Safety and Preliminary Efficacy in Patients with Relapsed/Refractory Mantle Cell Lymphoma Receiving Lisocabtagene Maraleucel in Transcend NHL 001

Abstract

Background: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL). Most patients with MCL relapse after first-line immunochemotherapy, with poor responses to salvage therapy. Chimeric antigen receptor (CAR) T cell therapy has shown clinical efficacy in patients with relapsed/refractory (R/R) NHL. We report the results of the dose-finding and dose-expansion parts of the ongoing phase 1 TRANSCEND NHL 001 study (NCT02631044) in patients with R/R MCL (MCL cohort) who received lisocabtagene maraleucel (liso-cel), an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Methods: Eligible patients had confirmed MCL (cyclin D1 expression, t[11;14]) with R/R disease after ≥1 prior line of therapy. After lymphodepleting chemotherapy, patients received liso-cel infusion at 1 of 2 dose levels (DLs): DL1 (50 × 106 CAR+ T cells) or DL2 (100 × 106 CAR+ T cells). Bridging therapy was allowed between leukapheresis and initiation of lymphodepleting chemotherapy. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included complete response (CR) rate, duration of response, progression-free survival, overall survival, and pharmacokinetics (PK). Results: At data cutoff, 41 patients had undergone leukapheresis and 32 had received liso-cel (DL1, n = 6; DL2, n = 26). Among the 32 patients who received liso-cel, the median (range) age was 67 (36‒80) years and 27 patients (84%) were male. Twelve patients (37.5%) had blastoid morphology, 23 (72%) had documented Ki67 ≥30%, 7 (22%) had a TP53 mutation, and 11 (34%) had a complex karyotype. Patients had a median (range) sum of the product of perpendicular diameters before lymphodepleting chemotherapy of 28.7 (0-209.6) cm2 and median lactate dehydrogenase of 251.5 (117-811) U/L. Patients had received a median (range) of 3 (1-7) prior systemic therapies, and most (72%) were refractory to their last prior therapy. Of 28 patients (87.5%) who had received a prior Bruton tyrosine kinase inhibitor, 11 (34%) were refractory to the therapy. Seventeen patients (53%) received bridging therapy. Eighteen patients (56%) had serious treatment-emergent adverse events (TEAEs), and 27 (84%) had grade ≥3 TEAEs, primarily neutropenia (41%), anemia (34%), and thrombocytopenia (31%). Grade ≥3 thrombocytopenia was more frequent at DL2 (n = 9/26 [35%]) than at DL1 (n = 1/6 [17%]). Prolonged grade ≥3 cytopenias (present at study Day 29) occurred in 11 patients (34%). Sixteen patients (50%; DL1, n = 2/6 [33%]; DL2, n = 14/26 [54%]) had cytokine release syndrome (CRS), including 1 grade 4 event at DL2. There were no grade 3 or 5 CRS events. Median (range) time to CRS onset and resolution was 6 (2‒10) days and 4 (2‒9) days, respectively. Nine patients (28%) had neurological events (NEs), all at DL2, including 3 grade 3 NEs. No grade 4 or 5 NEs were reported. Median (range) time to NE onset and resolution was 8 (2‒25) days and 3 (1‒51) days, respectively. Ten patients (31%) received tocilizumab and/or corticosteroids for treatment of CRS and/or NEs. Grade 5 TEAEs occurred in 2 patients (at DL2): one patient with high tumor burden had tumor lysis syndrome and 1 patient had cryptococcal meningoencephalitis. DL2 was selected for dose expansion. Of 32 patients, 27 responded to liso-cel (ORR, 84%: DL1, n = 4/6 [67%]; DL2, n = 23/26 [88%]), and 19 (59%) achieved a CR (DL1, n = 2/6 [33%]; DL2, n = 17/26 [65%]). Among the 12 patients with blastoid morphology, 9 patients had a response (ORR, 75%), including 7 (58%) who achieved a CR. Overall, the median (range) time to first CR was 1 (1-6) month. At data cutoff, 20 (74%) of 27 responders were censored with an ongoing response or had completed the study. Median (range) follow-up duration was 10.9 (1.2-24.8) months for DL1 and 3.1 (0.4-23.0) months for DL2. Preliminary PK analysis indicated that median maximum expansion was higher among patients at DL2 than at DL1. Conclusions: In this phase 1 study of patients with R/R MCL, treatment with liso-cel was associated with a low incidence of grade ≥3 CRS and NEs, late onset of CRS/NEs, and promising clinical activity. Dose confirmation is ongoing at DL2 in the MCL cohort. Disclosures Palomba: Pharmacyclics: Honoraria; Juno: Honoraria; Celgene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Regeneron: Research Funding; Juno: Research Funding; Genentech: Research Funding. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Siddiqi:Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; AstraZeneca: Other: Travel/accommodations/expenses; Astrazenca: Membership on an entity's Board of Directors or advisory committees; PCYC: Membership on an entity's Board of Directors or advisory committees. Abramson:Celgene: Honoraria, Other: Scientific Advisory Board; Juno Therapeutics: Other: Scientific Advisory Board; AbbVie: Other: Scientific Advisory Board; EMD Serono: Other: Scientific Advisory Board; Genentech/Roche: Other: Scientific Advisory Board; Janssen: Other: Scientific Advisory Board; Karyopharm: Other: Scientific Advisory Board; Gilead: Other: Scientific Advisory Board; Verastem: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board; Merck: Other; KIte Pharma: Other; Novartis: Other; Amgen: Other; Seattle Genetics: Other; Allogene: Other; Morphosys: Other; C4 Therapeutics: Other; BeiGene: Other; AstraZeneca: Honoraria; Incyte: Honoraria. Kamdar:Seattle Genetics: Speakers Bureau; Karyopharm: Consultancy; BMS: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy. Lunning:Acrotech: Consultancy; ADC Therapeutics: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; Curis: Research Funding; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria. Maloney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Bioline Rx: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Andreadis:Genentech: Other: Spouse Employee (salary and stock); Novartis: Research Funding; Celgene/Juno: Research Funding; Amgen: Research Funding; Merck: Research Funding; Gilead/Kite: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Astellas: Other: Advisor; Seattle Genetics: Other: Advisor; Karyopharm: Other: Advisor; Incyte: Other. Arnason:Regeneron: Consultancy; Juno: Consultancy. Ghosh:Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Genmab: Consultancy, Speakers Bureau; AbbVie: Speakers Bureau; Karyopharm: Consultancy; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Kite/Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Roche/Genentech: Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Celgene/Bristol-Myers Squibb: Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau. Mehta:Innate Pharmaceuticals: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding; Takeda: Research Funding; Roche-Genentech: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Affimed: Research Funding. Farazi:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Garcia:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Dehner:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Ogasawara:Bristol-Myers Squibb: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Gao:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current Employment. Wang:Juno: Consultancy, Research Funding; Acerta Pharma: Research Funding; Loxo Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Pulse Biosciences: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Targeted Oncology: Honoraria; BioInvent: Research Funding; VelosBio: Research Funding.

Relapsed Mantle Cell Lymphoma: Current Management, Recent Progress, and Future Directions

“…Lisocabtagene maraleucel (liso-cel; formerly JCAR017) is an autologous anti-CD19 CAR-T containing a 41BB signaling domain with a defined and separately administered CD4+ and CD8+ CAR-T dose currently under development for the treatment of B cell malignancies, including adult patients with r/r DLBCL and MCL. Results from the diffuse large B cell lymphoma patient cohort of the Phase 1/2 seamless design TRANSCEND NHL 001 study of liso-cel have recently been published [ 65 ], and preliminary results from 32 patients treated in the MCL cohort were recently presented in abstract form [ 66 ]. Baseline characteristics among the 32 treated MCL patients included blastoid morphology in 41%, TP53 mutation in 22%, ≥3 prior lines of treatment in 69%, and prior BTKi treatment in 88%.…”

A Review of Chimeric Antigen Receptor T-Cell Therapy for Myeloma and Lymphoma

“…CRS was seen in 50% of the cases, but only a single grade ≥3 CRS event occurred, and less than 10% experienced grade ≥3 neurologic events. 31 …”

CAR T-Cell therapies in lymphoma: current landscape, ongoing investigations, and future directions

“…Axi-cel, tisa-cel, and liso-cel have not been compared head-to-head, and probably never will be, but since all have been shown to produce durable remissions in a significant proportion of treated patients, choice of product for an individual patient may take into account additional factors including availability, processing time, and side effect profiles (discussed below). Real-world experience with axi-cel and tisa-cel shows that up to 62% of "real world" patients treated with a commercial product would not have met clinical trial eligibility criteria, but encouragingly, outcomes are similar for these patients compared to patients treated on the pivotal trials [21][22][23][24] .…”