Kymriah fails to extend EFS as second-line therapy for aggressive non-Hodgkin lymphoma
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Second-line tisagenlecleucel conferred identical EFS as standard treatment for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma, according to randomized phase 3 results presented at ASH Annual Meeting and Exposition.
A final analysis of the BELINDA trial — presented during ASH’s late-breaking abstract session and simultaneously published in The New England Journal of Medicine — showed slightly higher but not statistically significant increases in overall response rate and complete responses for patients who received tisagenlecleucel (Kymriah, Novartis).
“We were shocked by the results,” Michael R. Bishop, MD, director of The David and Etta Jonas Center for Cellular Therapy Program at The University of Chicago and BELINDA trial steering committee chair, told Healio.
Approximately two-thirds of patients with NHL are “essentially cured” with first-line treatment, which typically includes a combination of chemotherapy and immunotherapy, Bishop said during a press conference.
However, a subset of patients either do not respond to initial therapy or relapse very early in their treatment course. Outcomes for these patients typically are poor, with an expected survival of less than 12 months.
“Even for the subset of patients who are found to have chemotherapy-sensitive disease and are able to go on to autologous stem cell transplant, the outcomes are relatively poor,” he said. “Our hypothesis was that — based upon the results in more advanced large B-cell lymphoma — moving tisagenlecleucel into upfront therapy for this group of poor-risk patients would result in improved outcomes, specifically event-free survival.”
Issues with the trial design — including study endpoint definitions, the use of prior bridging therapies and time to infusion — influenced the results, Bishop said.
“We can learn from this trial, and this is the reason why we do phase 3 studies,” he told Healio. “We believe that if tisagenlecleucel had been used differently, then there would have been benefit derived from it.”
Tisagenlecleucel is an autologous, gene-edited, CD19-directed CAR T-cell therapy. In 2017, it became the first CAR T-cell therapy approved for commercial use in the United States as third-line or later therapy for children and young adults with relapsed or refractory acute lymphoblastic leukemia and adults with relapsed or refractory diffuse large B-cell lymphoma.
The multicenter BELINDA study included 332 patients (age 65 years or greater, 33.5%; 66.7% men) who had primary refractory aggressive B-cell NHL or whose disease relapsed within 12 months of first-line treatment.
Researchers randomly assigned patients to tisagenlecleucel or standard of care. The standard regimen began with salvage chemotherapy, and patients who responded subsequently received high-dose chemotherapy and autologous hematopoietic stem cell transplant.
EFS at 12 weeks after randomization assessed by blinded independent review committee served as the study’s primary endpoint. Secondary endpoints included OS, ORR, duration of response, time to response and safety.
Median follow-up was 10 months (range, 2.9-23.2).
The study failed to meet its primary endpoint, with efficacy results showing identical median EFS of 3 months for tisagenlecleucel and standard treatment (HR = 1.07; adjusted HR = 0.95).
An analysis of the best overall response during an assessment 12 weeks or more after therapy showed an ORR of 46.3% in the tisagenlecleucel group and 42.5% in the standard therapy group. Researchers reported complete response rates of 28.4% with tisagenlecleucel and 27.5% with standard treatment.
Investigators observed no new safety signals with tisagenlecleucel.
Nearly all patients (98.8%) experienced some type of adverse event, most of which were hematologic in nature.
More than half (58.6%) of patients assigned tisagenlecleucel developed cytokine release syndrome, with 4.9% of patients experiencing grade 3 or higher CRS. Neurotoxicity occurred among 10.3% of tisagenlecleucel-treated patients, with three (1.9%) developing grade 3 or higher cases.
Twenty-three patients died of treatment-related adverse events, including 10 (6.2%) in the tisagenlecleucel group and 13 (8.1%) in the standard treatment group.
Forty-two patients (25.9%) in the tisagenlecleucel group and 32 patients in the standard-of-care group (20%) died of progressive disease while waiting to receive treatment.
The time from treatment randomization until receiving CAR-T infusions may have been a large contributing factor to the lack of EFS benefit seen in the study, Bishop told Healio.
Median time to infusion was 52 days (range, 31-135), including 41 days (range, 31-91) for U.S. study participants and 57 days (range, 38-135) for non-U.S. patients.
Nearly twice as many patients in the tisagenlecleucel group than the standard treatment group had progressive disease 6 weeks after randomization evaluation (25.9% vs. 13.8%).
Patients who had progressive disease prior to CAR-T had a median survival of 1.2 months, Bishop noted, underscoring the importance of preventing progressive disease before treatment.
The results suggest that that less time should be spent on bridging therapies and patients should get to CAR T-cell therapy faster, he said.
Despite the results, Bishop said tisagenlecleucel remains beneficial for 40% of patients with advanced large B-cell lymphoma based on long-term data from the JULIET trial, in addition to its known efficacy for pediatric ALL.
“It's a very well-tolerated CAR-T, and our ability to use it gets better as we accumulate experience treating its known toxicities,” Bishop said. “Unfortunately, when it comes to the way we provided the treatment in BELINDA trial, I cannot say that tisagenlecleucel is of benefit for the subset of patients with early relapse or primary refractory diffuse large B-cell lymphoma.”
References:
Bishop MR, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2116596.
Schuster SJ, et al. Lancet Oncol. 2021;doi: 10.1016/S1470-2045(21)00375-2.
Perspective
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Shazia K. Nakhoda, MD
Treatment of primary refractory and early relapsed DLBCL after upfront R-CHOP-based regimens is particularly challenging, as patients are generally chemotherapy-insensitive. Prior studies have demonstrated suboptimal response rates with traditional salvage regimens followed by autologous stem cell transplant, identifying a critical unmet need in lymphoma.
The role of CAR-T as initial salvage therapy compared with standard-of-care chemotherapy and autologous HSCT has been unknown. However, in the multiple-relapse DLBCL population, CAR-T is now a standard-of-care option based on the ZUMA-1, JULIET and TRANSCEND studies evaluating axicabtagene ciloleucel, or axi-cel (Yescarta; Kite Pharma, Gilead), tisagenlecleucel, and lisocabtagene maraleucel, or liso-cel (Breyanzi, Bristol Myers Squibb), respectively.
At this year’s ASH Annual Meeting, we are presented with three pivotal phase 3 studies evaluating these CAR-T products in the second-line setting among patients with relapsed/refractory disease within 12 months of front-line therapy in comparison with autologous stem cell transplant.
The BELINDA study, in which patients were randomly assigned 1:1 to receive tisagenlecleucel or standard-of-care treatment with platinum-containing bridging therapy followed by autologous stem cell transplant, failed to meet its primary endpoint, with equivalent EFS of 3 months in both groups. In contrast, the similarly designed ZUMA-7 study, which evaluated axi-cel, and the TRANSFORM study of liso-cel both met their primary endpoints and demonstrated superior EFS compared with standard of care and complete response rates of approximately 65%.
In the absence of randomized head-to-head data, tisagenlecleucel has performed inferiorly to axi-cel and liso-cel on cross-trial comparison in the multiple relapsed DBLCL population, and as initial salvage therapy in the primary refractory/early relapse population being presented at ASH. These three CD19-targeted therapies have unique costimulatory domain and CD4/CD8+ T-cell ratio product manufacturing that contribute to unique toxicity and efficacy outcomes.
Differences in trial design and patient population may also play a role. The ZUMA-7 and TRANSFORM studies had higher rates of primary refractory disease (about 74%) compared with the BELINDA study (about 66%), which represents a more chemo-insensitive population among whom CAR-T is expected to perform better. The contribution of bridging therapy and differences in time from relapse to receipt of CAR-T product is less clear. Notably, similar response rates were seen in the CAR-T arms of the ZUMA-7 and TRANSFORM studies, but the former did not allow bridging chemotherapy and in the latter, 63% of patients received bridging therapy.
Further data on differences in patient characteristics presented at the conference and longer follow-up will provide additional insights into the role of tisagenlecleucel in this population going forward.
References:
Kamdar M, et al. Abstract 91. Presented at: ASH Annual Meeting & Exposition; Dec. 11-14, 2021; Atlanta.
Locke FL, et al. Abstract 2. Presented at: ASH Annual Meeting & Exposition; Dec. 11-14, 2021; Atlanta.
Meng J, et al. Front Oncol. 2021;doi:10.3389/fonc.2021.698607.
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Bishop MR, et al. Abstract LBA-6. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021.
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