In the race to bring CAR-T therapies to earlier lines of treatment for lymphoma, Gilead Sciences and Bristol Myers Squibb are squaring off with potentially practice-changing data. But debate could ensue over which drug turned in better results.
Back in June, BMS’ Breyanzi became the first CAR-T medicine to post a trial win against standard of care in large B-cell lymphoma (LBCL) patients who had failed just one prior therapy. Specifically, in data unveiled Saturday at the American Society of Hematology (ASH) annual meeting, investigators said the medicine cut the risk of a so-called event-free survival (EFS) complication by 65.1% in a phase 3 study.
Breyanzi’s magnitude of improvement looks largely in line with a 60.2% showing on a similar EFS measurement that Kite’s Yescarta had previously reported—and confirmed at the ASH event—in its own phase 3 trial in the same second-line LBCL setting.
The FDA has put an application for that Yescarta use under priority review with a target decision date set for April 1, 2022, according to Gilead. As for Breyanzi, BMS is completing a full evaluation of its data with the intention to file them with regulatory agencies, Anne Kerber, the company’s head of cell therapy development, told Fierce Pharma in an interview.
With the phase 3 data from the ZUMA-7 trial for Yescarta and TRANSFORM trial for Breyanzi, CAR-T drugs are now a “juggernaut” that will change more than 20 years of established practice and replace a regimen of high-dose chemotherapy followed by hematopoietic stem cell transplant as the new standard of care for second-line LBCL, Jason Westin, M.D., the leader of LBCL research at the MD Anderson Cancer Center, said in a separate interview. Westin is an investigator in ZUMA-7 and BELINDA, which is Novartis’ failed second-line trial for Kymriah.
Gilead’s Yescarta appears to have an upper hand in the battle for CAR-T supremacy, given its three-year head start over Bristol’s Breyanzi. In a recent survey Cowen conducted with 20 lymphoma-treating doctors after BMS and Gilead had touted their second-line wins, 60% of oncologists chose Yescarta or Gilead’s newer Tecartus as their likely favored CD19 CAR-T product in 2024. Breyanzi was selected by 25% of doctors, the analysts said.
Industry experts Cowen spoke with separately suggested they would consider Breyanzi in less-fit patients because of the potentially higher rate of neurotoxicity associated with Yescarta. They would also use the BMS drug in cases where Yescarta manufacturing slots aren’t available as a result of increased demand.
But before the two CAR-T products potentially move up the treatment ladder, doctors may want to debate which drug has the better data.
Longer follow-up and larger population
At first glance, Breyanzi’s 65.1% advantage on the EFS measurement looks better than Yescarta’s 60.2%. But the Yescarta number came from a median follow-up of over two years, while Breyanzi reported an interim analysis of the TRANSFORM trial with 6.2 months of median follow-up.
Kite designed the trial under the FDA's guidance, CEO Christi Shaw said in an interview.
“Ours is not an interim look, it’s a final outcome with two-year data that we can solidly say this is what just Yescarta does for patients if you use in the second line,” she said.
Still, MD Anderson’s Westin pointed out that longer follow-up might not make much of a difference because LBCL is a highly aggressive cancer, where disease-worsening events tend to happen quite early. Prior studies have typically showed that a CAR-T therapy’s advantage would really show at about six months, he noted.
Since the TRANSFORM analysis has passed that point, “I think those data are probably mature enough,” he argued. “But we do need more follow-up to be sure of it.”
Kite's Shaw also touted ZUMA-7 for being the larger trial of the two; TRANSFORM randomized 184 patients, while ZUMA-7 enrolled 359 patients.
For her part, Kerber argued BMS, having already expected a large benefit for Breyanzi, “effectively designed … the sample size to avoid too many patients being randomized to an inferior standard of care.”
As for the short follow-up time, Kerber said the current data package, which also includes results showing Breyanzi trumped standard of care in other markers such as tumor response rate, “is so consistent and so compelling that there is no ambiguity in the data.”
Another reason why BMS’ Breyanzi could need a longer follow-up lies in its trial design, Frank Neumann, M.D., Ph.D., Kite’s head of clinical development, said during an interview. Unlike Yescarta’s ZUMA-7 trial, Breyanzi patients in the TRANSFORM study were allowed to take chemotherapy as bridging treatment before they got the CAR-T.
Neumann compared the Breyanzi protocol to giving someone a head start in a race, arguing the extra use of chemo masked Breyanzi’s effect.
“I would definitely consider waiting for their data to get more mature” after the chemotherapy effect potentially wanes off, he said.
But BMS’ Kerber said allowing chemo bridging was a way to reach a more diverse patient population. Existing CAR-T drugs aren’t off-the-shelf products. Treatment centers take a patient’s own T cells and send them to manufacturing sites to be processed. The final product will then be shipped back to the center for infusion. The process could take around a month or even longer.
With bridging therapy, patients with the most aggressive disease could still enroll in the study, Kerber said. The initial chemo use is intended to control the disease and to “widen the spectrum of patients that can be enrolled,” she added.
MD Anderson’s Westin acknowledged the possibility that the lack of bridging chemo might deter people who can’t wait for cells to be manufactured and returned, but that didn’t seem to affect ZUMA-7. The two studies enrolled similar percentage of patients—both at about 74%—who were refractory to first-line treatment, which is a surrogate for really aggressive disease, he noted.
What’s more, Novartis’ Kymriah failed in its second-line trial despite allowing for the use of bridging chemo, he added.
“Although that is a structural difference in the trials, I don’t think we can blame or attribute the outcomes of the studies to the bridging chemotherapy,” Westin said.
Difference in event-free survival definition
Another difference between ZUMA-7 and TRANSFORM is their descriptions for the primary endpoint of event-free survival. Both trials count disease progression, death or start of a new therapy for EFS. But unlike ZUMA-7, TRANSFORM also includes failure to achieve complete response or partial response as an EFS event.
Westin once again pointed to LBCL being an “explosive cancer,” noting that stable disease isn’t common. Patients who don’t respond well to treatment would quickly progress to another therapy. Therefore, the difference in EFS description isn’t meaningful, he said.
All considered, because the outcomes Yescarta and Breyanzi have each shown are “very impressive,” Westin said he would like to start the CAR-Ts as the new standard of care in second-line patients that would have been eligible for the ZUMA-7 or TRANSFORM studies once the drugs cross the FDA finish line in the indication.