The Society for Immunotherapy of Cancer (SITC) is pleased to present a summary of the U.S. Food & Drug Administration (FDA) Meeting of the Oncologic Drugs Advisory Committee (ODAC). Below is a recap of highlighted research presented from Friday, March 15, 2024.
Morning session: Supplemental biologics license application (sBLA) 125746.7 for ciltacabtagene autoleucel
Ciltacabtagene autoleucel (cilta-cel, CARVYKTI), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy initially obtained approval for adult patients with relapsed or refractory multiple myeloma (r/r MM) after four or more prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. Approval in this disease setting was granted in February 2022 based on the results of the single-arm CARTITUDE-1 trial that demonstrated an overall response rate (ORR) of 97.9% and a median duration of response of 21.8 months in this heavily pretreated patient population. A supplemental Biologics License Application (sBLA) supported by the CARTITUDE-4 study to expand application of cilta-cel for the treatment of adult patients with r/r MM who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent and are refractory to lenalidomide is currently under review by the FDA with a Prescription Drug User Fee Act (PDUFA) date of April 5, 2024. Patients with lenalidomide-refractory multiple myeloma represent an unmet need as they often have poor outcome with standard therapy. The median PFS among patients who have lenalidomide-refractory multiple myeloma is < 12 months, and regimens that are based on continuous therapy until progression often have cumulative toxicity and significant treatment burden.
The study demonstrated that in the intent-to-treat (ITT) population, cilta-cel elicited a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with standard-of-care (SOC). Patients in the cilta-cel arm experienced a median PFS that was not estimable vs 11.8 months for patients in the SOC arm.
The main topic for discussion brought up by the FDA in front of the March 15 Oncology Advisory committee was the increased rate of early death observed among patients treated with cilta-cel in the CARTITUDE-4 study. The decrement in overall survival calls into question whether the risk/benefit assessment for cilta-cel in this patient population is favorable. The committee voted 11-0 that the risk-benefit assessment for cilta-cel for the proposed indication was favorable. Committee members universally agreed that while early deaths in the CARTITUDE-4 trials were concerning and worthy of exploration and mitigation, the long-term survival benefits and time off treatment associated with cilta-cel treatment at earlier stages of the disease outweighed the risks in this patient population. The committee agreed that lenalidomide-refractory multiple myeloma is a disease with significant and critical unmet medical need, and care providers will need to have in-depth conversations with patients to explore risks and benefits associated with cilta-cel versus alternative approved treatments.
Sponsor position
· Cilta-cel was associated with a statistically significant improvement in PFS, improved response rates, and improved minimal residual disease (MRD) negativity compared to the standard of care
· Trends to OS benefit continued to strengthen as the data matured
· Clinical benefits favored cilta-cel across all patient subgroups, including high-risk populations
· The imbalance in patient survival occurred in the first three months of the trial, and six of the seven patient deaths in the cilta-cel arm were due to disease progression prior to infusion
· Bridging therapy for patients in the cilta-cel arm prior to lymphodepletion was of a lower dose intensity than the SOC arm, which may have accounted for the imbalance of deaths and progressive disease in the cilta-cel arm
· Adverse events (AEs) were consistent with known safety of cilta-cel, and almost all events were manageable
FDA Position:
· The CARTITUDE-4 trial met its primary endpoint; cilta-cel was associated with a statistically significant improvement in median PFS compared to standard therapy (median PFS not reached and 11.8months, respectively)
· The OS data are immature, and longer-term follow-up is needed
· The cilta-cel arm exhibited an increased rate of early deaths
o In the 10 months after patient randomization, the cilta-cel arm was associated with an increased rate of deaths (14%) compared to the SOC arm (12%)
o Within 90 days of treatment start, 4% of patients in the cilta-cel arm died from treatment-emergent adverse events (TEAEs), compared to 0% of patients in the SOC arm
· There is statistical uncertainty surrounding the benefits and risks of cilta-cel in the patient population of CARTITUDE-4
Public Comments:
· Multiple myeloma (MM) is a disease of relapse and remission, and more effective therapies are needed earlier in the course of the disease to prolong remission periods
· Offering CAR T cell therapy earlier in treatment is in the best interest of patients
o Patients with MM can cycle through multiple lines of therapy in a short period of time, resulting in a weakened their immune system and progressive disease
o More effective options for bridging therapy are available for earlier lines of treatment versus later in the natural history of the disease
· CAR T cell therapy being a one-time treatment allows a “break” from continuous therapy; even patients whose disease recurred after CAR T cell therapy appreciate having had some time off continuous treatment
· CAR T cell therapy represents improved quality of life for many patients since post-treatment quality of life is often back to levels preceding the disease diagnosis
· Patients are aware of the risks associated with CAR T cell therapy for MM, and they discuss these risks with their providers
Rationale for the ODAC decision:
· In CARTITUDE-4 trial, cilta-cel was associated with robust PFS benefits
· Potential quality of life benefits such as time off treatment outweigh the risk of early deaths
· Differences in bridging therapy and/or infection with COVID-19 likely accounted for some of the early deaths
The committee also emphasized the need for physicians and patients to discuss the risks and benefits associated with CAR T cell therapy (versus the ones associated with SOC treatments). Because the CARTITUDE-4 was not designed to identify factors associated with early mortality, more studies are needed to explore predictive factors for risk of early death and approaches to mitigate this risk. While the committee recognized there was likely no clear cause for the early deaths, there is an unmet need to optimize bridging therapy and to prevent infection among patients awaiting CAR T cell therapy.
Afternoon session: Supplemental biologics license application (sBLA) 125736.218 for idecabtagene vicleucel
Idecabtagene vicleucel (ide-cel, ABECMA), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy initially obtained approval for adult patients with relapsed or refractory multiple myeloma (r/r MM) after four or more prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. Approval in this disease setting was granted in March 2021 based on the results of the single-arm KarMMa trial that demonstrated an overall response rate (ORR) of 72% and a complete response (CR) rate of 28%. It was estimated that 65% of patients who achieved a CR remained in CR for at least 12 months.
A sBLA to expand application of ide-cel for the treatment of adult patients with r/r MM who have received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody was submitted to FDA in February 2023 supported by the data from the phase 3 KarMMa-3 trial.
The KarMMA-3 trial was a randomized (2:1) open-label, phase 3 trial involving adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab) and who had disease refractory to the last regimen. Patients were randomized to receive ide-cel or an investigator’s choice of five SOC regimens.
The KarMMa-3 trial met its primary end point of PFS demonstrating a statistically significant improvement among patients randomized to the ide-cel arm vs patients randomized to the control arm. PFS benefits favoring ide-cel were observed across all patient subgroups, including those with triple class refractory disease and those with high-risk cytogenetics. Overall survival data were immature and preliminary analyses were confounded by patient crossover allowed by the patient-centric study design. However, there was an observed decrease in OS in the first 15 months of the trial in the ide-cel arm compared to the SOC arm, and an higher rate of early deaths observed among patients treated with ide-cel vs standard therapy within the first 90 days after treatment initiation attributed to treatment adverse effects, resulting in the FDA calling into question whether the risk-benefit assessment for ide-cel in this patient population is favorable which was the focus of the March 15 ODAC discussion.
In an 8 to 3 vote, the FDA’s ODAC decided that the risk/benefit assessment for ide-cel is favorable for the treatment of adult patients with relapsed/refractory multiple myeloma who have received an immunomodulatory (IMID) agent, a proteasome inhibitor (PI), and an anti-CD38 antibody. The committee agreed that the PFS data from the KarMMa-3 study were encouraging and represented clinical and quality of life benefits for patients. Concerns were raised regarding OS data, and the crossover design in the study, that while ethical and commendable, confounded the interpretation of OS data.
Sponsor Position:
· Ide-cel was associated with statistically significant and clinically meaningful gains in PFS and overall response rate
· As a one-time therapy, ide-cel provides patients with breaks from treatment, improving their quality of life
· The numeric increase in early deaths in the ide-cel arm was driven by patients who had not received ide-cel, and many of the issues related to bridging therapy and the washout period before CAR T cell infusion will be mitigated in a real-world setting
· Almost 60% of patients in the SOC arm crossed over to the ide-cel arm, confounding interpretation of OS
· No new safety concerns related to ide-cel were identified in the KarMMa-3 study
FDA Position:
· A higher rate of early deaths was observed in the ide-cel arm compared to the SOC arm, and this decrease in OS was observed in the first 15 months of the trial
· The ide-cel was associated with a higher rate of death from adverse events within the first 90 days of treatment compared to the SOC arm (2.7% vs 1.6%, respectively)
· The reasons for early death in patients who did not receive ide-cel therapy are varied and highlight uncertainties in patient selection, managing disease while waiting for treatment, and potential manufacturing issues
· The FDA considers the higher early death rate and treatment-emergent AEs in the ide-cel arm as crucial factors when evaluating the overall risk-benefit profile of the treatment
· The statistical methods used to account for crossing over relied on untestable assumptions and cannot provide convincing evidence that ide-cel treatment improves survival outcomes in the patient population of the KarMMa-3 study
Public Comments:
· There is a significant unmet medical need for more therapies with favorable benefit-risk profiles for the treatment of r/r MM
· There is a need for more guidance on bridging therapy for patients awaiting CAR T cell treatment
· Offering ide-cel earlier in the course of treatment may improve the likelihood of a significant and deep response
· CAR T cell therapy can result in long-term deep responses and breaks from continuous therapy
Rationale for the ODAC decision:
· The KarMMa-3 trial addresses a treatment gap in patients with r/r MM
· The early deaths in the ide-cel arm were likely due to disease progression, suggesting inadequate bridging therapy
The committee members who voted against the decision voiced concerns the KarMMa-3 study did not clearly demonstrate that earlier administration of ide-cel therapy was associated with clinical benefits, thus the potential benefits of ide-cel did not outweigh the risk of early death in this patient population. The committee speculated that the early deaths may have been impacted by bridging therapy and washout protocols in the KarMMa-3 trial, which would be mitigated in real-world settings. The committee also agreed that more work is needed to optimize bridging therapies for patients waiting to receive CAR T cell therapy. With regards to trial design, the committee agreed that while it confounded analysis of OS data, allowing patient crossover was ethical and patient-centered. As more trials implement this type of crossover between treatment arms, the unmet need for validated surrogate endpoints for assessing clinical efficacy needs to be addressed.