Rationale for Requested Change: On behalf of Bristol Myers Squibb, we respectfully request the NCCN B-Cell Lymphomas Guidelines Panel to review the enclosed data regarding the use of liso-cel for the treatment of adult patients with R/R FL. Liso-cel currently has a category 2A recommendation for third-line (3L) or later (3L+) FL in the NCCN Guidelines for B-Cell Lymphomas, Version 2.2024.
This new submission request is based on the results from the phase 2 TRANSCEND FL (NCT04245839) study evaluating the efficacy and safety of liso-cel in patients (n = 130) with R/R FL, including 2L patients who all had progression of disease = 24 months (POD24) from diagnosis after treatment with anti-CD20 antibody and alkylator = 6 months of FL diagnosis and/or met modified Groupe d'Etude des Lymphomes Folliculaires (mGELF) criteria, as well as patient-reported outcomes (PRO) data. These data were published in Nature Medicine on June 3, 2024 [2].
FL is currently an incurable disease, and patients with progressive disease can often experience multiple relapses with recycled treatments, indicating significant disease and treatment burden. Patients with POD24 of initial diagnosis have worse survival outcomes in as early as the first-line treatment, with 5-year survival of 50% for those with FL POD24 compared with 90% survival for non-POD24 FL [3]. A 2023 treatment patterns analysis revealed the use of anti-CD20 monotherapy remained high across all treatment lines for both commercially insured and Medicare-insured patients with POD24 R/R FL [4]. Time to next treatment was noticeably short across multiple lines of treatment settings, indicating a quick time to progression and potentially suboptimal responses to recycled treatments [4]. Real-world evidence suggests that there is a high unmet need and clinical disease burden for patients with fast-progressing POD24 FL, demonstrating the need for more innovative therapies such as a 1-time infusion [4-6].
TRANSCEND FL is a global, phase 2, open-label, single-arm, multicohort, multicenter study evaluating efficacy and safety of liso-cel in patients with R/R indolent non-Hodgkin lymphoma. For FL cohorts, the study enrolled patients = 18 years of age with histologically confirmed FL = 6 months of screening as assessed by local pathology. Patients with Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate bone marrow, kidney, liver, and cardiac function were eligible for the study. All patients must have received = 1 prior line of combination systemic therapy with an anti-CD20 antibody and alkylator. Cohort assignment was as follows: fourth-line or later (4L+) FL and 3L cohort patients had received = 3 and 2 prior lines of systemic therapy, respectively; 2L FL cohort patients had received 1 prior line of therapy and must have met POD24 criteria per protocol (ie, progressed = 24 months of diagnosis and treated with an anti-CD20 antibody and alkylating agent = 6 months of initial FL diagnosis) and/or = 1 of the mGELF criteria [2].
Eligible patients underwent leukapheresis for liso-cel manufacturing. Treatment consisted of lymphodepleting chemotherapy (LDC; intravenous fludarabine 30 mg/m2/day and intravenous cyclophosphamide 300 mg/m2/day for 3 days) followed 2—7 days later by a single liso-cel infusion at a total target dose of 100 × 106 CAR+ T cells. Optional bridging therapy was allowed per treating investigator for disease control during liso-cel manufacturing and required reconfirmation of positron emission tomography (PET)/computed tomography (CT)—positive disease before LDC. Retreatment with liso-cel was not allowed. Patients will be followed for safety, disease status, and survival until 5 years after liso-cel infusion [2].
The primary endpoint was overall response rate (ORR) per independent review committee (IRC) by PET/CT per Lugano 2014 criteria. Secondary efficacy endpoints were complete response (CR) rate, DOR, DOR in patients with a best overall response of CR, progression-free survival (PFS), and overall survival (OS). PET/CT assessments were performed at screening; at Days 29 and 90; and Months 6, 9, 12, 18, 24, 36, 48, and 60. Additional secondary endpoints were safety, cellular kinetics, and PROs. Efficacy subgroup analyses (conducted for subgroups with = 5 patients) and peripheral B-cell aplasia were assessed as exploratory endpoints [2].
Treatment-emergent adverse events (TEAE) were defined as an adverse event (AE) that started from liso-cel administration through and including 90 days after liso-cel infusion. AEs of special interest included infusion-related reaction, CRS, NEs (defined as investigator-identified neurological AEs related to liso-cel), macrophage activation syndrome/hemophagocytic lymphohistiocytosis, tumor lysis syndrome, grade = 3 infection, prolonged cytopenias (defined as grade = 3 laboratory abnormalities of neutropenia, anemia, or thrombocytopenia at Day 29), hypogammaglobulinemia, and second primary malignancy [2].
Hierarchical hypothesis testing was used to control type I error across lines of therapy (4L+ FL, 3L+ FL [4L+ and 3L FL cohorts], and 2L FL) and endpoints (ORR and CR rate) at a 1-sided a level of 0.025.
Safety was assessed in all liso-cel—treated patients (2L or later [2L+] FL; liso-cel—treated set). Efficacy was evaluated in the efficacy set (all patients in the liso-cel—treated set who had PET/CT-positive disease per IRC before liso-cel administration; excluded patients who did not have a baseline assessment repeated after bridging therapy) and reported by lines of therapy. Time-to-event endpoints were summarized with medians and 95% confidence intervals (CI) using the Kaplan–Meier method. For DOR and PFS, patients without documented progressive disease or death were censored at the date of the last adequate disease assessment. For assessment of OS, data from surviving patients was censored at the last time that the patient was known to be alive. Sensitivity analysis of efficacy was performed in leukapheresed patients (ie, the intent-to-treat set) [2].
From July 14, 2020, to January 27, 2023, 139 patients were enrolled and leukapheresed in the FL cohorts (2L+, n = 139; 3L+, n = 114; 2L, n = 25) at 31 sites in North America, Europe, and Japan. Liso-cel was successfully manufactured for 133/139 (96%) patients. Four patients were not infused, including 1 with an AE of acute respiratory failure (enterovirus/rhinovirus pneumonia), 1 with transformed FL, and 2 with PET/CT–negative disease at the pretreatment assessment; 5 received nonconforming product. Thus, 130 patients with 2L+ FL (2L, n = 23; 3L+, n = 107) received liso-cel (liso-cel—treated set) and 124 (2L, n = 23; 3L+, n = 101) were efficacy evaluable per IRC (efficacy set) [2].
At the data cutoff on January 27, 2023, median on-study follow-up was 18.9 months (range, 0.3—28.2). In the liso-cel—treated 2L+ set, median age was 60 years (range, 23—80; 3L+, median 62 years; 2L, median 53 years), 86% had Ann Arbor stage III/IV disease (3L+, 89%; 2L, 74%), 53% had high-risk FL International Prognostic Index (3L+, 57%; 2L, 35%), 45% had POD24 from diagnosis after treatment with an anti-CD20 antibody and an alkylating agent within the first 6 months of initial FL diagnosis (3L+, 43%; 2L, 52%), 56% met mGELF criteria (3L+, 53%; 2L, 70%), and 62% were double refractory (ie, refractory to both an anti-CD20 antibody and alkylating agent or to anti-CD20 maintenance, defined as patients whose disease did not respond or progressed during or up to 6 months after completing treatment with an anti-CD20 antibody and an alkylating agent or maintenance treatment with an anti-CD20 antibody; 3L+, 64%; 2L, 48%). Fifty-six percent of patients had POD24 from initiation of first-line systemic therapy with anti-CD20 antibody plus alkylator (3L+, 54%; 2L, 65%). The median time from diagnosis to liso-cel infusion was 4.7 years (range, 0.7—35.3; 3L+, median 5.1 years; 2L, median 2.0 years). Bridging therapy for disease control during liso-cel manufacturing was used in 38% of patients (3L+, 41%; 2L, 22%) [2].
2L FL results
In patients with 2L FL, the ORR was 96% (95% CI, 78.1—99.9; P < 0.0001), with all responders achieving a CR. Median DOR was not reached (NR; 95% CI, 19.3—NR) at a median follow-up of 16.8 months, and 12-month DOR rate was 90% (95% CI, 64.8—97.4). Median PFS was NR (95% CI, 20.2—NR) at a median follow-up of 17.8 months, and the 12-month PFS rate was 91% (95% CI, 69.5—97.8). Median OS was NR and 12-month OS rate was 96% (95% CI, 72.9—99.4). Results from the subgroup analyses (efficacy analysis set) were consistent with the primary analysis. ORR, CR rate, DOR, and PFS (defined by 12-month estimates of continued response rate and PFS rate) remained high across patient subgroups, including those with high-risk disease features. Response rates were similar in the intent-to-treat (leukapheresed) population, with ORR of 92% (95% CI, 74.0—99.0), with all responders achieving a CR [2].
Among 2L liso-cel—treated patients, 14 (61%) patients had grade = 3 TEAEs and 4 (17%) experienced serious TEAEs. The most common grade = 3 TEAEs were cytopenias, including neutropenia in 12 (52%) patients, and anemia and thrombocytopenia in 1 (4%) patient each. Two patients (9%) had febrile neutropenia. Any-grade CRS occurred in 12 (52%) patients with a median onset of 6 days and median duration of 3 days. Most CRS events were grade 1 (30%), with no grade = 3 events. CRS was managed with tocilizumab alone in 9% of patients and both tocilizumab and corticosteroids in 4%. No patients received vasopressors. Any-grade NEs occurred in 17% of patients, with a median onset of 8.5 days and median duration of 2.5 days. Most NEs in 2L+ were grade 1 (13%), with grade 3 in 4% of patients and no grade 4 or 5 events. NEs were managed with corticosteroids alone in 9% of patients and no patients received both tocilizumab and corticosteroids. Among other TEAEs of special interest, no grade = 3 infections were reported in 2L patients within the 90-day treatment-emergent period. Prolonged cytopenia (grade = 3 cytopenias based on laboratory values at Day 29) was reported in 13% of patients. Of patients with prolonged cytopenia and laboratory results after Day 29, 100% of patients with neutropenia and 100% with thrombocytopenia had recovered to grade = 2 by Day 90 [2].
3L+ FL results
In patients with 3L+ FL, ORR was 97% (95% CI, 91.6—99.4; P < 0.0001), with 92 of 95 responders achieving CR; CR rate was 94% (95% CI, 87.5—97.8; P < 0.0001). Median DOR was NR (95% CI, 18.0—NR) at a median follow-up of 16.6 months, and 12-month DOR rate was 82% (95% CI, 72.5—88.4). Median PFS was NR (95% CI, 19.0—NR) at median follow-up of 17.6 months, and 12-month PFS rate was 81% (95% CI, 71.4—87.2). Median OS was NR and 12-month OS rate was 92% (95% CI, 84.8—96.0). Results from the subgroup analyses were consistent with the primary analysis. ORR, CR rate, DOR, and PFS (defined by 12-month estimates of continued response rate and PFS rate) remained high across patient subgroups, including those with high-risk disease features. Response rates were similar in the intent-to-treat (leukapheresed) population, with ORR of 93% (95% CI, 86.6—96.9) and CR rate of 90% (95% CI, 83.4—95.1) [2].
Among 3L+ liso-cel—treated patients, 83 (78%) patients had grade = 3 TEAEs and 28 (26%) experienced serious TEAEs. The most common grade = 3 TEAEs were cytopenias, including neutropenia in 64 (60%) patients, and anemia and thrombocytopenia in 12 (11%) patients each. Six (6%) patients had febrile neutropenia. Any-grade CRS occurred in 63 (59%) patients with a median onset of 6 days and median duration of 4 days. Most CRS events were grade 1 (45%), with grade 3 in only 1 (1%) patient and no grade 4 or 5 events. CRS was managed with tocilizumab alone in 15% of patients and both tocilizumab and corticosteroids in 13%. Two (2%) patients received vasopressors. Any-grade NEs occurred in 15% of patients, with a median onset of 8.5 and median duration of 4.5 days. Most NEs were grade 1 (11%) with grade 3 in 2% of patients and no grade 4 or 5 events. NEs were managed with corticosteroids alone in 6% of patients and both tocilizumab and corticosteroids in 1%. Among other TEAEs of special interest, grade = 3 infections were reported in 7 (7%) patients within the 90-day treatment-emergent period. Prolonged cytopenia (grade = 3 cytopenias based on laboratory values at Day 29) was reported in 24% of patients. Of patients with prolonged cytopenia and laboratory results after Day 29, 89% of patients with neutropenia, 83% with anemia, and 56% with thrombocytopenia had recovered to grade = 2 by Day 90 [2].
PRO
For PRO measures, patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy - Lymphoma “Additional Concerns” Scale (FACT-LymS). Among patients with 2L and 3L+ FL, completion rates for EORTC QLQ-C30 assessments were 70%—95% from baseline through Month 18 (Day 545); completion rates were similar for FACT-LymS. In both 2L and 3L+ FL cohorts, the mean scores on most primary domains improved at the Day 29 visit compared with baseline and were generally maintained throughout subsequent visits. The mean scores for most secondary domains also showed improvement by Day 29, and this improvement was sustained throughout subsequent visits in both cohorts. Additionally, at some visits, the improvements exceeded the contemporary threshold for clinically meaningful improvement, similar to the primary domains [2].
Overall least squares mean changes from baseline through Day 730 showed statistically significant improvements in the following primary domains of interest: global health status (3L+ FL), fatigue (2L FL), pain (2L and 3L+ FL), and FACT-LymS (2L and 3L+ FL). Significant improvements were also observed in some secondary domains of interest in both cohorts. Median time to confirmed improvement occurred within 3 months across all primary domains in both cohorts, except for fatigue and FACT-LymS in 3L+ FL. In 3L+ FL, median time to confirmed improvement was 10.4 weeks for global health status, 11.1 weeks for physical functioning, 10.7 weeks for role functioning, 10.0 weeks for cognitive functioning, 27.1 weeks for fatigue, 5.0 weeks for pain, and 27.1 weeks for FACT-LymS. Median time to confirmed improvement was shorter for 2L FL than 3L+ FL for all primary domains except global health status. In individual-level analyses, from Day 29 onward, most 3L+ FL patients reported improvement or no change across all primary domains as follows: 60%—93% at Day 29, 71%—85% at Day 90, 67%—81% at Month 12, and 65%—83% at Month 18. Results were similar in 2L FL [2].
Copies of the TRANSCEND FL primary analysis publication (Morschhauser et al, 2024) and associated supplementary materials, and the BREYANZI full Prescribing Information, are enclosed for your review.
• BREYANZI® (lisocabtagene maraleucel) [package insert]. Bothell, WA: Juno Therapeutics Inc., a Bristol-Myers Squibb Company; June 2024.
• Morschhauser F, Dahiya S, Palomba ML, et al. Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med. 2024. doi: 10.1038/s41591-024-02986-9.
References
1. BREYANZI® (lisocabtagene maraleucel) [package insert]. Bothell, WA: Juno Therapeutics Inc., a Bristol-Myers Squibb Company; June 2024.
2. Morschhauser F, Dahiya S, Palomba ML, et al. Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med. 2024. doi: 10.1038/s41591-024-02986-9.
3. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol 2015;33:2516—2522.
4. Saunders A, LeMasters T, Ogando Y, Raina R. Treatment patterns, health care resource utilization, and cost among commercially insured patients with relapsed/refractory follicular lymphoma in the United States: MarketScan 2015-2021. J Manag Care Spec Pharm 2023;29(10a suppl):S30.
5. Saunders A, Milloy N, Bailey A, Biondi E. Real-world clinical characteristics and treatment patterns in fast-progressing patients with follicular lymphoma in the United States. J Manag Care Spec Pharm 2023;29(10a suppl):S30—S31.
6. Saunders A, LeMasters T, Raina R, Ogando Y. Patient characteristics, treatment patterns, and survival of older patients in the United States with relapsed or refractory follicular lymphoma: Surveillance, Epidemiology, and End Results: Medicare 2012-2019. J Manag Care Spec Pharm 2023;29(10a suppl):S29—S30.
Your consideration of this submission is appreciated.
Sincerely,
Doreen Valentine, PhD
Executive Director | Medical Communications, Hematology & Cell Therapy
Alberto Vasconcelos, MMed
Executive Director | Worldwide Medical Affairs, BREYANZI Lead
