The Lynx Group

CAR T-Cell Therapies Show Efficacy in Second-Line Treatment of Large B-Cell Lymphoma

February 2022, Vol 13, No 1 Online Only

The results from 2 phase 3 clinical trials highlighted the superiority of CAR T-cell therapies over current standard of care (SOC) when used earlier in the course of treatment for patients with large B-cell lymphoma (LBCL). These findings were reported at the ASH 2021 Annual Meeting and Exposition.

The ZUMA-7 Study

The primary analysis of the phase 3 ZUMA-7 trial showed the lasting benefit of axicabtagene ciloleucel (Yescarta), which significantly improved event-free survival (EFS) compared with SOC (additional chemotherapy and stem-cell transplantation for individuals whose disease responded to chemotherapy) in patients with aggressive LBCL, meeting the trial’s primary end point, said Frederick L. Locke, MD, Vice Chair, Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL.

Axicabtagene ciloleucel is currently approved by the FDA as a third-line therapy for LBCL; the ZUMA-7 trial assessed its use as a second-line therapy.

At 2 years of follow-up, patients treated with axicabtagene ciloleucel had a median EFS of 8.3 months versus 2.0 months for those treated with SOC. The 24-month EFS rate was 40.5% in the axicabtagene ciloleucel arm versus 16.3% in the SOC arm. At a median follow-up of 24.9 months, the difference in EFS translated into a 60% decrease in the hazard ratio in favor of axicabtagene ciloleucel (95% confidence interval, 0.308-0.514; P <.0001).

The results herald a paradigm shift, said Dr Locke. “Axicabtagene ciloleucel should be a new standard for patients with second-line relapsed/refractory large B-cell lymphoma,” he said. “[The finding] is remarkable and indicates that patients with lymphoma not responding to initial treatment or relapsing within 12 months should have the opportunity to get this therapy.”

In ZUMA-7, 364 patients with early relapsed or refractory LBCL were randomized to axicabtagene ciloleucel preceded by conditioning chemotherapy or to platinum-based chemoimmunotherapy, followed by high-dose therapy and transplantation. All patients enrolled were considered to be eligible for transplantation.

Of the 140 patients randomly assigned to axicabtagene ciloleucel, 94% were infused. Of the 179 patients randomly assigned to SOC, only 64 (36%) reached transplantation. Patients not responding to SOC could cross over to receive CAR T-cell therapy off protocol, as 56% did.

“By giving CAR T-cell therapy as an earlier line of treatment, we are able to reduce the amount of chemotherapy patients are exposed to and get them quickly to a definitive therapy that can eradicate lymphoma for many years, if not forever, without a stem-cell transplant,” said Dr Locke.

The rates of adverse events (AEs) were relatively similar between both study arms, with grade ≥3 toxicities occurring in 91% of patients receiving axicabtagene ciloleucel and 83% of those receiving SOC. The most common AE in both groups was low blood counts.

Previous studies have shown that CAR T-cell therapy leads to 2 types of acute toxicities, which are usually transient: cytokine release syndrome (CRS) and neurologic events.

In the ZUMA-7 trial, 6% of patients receiving axicabtagene ciloleucel experienced grade ≥3 CRS, and 21% experienced grade ≥3 neurologic events, with 12% experiencing changes in brain function (encephalopathy), which were temporary in most cases.

Among those receiving SOC, 27% experienced fever when their white blood cell counts were low due to chemotherapy, which is considered a serious event.

“For both study arms, the rates and types of adverse events were consistent with expectations based on previous trials and real-world experience,” Dr Locke noted.

Researchers will continue to follow patients for survival.

The TRANSFORM Study

The phase 3 TRANSFORM trial randomized 184 patients with relapsed/refractory LBCL requiring second-line therapy to lisocabtagene maraleucel (Breyanzi) or to SOC (salvage chemotherapy and, for responding individuals, additional high-intensity chemotherapy followed by stem-cell transplantation). The interim analysis presented at the meeting showed that patients assigned to lisocabtagene maraleucel survived for a median of 7.8 months longer without complications or disease progression compared with those assigned to SOC. The median EFS was 10.1 months in the lisocabtagene maraleucel arm versus 2.3 months in the SOC arm (hazard ratio, 0.349; P <.0001), reported Manali Kamdar, MD, Clinical Director, Lymphoma Services, University of Colorado Cancer Center, Aurora.

“Despite a relatively short follow-up period of just over 6 months, the positive results of this study suggest that CAR T-cell therapy has the potential to become the new standard of care for patients who do not respond to initial chemotherapy or who relapse within 12 months,” said Dr Kamdar.

Lisocabtagene maraleucel is currently FDA approved for the treatment of patients with relapsed or refractory LBCL after 2 or more lines of systemic therapy. The TRANSFORM study assessed its efficacy as a second-line therapy.

In addition to improving EFS (the study’s primary end point), treatment with lisocabtagene maraleucel extended progression-free survival by 9 months compared with SOC (P <.0001) and resulted in a superior complete response rate (66% vs 39%, respectively; P <.0001) and overall survival rate (not reached vs 16.4 months, respectively; P = .0257).

The safety profile of lisocabtagene maraleucel was consistent with the agent’s known toxicities, said Dr Kamdar. Half of the patients in the lisocabtagene maraleucel arm experienced CRS, but only 1 was of grade 3 severity. Neurologic events occurred in 11 patients, 4 cases of which were grade 3 in severity. No grade 4/5 toxicities occurred. Some patients were able to receive lisocabtagene maraleucel infusion in the outpatient clinic setting, she noted.

“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.”

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