Phase 1 Study of Anito-cel, a d-Domain BCMA CAR T Cell for Refractory or Recurrent Myeloma

Author(s): Matthew J. Frigault, M.D.1,2; Binod Dhakal, M.D.3; Andrzej J. Jakubowiak, M.D., Ph.D.4; Noopur Raje, M.D.1,2; Kamalika Banerjee, M.A.5; C. Jenny Mu, Ph.D.5; Kevin C. Hart, Ph.D.6; Sigal Shachar, Ph.D.5; Lawrence P. Andrews, Ph.D.5; Laurene S. Cheung, Ph.D.5; Faith M. Griffin, Ph.D.5; Alexandra R. Witter, Ph.D.5; Michael Hyde, Ph.D.6; Chester Pham, Ph.D.6; Nikitha Gandra, M.S.6; Tenzin Shakya, M.S.6; Bhargavi Rajan, M.S.6; Christa Cortesio, Ph.D.6; Samuel T. Haile, Ph.D.6; Heba Nowyhed, Ph.D.5; Priyanka Nair-Gupta, Ph.D.6; Priyam Mitra, Ph.D.5; Rebecca J. Chan, M.D., Ph.D.5; Ana Kostic, M.D.5; Christopher R. Heery, M.D.5; Jacalyn Rosenblatt, M.D.7; Michael R. Bishop, M.D.8;
Source: DOI: 10.1056/NEJMoa2603527
Original Article
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Dr. Anjan Patel's Thoughts

These are very compelling phase 1 numbers in a heavily pretreated, all triple-class–refractory population. All 38 patients responded, 79% had a complete response, median progression-free survival (PFS) was 30 mos, and 3-year overall survival (OS) was 65%. The safety profile is the real headline: at the recommended dose there was no grade 3 or higher CRS, only one grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS), and none of the delayed parkinsonism, cranial-nerve palsies, or colitis we’ve learned to watch for with cilta-cel. That said, it’s a small single-arm study, and the “cleaner binder” comparison to cilta-cel is in vitro and hypothesis-generating, so the iMMagine phase 2/3 data will tell us whether this truly earns a spot ahead of cilta-cel.

BACKGROUND

Anitocabtagene autoleucel (anito-cel), a B-cell maturation antigen (BCMA)–directed autologous chimeric antigen receptor (CAR) T-cell therapy with a synthetic d-domain binder (ddBCMA), may have efficacy in patients with relapsed or refractory multiple myeloma.

METHODS

In a phase 1 study, we evaluated the safety and efficacy of anito-cel (dose level 1, 100×106 CAR+ T cells; dose level 2, 300×106 CAR+ T cells) in patients with relapsed or refractory multiple myeloma who had received three or more lines of therapy previously or had triple-class refractory disease. Primary end points were adverse events during the treatment period and establishment of the recommended phase 2 dose. In complementary in vitro studies, we compared the anito-cel ddBCMA binder with a dual variable heavy-chain domain of a heavy chain–only antibody (dual-VHH) binder corresponding to the published sequence for ciltacabtagene autoleucel.

RESULTS

Of 40 patients enrolled, 38 received anito-cel. All 38 patients had an adverse event during the treatment period, and 37 patients (97%) had an adverse event of grade 3 or higher. Among patients who received the recommended phase 2 dose (100×106 CAR+ T cells), 94% had cytokine release syndrome of grade 1 or 2, with no events of grade 3 or higher. A total of 16% of the patients had immune effector cell–associated neurotoxicity syndrome (ICANS) of grade 1 or 2, and 1 patient (3%) had a grade 3 event. No non-ICANS or delayed neurotoxic effects occurred. a median follow-up of 38.1 months, all 38 patients (100%) had had a response, with 79% having a complete response. The 24-month progression-free survival was 57%; the median progression-free survival was 30.2 months. The 36-month overall survival was 65%. The ddBCMA binder had a faster off-rate than the dual-VHH binder; although cytotoxicity was similar with the two therapies, ddBCMA CAR T cells led to less cytokine release and did not result in activation without antigen or in off-target cytotoxic effects.

CONCLUSIONS

Anito-cel therapy led to a high incidence of response among patients with heavily pretreated relapsed or refractory multiple myeloma. Cytokine release syndrome and ICANS of grade 3 or higher were rare. (Funded by Arcellx and Kite, a Gilead company; ClinicalTrials.gov number, NCT04155749.)

Author Affiliations

1Cellular Immunotherapy Program, Mass General Brigham Cancer Institute, Boston; 2Department of Medicine, Harvard Medical School, Boston; 3Division of Hematology, Medical College of Wisconsin, Milwaukee; 4Section of Hematology–Oncology, Department of Medicine, University of Chicago, Chicago; 5Arcellx, Redwood City, CA; 6Kite, a Gilead company, Santa Monica, CA; 7Department of Medicine, Beth Israel Deaconess Medical Center, Boston; 8David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago

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