Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study.

Background: Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT.
Methods: PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/m ² and intravenous cyclophosphamide 300 mg/m ² daily for 3 days) followed 2-7 days later by two sequential lisocabtagene maraleucel infusions (equal target doses of CD8 ⁺ and CD4 ⁺ CAR ⁺ T cells for a total target dose of 100 × 10 ⁶ CAR ⁺ T cells). The primary endpoint was the overall response rate and was assessed in all patients who received lisocabtagene maraleucel and had confirmed PET-positive disease before lisocabtagene maraleucel administration based on an independent review committee according to the Lugano 2014 criteria. Safety was assessed in all patients who received lisocabtagene maraleucel. Patient follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT03483103.
Findings: Between July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70-78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1-18·0). 49 (80% [95% CI 68-89]; p<0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths.
Interpretation: These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended.
Funding: Juno Therapeutics, a Bristol-Myers Squibb company.
Competing Interests: Declaration of interests AS reports honoraria from OncLive and PeerView Live, and research funding from Kite/Gilead and Juno Therapeutics, a Bristol-Myers Squibb company. PAR reports grants or contracts paid to his institution from CRISPR Therapeutics, Fate Therapeutics, Tessa Therapeutics, Xencor, Bristol Myers Squibb (BMS), Kite Pharma, Novartis, MorphoSys, and Scripps Research Institute; consulting fees from Bayer Healthcare, BeiGene USA, BMS, Kite Pharma, and Novartis; honoraria from Kite Pharma, Novartis, and Bayer Healthcare; and participation on data safety monitoring boards or advisory boards from Karyopharm Therapeutics, Takeda Oncology, Novartis, Janssen Biotech, Celgene, a Bristol-Myers Squibb company, BMS, and Kite Pharma. NGh reports consulting fees from Seattle Genetics, TG Therapeutics, AstraZeneca, Pharmacyclics/Janssen, BMS, Gilead Sciences, BeiGene, Incyte, Karyopharm Therapeutics, Roche/Genentech, Novartis, Loxo/Lilly, Genmab, Adaptive Biotechnologies, and ADC Therapeutics; honoraria from Kite/Gilead, AstraZeneca, BMS, Pharmacyclics/Janssen, and Epizyme; and research funding from Pharmacyclics, TG Therapeutics, Genentech/Roche, BMS/Celgene, a Bristol-Myers Squibb company, Gilead Sciences, MorphoSys, and AbbVie. MH reports consulting fees from Incyte, ADC Therapeutics, Omeros, Verastem, MorphoSys, Kite, Genmab, Seagen, Gamida Cell, Novartis, and Legend Biotech; honoraria from Sanofi Genzyme, AstraZeneca, BeiGene, and ADC Therapeutics; research funding from Takeda Pharmaceutical, ADC Therapeutics, Spectrum Pharmaceuticals, and Astellas Pharma; and membership of a data monitoring committee for Myeloid Therapeutics. GCH reports consulting fees from Incyte, MorphoSys, Alexion Pharmaceuticals, Karyopharm Therapeutics, Seattle Genetics, and Janssen Pharmaceuticals; support for attending meetings or travel from Incyte, Falk Foundation, and Takeda; stock or stock options from Novartis, Insys Therapeutics, AbbVie, GW Pharmaceuticals, Cardinal Health, Immunomedics, Endocyte, Clovis Oncology, Cellectis, Aetna, CVS Health, Celgene, a Bristol-Myers Squibb company, Bluebird Bio, BMS, CRISPR Therapeutics, IDEXX Laboratories, Johnson & Johnson, Pfizer, Procter & Gamble, Vertex, Bayer, Scotts Miracle-Gro, Charlotte's Web, Aimmune Therapeutics, Medical Properties Trust, CareTrust REIT, ANGI, and Moderna Therapeutics; and research funding from Takeda, Jazz Pharmaceuticals, Pharmacyclics, Incyte, and AstraZeneca. JEG reports honoraria for speaker's bureau from BMS outside of the submitted work. PMR reports consulting fees from Kite Pharma, and research funding to his institution from Seagen and Genentech. NW-J reports participation on a data safety monitoring board or advisory board for Grünenthal, Epizyme, and ADC Therapeutics. JE reports honoraria for speaker's bureau from Kite and BMS. RN reports consulting fees from Actinium, and stock or stock options from Pfizer. RC reports honoraria for speaker's bureau from BMS and AbbVie. SF reports consulting fees from Takeda, BMS, Sanofi Aventis, TG Therapeutics, and AbbVie. NGu reports honoraria from Incyte and research funding from BMS. RD is an employee of BMS and current equity holder in BMS, Gilead Sciences, and Cellectis. AD'A is an employee of Celgene, a Bristol-Myers Squibb company; attended data safety morning board meetings for the study; and is a current equity holder in BMS. LW, KO, and JT are employees of BMS, and current equity holders in BMS. LIG reports consulting fees from AstraZeneca, Karyopharm Therapeutics, Janssen, Epizyme, and Kite/Gilead; a patent on gold nanoparticles for cancer; being co-founder of Zylem Biosciences; and being member of a Janssen data safety monitoring board (planned). All other authors declare no competing interests.
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