Source: Myeloma – Hematology Advisor
In a meeting of the Oncologic Drugs Advisory Committee (ODAC), the committee of 11 members unanimously voted that the potential benefits of ciltacabtagene autoleucel (cilta-cel) outweigh its risks for its proposed indication.1
The US Food and Drug Administration (FDA) convened the meeting on March 15, 2024, to obtain committee input on the results of the CARTITUDE-4 trial (ClinicalTrials.gov Identifier: NCT04181827).
The trial data served as the primary evidence for a supplemental Biologics Licensing Application submitted by Janssen Biotech, Inc. for CARVYKTI (cilta-cel) for the treatment of relapsed or refractory multiple myeloma (MM) in adults who have received at least 1 line of therapy and are refractory to lenalidomide. 2 Participants who had received 1 to 3 prior lines of therapy for MM were randomly assigned to receive cilta-cel or standard care.
Unmet Need
Based on data from the phase 1b/2 study CARTITUDE-1 (ClinicalTrials.gov Identifier: NCT03548207), cilta-cel is currently approved in the United States for the treatment of relapsed or refractory MM in adults who have received 4 or more prior lines of therapy.3
In the presentation from Janssen Biotech, Inc., Irene Ghobrial, MD, professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, outlined the current unmet need for the use of CAR-T therapy as early treatment in MM.
Dr Ghobrial cited data showing that 85% of multiple myeloma patients were unable to receive treatments beyond the third line of therapy. This underscores the need for administering effective treatments earlier in the disease course. “Initial treatment is the best chance for deep and durable remissions,” she said.
Additionally, T-cells become exhausted with disease progression. Administering CAR-T therapy earlier in the disease course, when T-cells are less exhausted, is associated with better long-term outcomes, Dr Ghobrial noted.
The current standard care for MM patients is continuous treatment, which contributes to “added toxicity and added burden for the patient,” said Dr Ghobrial. A one-and-done treatment such as cilta-cel early in the disease course creates the opportunity for patients to achieve remission without having to undergo continuous, burdensome treatments.
Trial Data
Jordan Schechter, MD, vice president of research and development for the Janssen Pharmaceutical Companies of Johnson & Johnson, presented data from CARTITUDE-4 at the meeting.1
Cilta-cel was associated with significant and meaningful PFS improvement compared to the standard care arm, and this finding was consistent across subgroups. Median PFS was not reached in the cilta-arm, while it was 11.8 months for the standard care arm.
Additionally, 85% of patients in the cilta-cel arm obtained a response, compared with 67% patients in the standard care arm.
Dr Schecter addressed an increased risk for early death in the cilta-cel arm. “The only period in which we see more deaths in the experimental arm versus standard of care arm is between 0 and 3 months,” he stated. Before 3 months, there were 7 deaths in the cilta-arm and 1 death in the standard care arm.
Dr Schechter noted that a cause for the disparity in early deaths prior to receiving treatment was disease progression in the cilta-cel arm, and not cilta-cel toxicity. For example, 6 out of the 7 deaths prior to 3 months were in patients randomized to cilta-cel, but who progressed prior to infusion with cilta-cel. Additionally, he noted that between 3 and 6 months, the OS curves began to balance and then trended towards fewer deaths in the cilta-cel arm.
“The depth and durability of response observed with cilta-cel is something not observed with any other modality and is important for long-term outcomes such as progression-free survival and of course, overall survival,” said Dr Schecter.
FDA Concerns
The FDA raised concerns over the lower overall survival (OS) in the first 10 months of treatment in the cilta-cel arm compared to the standard care arm. In the first 10 months of treatment, 14% of patients died in the cilta-cel arm, whereas 12% died in the standard care arm.
Additionally, 4.8% of patients in the cilta-cel arm died prior to receiving CAR-T therapy and 0.5% of patients in the standard care arm died before treatment.
“One might consider that since the subject did not receive cilta-cel, there is no treatment causality,” said Helkha Peredo-Pinto, MD, a clinical reviewer for the FDA, during the meeting. “However, it is [a] consequence of proceeding to receive treatment in the investigation arm. In this case, [the] CAR-T product, therefore, is relevant to the subject outcome.”
The FDA noted that it is the responsibility of Janssen Biotech, Inc. to demonstrate or prove that a more adequate bridging therapy regimen has the capacity to prevent death or early progression of disease. Additionally, the FDA stated that data is too immature to draw a conclusion about the OS benefit of cilta-cel.
“It represents a challenge for the agency to make a conclusive regulatory decision based solely on a speculative assessment of the benefit-risk profile rather than robust scientific evidence,” Dr Peredo-Pinto said.
Discussion
Based on the trial data, the FDA proposed 2 questions for the committee to discuss. These included:
Whether the results of the CARTITUDE-4 trial are sufficient to support a positive risk-benefit assessment of cilta-cel for the proposed indication; and
Whether the risk of early death associated with cilta-cel treatment is acceptable in the context of the PFS benefit.
Some committee members mentioned that the imbalance in early OS seemed to be a case of front-loaded risk, and that providers should be encouraged to inform patients of this before treatment.
“The curves really remind me of transplant related toxicities that are high early on,” said Mary Kwok, MD, clinical associate professor at the University of Washington School of Medicine.”
Additionally, some members mentioned that cilta-cel is an important consideration for early treatment because it would allow patients periods of nontreatment and a higher quality of life.
“We can’t understate the ability of individuals to have this period of nontreatment that allows them higher quality of life — that the data did support — and moving into a disease-free state,” Susan Lattimore, RN, a nonvoting member of the committee and consumer representative, stated during the meeting.
“The sense of the panel’s discussion here has been that there are issues upfront, but they are small, and perhaps balanced by the long-term benefits,” said Ravi Madan, MD, chair of ODAC, during the meeting. Dr Madan also noted that bridging therapy and protecting patients against infection are areas for further research and development to optimize cilta-cel treatment.