.0001) and complete response rate [CRR] of 54.1% (95% CI, 45.3% to 62.8%; P < 0.0001). The ORR and CRR end points were statistically significant based on the pre-specified null hypotheses of 40% or less and 20% or less, respectively. Overall, survival and response end points were deemed meaningful by clinical experts compared with expected outcomes in patients with DLBCL who did not receive a CAR T-cell treatment in the third-line setting.
Given the poor prognosis and high symptom burden in patients with advanced DLBCL in the third line of therapy, patients and clinicians identified a need for treatment options that provide better survival and response outcomes, with better health-related quality of life, and less toxicity. Patients are also seeking improved access to CAR T-cell therapies, which is currently limited. Given the totality of the evidence, pERC concluded that liso-cel may meet some of the needs identified by patients and clinicians compared to similar CAR T-cell therapies approved for use in Canada by providing an effective alternative option with a potentially different safety profile for most R/R LBCL patients.
Although no robust evidence has been provided to suggest that liso-cel is associated with improved efficacy and safety relative to other CAR T-cell therapies used to treat LBCL, feedback from the clinical experts consulted by CADTH indicated that liso-cel is likely similarly effective to other CAR T-cell therapies. Using the sponsor-submitted price for liso-cel and publicly listed prices for all other drug costs, liso-cel was more costly compared with other available CAR T-cell therapies (axicabtagene ciloleucel [axi-cel] and tisagenlecleucel [tisa-cel]) and considered similarly effective.
Reimbursement Conditions and Reasons.
Lymphomas comprise a complex group of hematological malignancies with varying molecular hallmarks and prognoses. Overall, they are divided into NHL and Hodgkin lymphoma. In Canada, the incidence of NHL is reported at 24.4 per 100,000, with age-standardized incidence rates of 29.3 per 100,000 and 20.2 per 100,000 among males and females, respectively. DLBCL is the most common type, comprising 30% to 40% of all NHL cases. Most people are diagnosed with DLBCL when they are in their mid-60s. The most common type of DLBCL is the “not otherwise specified” (NOS) form, which represents 80% to 85% of all cases. Other subtypes of DLBCL include PMBCL, a rare subtype of DLBCL. Patients with treatment failure after initial treatment often have a poor outcome — in particular, those with disease that is refractory to frontline or subsequent therapies — although some patients can have a durable remission and be cured after secondary therapies. Outcomes are worse in patients with chemotherapy-refractory disease, with only 7% achieving a complete response to standard treatment and OS of 6 months. People of older age (> 65 years), those with central nervous system (CNS) involvement, and those with comorbidities have a higher possibility of AEs. No more than 50% of patients with R/R LBCL achieve a response to subsequent treatment after a standard second-line salvage regimen, and few are cured.
Liso-cel (JCAR017) is a patient-specific cell suspension containing a target of 60 × 106 to 120 × 106 CAR-positive viable T cells for IV infusion. It has a Health Canada indication for the treatment of adult patients with R/R LBCL after 2 or more lines of systemic therapy, including DLBCL NOS, PMBCL, HGBCL, and DLBCL arising from FL. Liso-cel targets CD19, a marker expressed on B-cell precursors and malignant B cells present in DLBCL and other lymphomas. Liso-cel consists of purified CD8-positive and CD4-positive T cells in a defined composition that have been separately activated and transduced with a replication-incompetent lentiviral vector encoding an anti-CD19 CAR. Liso-cel must be administered in a qualified treatment centre under the supervision of health care professionals experienced in the treatment of hematological malignancies and familiarity with CAR T-cell toxicities and must be kept frozen at −130°C or less until it is ready to use. Some reported toxicities of liso-cel include CRS, hypogammaglobulinemia, neurologic toxicities, cytopenia, and tumour lysis syndrome.
To make their recommendation, the committee considered the following information:
Note that the CADTH Reimbursement Review was conducted before issuance of Health Canada Notice of Compliance.
Input was obtained from 1 patient group. Lymphoma Canada, a Toronto-based, national Canadian registered charity that empowers the lymphoma community through education, support, advocacy, and research, provided an anonymous survey of patients with LBCL conducted online from June 21 to August 25, 2021. The survey participants (total = 331, DLBCL = 126, FL = 191, other LBCLs = 14) were from Canada, the US, Europe, and other countries. Past survey data for the subgroup of patients with DLBCL (2018 and 2020 surveys), FL (2017 and 2018), and those with CAR T-cell therapy experiences (April 18 to June 15, 2018) were also provided to supplement the current survey.
Respondents (n = 63) highlighted night sweats (57%), fatigue and lack of energy (54%), and aches and pains (54%) as the top symptoms of lymphoma that impact their quality of lives. In addition, anxiety/worry (75%), stress related to the diagnosis (73%), and fear of progression (64%) were cited as the key psychosocial impacts. Diagnosis combined with symptoms and mental health effects significantly impact patients’ daily activities (43%), ability to sleep (41%), concentration (40%), and ability to attend work/school (40%). Of 230 respondents, 7% had not yet received therapy (“watch and wait”), 50% received 1 line of therapy, and 43% received 2 or more lines of therapies at the time of survey. For those patients with DLBCL on treatments, the most common side effects (n = 103) were hair loss (87%), fatigue (84%), and cognitive issues (68%); the most intolerable side effects (n = 85) were fatigue (41%), nausea/vomiting (19%), and “chemo-brain” (15%). For patients with FL on treatments, the most common side effects (n = 61) were fatigue (85%), nausea/vomiting (51%), and hair loss (39%); the most intolerable side effects (n = 49) were fatigue (37%), nausea/vomiting (10%) and pain (10%). Specific psychosocial impacts (n = 49) caused by treatments included fear of progression/relapse (67%), anxiety/worry (65%), and depression (47%). The most significant negative impacts on quality of life or daily living caused by treatments were treatment-related fatigue (57%, n = 273), late-onset/long-term side effects (41%, n = 49), and low activity level (39%, n = 176). In terms accessing treatment options, 13% of patients (n = 44) found these very difficult to access. Living in a community without a cancer centre (35%, n = 49) was the most common reason for difficulty accessing treatments. Absence from work (62%), travelling costs (28%), and supplementary drug costs (26%) were the top financial impacts associated with accessing necessary treatments (n = 39). The most desired outcomes from treatments included improved quality of life and performance of daily activities (93%, n = 176), longer survival (88%, n = 223), and longer disease remission (85%, n = 223). 47% of patients responded that they would be willing to tolerate the short-term side effects of a new effective treatment and 47% said they would take the treatment recommended by their physicians even if it has potentially serious side effects. According to the past survey data (2018), none of the patients had direct experience with liso-cel therapy. Of the 7 patients who had experiences with other CAR T-cell therapies through clinical trials, 5 responded to a questionnaire asking about the effect of CAR T-cell therapy on their quality of life. Patients rated all aspects of CAR T-cell therapy less than 3 (on a scale of 1 = no negative impact on my life to 5 = significant negative impact on my life): number of clinic visits (2.8), travel to treatment centre (2.8), CAR T-cell infusion (2.6), short-term side effects (2.5), activity level (2.5), treatment-related fatigue (2.5), lasting side effects (2.0), and leukapheresis (1.8). When asked about recommending CAR T-cell therapy to other eligible patients, 5 of 7 patients said they would recommend, 1 said they would not recommend, and 1 remained unsure.
Clinical experts consulted by CADTH agreed that there is an unmet need for drugs that are better tolerated and with better safety profiles that can be used more frequently in the outpatient setting and in a broader population of patients with lymphoma. The suboptimal availability of commercially available CAR T-cell products in some provinces generates the need to refer patients outside the province or country for commercial CAR T-cell therapies. Other innovative therapies (e.g., polatuzumab vedotin) may not be widely available or can be more costly.
Although liso-cel is not the first CAR T-cell therapy on the market for R/R DLBCL in Canada, some clinical experts mentioned that it may have a better safety profile in terms of fewer toxicities as suggested by the evidence from the TRANSCEND study, although others mentioned newer therapies may benefit from prior clinical experience with similar therapies. Liso-cel would still be used as third line of therapy (in patients who have already tried 2 lines of chemotherapy) but will have the advantage of being able to be used in a broader population.
The clinical experts suggested that the patients most likely to benefit from liso-cel have similar characteristics to those included in the TRANSCEND study (e.g., ECOG PS of 0 or 1, low lactate dehydrogenase), although the experts mentioned that more data on specific subgroups (e.g., ECOG PS of 2) are needed. Patients who have had an autologous stem cell transplant and then relapsed or those who are not eligible for a transplant are likely to be favoured by the liso-cel administration. The clinical experts mentioned that patients not suitable for treatment with liso-cel would be those who do not meet established criteria (i.e., eligibility criteria from TRANSCEND) for CAR T-cell therapy. However, as with other CAR T-cell therapies, it remains difficult to predict at the start of treatment which patients would likely benefit from treatment with liso-cel.
Improved survival, reduction in the frequency and severity of symptoms, and cure were considered adequate measurements of response in clinical practice. Imaging may also be used as an objective means of assessing response to treatment.
The clinical experts recommended assessments of patients every 1 to 3 months. Criteria for discontinuing treatment with CAR T-cell therapies was not discussed because it is a treatment administered as a single dose (although re-treatment may be possible in the future). Some patients may become clinically unstable during the liso-cel manufacturing process and require discontinuation (e.g., patients with ECOG PS of 4, sudden clinical deterioration, opportunistic infections).
CAR T-cell treatment is primarily done at transplant centres in Canada. Currently, most provinces in Canada have (or will have) the necessary expertise and resources to perform the administration of liso-cel. In some areas, however, access to these centres may be challenging (e.g., in rural areas). Therefore, access to Health Canada and Foundation for the Accreditation of Cellular Therapy (FACT)–accredited SCT centres in Canada is a limitation. The clinical experts expressed that outpatient therapy is feasible provided such programs have the appropriate infrastructure and accreditation.
The collection of clinician group response was coordinated by Lymphoma Canada. The clinician group stated that the addition of liso-cel to the current third-line therapies or beyond is important for the following reasons: As a curative therapy, liso-cel is expected to improve remission (e.g., complete and partial responses) and prolong survival (e.g., OS and PFS) of the eligible patients; the availability of liso-cel would prevent unnecessary delay in treatment caused by short supply of the existing CAR T-cell therapies; liso-cel was demonstrated to have less frequent AEs (i.e., CRS and neurotoxicity compared with axi-cel without compromising efficacy (however, no head-to-head trial is available); and liso-cel can be safely administered in an outpatient setting similarly to tisa-cel.
Another input was provided by Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee (OH-CCO Hem DAC). The OH-CCO’s committee indicated that liso-cel would fulfill the unmet needs of indications that are not covered by the other CAR T-cell therapies (e.g., FL3B and secondary CNS lymphoma). Moreover, the committee identified that the limited number of CAR T-cell therapy centres available across Canada could cause access issues for patients.
Input was obtained from the drug programs that participate in the CADTH Reimbursement Review process. 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 clinical study is included in this report evaluating the safety and efficacy of liso-cel in patients on the third line or more of treatment for R/R LDBCL. The TRANSCEND NHL 001 study (“TRANSCEND study” from hereon) is a single-arm, open-label, phase I (seamless design) multi-centre study conducted in the US. The population included in the study consisted of patients with DLBCL NOS (de novo, transformed FL, and transformed indolent NHL), HGBCL with myelocytomatosis oncogene (MYC) and B-cell lymphoma gene 2 (BCL2) and/or B-cell lymphoma gene 6 (BCL6) rearrangements, PMBCL, and FL3B; patients were eligible if they were R/R to at least 2 prior lines of therapy, and had ECOG PS of 0 to 2, PET-positive disease, secondary CNS involvement, prior autologous stem cell transplant or prior allogeneic stem cell transplant. Patients with primary CNS involvement and allo-HSCT within 90 days of leukapheresis were excluded. The seamless design allowed the study to go from dose-finding phases (groups of patients) to dose-expansion and then dose-confirmation groups. The study evaluated 3 levels of dose regimens, Dose level 1 at 50 × 106 CAR+ T cells, dose level 2 at 100 × 106 CAR+ T cells, and dose level 3 at 150 × 106 CAR+ T cells; of these, the dose level 2 regimen was selected for the current indication assessed in this review, for clinical use, and regulatory approval. Patients in the TRANSCEND study had a mean age of 60 years (median = 63 years) and were overall in relatively good health status.
After enrolment, patients went through leukapheresis to allow for the product (JCAR017/liso-cel) to be manufactured (bridging therapy consisting of systemic anticancer therapy was allowed) and were required to have PET-positive disease. After product generation, patients went through lymphodepleting chemotherapy with fludarabine plus cyclophosphamide followed by 1 or 2 doses of JCAR017/liso-cel administered intravenously on day 1. After day 29, patients were followed on this study for 2 years after the last dose of liso-cel for safety, disease progression, and survival. Of 427 screened patients (341 in the DLBCL cohort), 344 went through leukapheresis (the intention-to-treat set), of which 50 could not be treated with any product, 25 received a nonconforming product, and 269 patients were treated with liso-cel (the DLBCL-treated set) and analyzed as of the cut-off date of August 12, 2019. The main analysis was conducted on the PAS population consisting of those patients on the dose level 2 regimen.
Primary end points included AEs and ORR as assessed by an independent review committee (IRC). Secondary end points included CRR (as assessed by IRC), DOR, PFS, and OS. The ORR was defined as the proportion of patients with a best overall response of either complete response or partial response based on the Lugano 2014 criteria. A sequential testing procedure started with the first hypothesis test of ORR of 40% or less. The procedure proceeded to the second hypothesis test only after rejecting the null hypothesis in the first hypothesis test, and so on. Other efficacy end points were summarized. The Kaplan-Meier method was used to estimate the DOR, PFS, and OS rates at months 6, 12, 18, and 24. The manufacturing success rate using the proposed commercial manufacturing process was 90.0%, and the median time from leukapheresis to JCAR017/liso-cel product availability was 24.0 days (range = 17 to 51 days).
In this specific population of patients on the third line or more of treatment for DLBCL (i.e., those with DLBCL NOS, HGL, or transformed from FL) assigned to the recommended regimen of dose level 2 (100 × 106 CAR+ T cells), the ORR in the PAS (primary end point) was 74.4% (95% CI, 66.2% to 81.6%) against a null hypothesis of ORR of 40% or less. The CRR (key secondary end point) in the PAS was 54.1% (95% CI, 45.3% to 62.8%; 1-sided P < 0.0001). Sensitivity analyses using the per-protocol set showed similar results. The leukapheresed set (intention-to-treat population) included patients treated with a nonconforming product (N = 25) as well as those who received no treatment (N = 50). The primary reason for not receiving treatment was death (N = 33); most of those patients died from progressed disease (N = 27). The leukapheresed set had an ORR per IRC of ||||||||||| ||||||||||||||||||, and a CRR of ||||||||||||| |||||||||. The lower limit of each CI was equal to or higher than the null hypotheses used for the PAS (40% and 20%, respectively). With a median follow-up for PFS of || || months, the median PFS was 4.8 (95% CI, 4.3 to 7.3) months. With a median survival follow-up of 18.8 months, the median OS was 14.0 (95% CI, 11.1 to 21.1) months. The estimated survival rates at 6 and 12 months were 70.2% (95% CI, 65.0% to 74.8%) and 54.0% (95% CI, 48.5% to 59.2%), respectively. Only 7 of 269 patients were never hospitalized. Nineteen patients (7.1%) were admitted to the intensive care unit (ICU), with a variable duration from 2 to 88 days.
HRQoL outcomes improved during treatment with liso-cel, although not all HRQoL domains reached statistical significance as compared to a minimally important difference and were not included in the adjustment for multiplicity.
The most frequently reported treatment-emergent AEs were neutropenia (169 of 269 patients; 62.8%), anemia (129 of 269 patients; 48.0%), and fatigue (119 of 269 patients; 44.2%), followed by CRS (113 of 269 patients; 42.0%). CRS was also the most frequently reported serious AE (occurring in 44 of 269 patients; 16.4%), but grade 3 or higher CRS occurred in only 6 of 269 patients (2.2%). The second most frequently reported treatment-emergent serious AE was encephalopathy (|||||||||||||||||||||||||||||||||||), which is the most frequent symptom of investigator-identified neurologic toxicity. All other treatment-emergent SAEs were reported in less than 5% of patients. Grade 3 or higher CRS occurred in 6 of 269 subjects (2.2%); grade 3 or higher investigator-identified neurologic toxicity in 27 of 269 patients (10.0%), while no grade 5 CRS or investigator-identified neurologic toxicity AEs were reported. Admission to the ICU occurred infrequently. During initial hospitalization, 19 of 269 patients (7.1%) were admitted to the ICU; the median number of ICU days was | ||||||||||||||||. Considering all hospitalizations through the end of the study, ||||||||||||| ||||||| were admitted to the ICU; the median number of ICU days for those patients who were hospitalized was 8 days (range = 1 to 56 days).
The main limitation of the TRANSCEND study stems from the single-arm design and lack of comparator groups. In lieu of an available direct comparator, the investigators evaluated the primary end point of ORR against a null hypothesis (in the PAS population) of ORR of 40% or less, with an alternate hypothesis of greater than 40% and an effect size of 25% (ORR = 65%). The hypothesis testing and adjustment for multiplicity was evaluated only for the PAS population, which can instill uncertainty in the effect estimates for other sets, such as the leukapheresed set (intention to treat) and the DLBCL-treated set. An open-label design may also increase uncertainty in patient-reported outcomes (HRQoL), which introduces bias due to the inherent subjectivity of the outcome in an unblinded assessor (patients and investigators). Furthermore, HRQoL outcomes were evaluated as secondary end points with no adjustment for multiplicity and with decreasing sample sizes at later time points of evaluation, decreasing precision due to a diminishing number of patients available to be analyzed. Any magnitude of effect that the anticancer interventions (bridging therapies) could have on the outcomes evaluated in the TRANSCEND study in patients receiving liso-cel is unknown. Sensitivity analyses based on assessing the leukapheresed set, by per-protocol analysis, disease histology, and response determined by the investigator, were supportive of the robustness of results. No subgroup effects were informative because the sample size was small and only in the PAS population.
Issues of generalizability of the results originate from the differences in the population of patients included in the TRANSCEND study, which can be considered relatively young (mean age of 60.1 years in the DLBCL-treated set compared with a mean age of 65 years from clinical guidelines and reviews) and with fewer baseline risks (only 4 patients in the DLBCL-treated population was classified with ECOG PS = 2). This agreed with the input from the clinical experts consulted by CADTH, when considering the similarities between the populations from the TRANSCEND study and those likely to be encountered in clinical practice in Canada. However, the impact of these issues in the full implementation of the intervention is uncertain. Other issues of generalizability are the low number of patients with FL3B, DLBCL transformed from indolent lymphomas other than follicular lymphoma, and patients with secondary CNS lymphoma who were included in the TRANSCEND study. These numbers make it difficult to draw conclusions on the effects of liso-cel in these populations. Furthermore, the relatively short follow-up time for the main analysis on the study’s PAS population (median of 11.5 months in the DLBCL-treated set at the cut-off date of August 12, 2019) can cause some uncertainty in the effect estimates and in the generalizability of results in long-term outcomes. Additional data from the June 19, 2020 (median follow-up duration = 19.1 months) and January 4, 2021 (mean follow-up duration = 19.9 months) cut-off dates ameliorate these issues.
Two sponsor-submitted reports with 3 ITCs are included. The first 2 ITCs include comparisons evaluating individual patient data evidence from a single-arm study (TRANSCEND) compared against aggregated data from 2 published sources evaluating tisa-cel and axi-cel, respectively. In these 2 unanchored MAICs (one of liso-cel against tisa-cel, and the other against axi-cel), patients from these populations had R/R LBCLs and included the lymphoma subtypes that were common among the 3 bodies of evidence (i.e., DLBCL NOS, HGL, and transformed from FL). The second submitted report (ITC-2) includes an ITC as an unanchored MAIC comparing the same individual patient data from the TRANSCEND study against aggregated data from the SCHOLAR-1 study, which includes a population of patients with DLBCL treated with salvage therapies. The lymphoma subtypes included in the ITC-2 (i.e., those common among both bodies of evidence) were DLBCL, PMBCL, and transformed FL.
In the comparison of liso-cel versus tisa-cel, after matching and weighting 6 clinical factors, the primary analysis showed an ORR odds ratio (OR) favouring liso-cel over tisa-cel (OR = 2.77; 95% CI, 1.63 to 4.73; P < 0.001). For CRR, the OR significantly favoured liso-cel over tisa-cel (OR = 1.92; 95% CI, 1.17 to 3.17; P = 0.010). For survival outcomes, the results of the MAICs showed longer median PFS and OS for liso-cel than for tisa-cel. For instance, the liso-cel group had a median PFS of 6.7 months (95% CI, 3.5 to not reached) compared with tisa-cel of 2.8 months (95% CI, 2.3 to 4.2), and the rate of disease progression or mortality was significantly lower for liso-cel than for tisa-cel (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.92; P = 0.013). Similarly, for OS, liso-cel had a median OS of 28.9 (95% CI, 19.9, not reached) months compared with 11.7 (7.2 to not reached) for tisa-cel. For this comparison, the rate of mortality was significantly lower for liso-cel than for tisa-cel (HR = 0.66; 95% CI, 0.46 to 0.93; P = 0.019).
For the ITC analyzing the comparison of liso-cel versus axi-cel, the results of the MAICs showed no statistically significant difference for any of the end points (ORR, CRR, PFS, or OS).
The sponsor submitted an ITC evaluating liso-cel versus salvage chemotherapy in an MAIC that evaluated OS, CRR, and ORR. In the base-case analysis that accounted for 7 clinical factors to match and weight, the median OS for TRANSCEND was 21.1 (95% CI, 12.1 to not reached) months, with an effective sample size of 142 (from an original N = 257); The analysis resulted in an HR of 0.47 (95% CI, 0.37 to 0.60) relative to salvage chemotherapy. PFS was not reported in the SCHOLAR-1 study. Unadjusted median OS was 27.3 (95% CI, 16.8 to not reached) months for liso-cel (N = 257) and 6.0 months (95% CI, 5.6 to 6.8) for salvage chemotherapy (N = 603). Adjusted for 7 clinical factors, the CRR for liso-cel was 49.2% with an effective sample size of 142; compared with salvage chemotherapy (CRR = 7.0%; N = 523), the matched and adjusted treatment effect on CRR was greater with an OR of 12.89 (95% CI, 8.04 to 20.68; P < 0.001). No data on harms were available in ITC-2.
For harms, liso-cel had fewer AEs of special interest, such as CRS, neurotoxicity, and neutropenia, compared with axi-cel or tisa-cel. Compared with tisa-cel, liso-cel had lower odds of CRS (OR = 0.52; 95% CI, 0.31 to 0.87) and prolonged cytopenia (OR = 0.43; 95% CI, 0.26 to 0.73); however, the rest of AEs were similar. Relative to axi-cel, liso-cel had lower odds of CRS (OR = 0.03; 95% CI, 0.01 to 0.07), neurotoxicity (OR = 0.16; 95% CI, 0.08 to 0.32), febrile neutropenia (OR = 0.09; 95% CI, 0.03 to 0.28), prolonged thrombocytopenia (OR = 0.34; 95% CI, 0.13 to 0.86), infections (OR = 0.19; 95% CI, 0.07 to 0.47), and any grade 3 or higher AE (OR = 0.04; 95% CI, 0.01 to 0.19). No data on harms were available for the ITC comparing liso-cel against salvage chemotherapy.
Both ITC reports aimed at comparing individual patient data from a single-arm clinical trial (TRANSCEND) against aggregated data from observational studies. For the first report, 1 ITC compared liso-cel against axi-cel (ZUMA-1 study) and another ITC compared liso-cel against tisa-cel (JULIET study). The second report included 1 ITC that compared liso-cel against salvage chemotherapy (from the SCHOLAR-1 study). All ITCs compared the interventions via an unanchored MAIC. One main limitation of unanchored MAICs is the lack of inclusion of relevant prognostic variables and effect modifiers that are not included in the weighting process. Differences in baseline characteristics of variables between the included studies suggest that other potential unmeasured confounders might be present, and that these can be unevenly distributed between groups. In both ITCs, authors attempted to obtain all possible prognostic variables/effect modifiers to be included in the weighting process of the MAIC. This effort for finding relevant clinical factors was data driven and included a literature search and clinician input. However, as mentioned by the authors, data-driven methods can miss relevant factors and there is no guarantee that all relevant factors were identified. Important differences in the measured variables were detected (e.g., age, International Prognostic Index scores, ECOG PS) which can further increase the risk of bias. The effective sample size decreased in substantial numbers in both ITCs, which indicates the amount of information lost due to the matching and adjustment process, which introduces uncertainty and indicates heterogeneity among the original studies. There were also concerns of probable violations of the proportional hazards assumptions for time to event in end points such as OS in ITC-1. Overall, populations with R/R LBCL in the salvage chemotherapy lot had poor outcomes (e.g., OS close to a median of 6 months). Comparing the interventions used in these populations against newer CAR T-cell therapies might imply differences in baseline risks and uncertainty in the generalizability of effect estimates.
An ongoing study (TRANSCEND WORLD) is included as “other relevant evidence” in this report. This is a single-arm, open-label, multi-cohort, multi-centre, phase II clinical trial to test the efficacy and safety of liso-cel in adult patients with DLBCL NOS (de novo or transformed FL), HGBCL with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology and FL3B (European cohort 1, N = | | leukapheresed patients) and patients with DLBCL who are not eligible for transplant (Japanese cohort 3, N = 14 leukapheresed patients). Both cohorts included | | leukapheresed patients, | | who received JCAR017 (liso-cel) or other nonconforming product, and 37 who eventually received the JCAR017 (liso-cel) product. The median age of this cohort was also relatively young (58 years) and only 4 patients had an ECOG PS of 2.
The study met the primary efficacy end point, with an IRC-assessed ORR of ||||| |||||||||||||||||| in the efficacy evaluable set, thereby rejecting the null hypothesis of ORR of 40% or less (1-sided P value = 0.020). In the set of patients treated with liso-cel, the ORR based on IRC assessment was ||||||||||||||||| ||||||. Overall (N = 37), the Kaplan-Meier estimate median PFS was |||||||||||| ||||||||||||||||| The Kaplan-Meier estimate for the median OS was |||||||||||||||||||||||||||||| |||||||| and the median follow-up time was 6.39 (95% CI, 3.09 to 9.33) months. Only 1 of the total 37 patients was admitted to the ICU. The most common treatment-emergent AEs were neutropenia |||||||, anemia |||||||, and pyrexia |||||||. The most frequently reported treatment-emergent serious AEs were CRS ||||||| and aphasia ||||||. The deaths ||||||| observed in the enrolled set of patients | |||| were primarily due to progression of disease |||||||. The most frequent notable harms, known to be associated with CAR T-cell therapies, were CRS |||||||, prolonged cytopenia |||||||, investigator-identified neurologic toxicity |||||||, and hypogammaglobulinemia |||||||.
Limitations are in line with the TRANSCEND study and include a lack of control group that makes it challenging to make conclusions about efficacy and safety. Other methodological limitations are the small sample size and short follow-up period. An open-label design may also introduce bias in interpreting results. The study population included 1 patient with an ECOG PS score of 2, and none of the patients had CNS lymphoma at the beginning of the study. Patients may have developed secondary CNS lymphoma during the trial as noted in the study; however, there were no confirmed cases. This selected population could make it difficult to generalize to patients with more severe burden of disease.
Summary of Economic Evaluation.
CADTH identified the following key limitations with the sponsor’s analysis: the sponsor’s assumed market shares do not consider the differences in approved indications for treatments, refractory LBCL patients were not considered, differences in the pre-treatment assumptions between CAR T-cell products are uncertain, and individual CAR T-cell trial results may not reflect current AE experiences in Canadian practice. CADTH reanalyses included considering refractory patients in those eligible for CAR T cells, assuming all CAR T-cell therapies have pre-treatment inputs equivalent to liso-cel, and adjusting AE probabilities to match newer data sources.
Although the sponsor suggested that liso-cel would be associated with a budget impact of $3,183,747 over the 3-year time horizon, based on the CADTH combined reanalysis, the reimbursement of liso-cel for the indicated population may be associated with a budgetary increase of $655,908 in year 1, $4,014,550 in year 2, and $2,208,224 in year 3, for a total 3-year incremental cost of $6,878,682 when considering the drug plan perspective.
Literature on ethical considerations related to the use of liso-cel for the treatment of R/R LBCL was reviewed. Empirical and normative publications were reviewed for ethical content, using methods of qualitative description to highlight ethical considerations and themes. Sixty-one publications met the inclusion criteria and were included in the report; none directly reported on the use of liso-cel for the treatment of R/R LBCL, but instead explored LBCL incidence, treatment and outcomes, clinical trial access, clinical care, barriers to access for CAR T-cell therapies, and resource allocation considerations.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Matthew Cheung; Dr. Winson Cheung, Dr. Michael Crump, Dr. Leela John, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Christopher Longo, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik
Meeting date: April 13, 2022
Regrets: 1 expert committee member did not attend
Conflicts of interest: None
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Indication: For the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma
Sponsor: Celgene Inc., a Bristol Myers Squibb Company
Final recommendation: Reimburse with conditions
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