CAR-T vs. bispecifics for lymphoma: Using the evidence to sequence treatments
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Curative potential at a longer follow-up, logistics and patient risk and eligibility are all important considerations when sequencing bispecific antibodies and chimeric antigen receptor T-cell therapy for advanced large B-cell lymphoma.
As part of an education program session titled “How do we calibrate cellular therapy for lymphoma in 2023?” at ASH Annual Meeting and Exposition, Manali Kamdar, MD, associate professor of medicine-hematology at University of Colorado School of Medicine, outlined an evidence-guided approach to sequencing CAR-T and bispecific antibody treatments in this population.
“We obviously don’t have any randomized phase 3 studies comparing CD20 bispecific antibody treatments to CD19 CAR T-cell therapies,” she said. “This is a very timely topic because, at this point, we truly need to figure out the best option for each patient.”
CAR-T: the available evidence
Kamdar discussed the overall evolution of CAR T-cell therapy, which was initially approved for adults with relapsed or refractory large B-cell lymphoma who experienced disease progression after two previous lines of treatment. She noted three pivotal studies that evaluated CAR T-cell therapies in heavily pretreated patients.
“These were ZUMA-1, investigating axicabtagene ciloleucel [Yescarta; Kite Pharma, Gilead]; JULIET, investigating tisagenlecleucel [Kymriah, Novartis]; and TRANSCEND, investigating lisocabtagene maraleucel [Breyanzi, Bristol Myers Squibb],” she said. “All three of these clinical studies showed that in a heavily pretreated population, the overall response rates, complete response rates and progression-free survival rates were very impressive.”
Longer follow-up data up 5 years showed a plateau across the three studies, she said, adding this likely indicates that these treatments are curing roughly 30% to 40% of patients who otherwise would have succumbed to their disease.
“I believe that in the third-line setting, where the CAR T-cell therapy constructs are approved, they do offer a chance for a cure,” she said.
Kamdar also noted that CAR T-cell treatment is now approved for patients who are either primary refractory or experience relapse after front-line chemoimmunotherapy within the first year of treatment. For this patient population, the response to the current standard-of-care treatment — autologous hematopoietic stem cell transplant — “was dismal,” Kamdar said.
“Three pivotal randomized studies — ZUMA-7, TRANSFORM and BELINDA — compared CAR T-cell therapy versus salvage followed by autotransplant in this high-risk population,” Kamdar said. “Two of these studies were positive — namely ZUMA-7 and TRANSFORM — and the primary endpoint, event-free survival, was met, favoring CD19 CARs in the second-line setting.”
Based on the two positive studies, the FDA approved CD19-directed CARs in the second-line setting for transplant-eligible, high-risk diffuse large B-cell lymphoma, Kamdar said.
Patients ineligible for transplant are left with even fewer options for treating large B-cell lymphoma. Kamdar discussed a phase 2, open-label study evaluating lisocabtagene maraleucel, also known as liso-cel, in high-risk patients — 21% had relapsed within a year of diagnosis, 54% had primary refractory disease and 33% had double-hit lymphoma.
“The primary endpoint was overall response rate, which was met at 80%, and complete response rate was also met at 54%,” Kamdar said. “It’s very impressive that the median progression-free survival, even at a longer follow-up, is 9 months, with a median overall survival that has not been reached. Most impressively, there were no treatment-related deaths, and the incidence of cytokine release syndrome and neurological events were exceedingly low.”
Results from these studies provide additional options for patients with relapsed or refractory large B-cell lymphoma, Kamdar said.
“We have three CAR T-cell constructs that have now been approved in the third-line setting, and we have liso-cel and [axicabtagene cilolencel] approved in the second-line setting in transplant-eligible, high-risk large B-cell lymphoma,” she said. “For patients who are transplant ineligible, we have liso-cel, which is approved in the second-line setting.”
The ‘newest kid on the block’
Kamdar went on to discuss existing data on anti-CD20/anti-CD3 bispecific T-cell engagers, which she referred to as the “newest kid on the block.” Two of these agents — glofitamab (Columvi, Genentech) and epcoritamab (Epkinly; Genmab, AbbVie) — have been evaluated in the third-line setting. Glofitamab and epcoritamab gained FDA approval based on two pivotal studies in patients who experienced disease progression following two or more lines of treatment.
Similar results in terms of response rates emerged from both studies, Kamdar added.
“Interestingly, 33% of patients had prior CAR-T across the two studies, and roughly 18% to 20% of patients had prior autologous stem cell transplant,” she said. “The overall response rate was 50% to 60%, the complete response rate was 39%, and the complete response rates in patients who had prior CAR-T was 35%.”
These studies did show a difference in complete response rates between relapsed and refractory patients. Kamdar said relapsed patients achieved a 70% complete response rate, whereas primary refractory patients had a complete response rate of about 34%.
Kamdar noted that glofitamab is a time-limited, 12-cycle infusion, and data are now available on patients who have finished treatment.
“Sixty-seven percent of complete responders are still in remission at 18 months; that’s very striking,” she said. “Epcoritamab is given subcutaneously, but it’s given indefinitely. Regardless, CRS rates were all low-grade. There is very rare evidence of neurological events.”
Considerations for sequencing
Kamdar discussed the factors she weighs when sequencing treatment in the third-line setting. She emphasized the curative potential of CAR-T as a reason to use it before bispecific antibodies.
“You can make a case for one or the other, but I would say the case for using CAR T-cell therapy first is that they have a potential for cure in 30% to 45% of patients at the 5-year mark,” she said. “We just don’t have that kind of long-term follow-up with bispecifics yet.”
Other advantages of CAR-T include that it can be given as a single infusion, it has shown a higher response rate and progression-free survival, its cytotoxicity is independent of innate immunity and response to it is independent of CD20 or CD19 status.
CAR-T has also shown efficacy in patients with central nervous system involvement, whereas these patients were excluded from studies of bispecific T-cell engagers.
“Ultimately, I think the biggest factor is that there are prospective studies showing that CAR T-cell therapy failure does not mean [bispecific T-cell engager] failure, so people can demonstrate efficacy with bispecific T-cell engagers if they fail CAR-T,” Kamdar said. “The reverse has been shown in a retrospective setting, but a prospective study for patients who have failed [bispecific T-cell engagers] and then received CAR-T is not yet published.”
Kamdar noted that bispecific T-cell engagers confer advantages in terms of logistics and tumor burden. She cited their immediate treatment infusion as well as the lack of need for bridging therapy or lymphodepletion chemotherapy with this method.
“There’s an ability to administer this in the community setting with minimal logistical barriers, early access and easy access,” she said.
Overall, Kamdar said for patients with relapsed large B-cell lymphoma who have failed two or more lines of treatments, she would choose CAR T-cell treatment first and then bispecific antibodies.
“However, if they have failed one line of treatment and they have high risk, then I’m obviously trying to get them to CAR-T based on the TRANSFORM and ZUMA-7 studies,” she said. “If they have received CAR-T in the second-line setting, the third choice obviously would be bispecifics.”
For patients who are not high risk or have not had second-line relapse and are transplant eligible, Kamdar said autotransplant remains a curative option for chemotherapy-sensitive patients. For transplant-ineligible patients, however, Kamdar said CAR T-cell therapy would be the best choice.
“Basically, in the third-line setting, I prefer CAR-T followed by bispecifics,” she said. “In the second-line setting, if they have received CAR T-cell therapy and then relapsed, then I prefer bispecific agents.”
References:
- Abramson JS, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31366-0.
- Bishop MR, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2116596.
- Kamdar MK. How do we calibrate cellular therapy for lymphoma in 2023? Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
- Kamdar M, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)00662-6.
- Locke FL, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa211613.3.
- Neelapu SS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707447.
- Schuster SJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1804980.
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Kamdar MK. How do we calibrate cellular therapy for lymphoma in 2023? Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
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