Legend Biotech's CAR-T therapy recommended by FDA for early treatment of multiple myeloma

On the afternoon of March 15th, around 5:20 PM Eastern Time, during the FDA's Oncologic Drugs Advisory Committee (ODAC) meeting, the panel of experts voted unanimously (11-0) to conclude that Johnson & Johnson and Legend Biotech's Carvykti (cilta-cel) for the treatment of relapsed and refractory multiple myeloma (R/R MM) in adults who have received at least one prior line of therapy (including a proteasome inhibitor and an immunomodulatory agent) and who are refractory to lenalidomide, has a favorable benefit-risk profile. Currently, a supplemental Biologics License Application (sBLA) supported by the CARTITUDE-4 study is under FDA review, with a PDUFA date of April 5, 2024. In the Phase III CARTITUDE-4 study (NCT04181827), patients with R/R MM who had received 1-3 prior lines of therapy and were refractory to lenalidomide were randomized to receive cilta-cel (n=208) or physician's choice (n=211). Results showed a significant improvement in median progression-free survival (mPFS) in the cilta-cel group (not reached vs 11.8 months, HR=0.41, 95% CI 0.30-0.56, p<0.0001), thus meeting the primary endpoint; the key secondary endpoint of objective response rate (ORR) also showed benefit (85% vs 68%, p<0.0001), although the FDA noted a higher proportion of PFS events due to death in the cilta-cel group (8% vs 2%). Currently, midterm overall survival (OS) data are immature (34% information fraction), with median OS not reached and 26.7 months in the two groups, respectively (HR 0.78, 95% CI 0.51-1.20). The OS Kaplan-Meier curves crossed at ~11 months, indicating lower OS in the cilta-cel group during the first ~11 months. Regarding safety, cilta-cel demonstrated a profile consistent with previously reported results. A key issue discussed at the ODAC meeting was the increased early mortality rate in the cilta-cel group. In the intent-to-treat (ITT) population, in the first 10 months post-randomization, the mortality rate was higher in the cilta-cel group compared to the standard-of-care (SOC) group (14% vs 12%), with death due to adverse events occurring in 7.7% and 4.7% of patients, respectively. Specifically, 4.8% of patients in the cilta-cel group died due to disease progression before CAR-T therapy, compared to only 0.5% in the SOC group. Post-treatment, in the first 10 months, 9.1% of patients in the cilta-cel group died (disease progression: 1.4%, adverse events: 7.7%), compared to 11.3% in the SOC group (disease progression: 7.1%, adverse events: 4.2%). Regarding the reasons for the increased risk of early mortality with CAR-T therapy, FDA official Helkha Peredo-Pinto stated, "Although (we) recognize the impact of not receiving cilta-cel therapy on early mortality — these patients initiated the process of receiving cilta-cel therapy and underwent leukapheresis and bridging therapy — these results remain relevant to the benefit-risk assessment of cilta-cel." Ultimately, the committee unanimously agreed that cilta-cel has a positive benefit-risk profile in the proposed indication, with ODAC Chair Ravi A. Madan stating that although the data from the CARTITUDE-4 study are immature, they are favorable overall, and the risk of early mortality typically occurs before CAR-T therapy, which should not be overlooked in this discussion, but seems to be offset by the encouraging long-term potential benefits."