Caron A. Jacobson, MD, on the Interim Phase II ZUMA-5 Study Safety and Efficacy Findings

June 7, 2020

The study evaluated the use of axicabtagene ciloleucel (axi-cel) in patients with relapsed or refractory indolent non-Hodgkin lymphoma.

Results from the interim analysis of the phase II ZUMA-5 study, presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, indicated that axicabtagene ciloleucel (axi-cel) demonstrated significant and durable clinical benefit in patients with relapsed or refractory indolent non-Hodgkin lymphoma. 

Though this particular study requires further follow-up, the investigators suggested that axi-cel may be a promising therapeutic approach for this patient population.

In an interview with CancerNetwork®, Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute, explained the efficacy and safety findings observed in the interim analysis. 

Transcription:

Yep. So, in total 125 patients with follicular lymphoma were in enrolled and treated, and 16 patients with marginal zone lymphoma were enrolled and treated. The way this study was designed is that the first 80 patients with follicular lymphoma who reached 9-month follow-up would be included for efficacy analysis. And, but all patients treated were included in the safety analysis. The marginal zone lymphoma cohort was more of an exploratory cohort, there was no formal hypothesis being tested, but just to, you know, any findings would be more descriptive in nature. And so, we placed focus on that sort of efficacy cohort for follicular lymphoma since that was really the principal patient population for the primary endpoints of the study which was the overall response rate. The overall response rate was 95% in that group of patients and 81% of patients had a complete response to therapy. And those patients were then followed for some time, and the median follow up for that cohort was 15.3 months. And other patients who had had a complete response of those 81% of patients who had a complete response, 80% of them maintain that complete response at that median follow up time. 

So, it did appear that some, that many of these complete responses were durable out past at least now a year; we need longer follow up. The marginal zone lymphoma cohort had similarly high response rates and high (complete response; CR) rates. Although if you look at the absolute numbers in the in the presentation, they're a little bit lower than what we saw with follicular lymphoma, which actually probably isn't, doesn't reflect the activity in marginal zone lymphoma. It's an artifact of the fact that 19% of the marginal zone lymphoma patients that were enrolled in the study when an independent central radiology review looked at their pretreatment scans, they found that they didn't have what we call measurable disease. So, there's there are lots of ways that people can, people's lymphomas can relapse and show up but the measurable that may not necessarily be measurable. So, the sites that put the patients on felt that they had measurable disease, but it was sort of overruled in central radiology review. And so that caused the numbers to go down. So, the overall response rate was closer to the 80s and the CR rate was closer to the 70s for that cohort, so they had very short follow up. So, the it's very hard to say anything about durability of response in that group. 

And then the most important next thing to look at is looking at the safety. So, we know CAR T-cells have a unique safety profile and for these slow growing diseases, where they have very long natural history, safety is really incredibly important. And so, on a whole, the safety looked very similar to what we had seen in other studies. But when you sort of looked at the follicular lymphoma patients in particular, and then the marginal zone lymphoma patients separately, you can see that in the follicular lymphoma patients, the safety profile actually looks more favorable compared to what we're used to seeing with axi-cel. So actually, 23% of patients had no cytokine release syndrome (CRS) whatsoever. It was 95 plus with large cell lymphoma and the axi-cel, and that means that 19 to 23% of patients didn't even have a fever. And then in terms of patients who have high grade cytokine release syndrome, that it was actually only 7% compared to 16% with axi-cel in large cell lymphoma. And then in terms of high-grade neurologic toxicity, which is the other toxicity we worry about, the rates of high-grade neurologic toxicity were also lower by about 50%. So, they were about 15% compared to 30 plus percent with large cell lymphoma. And I think one of the other more interesting aspects was just that the cytokine release syndrome started later in these patients. So, whereas you can see it within day 1 and day 2, when large cell lymphoma patients are treated with axi-cel, the median time to onset was 4 days. So, the fact that 23% of people didn't even have a fever, and it took for those who did, it took 4 on average 4 days to develop, you could actually start to think about for follicular lymphoma patients dosing this outpatient. Within the marginal zone lymphoma cohort, the toxicity was likewise delayed. So, onset usually started around day 4, but the numbers of high, you know, the numbers of patients who had a fever and the number of patients who had high grade CRS or neurotoxicity, more closely resembled what we saw with axi-cel and large cell lymphoma.