Dr Sattva Neelapu: Axi-Cel Highly Effective as First-line Option in High-Risk Large B-Cell Lymphoma

Sattva S. Neelapu, MD, professor and deputy department chair in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, discusses findings of the ZUMA-12 study examining axicabtagene ciloleucel (axi-cel) as a first-line treatment option for high-risk patients with large B-cell lymphoma.

In addition to several studies showing chimeric antigen receptor (CAR) T-cell therapies as effective second-line options for patients with large B-cell lymphoma (LBCL) at the 63rd Annual American Society of Hematology Meeting and Exposition (ASH), research on axicabtagene ciloleucel (axi-cel) indicates its effectiveness as a first-line option in patients with high-risk LBCL, said Sattva S. Neelapu, MD, professor and deputy department chair in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center.

Neelapu is the lead author of the abstract presented at ASH 2021, titled, “Primary Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel As First-Line Therapy in Patients With High-Risk Large B-Cell Lymphoma.”


Your results for axi-cel in the first-line setting demonstrate 91% overall survival at 12 months in a high-risk population. Can you discuss how this compared with the use of axi-cel in the original ZUMA study?

In the ZUMA-1 study, we observed at the 2-year time point more than 50% of the patients were still alive, and long-term durability of responses had been observed in about 40% of the patients and these patients are likely cured. In fact, at this meeting, we are presenting an update on the 5-year analysis of the ZUMA-1 study; we found that at least 43% of the patients were still alive at 5 years.

In the ZUMA-12 study, we observed a very high overall response rate and a complete response rate of 78% in a very refractory patient population, where 40% of them are actually having progressive disease to first-line therapy after 2 cycles of chemotherapy.

So, in this patient population after a median follow-up of 16 months, we found that 73% of patients still remain in remission and 91% are still alive. This compares quite favorably to historical data in high-risk patients with LBCL where they have refractory disease to primary first-line therapy and outcomes were very poor. In fact, at the 2-year time point, only about 10% of these patients are alive.

So, even though this is not a randomized study, the data from this ZUMA-12 study indicate that it looks highly promising and axi-cel is highly effective in the first-line setting in these patients.

Were there any patient subgroups that had superior responses?

We looked at a number of different standard prognostic subgroups in these patients. We found consistent response rates, as well as duration of response across the various prognostic subgroups, including patients about age 65, patients who had high IPI [International Prognostic Index], as well as patients who had double- or triple-hit lymphoma.

In addition, patients who had refractory disease to first-line therapy also had comparable outcomes to patients who were chemo-sensitive. So far, we have not been able to identify a subgroup that performed less well compared with the overall patient population.

Some of the more anticipated results at ASH involve phase 3 results for different CAR T-cell therapies in the second-line setting in LBCL, and your results are already moving ahead to the first-line setting. What do you think the timeline will be for use of axi-cel in earlier settings?

I think from the 3 randomized trials being presented at ASH comparing CAR T-cell therapy head-to-head with stem cell transplant in patients with LBCL in the second-line setting, at least 2 of the trials are reported to be positive, with a durability of response in the 40%-45% range at 1 to 2 years after follow-up.

So, this therapy, we expect it to be approved in the second-line setting in the near future, probably within the first half of next year by the FDA, but eventually I think CAR T-cell therapy can be moved to the first-line setting based on the data from the ZUMA-12 study. But ultimately, we will need a randomized study to compare head-to-head with standard-of-care chemo immunotherapy in the first-line setting vs CAR T-cell therapy.

In the first-line setting in the ZUMA-12 study, we also compared the phenotype of these CAR T-cell products to that of the ZUMA-1 study, where CAR T-cell therapy was evaluated in third-line setting and beyond. We found a higher frequency of CCR7-positive, CD45RA-positive T-cells in the ZUMA-12 patients compared with ZUMA-1; this was associated with a greater CAR T-cell expansion and greater clinical efficacy.

So, to us that suggests that the T-cell fitness could be better as we move CAR T-cell therapy to earlier lines and that yields a better CAR T-cell product and better clinical outcomes for these patients.That provides further rationale to evaluate CAR T-cell therapy in earlier lines as opposed to waiting until a patient fails multiple lines of therapy.