Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial

TRANSFORM Investigators

Research output: Contribution to journalArticleAcademicpeer-review

321 Citations (Scopus)

Abstract

Background: Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL. Methods: TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed LBCL. Adults aged 18–75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET–positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 × 106 CAR+ T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously—R-DHAP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1–4, two infusions of cytarabine 2000 mg/m2 on day 2, and cisplatin 100 mg/m2 on day 1), R-ICE (rituximab 375 mg/m2 on day 1, ifosfamide 5000 mg/m2 on day 2, etoposide 100 mg/m2 on days 1–3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1–4, gemcitabine 1000 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1)—followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing. Findings: Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6·2 months (IQR 4·4–11·5). Median event-free survival was significantly improved in the liso-cel group (10·1 months [95% CI 6·1–not reached]) compared with the standard-of-care group (2·3 months [2·2–4·3]; stratified hazard ratio 0·35; 95% CI 0·23–0·53; stratified Cox proportional hazards model one-sided p<0·0001). The most common grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the liso-cel group vs 46 [51%] of 91 patients in the standard-of-care group), anaemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs three [3%]). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel safety concerns were identified in the second-line setting. There were no treatment-related deaths in the liso-cel group and one treatment-related death due to sepsis in the standard-of-care group. Interpretation: These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL. Funding: Celgene, a Bristol-Myers Squibb Company.

Original languageEnglish
Pages (from-to)2294-2308
Number of pages15
JournalThe Lancet
Volume399
Issue number10343
DOIs
Publication statusPublished - 18 Jun 2022

Bibliographical note

Funding Information:
This study was funded by Celgene, a Bristol Myers Squibb company. All authors contributed to and approved the manuscript; writing and editorial assistance were provided by Cindy Tsao, PhD (Bristol Myers Squibb, Princeton, NJ, USA), and Jeremy Henriques, PhD, Allison Green, PhD, and Lauren Connor, BS, ELS, of The Lockwood Group (Stamford, CT, USA), funded by Bristol Myers Squibb.

Funding Information:
MK is a consultant for ADC Therapeutics, Celgene, a Bristol Myers Squibb (BMS) company, Adaptive Biotechnologies, AbbVie, AstraZeneca, and BeiGene, outside of the submitted work; reports speakers bureau fees for Seagen outside of the submitted work; and reports research funding from TG Therapeutics, Genentech, and Novartis, outside of the submitted work. JA reports honoraria from Juno Therapeutics and BMS, outside of the submitted work. BG is a consultant for BMS, Roche, Kite, and Novartis, outside of the submitted work; reports research funding from Roche and Riemser, outside of the submitted work; reports speakers bureau from Roche outside of the submitted work; and is a current employee of Helios Klinik Berlin-Buch. VB reports membership on Board of Directors or advisory committees for Karyopharm, FATE, and Gamida Cell, outside of the submitted work; and research funding from Incyte, FATE, and Gamida Cell, outside of the submitted work. SI reports divested equity in the past 24 months from Karyopharm Therapeutics outside of the submitted work. SM reports speakers bureaus for Novartis, DNA Prime, and Celgene–BMS, outside of the submitted work; travel support and expert panel from Gilead Kite, outside of the submitted work; and is on the data safety monitoring board for Miltenyi Biotec and Immunicum, outside of the submitted work. PM is a consultant for BMS and received research funding from AstraZeneca, outside of the submitted work. FH-I reports advisory boards from Amgen, Kite, Pharmacyclics, BMS, Celgene, Incyte, Abbvie, Gilead, and Epizyme, outside of the submitted work. KI reports honoraria from Daiichi Sankyo, Eisai, Fuji Film Toyama Chemical, Genmab, Janssen, Kyowa Kirin, Novartis, Ono Pharmaceutical, Symbio, Takeda, Chugai, Celgene, AstraZeneca, Allergan Japan, and AbbVie outside of the submitted work; and research funding from Daiichi Sankyo, Eisai, Genmab, Incyte, Huya Biosciences, Janssen, Kyowa Kirin, Merck Sharpe & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Solasia, Takeda, Yakult, Chugai, Celgene, BeiGene, Bayer, and AstraZeneca, outside of the submitted work. FM is a member on Board of Directors or advisory committees for AstraZeneca, Novartis, Celgene, Incyte, Epizyme, BMS, F Hoffmann-La Roche, AbbVie, Gilead, and Genmab, outside of the submitted work; is a consultant for Genentech, Novartis, Epizyme, BMS, Servier, F Hoffmann-La Roche, AbbVie, and Gilead, outside of the submitted work; and reports honoraria from Janssen, F Hoffmann-La Roche, and Chugai; and reports speakers bureau from F Hoffmann-La Roche outside of the submitted work. ML is a consultant for Karyopharm Therapeutics, AstraZeneca, Legend, Verastem, Janssen, Myeloid Therapeutics, Daiichi Sankyo, Novartis, Spectrum, Celgene, a BMS company, AbbVie, Acrotech, Beigene, ADC Therapeutics, TG Therapeutics, MorphoSys, Kite, a Gilead company, and Kyowa Kirin, outside of the submitted work. DGM reports honoraria from Amgen, Celgene, A2 Biotherapeutics, BMS, Umoja, Janssen, Legend Biotech, Genentech, Novartis, MorphoSys, Navan Technologies, Kite Pharma, and Juno Therapeutics, outside of the submitted work; rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/BMS from Celgene, BMS, and Juno Therapeutics, outside of the submitted work; research funding paid to his institution from Celgene, Juno Therapeutics, and Kite Pharma, outside of the submitted work; stock options from A2 Biotherapeutics and Navan Technologies, outside the submitted work; and research funding from Celgene and Juno Therapeutics, outside of the submitted work. AC, AP, and SM are current employees of Celgene, a BMS company; and current equity holders in BMS. KO and LS are current employees of BMS; and current equity holders in BMS. TM was an employee of BMS at the time this research was conducted; and is a current equity holder in BMS. JSA is a consultant for Kymera, Genentech, Incyte Corporation, BeiGene, AstraZeneca, MorphoSys, Bluebird Bio, Genmab, EMD Serono, BMS, C4 Therapeutics, Karyopharm Therapeutics, AbbVie, Allogene Therapeutics, Kite Pharma, and Novartis, outside of the submitted work; and received research funding from BMS and Seagen, outside of the submitted work. SRS and PBJ declare no competing interests.

Publisher Copyright:
© 2022 Elsevier Ltd

Fingerprint

Dive into the research topics of 'Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial'. Together they form a unique fingerprint.

Cite this