The result of the FDA's Oncologic Drug Advisory Committee vote on idecabtagene vicleucel for the proposed indication is favorable.
In an 8 to 3 vote, the FDA’s ODAC decided that the risk/benefit assessment for idecabtagene vicleucel for the proposed indication 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 met to discuss the supplemental biologics license application (sBLA) of ide-cel in the proposed indication. During the meeting, the general discussion focused on the overall survival (OS) data observed in the KarMMa-3 study, as well as the risk/benefit profile of ide-cel in the intended population.
Main topics during the discussion included addressing the increased number of early deaths in the ide-cel arm and the clinical benefit of treatment with ide-cel. While ide-cel led to a significantly improved rate of progression-free survival (PFS), there was an observed decrease in OS in the first 15 months of the trial, resulting in the FDA calling into question whether the risk-benefit assessment is favorable.
However, the applicant’s stance noted that the numerically higher proportion of early deaths in the ide-cel arm was driven by patients who never received ide-cel, and most of the early deaths that occurred were due to disease progression.
Ide-cel is a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen on myeloma cells. The autologous CAR T-cell therapy is manufactured individually for each patient. Currently, ide-cel is FDA-approved for the treatment of adult patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an IMID agent, a PI, and an anti-CD38 monoclonal antibody.
In the open-label, multicenter KarMMa trial (NCT03361748), investigators compared ide-cel with standard of care regimens for the treatment of adults with relapsed/refractory multiple myeloma after 2 to 4 prior lines of therapy including a PI, an IMID, and daratumumab (Darzalex).2 All patients included in the trial were refractory to the last line of therapy and were randomized to receive a single infusion of ide-cel or investigator choice of 5 standard therapies.
1. Discuss whether the results of KarMMa-3 are sufficient to support a positive risk-benefit assessment of idecabtagene vicleucel for the proposed indication.
2. Is the risk of early death associated with idecabtagene vicleucel treatment acceptable in the context of the PFS benefit?
Is the risk-benefit assessment for idecabtagene vicleucel for the proposed indication favorable?
In the ide-cel arm, patients underwent leukapheresis followed by 1 cycle of optional bridging therapy which was given at investigator discretion during the time the product was manufactured. Between bridging and lymphodepleting chemotherapy, patients had to have a 14-day wash-out period, which was followed by lymphodepleting chemotherapy consisting of fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 intravenous for 3 consecutive days, then single infusion of ide-cel at a dose of 150 to 450 million CAR-positive T cells.
The primary end point was PFS and key secondary end points of the study included overall response rate (ORR) and OS.
A total of 386 patients underwent randomization, including 254 who received ide-cel and 132 who were given a standard regimen. Among these patients, 66% had triple-class–refractory disease, and 95% had daratumumab-refractory disease.1,2
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 (HR, 0.49; 95% CI, 0.379-0.647) based on a stratified log-rank test (P <.0001).
At a median follow-up of 18.6 months, the median PFS was 13.3 months among those treated with ide-cel vs 4.4 months among those in the standard regimen group (HR, 0.49; 95% CI, 0.38-0.65; P <.001).
Seventy-one percent of patients in the ide-cel group had an overall response vs 42% of patients in the standard regimen group (P <.001) with complete responses (CRs) seen in 39% and 5%, respectively. OS data was immature.
Among those treated with ide-cel, deep and durable responses were observed with stringent CRs (sCRs) seen in 28% (95% CI, 19%-38%) of patients. The median time to response was 30 days (range, 15-88) and responses were durable.
In the all-responder population, the median duration of response (DOR) was 11 months (95% CI, 10.3-11.4). Of the patients who achieved a sCR, the median DOR was 19 months (95% CI, 11.4-not evaluable). Notably, of the patients in the sCR population, remission lasted for 12 months or more in 65% (95% CI, 42%-81%).
For safety, 93% of the patients in the ide-cel group had grade 3 or 4 adverse events (AEs) vs 75% of those in the standard-regimen group. Eighty-eight percent of patients in the ide-cel group had cytokine release syndrome (CRS), 5% of whom had an event of grade 3 or higher. In this group, investigator-identified neurotoxic effects occurred in 15%, and 3% of patients had an event deemed grade 3 or higher.
“Importantly, very few deaths due to second primary malignancies were reported. They were balanced between the 2 arms, and there were no second primary malignancies of T-cell origin in the ide-cel arm,” said Mark Cook, MBChB, PhD, senior clinical trial physician, Bristol Myers Squibb, during the meeting.
“Overall, the safety profile of ide-cel remains consistent with no new safety signals identified,” added Cook.
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On February 15, 2023, an sBLA for ide-cel was submitted to the FDA. The applicant is seeking approval for the treatment of adult patients with relapsed or refractory multiple myeloma who have received an IMID, a PI, and an anti-CD38 monoclonal antibody. The intended dose range is 300-510 x 106 CAR-positive T cells per single-dose infusion.1
This proposed indication differs from the current indication of ide-cel in the FDA which is for adult patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an IMID agent, a PI, and an anti-CD38 monoclonal antibody.
“Since December last year, ide-cel was approved in Japan, Switzerland, and received a positive CHMP in the European Union based on the KarMMa-3 trial results,” said Anne Kerber, MD, senior vice president, head of late clinical development, hematology, oncology, cell therapy, Bristol Myers Squibb, during the meeting.
The KarMMa-3 study was the first large-scale randomized trial of a CAR T-cell therapy in this patient population to provide compelling evidence for the efficacy and safety of ide-cel. Compared with other standard treatments, ide-cel led to statistically significant and clinically meaningful improvements in PFS, the primary end point, and ORR.
Ide-cel is a 1-time therapy that potentially can extend treatment-free periods for patients with relapsed/refractory multiple myeloma vs continuous treatments. Also, those in the study who were treated with ide-cel reported better quality of life after receiving the single infusion vs those treated with a standard therapy.
“Using ide-cel earlier in the treatment course offers patients a better chance to bridge to CAR T-cell therapy and lowers the risk of not receiving ide-cel,” added Kerber.
According to the applicant, the KarMMa-3 study design allowed for crossover, confounding OS interpretation. While the study did observe a higher number of early deaths in the ide-cel group, a closer analysis revealed most of these deaths were due to disease progression and not ide-cel itself. The study design limited bridging therapy options and mandated a minimum waiting period, potentially impacting some patients' conditions.
The data on OS require careful interpretation due to the patient-centric design that allowed crossover to ide-cel after progression on standard treatments. Analyses adjusting for crossover suggest a trend towards improved OS with ide-cel, and in the standard arm, OS was longer than expected, potentially impacting the overall results.
“Since most patients in the KarMMa-3 trial received ide-cel, both arms of the trial exceeded the median overall survival expected for this patient population,” said Eric Bleickardt, MD, vice president, late clinical development, cell therapy, Bristol Myers Squibb.
“In the first 6 months, the rate of death was numerically higher in the ide-cel arm. The rates become similar in the 6- to 9-month timeframe at 7% and 5%, and after 9 months, are higher in the standard regimen arm. A landmark analysis at 6 months further confirms that the difference is driven by the first 6 months, and the curves are similar until month 15 where they begin to separate,” added Bleickardt.
The applicant also explained that for safety, the safety profile of ide-cel was consistent with its current use, and AEs were manageable. These AEs included cytopenias, CRS, and CAR T-associated neurotoxicity. Deaths due to AEs were comparable between those in the ide-cel and standard therapy arms.
“In the ide-cel arm…there was a median of 7 days until bridging. Bridging was not utilized in 17% of the patients. The median time from bridging to ide-cel infusion was 24 days,” explained Bleickardt. “This could account for the difference in early deaths in the ide-cel arm, driven by patients who did not cross the bridge and were not eligible to receive the ide-cel infusion.”
Overall, the applicant argues that the totality of data from KarMMa-3 demonstrates a favorable benefit-risk profile for ide-cel compared with standard treatments in this specific patient group, and early use of ide-cel is necessary to maximize the benefit of this therapy.
While ide-cel has shown promise for treating relapsed/refractory multiple myeloma, the FDA raised significant concerns about early deaths associated with the treatment. According to the FDA, a higher rate of early deaths were observed in the ide-cel arm compared with that seen in the standard of care arm.
“During the review of the application, the FDA identified the higher rate of early deaths in the ide-cel arm compared to the standard therapy as a major review issue,” explained Rob Sokolic, chief, malignant hematology branch, Office of Clinical Evaluation, Office of Therapeutic Products, Center for Biologics Evaluation and Research, FDA. “Specifically, visual inspection of the Kaplan-Meier curves for overall survival indicate a crossing hazards pattern with an early decrement in overall survival through the first 15 months.”
“The crossing hazard pattern renders the average hazard ratio uninterpretable,” added Sokolic.
They noted that the applicant's attempt to explain the mortality difference was not fully supported by their analyses. The FDA said that OS was looked at in the safety population; however, this group might be biased because patients who had a worse prognosis may have been excluded from the ide-cel arm.
A significant concern is the higher rate of early deaths observed among those treated with ide-cel vs standard therapy, noting this is especially concerning within the first 90 days after treatment initiation. Some deaths in the study were attributed to treatment adverse effects.
A higher proportion of patients died before disease progression in the ide-cel arm vs the standard of care arm. Notably, 20 out of 45 deaths in the ide-cel arm within the first 9 months occurred prior to receiving the treatment.
“Eighteen percent of patients in the ide-cel arm died in the first 9 months compared to 11% in the standard of care arm. This includes a higher rate of death from disease progression, and adverse events, and unknown causes,” Poornima Sharma, MD, medical officer, clinical reviewer, malignant hematology branch, Division of Clinical Evaluation Hematology, Office of Clinical Evaluation, Office of Therapeutic Products, CBER, during the meeting.
Of the 6 deaths observed from AEs in the standard of care arm in the first 9 months, 3 occurred after crossover to the ide-cel arm. Given the higher rate of death in the ide-cel arm in the first 9 months from randomization, the FDA further analyzed the data, showing that 8% of the patients in the ide-cel arm died without receiving the treatment in the first 9 months compared with those on the standard of care arm.
“These deaths are important to evaluate the benefit/risk profile of ide-cel,” added Sharma.
Additionally, 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.
They then noted that complex statistical methods were used to suggest treatment with ide-cel after progression on standard treatment may be as effective as upfront treatment. However, these methods rely on assumptions that are difficult to verify, including the effect of ide-cel being the same regardless of when it is given. Patients who stayed on standard treatment and received ide-cel upfront might be healthier than those who switched treatments later.
“In summary, no particular prognostic subgroup was associated with driving this higher early mortality. The study was not designed to characterize a heterogeneous study population, which may have contributed to higher early mortality with ide-cel,” said Sharma.
Ultimately, the FDA stated that the applicant's analyses do not provide enough evidence that ide-cel improves survival in this patient population. Therefore, the benefit of ide-cel in terms of OS remains unclear, especially considering the potential risks associated with the treatment.
At the end of the meeting, the FDA’s ODAC that the risk/benefit assessment for ide-cel for the proposed indication is favorable for treating relapsed/refractory multiple myeloma who have received an IMID agent, a PI, and an anti-CD38 antibody.
“The KarMMa-3 trial addresses a growing treatment gap in patients with myeloma. An important aspect for me as an investigator is the fact that this was a patient-centric design that allowed for crossover,” explained Noopur Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital, and professor of medicine, Harvard Medical School, during the meeting.
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