ASH 2021 | ZUMA-7: Axi-cel in r/r large B-cell lymphoma

The ZUMA-7 trial is a Phase III randomized trial of axicabtagene ciloleucel, or axi-cel, which is an autologous CAR-T cell therapy. The study was conducted in patients with relapsed, refractory large B-cell lymphoma. This therapy is approved for use as a third or later line and here in this trial, we’re testing out eligible patients with large B-cell lymphoma that either had primary refractory disease to frontline therapy or relapsed within 12 months of that initial therapy, and the intention was for them to proceed to autologous transplant. And those patients were randomized one to one, to either receive a single dose of axi-cel or the current standard of care, multi-step treatment paradigm, which consists on study one of four protocol-defined and investigator-selected platinum-based combination chemotherapy regimens. And if the patient had an objective response after two or three cycles, they’d be followed by high dose chemotherapy and autologous stem cell transplant.

And that’s really the current standard of care therapy for second line treatment of fit patients with diffuse large B-cell lymphoma. Important to note that in patients randomized to the axi-cel arm, bridging corticosteroid therapy was allowed to keep that patient from … to temporize their disease, keep them from progressing. It’s not a curative therapy, we know that, but bridging chemotherapy was not allowed for these patients because we didn’t want to cloud the results with a potential response to bridging chemotherapy. So only bridging corticosteroids was allowed. There was no built in crossover, so patients randomized to standard of care could not get axi-cel on study, however if they needed additional therapy, they could get any standard of care therapy available, including CAR-T cell therapy. And so here at the ASH annual meeting, we’re presenting the results. And first off, patients randomized to standard of care, 179 randomized to standard of care, 36% received high dose therapy and autologous transplant, in contrast to the 180 patients randomized to axi-cel, 94% received axi-cel therapy.

The patients enrolled on this trial were generally high risk. A third were 65 or older, three quarters had primary refractory disease, half had double hitter, double expressor lymphoma, half had an elevated LDH. So these are patients that could expect a poor chance for a good outcome. And in fact, the primary endpoint of the study was event-free survival, and in fact axi-cel was superior to the standard of care, with a hazard ratio of 0.39. The median event-free survival with axi-cel was 8.3 months and the median event-free survival standard of care was 2 months. And with a median follow of 24.9 months, importantly, the Kaplan-Meier estimate of 24 month event-free survival in the axi-cel arm was 40%. So 40% of patients randomized to axi-cel were not needing other therapy, had not progressed, were alive and well. In contrast, at 24 months that number was only 16% for patients randomized to standard of care. 16% of patients with standard of care didn’t need alternative therapy or had not progressed, so pretty remarkable result in favor of axi-cel.

Also important to note that the response rates were much higher with axi-cel. The objective response rate was 83% with the axi-cel versus 50% with standard of care and CR rate of 65% with axi-cel was double that of the CR rate of 32% with a standard of care. So clearly better efficacy outcomes with axi-cel. Importantly, overall survival was analyzed as a pre-planned interim analysis. And at that time, at the time of analysis, the median overall survival was yet to be reached for axi-cel, is 35 months for standard of care therapy, again at a median of 24.9 months. Overall survival was numerically higher for axi-cel but it did not reach statistical significance as being better than the standard of care with a hazard ratio of 0.73 and a 95% confidence interval of 0.53 to 1.007.

Important to note that 56% of patients on the standard of care arm crossed over off study, they got cellular therapy after progression as a standard of care. So 56% of those patients receive some cellular immunotherapy, like CAR-T, off protocol, and a pre-planned sensitivity analysis suggests that overall survival may be confounded in the analysis because these patients are getting CAR-T as third line or later. Toxicity was as expected. This isn’t easy therapy, but certainly we can manage the side effects, cytopenias in the standard of care arm, and we have certainly cytokine release syndrome and neurologic events in the CAR-T arm. 6% of patients with treated with axi-cel had a severe cytokine release syndrome and 21% of patients in the axi-cel arm had severe neurologic complications.

So really pretty remarkable results that we’re excited about and happy to be presenting at ASH, really ZUMA-7 is the first randomized CAR-T cell trial. It has 24.9 months median follow up and nearly three times the number of patients in the axi-cel arm got the definitive CAR-T cell therapy as compared to those who got the definitive autologous transplant therapy, with a fourfold greater event-free survival for axi-cel and really much higher objective response rate and CR rate. So really excited about those results and we think that this suggests that axi-cel should be the new standard for patients who are needing second line therapy with relapsed, refractory large B-cell lymphoma, certainly those who have primary refractory disease or relapse within one year and are otherwise fit and eligible.