Last month, Bristol Myers Squibb made the surprise announcement that the FDA will convene an advisory committee meeting to discuss the company’s bid to move the CAR-T therapy Abecma into earlier lines of treatment. Now, we know at least one reason why the FDA wants more opinions on the application.
Abecma showed no advantage in extending patients’ lives compared with standard combination regimens when used in multiple myeloma patients after two to four prior lines of therapy, according to an updated interim analysis of the phase 3 KarMMa-3 trial presented at the 65th American Society of Hematology annual meeting.
The statistical analysis revealed a negligible 1% increased risk of death for Abecma. But median overall survival looks better for Abecma, as patients lived a median of 41.4 months versus 37.9 months for control.
The lack of an overall survival showing came in stark contrast to the 51% reduction in the risk of progression or death that Abecma demonstrated after a longer follow-up of the KarMMa-3 trial. Patients on the Abecma arm went a median 13.8 months without disease worsening, versus 4.4 months for the control arm. An earlier readout of KarMMa-3 also showed the same level of progression-free survival (PFS) improvement, in which Abecma’s median PFS stood at 13.3 months.
Bristol Myers Squibb Chief Medical Officer Samit Hirawat, M.D., pointed to the crossover trial design to explain the large gap between the two efficacy endpoints. After relapsing on standard combo treatment, 56% of patients in the control arm crossed over to receive Abecma.
“One has to think about that impact of crossover when one thinks about overall survival calculations,” Hirawat said in an interview with Fierce Pharma.
After adjusting for the crossovers, Abecma was linked to a 31% reduction in the risk of death. BMS will also share a more detailed analysis at the upcoming advisory committee meeting to show that Abecma continues to offer a benefit for these patients, Hirawat added.
During Monday’s presentation of the updated KarMMa-3 data, Paula Rodríguez Otero from Clínica Universidad de Navarra in Spain offered two more reasons why the overall survival results didn’t fall in Abecma’s favor.
For one thing, the data included 17 patients (7%) who were randomized to Abecma but quickly died before receiving the CAR-T therapy. The number was zero for the standard regimen arm. After excluding those patients, Abecma showed a trend of 17% reduction in the risk of death, she pointed out.
These patients reflect the reality that the personalized therapy takes time to manufacture versus an off-the-shelf regimen, and a patient’s disease might worsen while they are waiting for the product.
In another observation, Rodríguez-Otero noted that a lower percentage of patients in the Abecma arm received what’s considered more effective bridging regimens to control their disease before the intended treatment, and that their overall dosing intensity was lower. This imbalance put Abecma at a disadvantage and might explain some of the early deaths, she said.
In an interview before the overall survival data release, Rahul Banerjee, M.D., a multiple myeloma expert at Fred Hutchinson Cancer Center, said he had already bought into the idea of using CAR-T in earlier lines of treatment based on Abecma’s PFS data alone. He called the company’s updated PFS result “extremely meaningful.” And even if the PFS were similar between the two arms, Banerjee argued there would still be some benefits for Abecma because it’s a one-time treatment, and no maintenance therapy is needed.
Nevertheless, Banerjee said he would want to see a median overall survival result of close to four years and at least three years. Right now, Abecma falls in the middle of that range. He also said a death-risk reduction of 30% is “always nice,” but he’s more focused on Abecma’s own median number—partly because of the crossover policy, and because the trial’s control arm isn’t necessarily reflective of some more advanced clinical practices.
“We’ve always wondered if you move CAR-T into earlier lines, do patients do better, because the T cells are healthier, the patient’s bone marrow wasn’t beaten up, etcetera,” Banerjee said of the KarMMa-3 trial. “This is good.”
However, from the FDA’s perspective, overall survival has grown increasingly important in the agency’s review of cancer drugs, especially when there’s a negative trend suggesting potential harm to a patient’s life expectancy. And as Novartis CEO Vas Narasimhan recently explained for a delayed filing of its radiotherapy Pluvicto, the FDA doesn’t value crossover analysis much.
BMS’ Hirawat said Abecma was effective across the third to fifth line of treatment in the current trial. Although the overall survival outcome may look similar without crossover adjustments, waiting for patients to relapse to get the novel agent in the control arm means selecting out patients who already passed away or could no longer be eligible for the cell therapy, he pointed out.
“That’s why looking at that adjusted analysis for crossover is going to be absolutely critical to understand” the difference between existing combination therapy and Abecma, Hirawat said.
Another potential risk for Abecma’s expansion bid is that the FDA often conducts subgroup analyses and as a result has excluded certain patient subsets where the benefit-risk profile is less favorable.
KarMMa-3 included patients in three different lines of treatment. While all patients had previously received three different classes of drugs, about 66% of patients had tumors refractory to all three classes, a status that indicates more aggressive disease and a more desperate need for stronger treatment. In its review, the FDA could decide to divide the data by line of therapy or by how many drug classes patients were refractory to.
At ASH, BMS is presenting Abecma data looking at patients with high-risk cytogenetic abnormalities and their risk of death within six months compared with the overall trial population.
“There are a few differences,” Hirawat said. “But this is again exploratory analysis, so one has to be very careful in interpreting the data. But certainly, I think […] this is a hypothesis for now that we’ll need to continue to explore as we look to the future in terms of selection of patients for [Abecma] treatment.”
BMS’ Abecma application is also complicated by a new FDA investigation targeting all existing CAR-Ts over the risk of developing secondary cancer following their treatment.
BMS has treated more than 4,700 patients across clinical and commercial settings for Abecma and its CD19-targeted CAR-T Breyanzi. To date, the company has not observed any CAR-positive T-cell malignancy, Hirawat said. The company will continue to work with the FDA and will continue developing its next-generation of CAR-T cell therapies, including in autoimmune disease, “with appropriate oversight from a safety perspective," the executive said.
Editor's Note: The story was updated with additional information from the presentation.