The Benefits Outweigh the Risks: Unpacking the Recent ODAC Decisions in Myeloma

Kenneth C. Anderson, MD

Following the consensus that the risk-benefit assessments for the proposed indications for ciltacabtagene autoleucel (cilta-cel, Carvykti) and idecabtagene vicleucel (ide-cel, Abecma) were favorable during the March 15, 2024, FDA Oncologic Drugs Advisory Committee (ODAC) meeting, both BCMA-targeted chimeric antigen receptor (CAR) T-cell therapies received approvals moving them up in the treatment paradigm for relapsed or refractory multiple myeloma.^1,2 However, during the meeting the FDA expressed overall concern regarding the risk-benefit profiles of both agents stemming from overall survival (OS) data that showed increased rates of early deaths.^3,4

“In the ide-cel trial, crossover was allowed so there was no OS advantage demonstrable. In the cilta-cel study, the median OS was not reached in either the cilta-cel or the standard-of-care [SOC] therapy arm,” Kenneth C. Anderson, MD, a 2014 Giants of Cancer Care® award winner in the Myeloma category, explained in an interview with OncologyLive. “In both cases, therefore, OS needs to be contin- ually followed both for efficacy and adverse effects [AEs]. Secondary cancers have [also] been raised as a concern. Overwhelmingly, the benefit is in favor of using CAR T-cell therapy, but we need to monitor [patients] very carefully as we get more experience with both CAR T-cell therapies.”

“One thing at the ODAC [meeting that stood out to] me was the patients who came and talked about [the CAR T-cell therapies],” Sundar Jagannath, MBBS, added in an interview with OncologyLive. “They were so impressed it was a one-and-done [therapy]—they were not on subsequent maintenance, got their life back, and were in deep remission. The patients had no ongoing symptoms from the cancer and felt for the first time the way they used to before the diagnosis of myeloma was made. For them, it was a life-changing treatment. This option should be made available to patients, and I’m very pleased that everything went [well].”

Examining the ODAC Decision on Ide-cel

In the phase 3 KarMMa-3 trial (NCT03651128), patients treated with ide-cel (n = 254) achieved a median progression-free survival (PFS) of 13.3 months (95% CI, 11.8-16.1) compared with 4.4 months (95% CI, 3.4-5.9) for patients treated with SOC therapy (n = 132; HR, 0.495; 95% CI, 0.379-0.647; P < .0001) at a median follow-up of 15.9 months.³

The FDA highlighted that this improvement in median PFS was statistically significant, but there was an OS detriment observed for up to 15 months in the ide-cel arm, according to findings from the first interim analysis of the trial at a median follow-up of 16.9 months with a pattern of crossing of the curves.

In the first 9 months, 18% of patients died in the ide-cel arm compared with 11% in the SOC arm. Beyond 9 months, 24% and 33% of patients died, respectively, with a data cutoff of April 28, 2023. The FDA also noted that 20 patients died before receiving ide-cel within 9 months
of random assignment and that in those who received the agent (n = 225), 85% received bridging therapy with a median time from random assignment to bridging therapy of 8 days (range, 1-51); bridging therapy was a median of 22 days (range, 1-88) and the median time from leukapheresis to product release was 35 days (range, 24-102).

Following disease progression, patients could cross over to the ide-cel arm, but the FDA noted that “sensitivity analyses cannot provide convincing evidence that ide-cel reduced the risk of death after adjusting for treatment crossover.”³

Using a rank-preserving structural failure time (RPSFT) model with recensoring in the intention-to-treat (ITT) population, the median OS was 41.4 months (95% CI, 30.9-not evaluable [NA]) in the ide-cel arm vs 27.6 months (95% CI, 21.7- NA) in the SOC RPSFT model arm (HR, 0.870; 95% CI, 0.581-1.878). The FDA highlighted the limitations of an early OS detriment persisting as well as a wide confidence interval and noted that average HR is no longer interpretable. The FDA added that the “detrimental effect of ide-cel lasted up to 9 months” with the OS disadvantage persisting up to 15 months following random assignment.³

With a PFS benefit and an improvement in overall response rate observed, but an increased rate of early death that the FDA wrote was unlikely to be overcome with additional follow-up, the ODAC voted 8 to 3 that the benefits of ide-cel outweigh its risks for the treatment of adult patients with relapsed or refractory multiple myeloma who have received an immunomodulatory drug (IMiD), proteasome inhibitor, and anti-CD38 monoclonal antibody.⁵ In April 2024, the agent received approval from the FDA for the treatment of this patient popula- tion following 2 or more prior lines of therapy.¹

“In these two more recent [CAR T-cell ther- apy] decisions where patients are being treated earlier, [it’s important to note that] there was a crossover in the ide-cel study which was not present in the cilta-cel study. As a consequence, no OS advantage was demonstrated in the ide-cel study, which could have contributed to the difference in the approval voting for these two modalities,” Anderson explained.

Cilta-cel Receives Unanimous Vote In Favor Of Risk-benefit Profile

Cilta-cel was granted approval from the FDA in April 2024 for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of ther- apy, including a proteasome inhibitor and an IMiD, and who are refractory to lenalidomide (Revlimid).2 This decision came after the 11-to-0 ODAC vote that the benefits of cilta-cel outweigh its risks for this patient population.⁵

In the phase 3 CARTITUDE-4 trial (NCT04181827), patients treated with cilta-cel (n = 208) achieved a statistically significant improvement in median PFS vs patients treated with SOC therapy (n = 211); median PFS was not evaluable (NE; 95% CI, 22.8-NE) vs 11.8 months (95% CI, 9.7-13.8), respectively (HR, 0.41; 95% CI, 0.30-0.56; P < .0001) at the November 1, 2022, data cutoff.⁴

The FDA noted that the “higher proportion of PFS events in the cilta-cel arm are due to deaths compared [with] standard therapy.” There were 17 deaths in the cilta-cel arm compared with 4 deaths in the SOC arm. Similarly to ide-cel, there was an increased rate of early death observed with cilta-cel, which the FDA cited as a “major issue” with cilta-cel and its primary concern as the early OS detriment was in the context of a PFS benefit. The FDA added that delayed administration of cilta-cel and toxicity of the agent could be possible causes of this.⁴

“Concerns [cited by the FDA] were early deaths in this trial in the cilta-cel arm. The issue there was that patients died having been randomly assigned to cilta-cel before receiving the cilta-cel therapy; in all likelihood, this was related to a number of factors including bridging therapy,” Anderson explained.

Jagannath added, “[Many] patients died in the study arm, but they had not gotten cilta-cel and had early progression of disease. Therefore, the patients who progressed early ran into early mortality. That can happen—why it didn’t happen on the standard arm I was surprised [at]—which was brought up by one of the ODAC committee members who said that on the control arm, if a patient progressed, there was a lot of censoring happening on that side. There was more censoring on the control arm because it was an open-label study; patients probably participated hoping that they would be randomly assigned to the CAR T-cell therapy arm and when they were not, they opted out of the study.”

The FDA noted that due to heavy censoring, longer follow-up data are needed to confirm the OS benefit with cilta-cel as of December 13, 2023. Using OS data from the ITT population at the November 1, 2022, data cutoff, the FDA found the piecewise OS HR was 1.04 (95% CI, 0.62-1.73) before crossing of the curves.⁴

In the 10 months following random assign- ment, 14% of patients in the cilta-cel arm died compared with 12% in the SOC arm; deaths were due to progressive disease (PD; 6.2% and 7.1%) and AEs (7.7% and 4.7%), respectively. Additionally, 32 patients had PD or died prior to receiving cilta-cel.

All patients who received cilta-cel who did not have early PD or death (n =176) received bridg- ing therapy for a median duration of 1.6 months (range, 0.41-6.1) with 1 (33%), 2 (59%), 3 (18%), or at least 4 (3%) cycles administered. The median time from leukapheresis to product release was 79 days (range, 45-246).

“One of the other ODAC members said that this is like a heart transplant—there is perioperative mortality earlier on, but then, looking at the survival of patients who got a heart trans- plant, they did well. Another hematology/ oncology physician said that like with an allogeneic transplant, there is early mortality during the transplant, but subsequently, the survival is very good,” Jagannath noted.

Considerations For Shifting CAR T-cell Therapy Up In Treatment Sequencing

“With the CAR T-cell therapy approvals [of ide-cel and cilta-cel] put together, it’s difficult to compare the 2 agents because they’re
in the setting of patients who have had different amounts of prior treatment. The patients who received ide-cel are representative of those who have had triple-class exposure, which is more common earlier in myeloma treatment. Nonetheless, both approvals will result in CAR T-cell therapy being moved earlier to treat patients,” Anderson said.

Jagannath explained that first relapse, clinical trials, and patient preference are the key factors that affect his decision to use ide-cel or cilta-cel therapy. “The major AEs of CAR T-cell therapy— cytokine release syndrome [CRS], immune effector cell–associated neurotoxicity syndrome [ICANs], or delayed neurotoxicity—revolves around the tumor burden at the time patients are getting CAR T-cell therapy,” Jagannath noted. “[With] uncontrolled growth of the cancer, if you give CAR T-cell therapy then the AE [risk] profile of CRS, ICANS, and delayed neurotoxicity is high. Whereas if you’re able to keep the cancer under control, almost in a partial remission or even very good partial response or better [before administering] the CAR T-cell therapy, the AE profile is much lower because the CAR T cells are living drugs and expand according to the amount of tumor they have to tackle.”

Jagannath added, “This now allows us to improve the safety profile of CAR T-cell therapy for patients who can receive it in an earlier line at a time when we have good control of the cancer because we have good treatments available for first relapse and second relapse. Therefore, this is a wonderful opportunity to improve the overall life expectancy of all patients with myeloma.”

Examining Safety With Both Agents

In the safety population of patients who received ide-cel (n =222), SOC including AEs after crossover (n =126), and SOC prior to cross-over (n =126), serious AEs were observed in 43%, 56%, and 36% of patients, respectively. Additionally, grade 3 or higher AEs occurred in 95% of patients in the ide-cel arm, 90% in the SOC following crossover group, and 75% in the SOC prior to crossover group; grade 4 AEs occurred in 64%, 51%, and 25% of patients, respectively. Further, 9% of patients in the ide-cel arm, 8% in the SOC including AEs after crossover, and 4% in the SOC prior to crossover arms experienced fatal AEs. Deaths from treatment-emergent AEs occurred in 36%, 43%, and 29% of patients, respectively.³

Any-grade AEs of special interest in the ide-cel vs SOC arm included CRS (91% vs 40%), neurotoxicity (46% vs 21%), hemophagocytic lymphohistiocytosis/macrophage activation syndrome (2% vs 1%), infection (56% vs 64%), second primary malignancy (6% vs 4%), neutropenia (100% vs 88%), and thrombocytopenia (92% vs 90%).

There was also a higher rate of deaths due to AEs in the cilta-cel safety population (n =188) compared with the SOC safety population (n =208); 11% and 8% of patients died in each arm, respectively. Grade 4 AEs occurred in 63% vs 56% of patients and serious AEs in 37.8% vs 38.9% of patients, respectively. Any-grade AEs of special interest included CRS (77.0% vs 1.0%), neurotoxicity (23.0% vs 0.0%), hemophagocytic lymphohistiocytosis/macrophage activation syndrome (1.0% vs 0.0%), infections (57.0% vs 71.0%), secondary primary malignancy (4.3% vs 6.7%), neutropenia (99.0% vs 98.0%), and thrombocytopenia (94.0% vs 87.0%).⁴

Additionally, 5% of patients in the cilta-cel arm died up to 90 days after the initiation of treatment—4% due to an AE—and no patients
in the SOC arm died at this time point. Deaths that occurred following 90 days after the initiation of treatment occurred in 8.5% and 22.0% of patients, respectively. Furthermore, no prognos- tic subgroup was associated with early mortality for either ide-cel or cilta-cel.^3,4

“The FDA and ODAC have been central to the progress to date in the treatment of [patients with] myeloma that has completely transformed the paradigm and improved outcomes for patients and their families,” Anderson said. “On April 12, 2024, the ODAC unanimously voted to include minimal residual disease–negative complete response as an end point for accelerated approval in myeloma, which will ensure that we have continued rapid approval of novel agents, [allowing] patients access to these new treatments more quickly.”

References

1. US FDA approves Bristol Myers Squibb and 2seventy bio’s Abecma for triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy. News release. Bristol Myers Squibb and 2seventy bio, Inc. April 5, 2024. Accessed April 23, 2024. bit.ly/3UykBhC
   Carvykti is the first and only BCMA-targeted treatment approved by the U.S. FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 6, 2024. Accessed April 23, 2024. bit.ly/44aJDXa
   Oncologic Drugs Advisory Committee Meeting. Idecabtagene vicleucel (Abecma) sBLA 125736.218. FDA. March 15, 2024. Accessed April 23, 2024. https://www.fda.gov/ media/177060/download
   Oncologic Drugs Advisory Committee Meeting introductory comments. FDA. March 15, 2024. Accessed April 23, 2024. https://www.fda.gov/media/177057/download
   FDA YouTube page. March 15, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube. com/watch?v=VSjdGeeXb40