EFS improvement with axi-cel CAR-T a ‘breakthrough’ in second-line treatment of DLBCL
Click Here to Manage Email Alerts
Second-line therapy with axicabtagene ciloleucel conferred a fourfold increase in EFS compared with standard-of-care treatment for diffuse large B-cell lymphoma, according to results of a randomized phase 3 study.
Long-term follow-up data from the ZUMA-7 trial also showed a 2.5-fold increase in the number of patients alive at 2 years who did not require additional therapy or have disease progression (40.5% vs. 16.3%).
Results of the study were presented during a plenary session at ASH Annual Meeting and Exposition by Frederick L. Locke, MD, co-leader of the immune-oncology program and vice chair of the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center and a member of the Cell Therapy Next Peer Perspective Board.
Study findings were simultaneously published in The New England Journal of Medicine.
Outcomes of patients who do not respond to first-line standard-of-care chemotherapy for DLBCL remain poor, according to Lori A. Leslie, MD, assistant professor at Hackensack Meridian School of Medicine, director of the indolent lymphoma and chronic lymphocytic leukemia research programs at John Theurer Cancer Center and one of the primary investigators for the ZUMA-7 trial.
Having axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead Sciences) as an option for second-line therapy would likely change the standard of care for patients with high-risk, refractory or chemoinsensitive disease while allowing them to bypass the toxicities associated with salvage therapy, Leslie added.
“The treatment of patients with high-risk diffuse large B-cell lymphoma after first relapse has been an area of unmet need since I have been in the field of medicine,” she told Healio. “This is the biggest breakthrough we have seen for patients with diffuse large B-cell lymphoma who are resistant to chemotherapy.”
Axicabtagene ciloleucel — also known as axi-cel — is an autologous, gene-edited, CD19-directed CAR T-cell therapy that has been approved in the U.S. for adults with relapsed or refractory large B-cell lymphoma who received two or more lines of systemic therapy.
The multicenter ZUMA-7 study includes 359 patients (age range, 22-81 years; 30% aged 65 years or older) with relapsed or refractory large B-cell lymphoma randomly assigned to received either axi-cel or standard of care for second-line therapy. Standard-of-care therapy consists of platinum-based salvage combination chemotherapy, followed by high-dose therapy and autologous hematopoietic stem cell transplant for those who responded to salvage chemotherapy.
Approximately three times as many patients ultimately received axi-cel compared with those who received high-intensity chemotherapy followed by autologous HSCT (94% vs. 36%).
Median follow-up was 24.9 months.
The study met its primary endpoint, with efficacy results showing axi-cel significantly improved EFS when compared with standard-of-care therapy (8.3 months vs. 2 months; HR = 0.398; 95% CI, 0.308-0.514) in the second-line setting.
The improvement in EFS was seen across several patient subgroups, according to the investigators.
Axi-cel also significantly improved the overall response rate when compared with standard-of-care therapy (83% vs. 50%; OR = 5.31; 95% CI, 3.1-8.9), in addition to doubling the complete response rate (65% vs. 32%)
Median OS favored axi-cel treatment but had not yet been reached, compared with 35.1 months in the standard-of-care group.
The researchers detected no new safety issues when compared with axi-cel use as third-line therapy. Most high-grade treatment-related adverse events were hematologic in nature.
Grade 3 or greater cytokine release syndrome occurred in 6% of 170 patients who received axi-cel and were eligible for the safety analysis. A further 21% in the axi-cel group had grade 3 or greater neurotoxicity. There were no cases of grade 5 CRS or neurotoxicity in the study.
“The results are very significant and I'm extremely excited for our patients,” Leslie said.
“With over 2 years of follow-up, approximately 40% of patients treated with CAR-T remain event-free compared with 16% for standard of care,” she added. “This shows that CAR-T is giving a long-term benefit with a one-and-done approach while avoiding the toxicities of salvage chemotherapy and autologous transplant for patients with high-risk disease."
Kite Pharma submitted a supplemental biologics license application to the FDA in October seeking to expand the axi-cel label to include second-line therapy for adults with relapsed or refractory large B-cell lymphoma.
Leslie believes the results merit some expansion of the label. She is interested to see which patients would qualify, allowing them to proceed straight to CAR T-cell therapy without prior autologous HSCT.
“If there is an approval, then it would immediately change the standard of care for high-risk patients who are either primary refractory or have early relapse after frontline therapy,” she told Healio.
References:
Locke FL, et al. Abstract 2. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021.
Locke FL, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2116133.
Perspective
Back to Top
Should CAR T-cell therapy be the preferred option for all patients with relapsed large B-cell lymphoma? This question was directly tested in the ZUMA-7 trial, which compared axi-cel with autologous HSCT as a second-line treatment option in patients with high-risk large cell lymphoma who relapsed within 12 months of front-line chemotherapy. In this population enriched with primary refractory patients (74%), the primary endpoint of EFS was met, with median EFS of 8.3 months for axi-cel compared with 2 months for standard of care.
Although these data demonstrate superiority of CAR T-cell therapy to autologous HSCT for relapsed large B-cell lymphoma, there are some caveats.
First, autologous HSCT is generally limited to chemosensitive patients. With the high percentage of primary refractory patients enrolled on this trial, most were not chemosensitive and autologous HSCT was not offered. Do these data mean that a patient relapsing 9 months from front-line chemotherapy should defer an opportunity for autologous HSCT? Retrospective data from the Center for International Blood and Marrow Transplant Research demonstrated a 5-year PFS of 41% among patients who have chemosensitive disease with autologous HSCT, which is similar to the outcomes seen in ZUMA-7.
Second, it is notable that despite receiving axi-cel at an earlier timepoint, the 2-year EFS (40.5%) was not markedly different than the outcomes achieved with CAR-T in a third or later line. In that case, should autologous HSCT be offered to chemosensitive patients first, reserving CAR-T for those who are deemed chemorefractory? These data make a strong case for earlier CAR-T, perhaps definitively among those with high-risk, primary refractory disease. But whether CAR-T should replace autologous HSCT for all patients with relapsed large B-cell lymphoma remains unclear.
References:
Cell Therapy Next Peer Perspective Board Member
Collapse
Locke FL, et al. Abstract 2. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021.
Click Here to Manage Email Alerts