CAR-T continues to show durable responses in indolent non-Hodgkin lymphoma
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Axicabtagene ciloleucel induced a 93% response rate among patients with relapsed or refractory indolent non-Hodgkin lymphoma, according to interim results of the phase 2 ZUMA-5 trial presented during the ASCO20 Virtual Scientific Program.
Responses among this cohort of patients with indolent non-Hodgkin lymphoma — which includes follicular lymphoma and marginal zone lymphoma — appeared durable, and the treatment had an acceptable safety profile.
Axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead) — an anti-CD19 autologous chimeric antigen receptor T-cell therapy also known as axi-cel — has been approved by the FDA for adults with relapsed or refractory large B-cell lymphoma after two or more previous lines of therapy.
“The efficacy of CAR T-cell therapy in other types of CD19-positive diseases has been transformative,” Caron A. Jacobson, MD, assistant professor of medicine at Harvard Medical School and director of the cell therapy program at Dana-Farber Cancer Institute, told Healio. “It makes sense to expand the indications to other CD19-positive B-cell malignancies.”
Despite indolent lymphomas being slower-progressing diseases, a large subset of patients have more aggressive disease and could benefit from more effective treatments, Jacobson said.
“Follicular lymphoma and marginal zone lymphoma are historically incurable in the absence of an allogeneic stem cell transplant, so exploring a therapy that could potentially transform the natural history of these diseases is certainly appealing,” she said.
This year’s ASCO program marked the first time data from the ZUMA-5 trial had been presented, Jacobson said.
The efficacy analysis included 96 patients (mean age 63 years; range, 34-79; 51% women) with median follow-up of 15.3 months (range, 1.9-28.8) as of data cutoff on Dec. 16, 2019. Eighty of the patients had follicular lymphoma, whereas 16 had marginal zone lymphoma.
All patients had a median three (range, 2-9) previous lines of therapy, and approximately half (52%) had stage IV disease. Nearly three-quarters (73%) of patients were refractory to their previous line of treatment.
Patients received a conditioning chemotherapy regimen followed by an infusion of axicabtagene ciloleucel dosed at 2 × 106 CAR T cells/kg.
Objective response rate assessed by independent radiology review committee served as the primary endpoint. Secondary endpoints included complete response rate, duration of response, PFS, OS and adverse events.
Results showed an ORR of 93% (95% CI, 86-97), with a complete response rate of 80% (95% CI%, 71-88). Patients with follicular lymphoma had an ORR of 95%, with a complete response rate of 81%. Patients with marginal zone lymphoma had an ORR of 81% and a complete response rate of 75%.
Median duration of response was 20.8 months for all patients. Sixty-eight percent of patients with follicular lymphoma had an ongoing response to therapy as of data cutoff.
Median PFS was 23.5 months (95% CI, 22.8 to not reached) for all patients, and median OS was not reached. One-year OS for all patients was 94.3% (95% CI, 86.8-97.6).
Jacobson said the response rates are clinically meaningful from a historical perspective. She highlighted the 70% response rate among patients who had three or more previous lines of therapy as particularly compelling.
“This is a very high response rate for a heavily pretreated population,” Jacobson told Healio.
“CD19-directed CAR T-cell therapy has a high response rate in indolent non-Hodgkin lymphomas, and although follow-up is relatively short for these diseases — which a have a long natural history — 80% of patients in this trial achieved a complete response to therapy,” she added. “Based on the follow-up we have so far, these responses appear to be durable.”
Data on 140 patients were available for the safety analysis, which showed nearly all patients (99%) had at least one treatment-related adverse event. Eighty-five percent of patients experienced a grade 3 or higher adverse event.
The most common grade 3 or higher adverse events included neutropenia (34%), decreased neutrophil count (34%) and anemia (22%).
Two patients died during the study; one had cytokine release syndrome (CRS)-related multisystem organ failure that was determined to be related to axicabtagene ciloleucel treatment.
Most patients (79%) had some form of CRS; however, only 8% of patients had grade 3 or higher CRS. Median time to onset of CRS was 4 days (range, 1-15), with a median duration of 6 days (range, 1-27).
Fifty-eight percent of patients experienced neurotoxicity during the study, with 17% having grade 3 or higher neurotoxicity. Median time to onset was 7 days (range, 1-177), with a median duration of 14 days (range, 1-452).
Jacobson highlighted the relatively low rate of CRS in the study, especially serious cases. She told Healio that the safety profile “could potentially allow for outpatient dosing in the future.”
The manufacturers of axicabtagene ciloleucel plan to submit a supplemental biologics license application to the FDA later this year to expand its indications, according to a company-issued press release.
Jacobsen said she is confident the FDA will approve axicabtagene ciloleucel for the indications examined in ZUMA-5, but that it will come down to the ability of the treatment to induce sustained responses.
“I think the data we have to date on this would surpass almost any other therapy we have available in the third line or beyond for these patients,” Jacobson told Healio.
Perspective
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Samantha M. Jaglowski, MD, MPH
This study comprises a high-risk patient population that typically lacks effective treatment options. Therefore, the response rates are very impressive.
Notably, incidence of grade 3 cytokine release syndrome and neurological events was relatively low compared with what has been reported for both B-cell and mantle cell lymphoma.
I believe axicabtagene ciloleucel will receive FDA approval for this indication based on its high response rates plus prolonged durability in a relatively refractory patient population. Combine this with its relatively good safety profile and track record with previously approved indications, and I think it is a matter of time before axicabtagene ciloleucel is approved for follicular and marginal zone lymphoma.
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Jacobson CA, et al. Abstract 8008. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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