First phase 3 results from CARTITUDE-4: Cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma.

person Binod Dhakal Medical College of Wisconsin, Milwaukee, WI info_outline Binod Dhakal, Kwee Yong, Simon J. Harrison, Maria-Victoria Mateos, Philippe Moreau, Niels W.C.J. van de Donk, Surbhi Sidana, Rakesh Popat, Nikoletta Lendvai, Carolina Lonardi, Ana Slaughter, Jordan Mark Schecter, Katherine Li, Enrique Zudaire, Ying Chen, Jane Gilbert, Lida Bubuteishvili-Pacaud, Nitin Patel, Jesús San-Miguel, Hermann Einsele

Authors person Binod Dhakal Medical College of Wisconsin, Milwaukee, WI info_outline Binod Dhakal, Kwee Yong, Simon J. Harrison, Maria-Victoria Mateos, Philippe Moreau, Niels W.C.J. van de Donk, Surbhi Sidana, Rakesh Popat, Nikoletta Lendvai, Carolina Lonardi, Ana Slaughter, Jordan Mark Schecter, Katherine Li, Enrique Zudaire, Ying Chen, Jane Gilbert, Lida Bubuteishvili-Pacaud, Nitin Patel, Jesús San-Miguel, Hermann Einsele Organizations Medical College of Wisconsin, Milwaukee, WI, University College London Cancer Institute, London, United Kingdom, Peter MacCallum Cancer Centre, Melbourne, Australia, University Hospital of Salamanca/IBSAL/CIC/CIBERONC, Salamanca, Spain, Hematology Clinic, University Hospital Hôtel-Dieu, Nantes, France, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands, Stanford University School of Medicine, Stanford, CA, University College London Hospitals NHS Foundation Trust, London, United Kingdom, Janssen Research & Development, Raritan, NJ, Janssen, Buenos Aires, Argentina, Cilag GmbH International, Zug, Switzerland, Janssen Research & Development, Spring House, PA, Janssen Research & Development, Shanghai, China, Janssen Research & Development, High Wycombe, United Kingdom, Legend Biotech USA Inc., Somerset, NJ, University of Navarra, Pamplona, Spain, Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Janssen Research & Development, LLC, Legend Biotech USA Inc Background: CARTITUDE-4 is a global, phase 3, randomized, controlled trial (NCT04181827) of ciltacabtagene autoleucel (cilta-cel), a dual-binding, BCMA-targeting CAR-T cell therapy, vs standard of care (SOC; pomalidomide, bortezomib, and dexamethasone [PVd] or daratumumab, pomalidomide, and dexamethasone [DPd]) in lenalidomide (len)-refractory patients (pts). Methods: Eligible pts had 1–3 prior lines of therapy (LOT), including PI and IMiD, and were len-refractory. After apheresis, pts randomized to cilta-cel received PVd or DPd (physician’s choice) bridging therapy, then 1 cilta-cel infusion 5–7 days after lymphodepletion. In the SOC arm, pts received PVd or DPd until progression. Primary endpoint was progression-free survival (PFS) in the intent-to-treat (randomized) population. Results: 419 pts were randomized (cilta-cel, n=208; SOC, n=211 [PVd, n=28; DPd, n=183]). 176 pts received cilta-cel as study treatment (tx), 20 more received it after PD on bridging therapy, and 208 received SOC. There were no manufacturing failures. Baseline characteristics were balanced (cilta-cel vs SOC: 59% vs 63% cytogenetic high risk [including gain/amp 1q]; 50% vs 46% PI refractory; 24% vs 22% anti-CD38 refractory; 33% vs 32% had 1 prior LOT). Median dose was 0.71×106 CAR+ viable T cells/kg. At Nov 1, 2022, data cut-off, median follow-up was 16 mo (range, 0.1–27). Primary endpoint was met; cilta-cel reduced risk of progression/death by 74% (HR=0.26; P<0.0001). Cilta-cel vs SOC significantly improved ORR, rate of ≥CR, and overall MRD negativity rate (Table), with a positive trend in OS (HR, 0.78; 95% CI, 0.5–1.2). 97% and 94% of pts treated in the cilta-cel or SOC arms, respectively, had grade (gr) 3/4 AEs, including infections (27% vs 25%) and cytopenias (94% vs 86%). In the cilta-cel and SOC arms, respectively, 39 and 46 pts died (14 and 30 due to PD). In pts who received cilta-cel as study tx (n=176), 76% had CRS (1% gr 3; no gr 4/5) and 5% had ICANS (all gr 1/2). 1 pt had a gr 1 movement/neurocognitive TEAE. Conclusions: A single cilta-cel infusion significantly improved PFS vs SOC in len-refractory pts with 1–3 prior LOT, with a favorable benefit/risk profile across pt populations. The 74% reduction in progression/death and high rates of CR and MRD negativity highlight the potential for cilta-cel to become a key therapy for pts with MM after first relapse. Clinical trial information: NCT04181827. Cilta-cel vs SOC outcomes (ITT). Cilta-cel (n=208) SOC (n=211) HRa Odds ratio Median PFS, mo (95% CI) NE (23–NE) 12 (10–14) 0.26 (0.18–0.38) (P<0.0001) 12-mo PFS, % (95% CI) 76 (69–81) 49 (42–55) ORR, n (%)b 176 (85) 142 (67) 3 (P<0.0001) ≥CRb 152 (73) 46 (22) 10 (P<0.0001) 10-5 MRD negative,c n (%) 126 (61) 33 (16) 9 (P<0.0001) aPer computerized algorithm by constant piecewise weighted log-rank test. bIn 176 pts who received cilta-cel as study tx: ORR, 175 (99%); ≥CR, 152 (86%). cFor MRD-evaluable pts: cilta-cel, 88% (126/144); SOC, 33% (33/101).