Axi-Cel Elicits Encouraging Activity in Indolent Follicular Lymphoma, Marginal Zone Lymphoma

An interim analysis of the phase 2 ZUMA-5 trial revealed that patients with follicular lymphoma and marginal zone lymphoma (MZL) derived significant and potentially durable responses with the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta), explained Caron Jacobson, MD.

The results, which were presented at the 2020 ASCO Virtual Scientific Program, showed that at a median follow-up of 15.3 months, axi-cel led to an overall response rate (ORR) of 93% (n = 96) and a complete response (CR) rate of 80% (n = 77) in patients with follicular lymphoma and MZL.

Moreover, in the follicular lymphoma cohort (n = 80), 80% of patients who achieved a CR (n = 65) remained in remission at follow-up.

In terms of safety, grade 3 or higher cytokine release syndrome (CRS) occurred in 8% of patients, and grade 3 or higher neurologic events were reported in 17% of patients.

“This is an early look at the data,” said Jacobson. “There are a lot of patient samples, correlative science to draw on, and patient disease characteristics to look at in terms of their associations with response and toxicity. All of that needs to come. However, from the early look of these data, the key take-home messages are the efficacy and adverse effect profile.”

In October 2017, axi-cel received regulatory approval for the treatment of patients with large B-cell lymphoma who have not responded to or who have relapsed after at least 2 prior treatments.

In an interview with OncLive, Jacobson, medical director of the Immune Effector Cell Therapy Program and physician at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, discussed the initial ZUMA-5 findings and the next steps with axi-cel in follicular lymphoma and MZL.

OncLive: How was the ZUMA-5 trial designed, and what type of patients were enrolled?

Jacobson: ZUMA-5 is a phase 2, open-label clinical trial, so every patient enrolled received the same therapy. The trial included patients with relapsed/refractory indolent B-cell non-Hodgkin lymphoma. Specifically, these patients had follicular lymphoma or MZL. The planned accrual was 125 patients with follicular lymphoma and 35 patients with MZL.

At the 2020 ASCO Virtual Scientific Program, interim data were presented on all 125 patients with follicular lymphoma and 16 patients with MZL.

These patients [had seen at least 2 lines of therapy]. Their prior treatments must have included chemoimmunotherapy with a CD20-directed antibody and an alkylating agent.

The median number of prior lines of therapy was 3, so for the majority of patients, [axi-cel] was their fourth line of therapy. Moreover, this was a heavily pretreated patient population; about 70% of patients had at least 3 prior lines of therapy.

In addition, this was a high-risk patient population. Patients had high tumor bulk by Groupe d'Etude des Lymphomes Folliculaires criteria and high-risk Follicular Lymphoma International Prognostic Index scores.

The number of patients who had progressed within the first 2 years after their first line of therapy was approximately 50%, making this a particularly high-risk group of patients.

Were high-risk patients the focus on the planned accrual population?

No, but patients in their third- or later-line of treatment tend to be an [innately] higher-risk patient population. Many patients with follicular lymphoma will have remissions for several years from their first- or second-line therapy. Additionally, many of these patients can be observed for a number of years. Therefore, calling on patients who already require a third line of therapy highlights a higher-risk group.

What did the results of the interim analysis show?

These were inspiring results. For patients with follicular lymphoma, the ORR was 95%. The percentage of patients who went into a CR was 81%. The median follow-up of the follicular lymphoma cohort was about 15.3 months. At that time, 80% of patients who had [achieved] a CR, were still in response.

This is early follow up for an indolent disease. We know patients can relapse many years after therapy, but the remissions look promising and durable.

The MZL cohort was smaller with 16 patients. Patients were required to have 1 month of follow-up so that we had at least 1 scan to look at for efficacy. The primary [end point] was response rate by independent radiology review. When the central radiology review looked at the pretreatment scans, they found that some of these patients did not meet measurable disease criteria.

The ORR was closer to 81% with a CR rate in the range of 70%. Additionally, 19% of patients were non-evaluable because they were not felt to have measurable disease prior to getting CAR T-cell therapy.

The numbers look a little bit worse [than the follicular lymphoma cohort], largely due to the fact that 19% of patients were not evaluable. No patients had progressive disease in that cohort.

Again, the follow-up time is very short. Most patients had a 6-month follow-up, so the duration of response curves were truncated early. I would say the data are immature in terms of durability of response in the MZL cohort.

Were the adverse effect (AE) profiles in the 2 cohorts consistent with what we know of axi-cel?

Interestingly, the safety profile was a little bit better in the follicular lymphoma cohort, so much so that it potentially raises the question of whether [axi-cel] could be dosed in the outpatient setting. About 23% of patients had no CRS whatsoever. Among those patients who did, the median onset [of CRS] was 4 days as opposed to 2 days with axi-cel in large-cell lymphoma. Additionally, only 7% of patients had high-grade CRS.

Similarly, with neurologic toxicity, 15% of patients with follicular lymphoma had high-grade neurologic toxicities. Both of these numbers are about half of what we [expect] with axi-cel in large-cell lymphoma.

The MZL cohort had a slightly higher incidence of CRS and higher-grade neurologic toxicity that was more aligned with what we see in diffuse large B-cell lymphoma (DLBCL). However, the median time to onset [of CRS] was about 4 days. Therefore, it was the same degree of toxicity, but occurred later than what we are used to seeing [in DLBCL].

What are the next steps for this research?

The data need to mature. We are still enrolling patients with MZL. The next important end point for the follicular lymphoma cohort is the 12-month analysis to [determine whether] these responses are durable.

The ZUMA-5 trial is designed as a pivotal study for axi-cel. [An FDA approval] would lead to an expanded indication for axi-cel among our patients with lymphoma. On top of that, if the durability proves to be robust and the safety profile continues to be reproducible, we could start thinking about designing clinical trials with axi-cel or other CAR T-cell therapies in earlier lines of therapy, particularly for patients who are higher risk, such as those who progress early after initial chemoimmunotherapy.

Reference:

Jacobson CA, Chavez JC, Sehgal AR, et al. Interim analysis of ZUMA-5: a phase II study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL). J Clin Oncol. 2020;38(suppl 15):8008. doi:10.1200/JCO.2020.38.15_suppl.8008