CAR T-Cell Therapy Makes Strong Case for Earlier Use in Lymphoma

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ATLANTA — Earlier use of chimeric antigen receptor (CAR) T-cell therapy for relapsed B-cell lymphoma substantially improved outcomes as compared with standard treatment, two randomized trials showed.

After 2 years of follow-up in the ZUMA-7 trial, patients treated with axicabtagene ciloleucel (axi-cel, Yescarta) had a median event-free survival (EFS) of 8.3 months versus 2.0 months with standard care, which consisted of chemotherapy and stem-cell transplantation (for patients who responded to chemotherapy). The 24-month EFS was 40.5% with axi-cel and 16.3% with standard care, reported Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa, Florida, at the American Society of Hematology (ASH) meeting.

In the second study, patients who received lisocabtagene maraleucel (liso-cel, Breyanzi) had a median EFS of 10.1 months versus 2.3 months with standard care. Median progression-free survival (PFS) more than doubled, from 5.7 to 14.8 months with the CAR T-cell therapy, reported Manali Kamdar, MD, of the University of Colorado Cancer Center in Aurora.

“ZUMA-7 met its primary event-free survival endpoint, demonstrating statistically significant and clinically meaningful improvement in efficacy with axi-cel versus second-line standard of care in relapsed and refractory large B-cell lymphoma (LBCL),” Locke said at an ASH press briefing. “Nearly three times the number of patients in the axi-cel arm received definitive therapy versus the standard-of-care arm. Axi-cel had a manageable safety profile consistent with previous studies.”

“Results from ZUMA-7 herald a paradigm shift. Axicabtagene ciloleucel should be a new standard for patients with second-line relapsed/refractory large B-cell lymphoma,” he stated.

Kamdar echoed Locke’s sentiments with regard to liso-cel.

“In my opinion, this is a breakthrough therapy, which has shown superiority over standard of care after decades, in terms of not just efficacy, but also an extremely favorable safety profile,” she said. “We are extremely excited about the potential of this study to change the existing standard of care in these high-risk patients.”

First Randomized Trial of CAR T-Cell Therapy

CAR T-cell therapy has transformed treatment of aggressive, relapsing, and refractory lymphomas, but approved indications remain limited to later lines of therapy. ZUMA-7, the first randomized trial of CAR T-cell therapy, compared axi-cel and the current standard of care for patients with LBCL in first relapse.

Locke pointed out that patients in first relapse initially receive platinum-containing chemotherapy. Patients who achieve a partial or complete response than receive high-dose chemotherapy and proceed to stem-cell transplantation. Patients who do not respond, including those who attain stable disease, are ineligible for transplantation. A majority of patients with relapsed LBCL do not respond to chemotherapy.

“These patients go on to get some third-line therapy,” he said. “It’s sort of a treatment walk to get to autologous transplant; these patients have the opportunity to progress at any step on the way.”

ZUMA-7 involved 364 patients with LBCL that had progressed during or after first-line treatment with chemotherapy, and all were considered to be eligible for transplantation. They were randomized to axi-cell (preceded by conditioning chemotherapy or to platinum-based chemoimmunotherapy, followed by high-dose therapy and transplantation. The primary endpoint was EFS (defined as disease progression, start of new lymphoma therapy, or death).

The results showed that 94% of patients assigned to axi-cel received the therapy, whereas 36% of patients in the transplant arm actually underwent transplantation. After a median follow-up of 24.9 months, the difference in EFS translated into a 60% decrease in the hazard ratio in favor of axi cel (95% CI 0.308-0.514, P<0.0001).

The safety profiles of the two treatment arms were consistent with the known toxicities of the treatments, said Locke. In the axi-cel arm, 91% of patients had grade ≥3 adverse events (AEs), and 42% had serious AEs. That compared with 83% and 40% in the standard-of-care arm. One treatment-related death occurred with axi-cel and two with standard of care.

Consistent Results

Kamdar reported data from the TRANSFORM trial, which had a design similar to that of ZUMA-7. Patients requiring second-line therapy for relapsed/refractory LBCL were randomized to liso-cel or standard-of-care chemotherapy/transplantation. As in ZUMA-7, the trial had a primary endpoint of EFS.

Data analysis included 184 randomized patients and showed that 97% of patients randomized to liso-cel received the treatment as compared with 46% of patients who understand transplantation. Liso-cel was associated with a 65% reduction in the EFS hazard (P<0.0001). Liso-cel demonstrated superiority for PFS (P<0.0001), complete response rate (66% vs 39%, P<0.0001), and overall survival (not reached vs 16.4 months, P-0.0257).

Liso-cel’s safety profile also was consistent with therapy’s known toxicities, said Kamdar. Half the patients in the liso-cel arm developed cytokine release but reached grade 3 severity in only one patient. Neurologic events occurred in 11 patients and reached grade 3 severity in four cases. No grade 4-5 toxic events occurred.

Press briefing moderator Laurie Sehn, MD, of the British Columbia Cancer Center in Vancouver, described the studies’ results as “remarkable.”

“What I think is very impressive is the consistent results that were shown,” she said. “For somebody who actually treats patients with large B-cell lymphoma, like I do, it’s incredibly frustrating when patients fail front-line therapy. We come in with more chemotherapy, and at higher doses, and try to slam things down harder… . It’s not surprising that coming in with a novel approach, a cellular therapy that has proven to have curative capacity in the third-line setting, may have outperformed coming in with more chemotherapy.”

“I think it’s inevitable that [CAR T-cell therapy] will become the standard of care,” Sehn added. “These studies that were presented are in different stages of presentation, but certainly in the axi-cel study, we’ve got very mature data and the 24-month follow-up suggests that there is a real difference in the durability of these two approaches.”

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Disclosures

ZUMA-7 was supported by Kite/Gilead.

Locke disclosed relationships with Novartis, Janssen, Kite, Iovance Biotherapeutics, GammaDelta Therapeutics, Umoja, Wugen, Takeda, Legend Biotech, EcoR1, Emerging Therapy Solutions, Gerson Lehrman Group, Cowen, Calibr, Cellular Biomedicine Group, Bristol Myers Squibb/Celgene, Bluebird Bio, Amgen, Allogene Therapeutics.

The TRANSFORM study was supported by Celgene.

Kamdar disclosed relationships with SeaGen,ADC Therapeutics, Celgene, TG Therapeutics, Karyopharm, Genentech, Adaptive Biotechnologies, AbbVie, Kite, and AstraZeneca.

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