CADTH Reimbursement Review

Lisocabtagene Maraleucel (Breyanzi)

Sponsor: Celgene Inc., a Bristol Myers Squibb Company

Therapeutic area: Relapsed or refractory large B-cell lymphoma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

NOC = Notice of Compliance.

^aNote that the CADTH Reimbursement Review was conducted before issuance of the Health Canada NOC and the scope was based on the anticipated indication.

Introduction

Lymphomas comprise a complex group of hematological malignancies with varying molecular hallmarks and prognoses. They are overall divided into non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma.¹ 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 men and women, respectively.² The median age at diagnosis for NHL is 66 years.³

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL, comprising 30% to 40% of all cases.¹ Most people are diagnosed when they are in their seventh decade of life. The DLBCL named “not otherwise specified” (NOS) is the most common type of DLBCL, representing 80% to 85% of all cases.^4,5 Other subtypes of DLBCL include primary mediastinal B-cell lymphoma (PMBCL), a rare subtype of DLBCL.^1,5 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 (CR) to standard treatment and overall survival (OS) of 6 months.⁶ People of older age (> 65 years) and those with central nervous system (CNS) involvement and comorbidities have higher possibility of adverse outcomes.⁷ No more than 50% of patients with relapsed or refractory (R/R) large B-cell lymphomas achieve a response to subsequent treatment after a standard second-line salvage regimen, and few are cured.⁸

The objective of this report is to perform a systematic review of the clinical efficacy and safety of lisocabtagene maraleucel (liso-cel) for the treatment of adult patients with R/R large B-cell lymphoma including DLBCL NOS (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, PMBCL, and follicular lymphoma grade 3B (FL3B) after at least 2 prior therapies. Of note, this CADTH Reimbursement Review was conducted before the issuance of the Health Canada Notice of Compliance for liso-cel and the scope was based on this anticipated indication.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

Input was obtained from 1 patient group. Raw patient group input is presented in the Stakeholder Input section. Overall, Lymphoma Canada, a Toronto-based, national Canadian registered charity that empowers the lymphoma community, provided an anonymous survey of patients with large B-cell lymphoma conducted online from June 21 to August 25, 2021. The survey participants (N = 331) were from Canada, US, Europe, and other countries. In this survey, patients highlighted symptoms such as fatigue and lack of energy as the most difficult part of living with lymphoma and how the treatments they receive impact on their QoL, such as hair loss, fatigue, nausea, vomiting, and fear of relapse or progression. Even though the access to the current lymphoma treatments was not a major concern, the patients surveyed were worried about not being able to get chimeric antigen receptor (CAR) T-cell therapies on time and/or high costs that would be incurred due to limited regional availability of CAR T-cell therapies. In addition, the majority of patients desired to have new treatments that improve QoL and extend remission and survival. None of the patients surveyed had direct experience with liso-cel therapy. To supplement this information, another survey was conducted from April 18 to June 15, 2018, which collected feedback from patients who underwent other CAR T-cell therapies through clinical trials. Out of 7 patients who had experiences with the CAR T-cell therapies, 5 responded to questionnaires asking about CAR T-cell therapy’s impact on QoL. These patients rated less than 3 (1 = no negative impact on my life; 5 = significant negative impact on my life) for all aspects of CAR T-cell therapy,(i.e., number of clinic visits, travel to treatment centre, CAR T-cell infusion, short-term side effects, activity level, treatment-related fatigue, lasting side effects, and leukapheresis). When asked about recommending CAR T-cell therapy to other eligible patients, 5 out of 7 patients said they would recommend, 1 said not to recommend, and 1 remained unsure. Lastly, the patients expressed that having a choice in treatment options is paramount.

Clinician Input

Input From Clinical Experts Consulted by CADTH

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 that can be used in a broader population of patients with lymphoma. Suboptimal availability of commercially available CAR T-cell products in some provinces generates the need to refer patients outside of the province or country for commercial CAR T-cell therapies. Other innovative therapies (e.g., polatuzumab vedotin) may not be widely available, or are likely 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 profile in terms of decreased toxicity, as suggested by the evidence from the TRANSCEND study, although others mentioned how newer therapies may benefit from prior clinical experience with similar therapies. Liso-cel would still be used as a third-line 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.

Clinical experts suggested that patients most likely to benefit from liso-cel have similar characteristics to those included in the TRANSCEND study (e.g., Eastern Cooperative Oncology Group Performance Status [ECOG PS] of 0 or 1, low lactate dehydrogenase [LDH]), 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 (auto-SCT) and then relapsed or those who are not eligible for a transplant are likely to be favoured for liso-cel administration. The clinical experts mentioned that patients who would not be suitable for treatment with liso-cel would be those not meeting established criteria (i.e., eligibility criteria from the TRANSCEND study) 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 therapy was not discussed as it is a treatment administered as a single dose (although re-treatment may be possible). 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, and so on).

CAR T-cell treatment is primarily performed in Canada at transplant centres. 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-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.

Clinician Group Input

The collection of clinician group responses was coordinated by Lymphoma Canada. The clinician group stated that addition of liso-cel to the current third-line therapies or beyond is important for the following reasons: 1) as a curative therapy, liso-cel is expected to improve remission, (e.g., CRs and partial responses [PRs], and prolong survival, (e.g., overall and progression-free survival [PFS], of the eligible patients); 2) availability of liso-cel would prevent unnecessary delay in treatment caused by short supply of the existing CAR T-cell therapies; 3) liso-cel has demonstrated fewer frequent adverse effects [AEs], (i.e., cytokine release syndrome [CRS] and neurotoxicity [NT], compared to axicabtagene ciloleucel (axi-cel) without compromising efficacy (note: no head-to-head trial is available.); 4) liso-cel can be safely administered in an outpatient setting similarly to tisagenlecleucel (tisa-cel).

Other input was provided by the Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee. The committee indicated that liso-cel would fulfill the unmet needs of indications that are not covered by the other CAR T-cell therapies such as 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.

Drug Program Input

The drug programs identified relevant implementation issues to be addressed through CADTH’s reimbursement review processes.

In terms of considerations for initiation of therapy, the drug program inquired if patient eligibility criteria would overlap with existing commercial CAR T-cell therapy eligibility criteria (e.g., tisa-cel and axi-cel). The clinical experts consulted by CADTH mentioned that overlap exists with axi-cel but not with tisa-cel as it does not include criteria for PMBCL.

The drug program detected that liso-cel was also evaluated in patients with DLBCL transformed from indolent lymphomas. The clinical experts considered that these patients would also need at least 2 lines of systemic therapy from the time of diagnosis of a transformation to be considered as failed treatment. Potential exceptions may include individuals with follicular lymphoma for which they already have received treatment (e.g., with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; gemcitabine, dexamethasone, and cisplatin, and auto-SCT) but then transforms to DLBCL/HGBL. For these cases, clinicians may want to move directly to offer CAR T-cell therapies since other options are limited. Clinical experts suggest criteria could stipulate the minimum types of therapy required in these situations.

The clinical experts believed that there were sufficient data to recommend liso-cel in patients older than 75 years, with FL3B, ECOG PS lower than 2, and with CNS involvement. More data are desirable, but all of the above have a class effect on CD19. The clinical experts mentioned that patients with comorbidities might be eligible for liso-cel use.

The drug programs also inquired about the use of liso-cel in patients who have already received a CAR T-cell therapy. The clinical experts consulted by CADTH were not aware of any evidence that supported this notion.

Clinical experts suggested that patients with CNS lymphoma (as long as their disease is controlled), should also be eligible to receive liso-cel. As mentioned in the clinical expert input and related to concerns about implementation from the drug programs, the administration of liso-cel would be done preferably in Health Canada and Foundation for the Accreditation of Cellular Therapy-accredited SCT centres (most centres are medium size, some are large). Outpatient therapy is feasible provided such programs have the infrastructure and accreditation.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

One clinical study⁹ is included in this report evaluating the safety and efficacy of liso-cel in patients on the third line or later (3L+) of treatment for R/R DLBCL. The TRANSCEND NHL 001 study (from now on, the TRANSCEND study) is a single-arm, open-label, phase I (seamless design) multi-centre study, conducted in the US. The population included in the study consists of patients with DLBCL NOS (de novo, transformed from FL [tFL], and transformed indolent non-Hodgkin lymphoma [iNHL]), high-grade B-cell lymphoma with myelocytomatosis oncogene (MYC) and B-cell lymphoma gene 2 (BCL2) and/or B-cell lymphoma gene 6 (BCL6) rearrangements, PMBCL, and FL3B 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 auto-SCT, and prior allogeneic (allo)-SCT. Patients with primary CNS involvement and allo-hematopoietic SCT (HSCT) within 90 days of leukapheresis were excluded. The seamless design allowed the study to go from dose-finding (DF) phases (groups of patients) to dose-expansion (DE) and then dose-confirmation groups. The study evaluated 3 levels of dose regimens, dose level 1 at 50 × 10⁶ CAR-positive T cells (2-dose regimen [DL1D] and single-dose regimen [DL1S]); dose level 2 at 100 × 10⁶ CAR-positive T cells, single-dose regimen (DL2S); and dose level 3 at 150 × 10⁶ CAR-positive T cells, single-dose regimen (DL3S); of these, the DL2S 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) and were overall in relatively good health status.

After enrolment, patients went through a leukapheresis to allow for the product (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 (LDC) with fludarabine plus cyclophosphamide followed by 1 or 2 doses of JCAR017 administered IV on day 1. After day 29, patients were followed on this study for safety, disease progression, and survival for 2 years after the last dose of liso-cel. Of 427 screened patients (341 in the DLBCL cohort), 344 went through leukapheresis (the intention-to-treat [ITT] set), of which 50 could not be treated with any product, 25 received 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 primary analysis set (PAS) population consisting of those patients at the DL2S regimen.

Primary end points included AEs and overall response rate (ORR) as assessed by an independent review committee (IRC). Secondary end points included complete response rate (CRR) (as assessed by IRC), duration of response (DOR), PFS, and OS. The ORR was defined as the proportion of patients with a best overall response (BOR) of either CR or PR based on the Lugano 2014 criteria.¹⁰ 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 product availability was 24.0 days (range = 17 days to 51 days).

Efficacy Results

In this specific population with 3L+ DLBCL (i.e., those with DLBCL NOS, HGL or tFL) assigned to the recommended regimen of DL2S (100 × 10⁶ CAR-positive T cells), the ORR in the PAS (primary end point) was 74.4% (95% confidence interval [CI], 66.2 to 81.6) against a null hypothesis of ORR of 40% or less. The CR rate (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 (PP) set showed similar results. The leukapheresed set (ITT population) included patients treated with 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 progressive disease (PD; n = 27). The leukapheresed set had an ORR per IRC of 60.5% (95% CI, 55.1 to 65.7), and a CR rate of 43.6% (95% CI, 38.3 to 49.0). The lower limit of each CI was equal 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 months (95% CI, 4.3 to 7.3). With a median survival follow-up of 18.8 months, the median OS was 14.0 months (95% CI, 11.1 to 21.1). 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 patient (7.1%) were admitted to the intensive care unit (ICU), with a variable duration from 2 to 88 days.

Health-related quality of life (HRQoL) outcomes improved during treatment with liso-cel, although not all HRQoL domains reached statistical significance as compared to a minimal important difference (MID) and were not included in the adjustment for multiplicity.

Harms Results

The most frequently reported treatment-emergent AEs (TEAEs) 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 (SAE; 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 SAE was encephalopathy (occurring in 14 of 269 patients; 5.2%), the most frequent symptom of investigator-identified neurologic toxicity (iiNT). 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%) and grade 3 or higher iiNT in 27 of 269 subjects (10.0%), while no grade 5 CRS or iiNT 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 7 days (range = 1 day to 56 days). Considering all hospitalizations through the end of the study, 33 of 269 patients (12.3%) were admitted to the ICU; the median number of ICU days in those hospitalized was 8 (range = 1 day to 56 days).

A summary of key results is presented in Table 2.

Table 2: Summary of Key Results from Pivotal and Protocol Selected Studies

AE = adverse event; CI = confidence interval; CR = complete response; DL1D = dose level 1, 2 dose; DL1S = dose level 1, single dose; DL2S = dose level 2, single dose; DL3S = dose level 3, single dose; DLBCL = diffuse large B-cell lymphoma; HSCT = hematopoietic stem cell transplant; liso-cel = lisocabtagene maraleucel; max. = maximum; min. = minimum; NA = not applicable; NR = not reached; OS = overall survival; PFS = progression-free survival; PR = partial response; SAE = serious adverse event.

Note: Data cut-off was August 19, 2019.

^aAll the CIs were 2-sided 95% exact Clopper-Pearson.

^bOne-sided P value was calculated based on the null hypothesis ORR of 40% or less.

^cOne-sided P value was calculated based on the null hypothesis CR of 20% or less.

Source: Clinical Study Report for the TRANSCEND Study.⁹

Critical Appraisal

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 an 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 were evaluated only for the PAS population, which can instill uncertainty in the effect estimates for other sets such as the leukapheresed set (ITT) and the DLBCL treated set. An open-label design may also increase uncertainty in patient-reported outcomes (PROs; i.e., HRQoL) introducing bias due to 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 fewer 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 PP analysis, disease histology, and response determined by the investigator were overall supportive of the robustness of results. No subgroup effects were informative since the sample size was small and only in the PAS population.

Issues of generalizability of the results originate from the differences in the population included in the TRANSCEND study, which can be considered relatively young (mean age of 60.1 years in the DLBCL treated set as compared to 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 as ECOG PS = 2). This agreed with input from 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. The impact of these issues on the full implementation of the intervention, however, 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 that 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 time of follow-up for the main analysis on the PAS population (median of 11.5 months in the DLBCL treated set at the cut-off date of August 12, 2019) in the study can include some uncertainty in the effect estimates and in the generalizability of results in long-term outcomes, although further data from the June 19, 2020 and January 4, 2021 cut-off dates with median study follow-up durations of 19.1 and 19.9 months, respectively, ameliorate these issues.

Indirect Comparisons

Description of Studies

Two sponsor-submitted reports with 3 indirect treatment comparisons (ITCs) are included. The first 2 ITCs^11,12 include comparisons evaluating individual patient data (IPD) evidence from a single-arm study (TRANSCEND) to be compared against aggregated data from 2 published sources evaluating tisa-cel and axi-cel, respectively . In these 2 unanchored matching-adjusted indirect comparisons (MAICs; 1 of liso-cel against tisa-cel, and the other against axi-cel), patients from these populations had R/R large B-cell lymphomas and included the lymphoma subtypes that were common among the 3 bodies of evidence, (i.e., DLBCL NOS, HGL, and transformed from follicular lymphoma). The second submitted report¹¹ (ITC-2) includes an ITC as an unanchored MAIC comparing the same IPD from the TRANSCEND study against aggregated data from the SCHOLAR-1¹³ 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 tFL.

Efficacy Results

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 than 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 [NR]) as compared to tisa-cel of 2.8 months (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 months (95% CI, 19.9 to NR) as compared to 11.7 (7.2 to not reached). 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 a MAIC, evaluating OS, CRR, and ORR. In the base-case analysis that accounted for 7 clinical factors to match and weight, the median OS for the TRANSCEND study was 21.1 months (95% CI, 12.1 to NR), with an effective sample size (ESS) of 142 (from an original N = 257); The analysis resulted in a HR of 0.47 (95% CI, 0.37 to 0.60) relative to salvage chemotherapy. Adjusted for 7 clinical factors, the CRR for liso-cel compared with salvage chemotherapy was greater with an OR of 12.89 (95% CI, 8.04 to 20.68; P < 0.001). PFS was not reported in the SCHOLAR-1 study. Unadjusted median OS was 27.3 months (95% CI, 16.8 to NR) for liso-cel (n = 257) and 6.0 months (95% CI, 5.6 to 6.8) for salvage chemotherapy (n = 603). In the base-case analysis that adjusted for 7 clinical factors, the median OS for TRANSCEND was 21.1 months (95% CI, 12.1 to NR), with an ESS of 142 (from an original N = 257); this results in a HR of 0.47 (95% CI, 0.37 to 0.60) relative to salvage chemotherapy. Adjusted for 7 clinical factors, the CRR for liso-cel was 49.2% with an ESS of 142, and when compared with salvage chemotherapy (CRR of 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 showed fewer AEs of special interest (AESI) such as CRS, NT, and neutropenia when compared to axi-cel or tisa-cel. Against tisa-cel, liso-cel had lower odds of CRS (OR = 0.52; 95% CI, 0.31 to 0.87) as well as for prolonged cytopenia (0.43; 95%CI, 0.26 to 0.73), but the rest of the AEs were similar overall. Relative to axi-cel, liso-cel had lower odds of CRS (0.03; 95% CI, 0.01 to 0.07), NT (0.16; 0.08 to 0.32), febrile neutropenia (0.09; 0.03 to 0.28), prolonged thrombocytopenia (0.34; 0.13 to 0.86), infections (0.19; 0.07 to 0.47), and any grade 3 or above level AE (0.04; 0.01 to 0.19). No data on harms were available for the ITC comparing liso-cel against salvage chemotherapy.

Critical Appraisal

Both ITC reports aimed at comparing IPD 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 includes 1 ITC which 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 still have the probability of missing 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 [IPI] scores, ECOG PS) which can further increase the risk of bias. The ESS decreased in substantial numbers in both ITCs, which speaks of the amount of information lost due to the matching and adjustment process which also begets uncertainty and speaks of heterogeneity among 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 large B-cell lymphoma in the salvage chemotherapy 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.

Other Relevant Evidence

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 efficacy and safety of liso-cel in adult patients with DLBCL NOS (de novo or tFL), HGL with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology and FL3B (Europe cohort 1, N = |||||| leukapheresed patients) and patients with DLBCL who are not eligible for transplant (Japan cohort 3, N = 14 leukapheresed patients). Both cohorts included |||||| leukapheresed patients, |||||| who received JCAR017 or a 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.

Efficacy Results

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 “liso-cel-treated set,” the ORR based on IRC assessment was ||||||||||||||||||||||||. Overall (N = 37), the Kaplan–Meier estimate median PFS was |||||||||||||||||||||||||||||||| Kaplan–Meier estimate for the median OS was |||||||||||||||||||||||||||||||||||||||||||||||||||||| and the median follow-up time was 6.39 months (95% CI, 3.09 to 9.33). Only 1 of the total 37 patients was admitted to the ICU.

Harms

The most common TEAEs were neutropenia (||||||), anemia |||||| and pyrexia |||||| The most frequently reported treatment-emergent SAEs were CRS |||||| and aphasia |||||| The deaths |||||| observed in the “enrolled set” |||||| were primarily due to progression of disease |||||| The most frequent notable harms, known to be associated with CAR T-cell therapies, were CRS |||||| prolonged cytopenias |||||| iiNT |||||| 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. In addition, the small sample size and short follow-up period are another methodological limitation. Lastly, an open-label design may introduce a 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 is no confirmed case. This selected population could make it difficult to generalize to patients with more severe burden of disease.

Conclusions

Evidence from a single-arm study (TRANSCEND) suggests that treatment with liso-cel is associated with benefits in outcomes deemed relevant to both patients and clinicians (OS, PFS, ORR, CRR) when compared to typical effects and evolution observed by clinical experts in patients with 3L+ R/R DLBCL not using a CAR T-cell treatment. The evidence also suggests that treatment with liso-cel may have benefits in terms of improving HRQoL and decreased health care utilization. Clinical experts considered that liso-cel safety profile was adequate and may perform better when compared to the 1 observed in clinical practice with other CAR T-cell therapies. Important limitations exist around these effect estimates due to lack of comparative evidence, risk of bias (attrition bias, no blinding), lack of adjustment for multiplicity, and imprecision in the effect estimates. Furthermore, there were concerns about the generalizability of the results due to characteristics of the populations in the TRANSCEND study that suggest a relatively stable and generally healthier population.

Evidence from sponsor-submitted ITCs using IPD from the TRANSCEND study matched and weighted in a MAIC against aggregated data from studies of 2 CAR T-cell therapies (axi-cel and tisa-cel) suggested improvements in ORR, CRR, PFS, and OS compared with tisa-cel, but not against axi-cel. Similarly, evidence from a second sponsor-submitted ITC using IPD from the TRANSCEND study against aggregated data of patients who underwent salvage therapies (SCHOLAR-1 study) suggests that liso-cel has greater improvements in efficacy and survival outcomes (OS, CRR, ORR) relative to the use of salvage chemotherapies. In all ITCs, liso-cel showed a better safety profile with fewer odds of AEs such as CRS and NT relative to axi-cel, tisa-cel, or salvage chemotherapy. The evidence from the ITCs has considerable limitations due to the observational nature of the included studies, difficulties in estimating all adequate prognostic variables, and possible residual confounding.

Overall, highly uncertain evidence from a single-arm trial and indirect comparative evidence suggest that liso-cel may be more efficacious than salvage chemotherapy and may provide clinical beneficial effects and a safety profile that are similar or better than what is expected of other CAR T-cell therapies.

Introduction

Disease Background

Lymphomas comprise a complex group of hematological malignancies with varying molecular hallmarks and prognoses. They are overall divided into NHL and Hodgkin lymphoma.¹

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 men and women, respectively.² It has been estimated that approximately 36,175 Canadians are living with, or are in remission from, a NHL. An estimated 8,000 new cases of lymphoma were diagnosed in Canada in 2016 and 10,400 estimated for the year 2020.² The median age at diagnosis is 66 years for NHL; however, it can present at any age.³

There are many subtypes of NHL, including B-cell lymphomas. Diagnosis of B-cell lymphomas relies on a comprehensive examination of tumour tissue, best achieved with an excisional biopsy specimen evaluated by an expert hematopathologist. In addition to morphologic characteristics, an accurate lymphoma classification can be achieved with specialized tests, including immunohistochemistry, flow cytometry, fluorescence in situ hybridization, and molecular testing.

DLBCL is the most common type of NHL, comprising 30% to 40% of all cases.¹ Most people with DLBCL are diagnosed when they are in their seventh decade of life. DLBCL is more common in men. DLBCL classified as NOS is the most common type of DLBCL, representing 80% to 85% of all cases.^4,5 Other subtypes of DLBCL include PMBCL, a rare subtype of DLBCL.^1,5 It occurs in the thymus or in lymph nodes in the mediastinum. It represents approximately 10% of all DLBCLs and it is more commonly seen in women in their third to fourth decades of life. DLBCL NOS and PMBCL both have a similar course and a similar treatment.¹ tFL or DLBCL arising from indolent lymphoma are additional DLBCL subtypes, which are all initially slow-growing types of B-cell lymphomas that transform into DLBCL.

Patients with treatment failure after frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (see Standards of Therapy) 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 CR to standard treatment and OS of 6 months.⁶ People of older age (> 65 years) and those with CNS involvement and comorbidities have higher possibility of adverse outcomes.⁷ No more than 50% of patients with R/R large B-cell lymphomas achieve a response to subsequent treatment after a standard second-line salvage regimen, and few are cured.⁸

Standards of Therapy

Treatment goals are directed at curing disease when possible, improving HRQoL with the ability for patients to return to work or daily activities, and prolong survival with the least symptoms, while minimizing adverse treatment effects.

Cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab has been the first-line treatment of DLBCL since the early 2000s. Further treatment of DLBCL that is refractory or relapsing following first-line therapy will depend on patient status in relation to the eligibility for further intensive therapy (i.e., SCT or CAR T-cell therapies). Approximately 40% of patients will be refractory or have relapsed disease and of these, approximately 50% will be eligible for SCT.¹

Patients eligible for SCT can further receive therapy with platinum-based salvage therapy (second line). Salvage therapy regimens may be gemcitabine, dexamethasone, and cisplatin, with or without rituximab, other options include rituximab plus ifosfamide-carboplatin-etoposide, rituximab plus dexamethasone, cisplatin, and cytarabine; and dexamethasone, ifosfamide, cyclophosphamide, etoposide, and procarbazine with existing variation in some regimens based on funding in specific jurisdictions across Canada. Patients with PR or CR to these regimens can enter into high-dose chemotherapy plus SCT. If despite these there is relapse and the patient is eligible for intensive therapy, then CAR T-cell therapy is an option. If the patient is not eligible for intensive therapy, then clinicians and patients can consider palliative care.

From the outset, patients who are not fit for intensive therapy or ineligible for SCT can be considered for salvage chemotherapy as second line.

Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, a component of the B-cell receptor complex, that is currently being used in combination with bendamustine and rituximab for patient’s ineligible for SCT.¹⁴

Eligible CAR-positive T-cell therapies (axi-cel, tisa-cel) are considered as third-line therapy. Some patients who are fit for intensive therapy and eligible for SCT may still be unable to undergo the transplant due to unsuccessful stem cell collection (which occurs in approximately 10% of attempts).

Patients with secondary CNS disease will follow similar pathways, but with the necessary use of CNS active regimens such as “MATRix-RICE” or high-dose methotrexate added to gemcitabine, dexamethasone, and cisplatin plus rituximab; or carboplatin, etoposide, ifosfamide, and Mesna; or dexamethasone, cytarabine, and cisplatin plus rituximab; or multiple doses of intrathecal chemotherapy.¹⁵

Palliative care usually includes gemcitabine, dexamethasone, and cisplatin, or methotrexate, etoposide, cisplatin, or prednisone, chlorambucil, etoposide, or combinations of these.

Drug

Liso-cel (also known as JCAR017) is a patient-specific cell suspension containing a target of 60 × 10⁶ to 120 × 10⁶ CAR-positive viable T cells (consisting of CD4 and CD8 components at a ratio range from 0.8 to 1.2) with each component supplied separately in 4 single-dose vials, for IV infusion. It has a proposed Health Canada indication for the treatment of adult patients with R/R large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL NOS, PMBCL, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Liso-cel targets CD19, a marker expressed on B-cell precursors and malignant B cells present in DLBCL and other lymphomas. When CD19 markers are detected, T-cell activation ensues, and localized secretion of cytokines follows, leading to destruction of targeted cancer cells. Liso-cel consists of purified CD8+ and CD4+ T cells in a defined composition, that have been separately activated and transduced with a replication-incompetent lentiviral vector encoding an anti-CD19 CAR.

CADTH has not reviewed liso-cel for other indications, and the sponsor’s reimbursement request did not differ from the proposed Health Canada indication. The product was granted a Notice of Compliance by Health Canada on May 6, 2022.

In Table 3, characteristics of liso-cel and the other available CAR T-cell therapies are presented.

Table 3: Key Characteristics of Liso-Cel and Main Comparators

ALL = acute lymphoblastic leukemia; axi-cel = axicabtagene ciloleucel; CAR = chimeric antigen receptor; CRS = cytokine release syndrome; DLBCL = diffuse large B-cell lymphoma; liso-cel = lisocabtagene maraleucel; R/R = relapsed or refractory; tisa-cel = tisagenlecleucel.

^aThis is the Health Canada Notice of Compliance approved indication as of May 6, 2022. This CADTH Reimbursement Review was conducted before issuance of the Health Canada Notice of Compliance.

Source: Product monographs of liso-cel,¹⁶ axi-cel,¹⁷ and tisa-cel.¹⁸

Stakeholder Perspectives

Patient Group Input

Input was obtained from 1 patient group. Raw patient group input is presented in the Stakeholder Input section.

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 large B-cell lymphoma conducted online from June 21 to August 25, 2021. The survey participants (total = 331; DLBCL = 126, FL = 191, other LBCLs = 14) were from Canada, US, Europe, and other countries. Past survey data for subgroup of patients with DLBCL (2018 and 2020 surveys), follicular lymphoma (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 sweat (57%), fatigue and lack of energy (54%), and aches and pains (54%) as the top symptoms of lymphoma that impact their quality of life. In addition, anxiety or worry (75%), stress related to the diagnosis (73%), and fear of progression (64%) were cited as the key psychosocial impacts. Diagnosis, symptoms, and mental health effects altogether significantly impacted patients’ daily activities (43%), ability to sleep (41%), concentration (40%), and ability to attend work or school (40%).

Of 230 respondents, 7% of patients 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 patients with DLBCL receiving treatment, the most common side effects (n = 103) were hair loss (87%), fatigue (84%), and cognitive issues (68%), and the most intolerable side effects (n = 85) were fatigue (41%), nausea/vomiting (19%), and “chemo-brain” (15%). For patients with follicular lymphoma receiving treatment, the most common side effects (n = 61) were fatigue (85%), nausea or vomiting (51%), and hair loss (39%), and the most intolerable side effects (n = 49) were fatigue (37%), nausea or vomiting (10%), and pain (10%). Specific psychosocial impacts (n = 49) caused by treatments included fear of progression or relapse (67%), anxiety or 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 or long-term side effects (41%, n = 49), and low activity level (39%, n = 176). In terms of difficulty accessing treatment options, 13% of patients (n = 44) found it very difficult to access. Living in a community without a cancer centre (35%, n = 49) was the most common reason for difficulty accessing treatment. 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). Forty-seven percent of patients (n = 297) responded that they would be willing to tolerate the short-term side effects of a new effective treatment and 47% (n = 297) 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 a direct experience with liso-cel therapy. Out of 7 patients who had experiences with other CAR T-cell therapies through clinical trials, 5 responded to questionnaire asking about CAR T-cell therapy’s impact on quality of life. These patients rated less than 3 (1 = no negative impact on my life; 5 = significant negative impact on my life) for all aspects of CAR T-cell therapy, meaning the 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 out of 7 patients said they would recommend, 1 said they would not recommend, and 1 remained unsure.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist 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 (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). In addition, as part of the liso-cel review, a panel of 4 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations where there are gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with a condition, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this clinical discussion from panel and the clinical experts is presented below.

Unmet Needs

Clinical experts consulted by CADTH agreed that there is an unmet need for drugs that are better tolerated (better safety profiles), that can be used more frequently in the outpatient setting and that can be used in a broader population of patients with lymphoma (i.e., in patients with transformed from iNHL, FL3B, and CNS disease). Suboptimal availability of commercially available CAR T-cell products in some provinces generated the need to refer out of province or out of country for commercial CAR T-cell therapies.

Other therapies (e.g., polatuzumab) may not be widely available, or are costly.

Place in Therapy

According to the clinical experts consulted by CADTH, liso-cel would be used in a similar manner as the other available CAR T-cell therapies, as third-line therapy (in patients who have already tried 2 lines of chemotherapy). However, the clinical experts noted that the proposed indication for liso-cel includes a broader population than the indications for axi-cel and tisa-cel, such as those patients with iNHL (including chronic lymphocytic leukemia) and FL3B. The clinical experts noted that liso-cel would also be considered for use in patients with CNS disease. It was a consensus among clinical experts that patients who have had a previous CAR T-cell therapy would not be recommended to receive liso-cel as the evidence for this strategy is absent.

Patient Population

The clinical experts considered that patients most likely to benefit from liso-cel would be those with similar characteristics of the TRANSCEND study (e.g., ECOG PS of 0 or 1, low LDH), but the data on specific subgroups is still uncertain. Patients who have had an autologous stem-cell transplant (ASCT) and then relapsed or those who are not eligible for a transplant are likely to be favoured for liso-cel administration.

Clinicians mentioned that patients that would not be suitable for treatment with liso-cel would be those not meeting established criteria (i.e., eligibility criteria from TRANSCEND) for CAR T-cell therapy and would be excluded from therapy with liso-cel; however, the information is still uncertain to provide a definitive answer. For this same reason, is difficult to predict which patients would likely exhibit a response to treatment with liso-cel.

Assessing Response to Treatment

Clinicians considered that to determine a response to liso-cel, using commonly known parameters of efficacy and survival will suffice in clinical practice, such as survival with better HRQoL measures.

Overall, improved survival and reduction in the frequency and severity of symptoms, and cure would be good measurements of response throughout follow-up of patients.

When asked about clinically meaningful effects, the clinical experts considered that the hypotheses tested by the investigators in the TRANSCEND study with effect sizes of 25% improvement in survival and progression were deemed meaningful, but any improvement in survival or symptoms is desirable. Some clinicians prefer imaging as it is sometimes considered more objective to assess response to treatment. All these measurements are widely used by clinical experts without significant variations.

Experts preferred assessments of patients every 1 month to 3 months with varying frequency at the beginning of treatments.

Discontinuing Treatment

Discontinuation of CAR T-cell therapies would not be relevant as it is a single dose (although re-treatment is possible). However, some patients might be inherently unstable such that during the process that it may be necessary to discontinue (e.g., ECOG 4, sudden deterioration, opportunistic infections, and so on). This is when patients, after leukapheresis, are no longer able to receive liso-cel.

Prescribing Conditions

Patients and clinicians will need to be in large transplant centres in Canada. Currently, most provinces in Canada have (will have) the necessary expertise. In some areas, however, it cannot be done (e.g., a rural area). Outpatient is possible in well-resourced outpatient programs. According to the experts, Health Canada and Foundation for the Accreditation of Cellular Therapy-accredited SCT centres in Canada are needed (most are medium size, some are large). Outpatient therapy is feasible provided such programs have built the infrastructure to do so. Foundation for the Accreditation of Cellular Therapy accreditation is not uniform in Canada, but the clinical experts expect that the manufacturers may require this as a stipulation for distribution.

Additional Considerations

Experts noted that liso-cel may be associated with fewer toxicities than other CAR T-cell products (although no direct comparison were conducted), with CRS events of equal or greater severity in only 2% and NT in 10% (referring information from the TRANSCEND NHL001 study). For many patients with aggressive B-cell lymphoma, outcomes from currently available treatments are good. However, not all patients respond to currently available treatments. For those who achieve CR, the latter is not always sustained, and patients may relapse. Toxicity of treatments including intensive chemotherapy, SCT, and currently approved CAR T-cell therapies can be substantial. For transplant and even more so, CAR T-cell therapy, patients may need to travel out of province or even out of country to get treatment. Significant health care system resources are needed to safely provide these treatments.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. Raw clinician group input can be found in the Stakeholder Input section.

Two clinician groups provided input on behalf of Lymphoma Canada and Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee. Lymphoma Canada is a national, non-for-profit organization for lymphoma and patients with chronic lymphocytic leukemia. The Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee is a committee that offers timely evidence-based clinical and health system guidance on drug-related matters.

The Lymphoma Canada clinician group stated that addition of liso-cel to the current third-line therapies or beyond is important for the following reasons: 1) as a curative therapy, liso-cel is expected to improve remission (e.g., CR and PRs) and prolong survival (e.g., overall and PFS) of the eligible patients; 2) availability of liso-cel would prevent unnecessary delay in treatment caused by short supply of the existing CAR T-cell therapies; 3) liso-cel has shown less frequent adverse effects (i.e., CRS and NT) compared to axi-cel without compromising efficacy (note: no head-to-head trial is available); 4) liso-cel can be safely administered in an outpatient setting similarly to tisa-cel.

The Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee recognized 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 Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee identified that the limited number of CAR T-cell therapy centres available across Canada could cause access issues for patients.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

allo = allogeneic; auto = autologous; axi-cel = axicabtagene ciloleucel; CAR = chimeric antigen receptor; CLL = chronic lymphocytic leukemia; CNS = central nervous system; CRS = cytokine release syndrome; DHAP = dexamethasone, cytarabine, and cisplatin; DLBCL = diffuse large B-cell lymphoma; ECOG = Eastern Cooperative Oncology Group; FACT = Foundation for the Accreditation of Cellular Therapy; GDP = gemcitabine, dexamethasone, and cisplatin; iNHL = indolent non-Hodgkin lymphoma; liso-cel = lisocabtagene maraleucel; pERC = CADTH pCODR Expert Review Committee; R-CHOP = rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; SLL = small lymphocytic lymphoma; tisa-cel = tisagenlecleucel.

Clinical Evidence

The clinical evidence included in the review of liso-cel is presented in 3 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of liso-cel for the treatment of adult patients with R/R large B-cell lymphoma including DLBCL NOS (including DLBCL arising from indolent lymphoma), HGL, PMBCL, and FL3B after at least 2 prior therapies.

Methods

Studies selected for inclusion in the systematic review include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans. Of note, the systematic review protocol presented below was established before the granting of a Notice of Compliance from Health Canada.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; CAR = chimeric antigen receptor; CRR = complete response rate; CRS = cytokine release syndrome; DHAP = cytarabine, dexamethasone, cisplatin, and etoposide; DLBCL = diffuse large B-cell lymphoma; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; EFS = event-free survival; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L = EuroQol 5-Dimensions 5-Levels questionnaire; FACT-Lym = Functional Assessment of Cancer Therapy–Lymphoma; FL = Follicular lymphoma; FL3B = follicular lymphoma grade 3B; GDP = gemcitabine, dexamethasone, and cisplatin; GemOx = gemcitabine and oxaliplatin; HGBCL = high-grade B-cell lymphoma; HRQoL = health-related quality of life; HSCT = hematopoietic stem cell transplant; ICAN = immune effector cell-associated neurotoxicity syndrome; ICE = carboplatin, etoposide, ifosfamide, and Mesna; MEP = methotrexate, etoposide, cisplatin; OS = overall survival; PEP-C = prednisone, etoposide, procarbazine, cyclophosphamide; PFS = progression-free survival; PMBCL = primary mediastinal large B-cell lymphoma; RCT = randomized controlled trial; SAE = serious adverse event; TTR = time to response; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.¹⁹

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) via Ovid and Embase (1974‒) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Patient Headings), and keywords. The main search concepts were Breyanzi (liso-cel). Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register. No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on September 2, 2021. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee on April 13, 2022. Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool for Searching Health-Related Grey Literature checklist. Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy. These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the sponsor of the drug was contacted for information regarding unpublished studies. Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

Two studies were identified as potentially relevant from other sources and from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 4 with reasons for exclusion.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Study

AE = adverse event; CAR = chimeric antigen receptor; CR = complete response; DLBCL = diffuse large B-cell lymphoma; DLT = dose-limiting toxicity; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L = EuroQol 5-Dimensions 5-Levels questionnaire; FISH = fluorescence in situ hybridization; HRQoL = health-related quality of life; ICU = intensive care unit; LDC = lymphodepleting chemotherapy; liso-cel = lisocabtagene maraleucel; mCRM = modified continual reassessment method; NHL = non-Hodgkin lymphoma; ORR = objective response rate; OS = overall survival; PCR = polymerase chain reaction; PD = progressive disease; p[DLT] = probability of DLT; PFS = progression-free survival; PK = pharmacokinetic; PR = partial response; R/R = relapsed or refractory.

Source: Clinical Study Report for the TRANSCEND study.⁹

Description of Studies

The TRANSCEND study is a phase I (stated as seamless), single-arm, multi-centre, multi-cohort trial conducted in 14 cancer centres in the US. The first patient was enrolled on January 6, 2016, and last data cut-off date available was August 12, 2019. The study will be considered completed when all patients in each cohort have been followed for safety, disease progression, and survival for 2 years after their last dose. The main objective of the study was to evaluate the safety of liso-cel in adult patients with R/R B-cell NHL including DLBCL NOS (de novo and transformed from indolent lymphoma), high-grade B-cell lymphoma (HGL) with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology, PMBCL, FL3B, and mantle cell lymphoma (MCL), as well as the antitumour activity of liso-cel (measured as ORR). The key secondary objectives include assessing the rate of CR and durability of antitumour activity (measured as DOR) of liso-cel and estimate the PFS and OS an HRQoL of patients treated with liso-cel.

The study consisted of 3 main periods: pre-treatment, treatment, post-treatment. A schematic of the treatment plan is depicted in Figure 2.

Figure 2: Study Schematic of TRANSCEND NHL 001

d = day; flu/cy = fludarabine/cyclophosphamide; LTFU = long-term follow-up; mCRM = modified continual reassessment method.

Source: Clinical Study Report TRANSCEND study.⁹

Two cohorts based on disease specifics were evaluated: the DLBCL cohort (patients with DLBCL NOS [de novo or transformed from indolent lymphoma]), HGL, PMBCL, and FL3B having received at least 2 prior therapies; and the MCL cohort, with MCL having received at least 1 prior therapy. Data from the ongoing MCL cohort are not included in this report.

The pre-treatment phase consisted of screening and enrolment of eligible patients who then underwent leukapheresis to enable the product (liso-cel) generation. In addition, disease assessments and other measures were taken. If necessary, bridging therapy, consisting of systemic anticancer therapy for disease control was allowed while the product was being manufactured (i.e., during the period between screening and LDC). In this case, patients were required to have PET-positive disease and meet relevant eligibility criteria before treatment with LDC and liso-cel.

Upon liso-cel product generation, patients entered the treatment phase of the study, which commenced with LDC and ended with the day 29 evaluation. The treatment cycle included LDC with fludarabine and cyclophosphamide followed by 1 (single-dose schedule) or 2 (2-dose schedule) doses of liso-cel administered IV on day 1. Day 1 was defined as the day of first liso-cel administration. In the single-dose schedule, liso-cel was administered 2 to 7 days after completion of LDC. In the 2-dose schedule, patients received the first dose as described above, and a second dose of liso-cel was given 14 days after the first dose of liso-cel (without further LDC between the 2 doses).

The post-treatment follow-up phase consisted, after day 29, of patients who were followed in this study for safety, disease progression, and survival for 2 years after their last dose of liso-cel, including after disease progression and/or the initiation of additional anticancer therapies.

After completion of the final efficacy and safety assessments, long-term follow-up for survival, long-term toxicity, and viral vector safety is to be continued under a separate protocol for up to 15 years post-last dose of liso-cel per FDA guidance on viral vector-based gene therapy products.

As of the data cut-off date of August 19, 2019, 6 amendments to the protocol study were filed and implemented during the conduct of the TRANSCEND study. A summary of the substantive changes made in each amendment is provided in Appendix 4.

Further data from the cut-off dates of June 19, 2020, and January 4, 2021, were also submitted by the sponsor to assess outcomes at later points and were included in this report to address key efficacy end points (ORR, CRR, DOR, PFS, and OS) and harms. However, these later cut-off dates data will be considered supplemental evidence to the main analysis (August 19, 2019) which was based on the PAS population and where the end points were tested and adjusted for multiplicity.

Populations

Inclusion and Exclusion Criteria

As described in Table 6, patients 18 years of age and older with R/R B-cell NHL of the following histologies were included. The DLBCL cohort included DLBCL and NOS, including transformed DLBCL from indolent histology [transformed iNHL]), HGL with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology, PMBCL, and FL3B. These patients must have been treated with an anthracycline and rituximab (or other CD20-targeted agent) and have R/R disease after at least 2 lines of therapy or after auto-HSCT. Exclusion criteria included CNS pathology, cardiovascular conditions, graft-versus-host disease, use of corticosteroids, low-dose chemotherapy, other cytotoxic or lymphotoxic chemotherapy, experimental agents, and use of immunosuppressive agents.

Of note, a PET-positive disease was necessary according to the Lugano Classification¹⁰ and an ECOG PS of 2. An ECOG PS status of 0, 1, or 2 was allowed initially, but it was changed after the Protocol Amendment 5 to include only an ECOG PS status of 0 or 1.

All patients included had to have adequate organ function (i.e., bone marrow, renal, liver, pulmonary, and cardiac). Patients with secondary CNS involvement were allowed, except if it was a CNS-only involvement by malignancy. Patients with other malignancies, uncontrolled systemic infections, and treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis, were not eligible to enter the study.

Baseline Characteristics

Baseline demographic information, disease characteristics, and prior medications of patients included in the TRANSCEND study (DLBCL treated set) are described in Table 7. Since the main study effects of end points were analyzed in the PAS population, the baseline characteristics for this population are presented in Table 8.

In the DLBCL treated set, the study included mostly male patients (65%) with a diagnosis of R/R DLBCL; the total population had a median age of 63 years (range = 18 to 86) and a mean age of 60.1 (standard deviation = 13.35) years, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||; this is a relatively young population below the median age of diagnosis of 65 years of age commonly reported in epidemiology reviews and current clinical guidelines.^1,21 A total of 25 patients were allowed to be treated as outpatients (13 in the DL2S group).

Based on baseline disease characteristics, most patients did not exhibit severe status and had a relatively stable health status, beyond their R/R DLBCL condition. For instance, only 4 patients (3 in the D2LS subpopulation) had an ECOG PS of 2 at baseline, 83.6% had a creatinine clearance (CrCl) pre-LDC greater than 60 mL/min, and 96% had a left ventricular ejection fraction (LVEF) greater than 50%.

DLBCL NOS was the most common histologic type among patients with DLBCL (51%), with 35% of patients having a previous SCT, and a median of 3 previous systemic treatments. Only 4 patients in the DL2S treatment group had CNS involvement, mainly due to the amendment that allowed the eligibility and inclusion of these patients in the study. Of the leukapheresed set of patients (N = 344), 214 (62.2%) received anticancer therapies before LDC (140 in the DL2S group, 61.7%), which included bridging therapies.

Table 7: Summary of Baseline Characteristics, DLBCL Treated Set

ASCT = autologous hematopoietic stem cell transplant; BMI = body mass index; CAR = chimeric antigen receptor; CLL = chronic lymphocytic leukemia; CNS = central nervous system; CrCl = creatinine clearance; DL = dose level; DL1D = dose level 1 (50 × 10⁶ CAR-positive T cells), 2-dose regimen; DL1S = dose level 1 (50 × 10⁶ CAR-positive T cells), single-dose regimen; DL2S = dose level 2 (100 × 10⁶ CAR-positive T cells), single-dose regimen; DL3S = dose level 3 (150 × 10⁶ CAR-positive T cells), single-dose regimen; DLBCL = diffuse large B-cell lymphoma; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FL3B = follicular lymphoma grade 3B; GCB = germinal centre B-like; HGL = high-grade lymphoma; LDC = lymphodepleting chemotherapy; liso-cel = lisocabtagene maraleucel; LVEF = left ventricular ejection fraction; NOS = not otherwise specified; PMBCL = primary mediastinal B-cell lymphoma; SLL = small lymphocytic lymphoma.

^aThe status was chemorefractory if a patient achieved stable disease or progressive disease to last chemotherapy-containing regimen or relapsed less than 12 months after ASCT; otherwise, the status was chemosensitive.

Source: Clinical Study Report for the TRANSCEND study.⁹

Table 8: Summary of Baseline Characteristics, Primary Analysis Set

Note: Redacted rows have been deleted.

Source: Clinical Study Report for the TRANSCEND study.⁹

Interventions

Leukapheresis

For each patient, leukapheresis was performed after meeting eligibility criteria to obtain a sufficient quantity of peripheral blood mononuclear cells for the production of liso-cel. If liso-cel could not be manufactured, patients could have additional leukaphereses performed. Patients were required to continue to meet eligibility requirements for additional leukaphereses, but no repeated PET or electrocardiogram was necessary.

Anticancer Therapies Between Screening and LDC

Anticancer treatment was allowed for disease control while liso-cel was being produced. Low-dose chemotherapy (e.g., vincristine, rituximab, cyclophosphamide ≤ 300 mg/m²) was allowed if completed at least 7 days before the start of LDC. If other agents were used, the washout periods noted in the exclusion criteria must had been met. Pre-treatment PET and CT (CT) assessments and other pre-treatment study procedures were to have been performed after the anticancer treatment was completed. For the purpose of this review, any anticancer therapy received during this period was considered a bridging therapy.

Lymphodepleting Chemotherapy

Eligibility criteria were confirmed before starting LDC. If patients experienced a significant worsening in clinical status compared with that during eligibility screening, they were not treated with liso-cel.

LDC was performed by administering fludarabine (30 mg/m²/day for 3 days) plus cyclophosphamide (300 mg/m²/day for 3 days) before treatment with liso-cel. Dose reductions of either or both agents were allowed at the discretion of the investigator and/or in compliance with approved labels for these products. LDC was completed between 2 and 7 days before the liso-cel administration.

Liso-cel (JCAR017) Product

To establish a recommended regimen for liso-cel, the study design included a DF group or phase, followed by DE and DC groups. The DF and DE portions of this study were designed to evaluate and refine the dose and schedule of liso-cel needed for adequate safety and antitumour activity, to be tested further in the DC group.

Liso-cel dosing started at 50 × 10⁶ CAR T cells single dose (DL1S) and the dose could escalate or de-escalate based on a modified continual reassessment method (mCRM) algorithm that implements a Bayesian methodology to estimate the probabilities of dose-limiting toxicity and informed by the cumulative data from included patients. Clinical experience with 2 other CAR T-cell products (each using the same CAR construct, transgene, and lentiviral vector as liso-cel) informed the starting dose selection of 50 × 10⁶ CAR-positive T cells. Then, dose escalation using the mCRM method to 2 other dose levels (100 × 10⁶ CAR-positive T cells [DL2] and 150 × 10⁶ CAR-positive T cells [DL3]) was performed if safety and efficacy data from the lower doses were acceptable. The enrolling of eligible patients was defined as an open enrolment assignment to the dose regimen best considered for each next patient based on the information obtained from the algorithm. Assignment on the DE group was based on the aforementioned dose-limiting toxicity (DLT) of the liso-cel product and on criteria of the probability of the product to be safe (probability of dose-limiting toxicity) and probability of being efficacious (probability of CR). Dose selection for each patient occurred after leukapheresis (and before LDC) and was dependent on the dosing groups open at the time of assignment (for example, DL1S DE group and DL2S DF group) and other factors such as gating of patients for DLT information collection. Based on cumulative data from the DF and DE phases of the study, a recommended regimen for the DLBCL cohort was selected as a DC group or portion of the flow of the study (i.e., the DL2S regimen, see Figure 3).

Figure 3: Redacted

This figure has been redacted.

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Initially, patients could be assigned to receive either 1 or 2 doses of liso-cel per treatment cycle. In the single-dose schedule, liso-cel was given 2 to 7 days after completion of LDC. In the 2-dose schedule, liso-cel was given on day 1 (2 to 7 days after completion of LDC), and again 14 days later. The allocation to a 1-dose or 2-dose schedule was also based on the mCRM algorithm during the DF process. LDC was not given before the second dose of liso-cel in the 2-dose schedule.

Patients were premedicated with 650 mg acetaminophen orally and 25 mg to 50 mg diphenhydramine hydrochloride or equivalent antihistamine (orally or IV) 30 to 60 minutes before liso-cel administration. Liso-cel was administered as separate IV infusions that consisted of CD8+ CAR c and CD4+ CAR-positive T cells. The CD8+ drug product component was administered first, followed by the CD4+ drug product component; this order was set by the sponsor based on the concept that CD8+ cells play a greater role in tumour killing than the CD4+ cells. The product had to be administered within 2 hours of removing it from the shipping container. Monitoring of all patients was required after IV administration. Liso-cel could had been delivered in an outpatient setting at the investigator’s discretion.

Nonconforming Product

The sponsor defines a product that does not meet the specification criteria for certain non-safety attributes as a “nonconforming product.” This was identified as “any product wherein a component did not meet a release specification limit.” Nonconforming product could be administered under certain conditions (e.g., that there were not issues about safety). Patients receiving nonconforming product were analyzed separately.

Additional Cycles or Re-treatment

Re-treatment cycles with liso-cel were allowed but only under 3 pre-specified situations:

• 2-dose schedule: This was a protocol-defined schedule into which a patients may have been assigned at study enrolment to receive 2 doses of liso-cel approximately 14 days apart as their treatment cycle.

• Re-treatment cycles: Subsequent liso-cel cycles may have been administered to a patient only if PD occurred following CR to liso-cel.

• Additional cycles: Additional liso-cel cycles may have been administered to a patient only if stable disease (SD) or PR was their BOR after the initial response assessment. (Note: this option for additional cycles was removed in Amendment 6.)

“Dose” refers to infusion of liso-cel product, while the word “cycle” refers to repeating the complete LDC, liso-cel product infusion.

Outcomes

The objective of the TRANSCEND study was to evaluate the safety of liso-cel in patients with R/R large B-cell lymphomas as well as the antitumour activity based on the ORR (CR + PR). Key secondary objectives were the assessment of rate of CR and durability of antitumour activity of liso-cel (CR rate and DOR, defined as the time from first response to PD or death); to estimate the PFS and OS (PFS, OS); estimate the pharmacokinetic (PK) profile, and HRQoL and health economics (ICU and non-ICU inpatient days). Exploratory end points included antitumour activity using Bayesian methods, pharmacodynamic effects, and the effect of tumour and tumour microenvironment on liso-cel.

A list of efficacy end points identified in the CADTH review protocol that were assessed in the pivotal clinical trial included in this review is provided in Table 9. These end points are further summarized below. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 3.

Table 9: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L = EuroQol 5-Dimensions 5-Levels questionnaire; FACT-Lym = Functional Assessment of Cancer Therapy–Lymphoma; HRQoL = health-related quality of life.

^aOverall response rate was changed from a secondary to a primary end point in amendment 3 of the protocol and it is defined as complete response plus partial response.

^bThis measurement tool was identified in the CADTH protocol for this review, but it was not assessed in the pivotal trial.

The ORR was defined as the proportion of patients with BOR of either CR or PR based on the Lugano 2014 criteria.¹⁰ The BOR is the BOR recorded from the time of the final liso-cel infusion (i.e., the first dose of the 1-dose schedule and the second dose for 2-dose schedule) until disease progression, end of study, or the start of another anticancer therapy or HSCT. Best response was assigned according to the following order: CR, PR, SD, PD, not evaluable, or not done. The ORR was included as a primary end point (IRC review based) and as determined at the end of each treatment cycle and approximately 3, 6, 9, 12, 18, and 24 months following the last dose of liso-cel. Radiographic disease assessments by PET and/or diagnostic quality CT scans (chest, neck, abdomen, and pelvis) were performed pre-treatment, after any anticancer therapy for disease control (if applicable), at the end of the treatment cycle, and approximately 3, 6, 9, 12, 18, and 24 months following the last dose of liso-cel or until disease progression or treatment with additional anticancer therapy.

The CR rate was defined as the proportion of patients with a BOR of CR by IRC assessment based on the Lugano 2014 criteria, while the DOR was defined as the interval from the first documentation of CR or PR to the earlier date of disease progression or death. The first documentation of CR or PR was defined as the latest of all dates of required measurements to establish the response. DOR was evaluated based on the IRC evaluations for patients who achieved a CR or PR based on the Lugano 2014 criteria.¹⁰

The PFS was defined as the time from the date of the first JCAR017 infusion to the earlier date of disease progression or death due to any cause. The progression date was defined as the earliest date of all assessments that led to a progression. The date of progression was provided by the IRC for PFS analysis.

OS was defined as the interval from the date of the first JCAR017 infusion to the date of death due to any reason. The OS analysis included all available survival information with long-term follow-up data. Data from surviving patients were censored at the last time that the patient was known to be alive.

HRQoL changes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) questionnaire. EORTC QLQ-C30 is 1 of the most commonly used PRO measures in oncology clinical trials.²² It is a multi-dimensional, cancer-specific, evaluative measure of HRQoL. It consists of 30 questions that are scored to create 5 multi-item functional scales, 3 multi-item symptom scales, 6 single-item symptom scales, and a 2-item quality of life (QoL) scale, and uses a 1-week recall period in assessing function and symptoms. Most questions have 4 response options (“not at all,” “a little,” “quite a bit,” “very much”), with scores on these items ranging from 1 to 4. For the 2 items of the global QoL scale, however, the response format is a 7-point Likert-type scale, with anchors between 1 (very poor) and 7 (excellent). All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denotes a better level of functioning (i.e., a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e., a worse state of the patient). Each raw scale score is converted to a standardized score that ranges from 0 to 100 using a linear transformation, with a higher score reflecting better function on the function scales, higher symptoms on the symptom scales, and better QoL (i.e., higher scores simply reflect higher levels of response on that scale). MIDs for improvement in the global QoL scale range from 5 to 8 in the global scale, while a decrease of –10 to –5 is used as MID for deterioration.

The EQ-5D-5L is a generic, preference-based measure of health outcomes. This instrument is applicable to a wide range of health conditions and treatments and provides a simple descriptive profile or health state and a single value for health status. The EQ-5D-5L is a self-administered instrument comprising of the EQ-5D-5L index scale and a visual analogue scale. The EuroQol Visual Analogue Scale (EQ VAS) records the respondent’s self-rated health status on a vertical graduated scale and assesses current health status, ranging from 0 to 100, with 0 representing the “worst imaginable health state” and 100 representing the “best imaginable health state.” The EQ-5D-5L index scale is scored on the UK value set scale, with a score of 0 indicating “death,” 1.00 indicating “full health,” and negative scores reflecting states perceived to be “worse than death.” No specific MID for patients with myeloma has been estimated.

The health economics and outcomes research end point was hospital resource utilization, including numbers of ICU inpatient days and non-ICU inpatient days and reasons for hospitalization.

Statistical Analysis

Since the TRANSCEND study is referred as a phase I study, 1 of the primary end points of the study was stated as the type, frequency, and severity of AEs and laboratory abnormalities and all AEs are listed and summarized in the Harms section.

The study investigators estimated that the ORR and CR rates in patients with large aggressive B-cell lymphomas who have received at least 2 prior therapies was 12% to 46% and 6% to 38%, respectively, and median PFS and OS results are also poor, less than 6 months and less than 12 months, respectively. Based on a meta-analysis data from 8 published studies²³ of recommended regimens for patients with R/R aggressive large B-cell NHL, the estimated ORR was 30% (95% CI, 24 to 38) and CR is 19% (95% CI, 13 to 26). For the primary analysis in the TRANSCEND study, the efficacy end point of ORR was based on the null hypothesis of an of ORR 40% or less and an alternative hypothesis of ORR of greater than 40% with the effect size of 25% (ORR = 65%).

The analysis for ORR was conducted on the PAS based on the IRC assessments. The ORR was calculated along with the 2-sided 95% exact Clopper-Pearson CIs.

The study tested the hypothesis of a CR rate of greater than 20% against the null hypothesis of a CR rate of 20% or less, at a 1-sided 2.5% level of significance for the primary analysis of the study.

The analysis of CR rate was conducted similarly to the analysis of the primary efficacy end point.

DOR was defined as the interval from the first documentation of CR or PR to the earlier date of disease progression or death. The first documentation of CR or PR was defined as the latest of all dates of required measurements to establish the response. In the case that a patient did not have disease progression or death before the data cut-off date, DOR was censored at the date of the last adequate disease assessment on or before the earliest censoring event.

The censoring reason could have been:

• ongoing

• completed the study

• discontinued the study

• received re-treatment

• received a new anticancer therapy

• proceeded to HSCT

• experienced an event after missing at least 2 consecutive scheduled disease assessments.

The Kaplan–Meier method was used to estimate the median DOR along with the 95% CI. The estimated percentage of patients with response duration of 6, 12, 18, and 24 months or greater was also presented with 95% CIs using the Kaplan–Meier method. Sensitivity analyses were performed (1) without censoring HSCT and (2) in alignment with the European Medicines Agency guidelines, without censoring new anticancer therapy, HSCT, and missing at least 2 consecutive scheduled disease assessments.

PFS was defined as the time from the date of the first JCAR017 infusion to the earlier date of disease progression or death due to any cause. The progression date was defined as the earliest date of all assessments that led to a progression. If a patient did not experience disease progression or death before the data cut-off date, PFS was censored at the date of the last adequate disease assessment on or before the earliest censoring event.

The censoring reasons were the same as with DOR.

The Kaplan–Meier method was used to estimate the PFS rate at months 6, 12, 18, and 24, and the median PFS along with the 95% CI.

Sensitivity analyses were performed (1) without censoring HSCT and (2) in alignment with European Medicines Agency guidelines, without censoring new anticancer therapy, HSCT, and missing at least 2 consecutive scheduled disease assessments. These sensitivity analyses were performed using the investigators’ assessment of disease response.

OS was defined as the interval from the date of the first JCAR017 infusion to the date of death due to any reason. The OS analysis included all available survival information with long-term follow-up data. Data from surviving patients were censored at the last time that the patient was known to be alive. The Kaplan–Meier method was used to estimate the OS rate at months 6, 12, 18, and 24, and the median OS along with the 95% CI.

All PRO/HRQoL analyses were performed on the PRO (EORTC QLQ-C30 or EQ-5D-5L) evaluable population. For continuous variables, descriptive statistics (n, mean, standard deviation, minimum, 25th percentile, median, 75th percentile, and maximum) for baseline, raw score at specified visits, and change from baseline were provided. Categorical variables were summarized with frequency tabulations (counts and percentages). For time-to-event analyses, the Kaplan–Meier method, including Kaplan–Meier plot were used to estimate the survival distribution with the median and its 2-sided 95% CI. Cumulative distribution frequency plots were generated for post-baseline assessment points.

The ICU inpatient days, non-ICU inpatient days, and reasons for hospitalization were assessed using descriptive statistics for patients in the JCAR017-treated analysis set . The number and percent of outpatient patients who were treated with JCAR017 cell product and who were admitted post-JCAR017 infusion were also summarized.

Sensitivity analyses of primary and secondary efficacy end points, including ORR, CR rate, ORR for chemorefractory patients, CR rate for chemorefractory patients, DOR, PFS, and OS, were performed based on the:

• leukapheresed set (ITT set)

• PP analysis set and/or PP DLBCL analysis set

• disease histology determined by central pathology review

• response determined by investigator

A patient in the leukapheresed set who did not receive cell product was considered not evaluable (i.e., a nonresponder) for the sensitivity analysis of ORR and CR rate. The analysis method was the same as previously described for the corresponding end points.

Missing data were not imputed. Further detail was not provided for how missing data were handled for specific end points. However, based on reported results, it seems likely patients with missing data were treated as non-responders with exception of the time-to-event end points where such patients were censored.

Subgroup Analysis

In the PAS and treated efficacy analysis set, efficacy subgroup analyses were performed on the following variables:

• age: (1) younger than 40, 40 or older to younger than 65, and 65 years or older; (2) younger than 65 versus 65 years or older; (3) younger than 75 versus 75 years or older at the time of the first JCAR017 infusion

• sex: male versus female

• ethnicity: Hispanic or Latino versus not Hispanic or Latino

• race: White versus other races

• prior HSCT status: yes versus no

• prior response status: refractory versus relapsed to last prior therapy; the status was refractory if a patient achieved less than a CR to last prior therapy, otherwise the status was relapsed

• prior chemo-response status: chemorefractory versus chemosensitive to last prior chemotherapy-containing therapy; the status was chemorefractory if a patient achieved SD or PD to last chemotherapy-containing regimen or relapsed less than 12 months after auto-HSCT, otherwise the status was chemosensitive

• CNS disease status: known CNS disease versus no known CNS disease at the time of the first JCAR017 infusion

• cell of origin: germinal centre B-like versus non-germinal centre B-like.

Subgroup analyses and forest plots were performed for the primary efficacy end point and secondary efficacy end points, including ORR, CR rate, DOR, PFS, and OS. Some grouping of classes was considered if there were too few patients in some subgroups. Other subgroup analyses were also performed if deemed appropriate.

Power and Sample Size

As described in the statistical methods above, the study investigators estimated that the ORR and CR rates in patients who had received at least 2 prior therapies was 12% to 46% and 6% to 38%, respectively, and median PFS and OS results were also poor, at less than 6 months and less than 12 months, respectively. Based on a meta-analysis of data from 8 published studies²³ of recommended regimens, the estimated ORR was 30% (95% CI, 24 to 38) and CR was 19% (95% CI, 13 to 26). For the primary analysis in the TRANSCEND study, for the efficacy end point of ORR, based on the null hypothesis of an ORR of 40% or less with the effect size of 25% (ORR = 65%), a sample size of 75 patients in the PAS will provide approximately 98% power to demonstrate statistical significance at a 1-sided significance level of 0.021 based on an exact test. For the efficacy end point of CR rate, based on the null hypothesis of a CR rate of 20% or less and an alternative hypothesis of CR rate of greater than 20% with the effect size of 20% (CR rate = 40%), 75 patients in the PAS will provide approximately 96% power to demonstrate statistical significance at a 1-sided significance level of 0.021 based on an exact test.

Across protocol amendments, the study sample size was increased as deemed appropriate by the sponsor. The number of patients allocated to each DF group depended on the Bayesian assessment of safety and efficacy. It was anticipated that at least 274 patients would be enrolled in the study. The maximum planned sample size for the DF phase was 114 patients; the planned sample size for DL1 and/or DL-1 was 60 patients across the 2 disease cohorts with a maximum of 35 patients within each disease cohort. The planned sample size for DL2 was 30 patients across the 2 disease cohorts with a maximum of 20 patients within each disease cohort. For DL3, the planned sample size was 24 patients across the 2 disease cohorts with a maximum of 12 patients within each disease cohort, and for a DC group the planned sample size was at least 100 patients to ensure at least 75 patients in the PAS. The number of patients allocated to each DF group depended on the Bayesian assessment of safety and efficacy.

Multiple Comparisons or Multiplicity

Adjustment of multiple comparisons was designed to preserve the overall type I error rate at 0.025 for both the preplanned interim and primary analysis. However, since the planned interim analysis was ultimately not conducted, the full alpha was preserved for the primary analysis. Thus, for the primary analysis, 4 hypothesis tests were performed in the following sequential order at a 1-sided significance level of 0.025:

1. Null hypothesis that ORR was 40% or less against alternative hypothesis that ORR was greater than 40%

2. Null hypothesis that CR rate was 20% or less against alternative hypothesis that CR rate was greater than 20%

3. Null hypothesis that ORR was 30% or less against alternative hypothesis that ORR was greater than 30% for chemorefractory patients

4. Null hypothesis that CR rate was 10% or less against alternative hypothesis that CR rate was greater than 10% for chemorefractory patients

Analysis Populations

Patients were enrolled into 1 of 2 disease-specific cohorts in the study, as follows:

• DLBCL cohort, including patients with the following histologies: DLBCL NOS (de novo or transformed from indolent lymphoma), HGL, PMBCL, and FL3B failing at least 2 prior lines of therapy

• MCL cohort, including patients with MCL failing at least 1 prior line of therapy; this cohort is not described in this CADTH report

Within the DLBCL and MCL cohorts, patients were enrolled into DF, DE, or DC groups after leukapheresis depending on the study status.

For the statistical analyses, within each cohort, patients were categorized into analysis sets. The definitions of each set and distribution during the study are represented in Figure 4.

ITT Analysis Set (Leukapheresed)

The ITT (leukapheresed) set included all patients who had signed informed consent, who met all inclusion and exclusion criteria, and who underwent leukapheresis. In the case of protocol deviations where patients underwent leukapheresis without having met all inclusion and exclusion criteria, the patients were still included in the leukapheresed set.

Liso-cel Treated Set

The liso-cel-treated analysis set included all patients who received at least 1 dose of liso-cel. In the case where a patient received multiple liso-cel doses, the first dose of liso-cel should have been the conforming product, which met specifications at the time of product release. In the Clinical Study Report, the DLBCL cohort liso-cel-treated analysis set is referred as the “DLBCL treated set.”

Safety end points were analyzed in this liso-cel-treated set.

Liso-cel-Treated Efficacy-Evaluable Set

The liso-cel-treated efficacy-evaluable analysis set is a subset of the treated set and included all patients who had PET-positive disease present before liso-cel administration based on the IRC assessment. Patients who did not have a baseline PET or CT assessment repeated after bridging therapy (when bridging therapy was indicated) and before liso-cel administration were excluded from the liso-cel-treated evaluable set. In the sponsor’s Clinical Study Report, this set is referred as the DLBCL efficacy set.

Primary Analysis Set

The PAS was a subset of the liso-cel-treated efficacy-evaluable set that focused on patients who were treated at dose level 2. This set included patients in the DF, DE, and DC groups who failed at least 2 therapies in the DLBCL cohort treated at 1 recommended regimen (determined to be DL2S). The PAS was used for the primary efficacy analysis.

This set excluded patients with an ECOG PS of 2 before LDC, prior allo-HSCT, PMBCL, FL3B, or transformation from indolent lymphoma other than follicular lymphoma; these patients were analyzed separately. Patients in the PAS must have had PET-positive disease present before liso-cel administration based on IRC assessment. Those who did not have a baseline PET or CT assessment repeated after anticancer therapy for disease control and before liso-cel administration were excluded from the PAS.

DLT-Evaluable Analysis Set

The DLT-evaluable analysis set included all patients in the DF and DE groups who received liso-cel, and who either experienced a DLT or were followed for the full DLT-evaluation period. This analysis set was used for DF purposes.

Figure 4: Sankey Diagram of the Analysis Sets Defined in the TRANSCEND Study

DLBCL = diffuse large B-cell lymphoma; ITT = intention to treat; liso-cel = lisocabtagene maraleucel; MCL = mantle cell lymphoma.

^a Three patients were excluded because they could not be leukapheresed, plus 6 originally screen failure patients who were leukapheresed and entered the leukapheresed set.

^b The leukapheresed or intention-to-treat analysis set included all patients who underwent leukapheresis. Bridging therapy could be offered between this phase and the administration of liso-cel or nonconforming product.

^c Only received liso-cel, but not the nonconforming product. Harms (safety) end points were analyzed in this set.

^d The DLBCL efficacy set (or liso-cel-treated efficacy-evaluable set) included all patients in the liso-cel-treated set who had confirmed PET-positive disease before liso-cel administration based on independent review committee assessment.

^e A subset of the DLBCL efficacy set. This set focused on patients who were treated at dose level 2.

Source: Adapted from data from Clinical Study Report for the TRANSCEND study.⁹

Results

Patient Disposition

The TRANSCEND study screened a total of 427 patients, of which 61 failed the eligibility criteria as shown in Figure 5 and Table 10. The study was then divided in the MCL (n = 24) and DLBCL (n = 341) cohorts, of which the latter is the main focus of this report.

A total of 344 patients underwent leukapheresis and were considered in the enrolled (ITT) population, or leukapheresed set (a net gain of 3 patients from the screened cohort due to 6 screen failures that were leukapheresed). A majority of patients (294 [85.4%]) who were leukapheresed received an infusion with either the liso-cel or a nonconforming product.

Of the 344 patients in the DLBCL cohort who underwent leukapheresis, 25 patients received nonconforming product and were not included in the DLBCL cohort liso-cel-treated analysis set. Additionally, 50 patients in the DLBCL cohort did not receive treatment with liso-cel. The reasons, per investigator assessment, that patients did not receive treatment after leukapheresis were death (n = 33), PD (n = 27), unknown reasons (n = 3), bowel perforation (n = 1), cardiogenic shock (n = 1), and AE (n = 1; sepsis considered related to protocol-mandated procedures). Six others had disease-related complications, 3 no longer met eligibility criteria, and 2 withdrew consent. In 2 patients, the product could not be manufactured.

At the time of the data cut-off date, out of the 269 patients in the DLBCL cohort liso-cel-treated analysis set who received treatment with liso-cel, 35 had completed the study, 103 were still on study in the post-treatment follow-up portion of the study, and |||||| had discontinued. Twenty-one of the 35 patients who completed the study had consented to the long-term follow-up study to be followed for up to 15 years after liso-cel treatment. Among the |||||| patients who discontinued, the most common reason for discontinuation was death (||||||||||||)

Figure 5: Redacted

This figure has been redacted.

Source: Clinical Study Report for the TRANSCEND study.⁹

At the cut-off date of August 12, 2019, patients were followed up for a median of 11.5 months in the total DLBCL treated set population (n = 269) and |||||| months in the DL2S subgroup (n = 177). A total of 199 patients (74.0%) had 6 months or more of follow-up, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Table 10: Patient Disposition, TRANSCEND Study

DLBCL = diffuse large B-cell lymphoma; ITT = intention to treat; liso-cel = lisocabtagene maraleucel; MCL = mantle cell lymphoma.

Note: Values are expressed as n (%).

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

^bStated as “Disease-related complications.”

^cReceived either liso-cel or nonconforming product.

^dReceived only liso-cel but not the nonconforming product.

^eThis is the Primary Analysis Set population in which the primary efficacy end points were analyzed.

^fThis is the leukapheresed analysis set.

^gAnalyzed in the liso-cel-treated analysis set.

Source: Clinical Study Report for the TRANSCEND study.⁹

The DF and DE portions of this study were designed to evaluate and refine the dose and schedule of liso-cel needed for adequate safety and antitumour activity, to be tested further in the DC group. Dosing started at DL1S (single dose of 50 × 10⁶ CAR-positive T cells), then proceeded to 2 doses of 50 × 10⁶ CAR-positive T cells given 14 days apart (DL1D), a single dose of 100 × 10⁶ CAR-positive T cells (DL2S), and eventually a single dose of 150 × 10⁶ CAR-positive T cells (DL3S). Dose escalation or de-escalation in this study was guided by a mCRM that implemented Bayesian methodology to estimate the probabilities of DLT and CR. With each patient’s information, the dose–toxicity and dose–response model was updated, and new probability of DLT and probability of CR were estimated.

The number and distribution of patients by dose levels are presented in Table 11.

Table 11: Analysis Populations by Dose Level, DLBCL Cohort

DE = dose expansion; DF = dose finding; DL1D = dose level 1, 2 dose; DL1S = dose level 1, single dose; DL2S = dose level 2, single dose; DL3S = dose level 3, single dose; DLBCL = diffuse large B-cell lymphoma; DLT = dose-limiting toxicity; ITT = intention to treat; liso-cel = lisocabtagene maraleucel; mCRM = modified continual reassessment method; NR = not reported; PAS = Primary Analysis Set; PRO = patient-reported outcomes; QLQ-C30 = Quality of Life Questionnaire Core 30; QoL = quality of life.

Note: The denominator is the number of patients in the leukapheresed set. Data cut-off date: August 12, 2019.

^aMore patients are included in the leukapheresed set than the eligible set due to patients having enrolled in the study although they did not meet eligibility criteria. In some cases, the patients were allowed on study after discussion with the sponsor and in other cases the deviations were identified retrospectively.

^bThe PAS was the population used for the primary end point analyses.

^cOnly used for mCRM calculations in the DF and DE groups.

Source: Clinical Study Report for the TRANSCEND study.⁹

Exposure to Study Treatments

Lymphodepleting Chemotherapy

After leukapheresis, it was possible to obtain from 294 patients either the liso-cel (JCAR017) or nonconforming product, defined by the sponsor as “any product wherein a component did not meet a release specification limit.” Of these patients, 25 (9%) patients received a nonconforming product (described in the interventions section and Figure 4).

LDC was completed between 2 days to 7 days before liso-cel administration. LDC consisted of fludarabine 30 mg/m²/day for 3 days plus cyclophosphamide 300 mg/m²/day for 3 days. All 269 patients from the DLBCL treated dataset completed LDC before cycle 1 of liso-cel. The median time from last dose of LDC to JCAR017 treatment was 4 days (range = 3 days to 9 days). Of note, 4 patients received LDC but did not receive JCAR017. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Liso-cel Product

The dose regimens assigned in the TRANSCEND study were:

• DL1S: 50 × 10⁶ CAR-positive T cells (25 × 10⁶ CD8+ CAR-positive T cells and 25 × 10⁶ CD4+ CAR-positive T cells), single-dose regimen

• DL1D: 50 × 10⁶ CAR-positive T cells, 2-dose regimen

• DL2S: 100 × 10⁶ CAR-positive T cells (50 × 10⁶ CD8+ CAR-positive T cells and 50 × 10⁶ CD4+ CAR-positive T cells), single-dose regimen

• DL3S: 150 × 10⁶ CAR-positive T cells (75 × 10⁶ CD8+ CAR-positive T cells and 75 × 10⁶ CD4+ CAR-positive T cells), single-dose regimen

The median CD8 dose in the DLBCL treated set and within the DL2S group was ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The median ratio of CD4 to CD8 cells was 1 in all dose groups.

Additional Cycles and Re-treatment

Under the original protocol and Amendments 1 through 5 (and as defined in the “interventions” section), patients could have received additional cycles of liso-cel if “SD” or “PR” was their BOR after the initial response assessment.

A total of 7 patients in the DLBCL treated set (3 in the DL2S and 4 in the DL1S groups) received more than 1 cycle of liso-cel (maximum, 3 cycles) after achieving SD or PR to initial treatment. Meanwhile, 16 patients received re-treatment cycles with liso-cel for PD following CR.

Manufacturing Failure

Manufacturing failure was defined as the inability to manufacture liso-cel-conforming product (as defined before). Manufacturing failure rate was defined as the number of patients for whom liso-cel could not be manufactured divided by the number of patients who had leukapheresis and manufacturing information available. Manufacturing failure occurred in 39 of 341 patients (manufacturing failure rate, 11.4%); 25 of these patients received infusion of the nonconforming product.

Nonconforming Product

As defined previously in the “Interventions” section, when pre-specified criteria were met, patients could have been treated with nonconforming product if the sponsor and the investigator agreed that the benefit/risk profile was acceptable. In the DLBCL cohort, 25 patients received nonconforming product because 1 of the drug product components (either CD8+ or CD4+) did not meet 1 of the release specification limits. The reasons products were considered to be nonconforming for patients in the DLBCL cohort were:

• Received CD8+ component only (no CD4+ component administered), n = 10

• Received CD4+ component only (no CD8+ component administered), n = 3

• Received both components (n = 12), nonconforming due to 1 component not meeting the following specification: potency (n = 5); purity (n = 1); sterility (n = 1); passed initial release for infusion but failed final; and viability (n = 5)

In cases where the patient was treated with only 1 drug product component (CD8+ or CD4+ CAR-positive T cells), they were infused with half of the assigned dose, using the conforming component. Data from patients treated with nonconforming product were analyzed separately from those treated with liso-cel.

Outpatient Treatment

After Amendment 4 in the protocol, guidance was provided regarding outpatient treatment of patients at investigator discretion. Patients were considered to have received outpatient treatment if their first JCAR017 infusion day did not overlap with any hospitalization stays during the study. A total of 25 of 269 patients in the DLBCL treated set were treated in the outpatient setting.

Efficacy

Survival

Results are presented separately for the leukapheresed set, the DLBCL efficacy set, and the PAS below. A summary of the results for PFS and OS across all dose regimens is presented in Table 12.

Leukapheresed Set

OS in the DLBCL-leukapheresed set was defined as the interval from the date of leukapheresis to the date of death. With a median survival follow-up of 18.8 months, patients had a median OS of 14.0 months (95% CI, 11.1 to 21.1 months) in all dose levels, while the median OS in the DL2S regimen was 12.8 months (95% CI, 9.7 to 18.7). The estimated survival rate at 6 months and 12 months was 70.2% (95% CI, 65.0 to 74.8) and |||||||||||||||||||||||||||||||||||||||||||||||||||||||| respectively.

PFS in the DLBCL-leukapheresed set (ITT) analysis was defined as the time from leukapheresis to the earlier date of PD or death due to any cause. With a median PFS follow-up of 13.5 months, patients in the DLBCL-leukapheresed set had a median PFS of 4.8 months (95% CI, 4.3 to 7.3) in all regimen groups, while it was 5.3 months (95% CI, 4.3 to 8.9) in the DL2S liso-cel regimen. The estimated PFS rate at 6 months and 12 months was 46.3% (95% CI, 40.5 to 51.8) and 38.2% (95% CI, 32.5 to 43.9), respectively.

Table 12: Efficacy Outcomes, Survival

CI = confidence interval; DL1D = dose level 1, 2 dose; DL1S = dose level 1, single dose; DL2S = dose level 2, single dose; DL3S = dose level 3, single dose; DLBCL = diffuse large B-cell lymphoma; HSCT = hematopoietic stem cell transplant; ITT = intention to treat; max. = maximum; min. = minimum; NA = not applicable; NR = not reached; OS = overall survival; PFS = progression-free survival.

Note: Redacted rows have been deleted.

Source: Clinical Study Report for the TRANSCEND study.⁹

DLBCL Efficacy Set

The summary of OS for the DLBCL efficacy set in all regimens is shown in Table 12. With a median survival follow-up of 17.5 months, patients had a median OS of 21.1 months (95% CI, 13.3 to NR) in all regimens, and 19.9 months (95% CI, 11.3 to NR months) in the DL2S regimen group. The estimated survival rate at 6 months and 12 months was 74.7% (95% CI, 68.9 to 79.6%) and 57.9% (95% CI, 51.3 to 63.8%), respectively (Figure 6).

Patients in the DLBCL efficacy set, with a median follow-up of 12.3 months, had a median PFS of 6.8 months (95% CI, 3.3 to 14.1) in all dose regimens, while the PFS was 9.5 months (95% CI, 3.2 to NR) in the DL2S regimen group. The estimated PFS rate at 6 months and 12 months was 51.4% (95% CI, 44.6% to 57.7%) and 44.1% (95% CI, 37.3% to 50.7%), respectively (Figure 7).

Figure 6: Overall Survival by Best Overall Response, DLBCL Efficacy Set

CR = complete response; DLBCL = diffuse large B-cell lymphoma; PR = partial response.

Note: Data as of the August 12, 2019 cut-off date.

Source: Clinical Study Report for the TRANSCEND study.⁹

Figure 7: Progression-Free Survival Per Independent Review Committee Assessment by Best Overall Response, DLBCL Efficacy Set

CR = complete response; DLBCL = diffuse large B-cell lymphoma; PR = partial response.

Note: Data as of the August 12, 2019 cut-off date.

Source: Clinical Study Report for the TRANSCEND Study.⁹

Response/Remission Rates

Results are presented separately for the leukapheresed set, the DLBCL efficacy set, and the PAS below. A summary of the results for response and remission across all dose regimens is presented in Table 13

Leukapheresed Set

The leukapheresed set (ITT) analysis was performed as a sensitivity analysis by the sponsor. The ORR was 60.5% (95% CI, 55.1 to 65.7), and the CR rate was 43.6% (95% CI, 38.3 to 49.0). In the DL2S regimen, the ORR was 60.4% (95% CI, 53.7 to 66.8), and the CR rate was 41.9% (95% CI, 35.4 to 48.6).

The DOR was based on IRC assessment for the DLBCL-leukapheresed set across assigned dose regimens. With a median follow-up of 12.4 months, the median DOR was 18.2 months (95% CI, 8.2 to NR). In total, 117 of the 208 patients who achieved a CR or PR (56.3%) were censored, and 91 of the 208 patients (43.8%) relapsed or died after initial response. Ninety of 208 patients (43.3%) were censored with ongoing response or had completed the study. Twenty-four of 208 patients (11.5%) were censored for receipt of new anticancer therapy and 3 were censored for subsequent HSCT.

Table 13: Efficacy Outcomes, Response

CI = confidence interval; CR = complete response; DL1D = dose level 1, 2 dose; DL1S = dose level 1, single dose; DL2S = dose level 2, single dose; DL3S = dose level 3, single dose; DLBCL = diffuse large B-cell lymphoma; ITT = intention to treat; NA = not applicable; NR = not reached; PR = partial response.

^aOne-sided P value was calculated based on the null hypothesis overall response rate of 40% or less.

^bOne-sided P value was calculated based on the null hypothesis CR of 20% or less.

Source: Clinical Study Report for the TRANSCEND study.⁹

DLBCL Efficacy Set

The ORR (based on IRC) was 72.7% (95% CI, 66.8 to 78.0%), and the CR rate was 53.1% (95% CI, 46.8 to 59.4%). Responses, including CRs, were seen in all assigned dose regimens tested, with no evidence of a relationship between assigned dose regimen and response (overlapping CIs across all assigned dose regimens). Sensitivity analysis using the PP DLBCL analysis set (N = 259) for the ORR per IRC assessment was ||||||||||||||||||||||||||||| and the CR rate was |||||||||||||||||||||||||||||||||||||||||| Also, the concordance between IRC and investigator assessments was high (||||||||||||||||||||||||||||)

With a median follow-up of 12.0 months, the median DOR was NR (95% CI, 8.6 to NR months). After initial response, the probability of continued response at 6 months and 12 months was ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Primary Analysis Set

The primary efficacy end point of the TRANSCEND study was the ORR (per IRC) based on the PAS. A summary of response rates per IRC assessment in the PAS (by definition, assigned to DL2S) is also shown in Table 13. The ORR for patients in the PAS was 74.4% (95% CI, 66.2% to 81.6%). Based on data with a cut-off date of April 12, 2019, the study met its primary efficacy end point by rejecting the null hypothesis of an ORR of 40% or less (P < 0.0001). The CR rate for patients in the PAS was 54.1% (95% CI, 45.3% to 62.8%). Based on data with a cut-off date of April 12, 2019, the study rejected the null hypothesis of a CR of 20% or less (P < 0.0001). No additional hypothesis testing was conducted for the current data cut-off of August 12, 2019.

DOR was also based on IRC assessment for the PAS. With a median follow-up of 16.4 months, among the 99 patients achieving CR or PR, the median DOR was 16.8 months (95% CI, 6.0 to NR). After initial response, the probability of continued response at 6 months and 12 months was (||||||||||||||||||||||||||||||||||||||||||||||||||||||||), respectively. The most common reason for censoring was that the patient was still ongoing in the study (||||||||||||||||||||||||||||||||||||||||||%). Among the 72 patients in the PAS achieving CR, the median DOR was NR (95% CI, 13.3 to NR), ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||).

Intensive Care Admission and Utilization

In the total population (N = 269), 7 patients were never hospitalized. The median time for the initial hospitalization from liso-cel administration (N = 262) was 11 days (range = 2 days to 88 days). During the initial hospitalization, 19 of 269 patients (7.1%) were admitted to the ICU; the median number of ICU days was 7 days (range = 1 days to 56 days). Considering all hospitalizations through the end of the study, the median total days of hospitalization was 17 days (range = 2 days to 127 days). During this time, 33 of 269 patients (12.3%) were admitted to the ICU; the median number of ICU days was 8.0 (range = 1 days to 56 days).

In the patients who received liso-cel in the inpatient setting (N = 244), the median time from liso-cel infusion to discharge for the initial hospitalization was 11 days (range = 3 days to 88 days).

During the initial hospitalization, 18 of 244 patients (7.4%) were admitted to the ICU; the median number of ICU days was 7.5 (range = 1.0 days to 56.0 days). Considering all hospitalizations through the end of the study, the median total days of hospitalization after liso-cel infusion was 18 days (range = 3 days to 127 days). Throughout the entire study period, 32 of 244 patients (13.1%) were admitted to the ICU; the median number of ICU days was 8 (range = 1 days to 56 days).

In the patients who received liso-cel in the outpatient setting (N = 25), 18 (72.0%) were admitted to the hospital (all for AEs), a median of 5 days after liso-cel administration (range = 3 days to 22 days). The median time of first hospitalization was 6 days (range = 2 days to 23 days). During the initial hospitalization, 1 of 25 patients (4.0%) was admitted to the ICU for 3 days. Considering all hospitalizations through the end of the study, the median total days of hospitalization was 6.5 days (range = 2.0 days to 48.0 days).

HRQoL: Patient-Reported Outcomes

The PRO evaluable populations of the DLBCL cohort of the TRANSCEND study reported numerically decreased symptoms and increased PRO and QoL compared to pre-treatment baseline assessments through months 6 and 18. Specifically, patients in the PRO (EORTC QLQ-C30 and EQ-5D-5L) evaluable population of the DLBCL treated set were observed to numerically increase in HRQoL across several validated domains as early as month 1 post-liso-cel infusion. Specific results are presented in Table 14 and Table 15, and Figure 8 and Figure 9.

Table 14: Patient-Reported Outcomes: HRQoL, EORTC QLQ-C30

DLBCL = diffuse large B-cell lymphoma; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; HRQoL = health-related quality of life.

^aEvaluable population in DLBCL treated set. The range of EORTC QLQ-C30 scales is 0 to 100; a higher functional score indicates a more preferred health status, whereas a higher symptom score (fatigue and pain) indicates increased symptom impact. A minimal important difference of 10 points was considered significant by the sponsor and investigators.

^bP values not adjusted for multiple comparisons.

Source: Clinical Study Report for the TRANSCEND study.⁹

Table 15: Patient-Reported Outcomes: HRQoL, EQ-5D-5L

DLBCL = diffuse large B-cell lymphoma; EQ-5D-5L = EuroQol 5-Dimensions 5-Levels questionnaire; HRQoL = health-related quality of life.

^aEvaluable population in DLBCL treated set.

Source: Clinical Study Report for the TRANSCEND study.⁹

Figure 8: Mean Change From Baseline in Global Health Status in PRO (EORTC QLQ-C30) Evaluable Population in DLBCL Treated Set

DLBCL = diffuse large B-cell lymphoma; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; MID = minimal important difference; PRO = patient-reported outcome; SE = standard error.

Note: The Wilcoxon signed rank test was used. The test was performed only if the sample size at any given assessment visit was at least 10. Month 0 represents baseline; month 1 = day 29.

*Indicates data point of a significant change from baseline with a P value of less than 0.05 based on the 2-sided unadjusted for multiple comparisons.

Source: Clinical Study Report for the TRANSCEND study.⁹

Figure 9: Mean Change From Baseline for EQ-5D-5L Index Scores in PRO (EQ-5D-5L) Evaluable Population in DLBCL Treated Set

DLBCL = diffuse large B-cell lymphoma; EQ-5D-5L = EuroQol 5-Dimensions 5-Levels questionnaire; PRO = patient-reported outcome; SE = standard error.

Note: The Wilcoxon signed rank test was used. The test was performed only if the sample size at any given assessment visit was at least 10. Month 0 represents baseline; month 1 indicates day 29.

* Indicates data point of a significant change from baseline with a P value of less than 0.05 based on the 2-sided unadjusted for multiple comparisons.

Source: Clinical Study Report for the TRANSCEND study.⁹

At the data cut-off date (August 12, 2019), the PRO (EORTC QLQ-C30) evaluable population included 181 out of 269 patients in the DLBCL treated set. The mean change from baseline demonstrated numerical differences that ranged between 19.67 in global health status, 6.93 in physical functioning, –15.1 for fatigue, and –8.67 in pain scores through month 18. However, the number of evaluated patients also decreased to 25 by 18 months.

The evaluable population for the PRO of EQ-5D-5L included 186 out of 269 patients in the DLBCL treated set, who received liso-cel. At 18 months of follow-up, only 25 patients remained to be evaluated. At baseline, mean (standard deviation) EQ-5D-5L health utility index scores and EQ VAS scores were 0.82 (0.20) and 68.3 (19.5), respectively. By month 18, the utility index score dropped to |||||||||||||||||||||||||||| with a change from baseline ||||||||||||||||||||||||||||||||||||| (not adjusted for multiple comparisons); and ||||||||||||||||||||||||||||) in the EQ VAS.

Harms

AEs were summarized from the DLBCL treated set population (n = 269). Only those harms identified in the review protocol are reported below. See Table 16 for detailed harms data.

Table 16: Summary of Harms, DLBCL Treated Set

DL1D = dose level 1, 2 dose; DL1S = dose level 1, single dose; DL2S = dose level 2, single dose; DL3S = dose level 3, single dose; DLBCL = diffuse large B-cell lymphoma; liso-cel = lisocabtagene maraleucel; NA = not applicable; SAE = serious adverse event.

Note: Values are represented as n (%).

^aFrequency of greater than 10%.

Source: Clinical Study Report for the TRANSCEND study.⁹

Adverse Events

The investigators considered TEAEs to be those defined as an AE that started any time from initiation of liso-cel administration through and including 90 days following the final cycle (i.e., final infusion) of liso-cel. Any AE occurring after the initiation of another anticancer therapy or liso-cel re-treatment was not considered a liso-cel TEAE. Data from the regimen DL2S appears in the left-most column of all by-dose regimen tables, because it was the recommended regimen selected by the sponsor for evaluation in the DC group in the DLBCL cohort of the TRANSCEND study.

AEs occurred in 267 of 269 patients in all regimens and in all of the patients from the DL2S regimen. TEAEs occurred most frequently in the system organ class (SOC) of blood and lymphatic system disorders (209 of 269 patients; 77.7%). The 3 most frequently reported TEAEs (any grade) were neutropenia (169 of 269 patients; 62.8%), anemia (129 of 269 patients; 48.0%), and fatigue (119 of 269 patients; 44.2%). The fourth most commonly reported TEAE was CRS (113 of 269 patients; 42.0%). Grade 3 or higher TEAEs occurred most frequently in the SOC of blood and lymphatic system disorders (198 of 269 patients; 73.6%) and were neutropenia, anemia, and thrombocytopenia. Grade 3 or higher CRS occurred in 6 of 269 patients (2.2%), and no patient was reported to have grade 5 CRS.

From screening to leukapheresis, 94 of 347 patients (27.1%) reported AEs, including 13 of 347 patients (3.7%) with grade 3 to grade 4 AEs and 2 of 347 patients (0.6%) with SAEs. No grade 5 AEs were reported during this time period.

From leukapheresis to LDC, 192 of 344 patients (55.8%) reported AEs, including 48 of 344 patients (14.0%) with grade 3 to grade 4 AEs, 1 of 344 patients (0.3%) with a grade 5 AE of sepsis, and 20 of 344 patients (5.8%) with SAEs.

From LDC (from first day of last LDC) to first JCAR017 infusion, 272 of 298 patients (91.3%) reported AEs, including 113 of 298 patients (37.9%) with grade 3 to grade 4 AEs and 25 of 298 patients (8.4%) with SAEs. No grade 5 AEs were reported during this time period. During this time period, 225 of 298 patients (75.5%) experienced an AE related to LDC. LDC-related TEAEs occurred most frequently in the SOC of blood and lymphatic system disorders (198 of 269 patients: 73.6%). The 3 most frequent TEAEs considered related to LDC were neutropenia, occurring in 161 of 269 patients (59.9%); anemia, occurring in 113 of 269 patients (42.0%), and thrombocytopenia, occurring in 73 of 269 patients (27.1%).

A total of 10 patients were retreated at DL2S, 5 at DL1S, and 1 at DL3S. AEs were reported after re-treatment in 15 of 16 patients (93.8%), grade 3 or grade 4 AEs were reported in 13 of 16 patients (81.3%), and 1 of 16 patients (6.3%) had a grade 5 AE. AEs after re-treatment occurred most frequently in the SOC of blood and lymphatic system disorders (13 of 16 patients; 81.3%). The most frequent AEs after re-treatment were neutropenia (10 of 16 patients; 62.5%), anemia (8 of 16 patients; 50.0%), pyrexia and nausea (each in 6 of 16 patients; 37.5%), and headache and CRS (each in 5 of 16 patients; 31.3%). CRS occurred after re-treatment in 5 of 16 patients (31.3%), with 1 patient (6.3%) reporting grade 3 CRS. One patient experienced neurotoxicity (iiNT) after re-treatment.

Serious Adverse Events

In the DLBCL treated set, 122 of 269 patients (45.4%) reported treatment-emergent SAEs. SAEs were reported most frequently in the SOCs of immune system disorders (44 of 269 patients; 16.4%), nervous system disorders (41 of 269 patients; 15.2%), and infections and infestations (28 of 269 patients; 10.4%). The most frequent treatment-emergent SAEs were CRS (44 of 269 patients; 16.4%) and encephalopathy (14 of 269 patients; 5.2%). All other treatment-emergent SAEs were reported in less than 5% of patients.

Withdrawals Due to Adverse Events

Withdrawals due to AEs were not applicable as liso-cel was a single dose for most patients, and follow-up continued for patients regardless of AEs.

Mortality

Forty-four of 344 patients (12.8%) died before treatment with JCAR017 or nonconforming product. Deaths in these 44 patients were attributed to disease progression (n = 37), unknown causes (n = 3), other causes (n = 3), and sepsis (n = 1) considered related to protocol-mandated procedures.

A total of 137 deaths among the 344 patients (39.8%) were reported at any time after the first infusion of JCAR017 or nonconforming product. Deaths in these patients were attributed to disease progression (n = 116), AE (n = 12), other causes (n = 5), and unknown causes (n = 4).

Twelve patients in the DLBCL-leukapheresed set died due to AEs after treatment with JCAR017 (n = 10) or nonconforming product (n = 2).

Notable Harms

CRS was reported in 113 of 269 patients (42.0%) in the DLBCL treated set. Grade 3 or grade 4 CRS was reported in 6 of 269 patients (2.2%). No grade 5 CRS was reported. CRS was reported as an SAE in 44 of 269 patients (16.4%) in the DLBCL treated set. In the 113 patients with all-grade CRS, the median time to onset was 5 days (range = 1 days to 14 days). The events have resolved in 111 of these 113 patients. The median time to resolution of CRS in those with resolution as of the data cut-off date was 5 days (range = 1 days to 17 days). At DL3S, the incidence of all-grade CRS was more than 20% higher than at DL2S or DL1S. Treatment for CRS included tocilizumab, corticosteroids, vasopressors, supplemental oxygen, and empiric treatment with antibiotics.

In the DLBCL treated set, iiNT was reported in 80 of 269 patients (29.7%). The events resolved in 72 of these 80 patients. The median time to resolution of iiNT in those with resolution as of the data cut-off date was 11 days (range = 1 days to 86 days). Grade 3 or grade 4 iiNT was reported in 27 of 269 patients (10.0%). No grade 5 iiNT was reported. iiNT events were reported as SAEs in 39 of 269 patients (14.5%). In 45 of 269 patients (16.7%) corticosteroids and/or tocilizumab for iiNTs were used as treatment.

Other AESIs included tumour lysis syndrome which was reported in 2 of 269 patients (0.7%) in the DLBCL treated set (not reported as SAE); while 3 of 269 patients (1.1%) reported an infusion-related reaction to liso-cel. Hypogammaglobulinemia was reported in 37 of the total 269 patients (13.8%) in the DLBCL treated set, and, after the treatment-emergent period, it was reported in 12 of 247 (4.9%) of patients in the DLBCL treated set, with all events reported as grade 1 or grade 2. Treatment with IV immunoglobulin was not specified PP but rather left at investigator discretion following local guidelines. IV immunoglobulin was reported as a concomitant medication for 58 of 269 (21.5%) patients in the DLBCL treated set. In some cases, at the investigators’ discretion, IV immunoglobulin was administered for other reasons (e.g., low immunoglobulin G levels, thrombocytopenia, among others).

Updated Data

Data from 3 data cut-off dates were included in the sponsor’s submission for this review: August 19, 2019, June 19, 2020, and January 4, 2021, with median study follow-up duration of 11.5, 19.1, and 19.9 months, respectively. The 2 latest sponsor-provided updates also address efficacy and harm outcomes. However, the main analysis considered by CADTH for this review is from the August 12, 2019, cut-off date since the main hypothesis tests and adjustments for multiplicity were defined a priori and based on this date and using the PAS. Therefore, key end points from the updated cut-off dates were considered supplemental and supportive for the main analyses and are presented descriptively in Appendix 5.

Overall, the results of the new cut-off dates agree with the main analyses of the base-case data from the PAS and initial cut-off date of August 19, 2019. A total of 257 and 270 patients for the DLBCL efficacy and treated analysis sets, respectively, were included in both cut-off dates.

As of the cut-off date of January 4, 2021, in the total population of the DLBCL efficacy set, an ORR was reached in 187 (72.8%) patients (95% CI, 66.9 to 78.1), median DOR of 23.1 months (95% CI, 8.6 to NR), a median of PFS of 6.8 months (95% CI, 3.3 to 12.7), and median OS of 27.3 months (95% CI, 16.2 to 45.6). Deaths occurring at any point after the first infusion of liso-cel occurred in 40 patients (11.6%). AEs, SAEs, and deaths were observed in similar numbers at these later cut-off dates when compared to the initial cut-off date. These data are presented in Table 45 and Table 46 as well as Figure 25, Figure 26, Figure 27, and Figure 28 of Appendix 5.

Critical Appraisal

Internal Validity

The TRANSCEND study is a single-arm, open-label, phase I, seamless design study. The main limitation from the study stems from the single-arm design and lack of comparator groups giving place to risk of selection bias. In lieu of an available direct comparator, the investigators evaluated the primary end point of ORR against a null hypothesis of an ORR of 40% or less, with an alternate hypothesis of greater than 40% and effect size of 25% (ORR = 65%) based on a random effects meta-analysis of 8 studies of current recommended regimens for patients with 3L+ R/R aggressive large B-cell lymphoma. The hypothesis testing and adjustment for multiplicity was evaluated only for the PAS population; this situation can instill uncertainty in the effect estimates due to selection bias since it deviates from the ITT principle by not focusing on the population that provides most of the information as it would occur in a randomized controlled trial (i.e., the ITT population and the DLBCL treated set population) All patients in the enrolled population after screening (leukapheresed or ITT population) should be considered critical in any analysis that intends to evaluate the effect of assigning patients to an intervention (i.e., liso-cel) to evaluate the effects of all the procedures and co-interventions involved once it has been decided to start treatment; this is, including the manufacturing process, LDC, bridging therapy, and all possible consequences of these steps. An analysis based on the PAS could bias the effect estimate against a null hypothesis favouring the intervention.

An open-label design may also increase uncertainty in PROs (HRQoL) introducing bias due to inherent subjectivity of the outcome in an unblinded assessor. This bias would be less likely in more objective outcomes such as ORR, OS, or PFS. 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 resulting in increasing imprecision and potential bias from missing data.

Anticancer treatments (which occurred in 62.2% of the leukapheresed patients) were considered an intervention needed for patients waiting for the manufactured product to be administered. These included bridging therapies. Any magnitude of effect that these anticancer interventions could have on the outcomes evaluated in patients who received liso-cel in the TRANSCEND study is uncertain.

Deviations from the protocol occurred in 10 of 269 (3.7%) patients in the DLBCL treated set. Sensitivity analyses were overall supportive of the robustness of results among populations. Some subgroups were pre-specified in the protocol; however, information on any subgroup effects was not possible to obtain since the sample size was small and only performed in the PAS population.

External Validity

Issues of generalizability of the results originate from the differences in the population included in the TRANSCEND study, which can be considered relatively young (mean age of 60.1 years in the DLBCL treated set). This is a relatively young population below the median age of diagnosis of 65 years of age commonly reported in epidemiology reviews and current clinical guidelines.^1,21 Baseline and disease characteristics were overall similar between the DLBCL treated set and the PAS population, hence the issues of generalizability would apply to both populations for these variables.

Patients have good baseline performance status (only 4 patients in the DLBCL treated population and 1 in the PAS were classified as ECOG PS = 2) compared with patients typically seen in Canadian clinical practice. This agreed with input from clinical experts consulted by CADTH, when considering the similarities between the populations from TRANSCEND and those likely to be encountered in clinical practice in Canada. Also, some other baseline disease characteristics suggest that the included population might be healthier when compared to the Canadian clinical practice (e.g., low number of patients with ECOG PS = 2). The clinical experts consulted by CADTH noted that re-treatment cycles might be unusual in Canada; however, re-treatment in the TRANSCEND study was more common than they would expect in their clinical practice.

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 that were included in the TRANSCEND study. These numbers make it difficult to draw conclusions on the effects of liso-cel in these populations.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

The objective of this section is to summarize and appraise indirect evidence comparing the relative effects and safety of liso-cel against relevant comparators in patients with R/R large B-cell lymphomas, as established in the protocol for this review. The main objective of performing ITCs is to fill a gap created by the absence of trials directly comparing available CAR T-cell therapies or comparing liso-cel to other 3L+ treatments.

A supplemental literature search was conducted by CADTH to identify further ITCs. A focused literature search for network meta-analyses dealing with large B-cell lymphoma was run in MEDLINE All (1946-) on September 2, 2021. No limits were applied. Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers made a final selection of studies included in the review, and differences were resolved through discussion. Based on this literature search conducted by CADTH, out of 22 search titles found and screened, 5 were evaluated as full texts, with no additional ITCs identified that assessed the relative effects of liso-cel against included comparisons (i.e., tisa-cel, axi-cel, or salvage therapy). One Cochrane systematic review assessed the effects of CAR T-cell therapies for people with R/R DLBCL but did not evaluate relative effects and reported results narratively.²⁴

Description of Indirect Comparisons

Two ITC reports were provided by the sponsor and included a total of 3 ITCs in this clinical review report. The first ITC report¹² comprises unanchored MAICs of liso-cel against 2 CAR T-cell therapies (i.e., tisa-cel and axi-cel), in patients with R/R large B-cell lymphomas. Data were obtained as IPD from the TRANSCEND study and as aggregated level data from the single-arm studies ZUMA-1²⁵ (axi-cel) and JULIET²⁶ (tisa-cel).

The second ITC¹¹ is an unanchored MAIC of the efficacy of liso-cel versus salvage chemotherapy by using IPD from the TRANSCEND NHL 001 study and aggregated level data from the SCHOLAR 1 study, respectively.

A description of the study selection criteria and methods is presented in Table 17.

Table 17: Study Selection Criteria and Methods for ITC reports

3L+ = third line or later; AD = aggregated data; allo = allogeneic; auto = autologous; axi-cel = axicabtagene ciloleucel; CAR = chimeric antigen receptor; CNS = central nervous system; CRR = complete response rate; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; HGL = high-grade lymphoma; HSCT = hematopoietic stem cell transplant; IPD = individual patient data; ITC = indirect treatment comparison; liso-cel = lisocabtagene maraleucel; NOS = not other specified; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; tisa-cel = tisagenlecleucel; tiNHL = transformed indolent non-Hodgkin lymphoma.

Source: Sponsor-submitted study reports; ITC1¹² and ITC2.¹¹

Methods of ITC Report-1

Objectives

The objective of the ITC report-1 was to determine the comparative efficacy and safety of liso-cel relative to 2 other CAR T-cell therapies, tisa-cel and axi-cel, in patients with R/R large B-cell lymphoma on third-line therapy using MAICs for regulatory and health technology assessment purposes. An overview of the ITCs methods is presented in Table 18.

Table 18: ITC Report-1 Analysis of MAIC Methods

AD = aggregated data; AESI = adverse events of special interest; allo = allogeneic; axi-cel = axicabtagene ciloleucel; CNS = central nervous system; CRR = complete response rate; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HSCT = hematologic stem cell transplant; IPD = individual patient data; ITC = indirect treatment comparison; ITT = intention to treat; liso-cel = lisocabtagene maraleucel; MAIC = matching-adjusted indirect comparison; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; SCT = stem cell transplant.

Source: Sponsor-submitted ITC-1 report.¹²

Study Selection Methods

ITC report-1 included a systematic literature search strategy to identify randomized and non-randomized studies of therapies used as 3L+ in patients with R/R LBCL, including DLBCL, FL3B, PMBCL, DLBCL transformed from iNHL, HGL, and DLBCL with CNS involvement. The search strategy included databases such as MEDLINE, Embase, Cochrane CENTRAL, and grey literature restricted to certain high-income countries and language (articles published in English, French, German, Italian, Spanish, Japanese, Danish, Finnish, Norwegian, or Swedish). The search criteria were also restricted to studies published from January 2003 to December 2019. Authors conducted, by pairs, the screening, selection, and data extraction of studies with specific inclusion or exclusion study criteria, and resolved disagreements with a third investigator. Data extraction was performed by investigators using pre-specified and piloted data extraction forms. Quality assessment of the included studies was assessed using checklists recommended by the National Institute for Health and Care Excellence.

The authors included and assessed data from 3 selected studies. For tisa-cel and axi-cel, authors used the peer-reviewed publications of the latest data cut-offs for the JULIET²⁶ (data cut-off = December 8, 2017) and ZUMA-1²⁵ (data cut-off = August 11, 2018) trials, respectively, while using IPD from the TRANSCEND study for liso-cel. Secondary data sources for JULIET and ZUMA-1 from the same data cut-offs were assessed only when information was not available in the primary publication or when additional clarity was required.

First, the authors performed a feasibility assessment to conduct the ITC. This was an assessment of how similar, with regard to study design and patient characteristics, the pivotal studies to be included were to allow for adequate adjustment of the liso-cel IPD to the published aggregated data for the comparators tisa-cel and axi-cel. Thus, a qualitative comparison of the pivotal trials of liso-cel (TRANSCEND), tisa-cel (JULIET), and axi-cel (ZUMA-1) was conducted to assess the feasibility of ITCs in terms of study design and eligibility criteria (e.g., bridging therapy and median follow-up time), reporting of baseline characteristics, efficacy outcomes, safety outcomes, clinical definitions of baseline characteristics, and reported categorizations of clinical variables, as well as based on a quantitative assessment of the degree of imbalances between studies across baseline clinical factors.

The authors concluded that it was feasible to conduct the ITC for 4 efficacy outcomes (ORR, CRR, PFS, and OS) in comparisons of liso-cel to tisa-cel and liso-cel to axi-cel. For AESI, MAICs were feasible for grade 3 or grade 4 AEs, CRS, study-defined NT, encephalopathy, infections, hypogammaglobulinemia, and febrile neutropenia in comparisons of liso-cel to tisa-cel and liso-cel to axi-cel. MAICs of grade 3 or higher and grade 5 AEs were possible for liso-cel versus axi-cel.

The feasibility assessment was determined based on differences in study populations and design between trials that necessitated adjustment of variables to permit comparison of outcomes but were not large enough to preclude the comparison of outcomes altogether. Comparison of the study design, eligibility criteria, and baseline characteristics of the TRANSCEND, JULIET, and ZUMA-1 studies showed sufficient similarities between the studies to allow comparison, although there were still differences across trials that needed adjustment in a MAIC to reduce bias when indirectly comparing liso-cel to tisa-cel and axi-cel. Large differences in the definitions or categorizations of patient characteristics such as IPI score, disease histology, number of prior lines of therapy, and R/R to last therapy between trials were redefined within the liso-cel IPD to align more closely to those in each comparator study.

ITC Analysis Methods

The analyses in the ITCs included 2 sets of patients. The first set was composed of all patients who were enrolled and had received (were infused with) CAR T-cell therapy in the studies (i.e., the infused patients). The second set included all patients who were enrolled in the study and were leukapheresed (i.e., the leukapheresis set, also referred as the ITT).

To account for study heterogeneity, study eligibility criteria and baseline characteristics were examined. For each comparison, patients from the TRANSCEND study were removed from the IPD set if they did not satisfy the eligibility criteria and treatment protocol of the comparator trial (i.e., the ZUMA-1 or JULIET studies; refer to Table 19). Other clinical factors relevant for weighting were identified through a targeted literature search for variables that were prognostic factors in patients with 3L+ R/R large B-cell lymphoma and from inspection of clinical factors reported in the TRANSCEND, JULIET, and ZUMA-1 trials, as well as input from external clinical experts. Five clinical experts from different countries (Canada, France, Germany, the UK, and the US) supervised the identification and rank of the prognostic factors or effect modifiers relative to the outcomes of interest evaluating each efficacy outcome (4 lists of factors, 1 for each efficacy outcome), and all AEs (1 list of factors for all AEs). A final ranked list of clinical factors important for each efficacy outcome was derived using an evidence-informed ranking process that considered both the ranks informed by clinical experts and statistical approaches (i.e., random forest methodology²⁷) to obtain data-driven rankings of the included factors. For safety outcomes, the identification and ranking methods underwent an expedited approach based on input from the clinical experts since, according to the authors, AEs would have fewer factors to consider and would be more difficult to rank.

Table 19: ITC Report-1. Patient Exclusions in Liso-cel Versus Tisagenlecleucel and Liso-cel Versus Axi-cel Comparisons

AESI = adverse events of special interest; allo = allogenic; auto = autologous; axi-cel = axicabtagene ciloleucel; CNS = central nervous system; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FL3B = follicular lymphoma grade 3B; HSCT = hematologic stem cell transplant; ITC = indirect treatment comparison; liso-cel = lisocabtagene maraleucel; PMBCL = primary mediastinal large B-cell lymphoma.

Source: Sponsor-submitted ITC-1 report.¹²

Both the TRANSCEND and JULIET studies allowed bridging therapy for most patients. These studies provided bridging therapy as needed to patients awaiting CAR T-cell infusion. In contrast, the ZUMA-1 study did not permit bridging therapy. Due to this issue, analyses of liso-cel (from TRANSCEND) versus tisa-cel (from the JULIET study) included treated patients regardless of whether they received bridging therapy, while analyses of liso-cel (from the TRANSCEND study) versus axi-cel (from the ZUMA-1 study) involved removing patients from the TRANSCEND study who received bridging therapy. Sensitivity analyses were conducted that included patients who received bridging therapy.

After the exclusion of patients based on eligibility, the patients that remained and were included from the TRANSCEND study were weighted, using a method-of-moments propensity score algorithm for each comparison aimed at balancing clinical factors between the studies of interest. That is, after weighting patients, the means (or proportions) and standard deviations of clinical factors from the TRANSCEND study should be equal to those published in the JULIET and ZUMA-1 studies.

The final clinical factors deemed relevant to efficacy outcomes are depicted in Table 20. Of note, there were a total 24 clinical factors considered relevant to efficacy outcomes and available for analysis in the TRANSCEND study IPD data, and 17 were reported and available within the JULIET safety set/full analysis set data for comparison of OS and PFS. The 7 factors not available were:

1. tumour burden LDH

2. C-reactive protein

3. refractory subgroups (i.e., chemorefractory to last therapy, relapsed to prior auto-HSCT, chemosensitivity)

4. best response to any prior therapy

5. tumour burden sum of the products of diameters

6. extranodal disease

7. bulky disease.

For the CRR and ORR end points, 15 clinical factors were available within the JULIET efficacy analysis set, and 9 factors were not available, including tumour burden LDH, CRP, refractory subgroups (i.e., chemorefractory to last therapy, relapsed to prior auto-HSCT, chemosensitivity), best response to any prior therapy, tumour burden sum of the products of diameters, extranodal disease, bulky disease, age, and sex.

Of the 16 clinical factors deemed relevant to AESI, 8 were available for comparison between the TRANSCEND and JULIET studies’ safety set or full analysis set, and included secondary CNS involvement, number of prior lines of therapy, bone marrow involvement, bridging therapy, age, ECOG PS, prior allo-HSCT, and prior auto-HSCT.

The comparative efficacy of liso-cel relative to tisa-cel and axi-cel was assessed as the difference between (1) an estimate of the outcome of interest for liso-cel based on adjusted IPD from the TRANSCEND study (to align with patients in the JULIET or ZUMA-1 studies), and (2) the estimated outcome for tisa-cel or axi-cel based on published aggregated data from the JULIET or ZUMA-1 studies, respectively.

For binary end points, after exclusion of patients from the TRANSCEND study, a weighted estimate of the liso-cel outcome was derived using MAIC adjustment weights. Estimates of binary outcomes (ORR, CRR, AESI) were derived from an intercept-only logistic regression model with MAIC adjustment weights. The intercept represents a prediction of the log odds of the outcome of interest if a typical patient from the JULIET or ZUMA-1 studies had received liso-cel. Robust standard errors were estimated using the sandwich estimator via the R package “sandwich.” An estimate of the log OR for liso-cel versus tisa-cel or axi-cel was derived as the difference between the predicted log odds for liso-cel and the estimated log odds based on aggregated data from the JULIET or ZUMA-1 studies. The variance of the log OR between liso-cel versus tisa-cel or axi-cel was estimated as the sum of the variances of the log odds for liso-cel and tisa-cel or axi-cel.

Table 20: ITC Report-1. Clinical Factors and Rankings Used to Inform the Adjusting Process for Efficacy Analyses in the Comparison of Liso-cel to Tisagenlecleucel

allo = allogenic; auto = autologous; CNS = central nervous system; CrCl = creatinine clearance; CRR = complete response rate; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HSCT = hematologic stem cell transplant; IPI = International Prognostic Index; ITC = indirect treatment comparison; liso-cel = lisocabtagene maraleucel; LVEF = left ventricular ejection fraction; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; R/R = relapsed or refractory.

^aFactors are ranked in order of importance where 1 represent the most important factor and 17 represents the least important factor.

^bOnly 17 of the 24 factors available for analysis in the TRANSCEND individual patient data were available for comparison with the JULIET phase I and II safety analysis set.

^cFactor was available for JULIET safety set and full analysis set, but not for JULIET efficacy analysis set.

Source: Sponsor-submitted ITC-1 report.¹²

For time-to-event end points (PFS and OS), weighted IPD from the TRANSCEND study were combined with pseudo-IPD (setting weights for pseudo-observations = 1) representing patients from the JULIET or ZUMA-1 studies. This dataset was then used to fit a weighted Cox proportional hazards model with a binary treatment indicator (i.e., liso-cel versus tisa-cel or axi-cel). The estimated regression coefficient for the treatment indicator was used to represent the log HR for liso-cel versus tisa-cel or axi-cel. Pseudo-IPD for PFS and OS from the JULIET or ZUMA-1 studies were generated by first digitizing the Kaplan–Meier survival curves and then using the Guyot 2012 approach to derive time-to-event data for both outcomes.²⁸ “Log transformation” was used to estimate CIs of the median time-to-event. The authors did not adjust for multiplicity.

The following criteria were used to assess the performance and suitability of each MAIC model:

• ESS: a low ESS compared to the original sample size (N) indicates large differences in patient weights due to large imbalances in patient populations before reweighting

• Distribution of patient weights: extreme patient weights can indicate uncertainty in the resulting relative treatment effect

• Summary statistics (e.g., means, proportions): for each clinical factor, before and after weighting were assessed to evaluate the improvement in balance between trial populations; balance was assessed using the absolute value of the standardized mean difference for each covariate and a standardized mean difference of 0.10 or greater was considered indicative of potentially important imbalances between comparisons.²⁹

• OS and PFS: the assumption of proportional hazards underlying Cox proportional hazards models was assessed by examining crossover in Kaplan–Meier curves and applying the Grambsch-Therneau statistical test for proportional hazards³⁰

The primary analysis of the MAIC model was chosen based on achieving a balance between these criteria, while also considering the number of clinical factors included. Sensitivity analysis was chosen by incorporating the additional clinical factors for each outcome.

Results of ITC Report-1

Summary of Included Studies

The 3 studies included in the ITC were the TRANSCEND, ZUMA-1, and JULIET trials.

The TRANSCEND study is the pivotal study included in this CADTH report and has been described in the respective sections. Briefly, it is a phase I, single-arm, multi-centre, open-label trial assessing the efficacy and safety of liso-cel as a 3L+ treatment in patients with R/R large B-cell lymphoma. Primary end points were AEs and ORR as assessed by an IRC. Secondary end points included CRR (as assessed by IRC), DOR, PFS, and OS. A total of 270 patients received liso-cel, of which 257 formed the DLBCL efficacy analysis set.

The JULIET study was a phase I, single-arm, multi-centre, open-label, registrational trial of the efficacy and safety of tisa-cel in patients with R/R large B-cell lymphoma. This study did not include patients with PMBCL, transformed iNHL, and FL3B categories of lymphoma. The ECOG PS status in patients in this study was also different and set at 1 or lower. Patients were excluded if they had received allo-HSCT or had secondary CNS involvement. The primary end point was ORR and key secondary end points included DOR, OS, and safety. In total, 111 patients received an infusion and were included in the evaluation of efficacy, among which 93 patients were assessed for response rates. Median follow-up time was 14 months (range = 0.1 to 26).

Finally, the ZUMA study was a phase I/II, single-arm, multi-centre, open-label study evaluating the efficacy and safety of axi-cel in patients with refractory large B-cell lymphoma. The study included patients with the same types of lymphoma as in the TRANSCEND study (i.e., DLBCL, PMBCL, or tFL), but it did not include patients with FL3B. Patients were refractory to the most recent chemotherapy regimen or relapsed after auto-HSCT. Patients had an ECOG PS similar to those in the JULIET study (0 to 1), but lower than the TRANSCEND study. Furthermore, patients were excluded if they had secondary CNS lymphoma or prior allo-HSCT. The primary end points were safety for phase I and ORR for phase II. Key secondary end points were PFS, OS, and DOR. Of the 108 patients who received axi-cel, 101 were evaluable for efficacy in the phase II study. Median follow-up time was 27.1 months (interquartile range = 25.7 to 28.8).

A comparison of the characteristics of the included studies is presented in Table 21.

Table 21: ITC-1. Characteristics of Included Studies and Patient Characteristics

allo = allogenic; auto = autologous; axi-cel = axicabtagene ciloleucel; CAR = chimeric antigen receptor; CNS = central nervous system; CRR = complete response rate; DLBCL = diffuse large B-cell lymphoma; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FL3B = follicular lymphoma grade 3B; HGL = high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6; HSCT = hematopoietic stem cell transplant; IQR = interquartile range; ITC = indirect treatment comparison; liso-cel = lisocabtagene maraleucel; mITT = modified intention to treat; NA = not applicable; NHL = non-Hodgkin lymphoma; NOS = not otherwise specified; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PMBCL = primary mediastinal B-cell lymphoma; R/R = relapsed or refractory; tFL = DLBCL transformed from follicular lymphoma; tiNHL = DLBCL transformed from other indolent non-Hodgkin lymphoma; WBC = white blood cell.

Source: Sponsor-submitted ITC-1 report.¹²

Studies also differed in their enrolment process. Specifically, the ZUMA-1 study did not permit enrolment and leukapheresis unless a CAR T-cell manufacturing slot was available. In contrast, the TRANSCEND and JULIET studies enrolled patients before confirming a manufacturing slot, and therefore allowed bridging therapy as needed to patients awaiting leukapheresis. This difference is evident in the median time from leukapheresis to product availability, which varied across studies (the TRANSCEND study = 24 days [range, 17 to 51], the JULIET trial = 113 days [range, 47 to 196], and the ZUMA-1 trial = 17 days [range, 14 to 51]).

In the comparison of trials, redefinition of some of the variables was undertaken for the weighting process, as presented in Table 22 and Table 23.

Table 22: ITC-1. Main Baseline Characteristics Differences Between TRANSCEND and JULIET

allo = allogenic; auto = autologous; DLBCL = diffuse large B-cell lymphoma; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FL3B = follicular lymphoma grade 3B; HGL = high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6; HSCT = hematopoietic stem cell transplant; IPD = individual patient data; IPI = International Prognostic Index; ITC = indirect treatment comparison; liso-cel = lisocabtagene maraleucel; NOS = not otherwise specified; PMBCL = primary mediastinal B-cell lymphoma; R/R = relapsed or refractory; SPD = sum of the longest perpendicular diameters; tFL = DLBCL transformed from follicular lymphoma; tiNHL = DLBCL transformed from other indolent non-Hodgkin lymphoma.

Source: Sponsor-submitted ITC-1 report.¹²

Table 23: ITC-1. Main Baseline Characteristics Differences Between TRANSCEND and ZUMA-1

auto = autologous; axi-cel = axicabtagene ciloleucel; DLBCL = diffuse large B-cell lymphoma; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FL3B = follicular lymphoma grade 3B; HGL = high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6; HSCT = hematopoietic stem cell transplant; IPD = individual patient data; IPI = International Prognostic Index; ITC = indirect treatment comparison; liso-cel = lisocabtagene maraleucel; NOS = not otherwise specified; PMBCL = primary mediastinal B-cell lymphoma; R/R = relapsed or refractory; tFL = DLBCL transformed from follicular lymphoma tiNHL = DLBCL transformed from other indolent non-Hodgkin lymphoma.

Source: Sponsor-submitted ITC-1 report.¹²

For the liso-cel versus tisa-cel comparison, primary analyses of efficacy outcomes included 2 clinical factors in the weighting process. The investigators limited inclusion to these factors to ensure sufficient ESS across all outcome comparisons. The factors included were specific to each outcome based on a ranking system informed by expert opinion. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

For the liso-cel versus axi-cel comparison, analyses of efficacy outcomes were conducted for patients who did not receive bridging therapy (i.e., patients who received bridging therapy were excluded from the TRANSCEND study). In total, 5 clinical factors were included in the weighting. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Sensitivity analyses were also performed: first, a repeat of the primary analysis but including patients who received bridging therapy in the TRANSCEND study. Second, a repeat of the primary analyses but including patients who received bridging therapy in the TRANCSEND study and weighting for additional factors (exact factors were not specified). This was conducted to assess the effect of balancing more factors after gaining ESS upon including patients who received bridging therapy.

Results

Comparison of Liso-cel Versus Tisa-cel

For each set of efficacy outcomes, comparisons of ranked clinical factors at baseline were conducted without weighting patients from the TRANSCEND study. This exercise showed that few factors were similar between liso-cel and tisa-cel. Notable differences (i.e., standardized mean differences ≥ 0.2) were observed for age, ECOG PS, secondary CNS involvement, disease histology, cell of origin, prior allo-HSCT, prior auto-HSCT, bridging therapy, number of prior lines of therapy, CrCl before LDC, and pre-leukapheresis absolute lymphocyte count. After the weighting process, some key factors remained different between the data from the TRANSCEND and JULIET studies, such as age, bridging therapy, and prior lines of therapies. A comparison of clinical factors and standardized mean differences before and after weighting based on the MAIC for the end point of OS is presented in Table 24.

Table 24: ITC-1. Comparison of Clinical Factors and SMDs Before and After MAIC for Primary Analysis of Overall Survival for Liso-cel and Tisagenlecleucel