Primary Analysis of Phase 3 TRANSFORM Study Confirms Benefit of Liso-Cel in LBCL

The primary analysis of the TRANSFORM study (NCT03575351) confirmed the clinical benefit of lisocabtagene maraleucel (Breyanzi; liso-cel) with statistically significant and clinically meaningful improvements in survival when compared with standard of care treatment in patients with relapsed or refractory large B-cell lymphoma (LBCL).

The global, randomized, multicenter, phase 3 study TRANSFORM study sought to compare the efficacy and safety of liso-cel compared with the standard of care in adult patients aged 18-75 with LBCL. Patients included in the study had LBCL primary refractory to first-line therapy or who had relapsed ≤ 12 months after first-line therapy, were eligible for autologous stem cell transplant (ASCT), had an ECOG performance status of 0 or 1, and adequate organ function.

Investigators evaluated the primary end point of event-free survival (EFS) by independent review committee (IRC) and the secondary end points of IRC-assessed complete response (CR) rate, progression-free survival (PFS), and overall survival (OS).

At a median follow-up for the primary analysis of 17.5 months (range, 0.9‒37.0), 184 patients with LBCL were randomized, consisting of 92 patients in the experimental arm and 92 in the control arm. Thirty-three percent of patients were aged 65 years and older, 64% had DLBCL, 12.5% had double-hit lymphoma, and 73% were refractory to first-line therapy.

Findings showed that the primary end point of EFS was not reached (NR) with liso-cel (95% CI, 9.5-NR) vs 2.4 months (95% CI, 2.2-4.9) with the standard of care. The complete response rate was 74% for liso-cel vs 43% with the standard of care (P <.0001) and median PFS was NR for the liso-cel arm (95% CI, 12.6-NR) compared with 6.2 months (95% CI, 4.3-8.6) for the standard of care arm (HR, 0.400; P <.0001).

Twenty-six patients had a partial response at the interim analysis which turned into a CR for 9 pts at the time of the primary analysis, including 6 of 12 given liso-cel and 3 of 8 given standard of care. Among the 91 patients enrolled in the standard of care arm, 61 (67%) crossed over to receive liso-cel. Moreover, the median OS favored liso-cel, although it did not meet statistical significance, compared with standard of care, which had an OS of 29.9 months, respectively (HR, 0.724; P =.0987).

Regarding safety, findings were consistent with those reported in the interim analysis. The most frequent cause of death was disease progression and 66 patients had died in the study, including 28 in the liso-cel arm, 38 in the standard of care arm, and 29 after crossover.

In an interview with Targeted Oncology^TM, Jeremy Abramson, MD, director of the Center for lymphoma at Massachusetts General Cancer Center, associate professor of medicine at Harvard Medical School, discussed findings of the phase 3 TRANSFORM study which were presented at the 2022 American Society of Hematology (ASH 2022) Annual Meeting.

Targeted Oncology: Can you discuss the Phase 3 TRANSFORM study?

Abramson: At ASH 2022, we presented the primary analysis of the TRANSFORM trial, which is a randomized phase 3 trial comparing liso-cel with standard of care as second-line therapy for patients with relapsed and refractory large B-cell lymphomas. Historically, platinum-based chemotherapy followed by high-dose chemotherapy and stem cell transplant has been the standard of care for decades for patients in the second-line setting for large B-cell lymphomas after frontline chemoimmunotherapy. But in the modern era, it turns out that very few patients will be cured with that approach. Patients with primary refractory disease or patients who progressed within 1 year of initial chemoimmunotherapy have a particularly poor outcome with what has been our standard treatments. Given the encouraging efficacy of anti-CD19 directed CAR T cells in the third-line or later setting, we designed the TRANSFORM study to compare liso-cel, a CD19-directed CAR T-cell, compared with a historic chemotherapy-based standard of care, a second-line treatment specifically in this high-risk population of patients who progress within 1 year of initial chemo immunotherapy.

What were the methods and design of the study?

This was a randomized phase 3 trial between liso-cel and the standard of care. Patients on the standard of care arm would receive 3 cycles of platinum-based chemotherapy followed by response assessment. Responding patients would precede the high-dose chemotherapy and autologous stem cell transplant. Patients on the liso-cel arm could receive up to 1 cycle of bridging therapy at the discretion of their treating investigator using 1 of the regimens that was employed on the standard of care arm, and then once product was prepared for them, they would initiate lymphodepleting chemotherapy followed by their 1-time infusion of liso-cel. Patients on the standard of care arm had built in crossover if standard of care failed, so all patients in the study underwent leukapheresis prior to randomization. The primary end point was event-free survival. Secondary end points included complete response rate, progression-free survival, and overall survival.

What were the updated findings presented at ASH 2022?

We randomized 92 patients to each arm of the study. Our study confirmed the superiority for liso-cel over the standard of care. Our primary end point was event-free survival, which was not reached for the liso-cel arm and was only 2 months for standard of care. At 18 months, which was our median duration of follow-up, the 18-month event-free survival was 54% for liso-cel and only 21% for standard of care. Our secondary end points were also consistently in favor of liso-cel. The complete response rate was significantly improved favoring liso-cel with a complete response rate of 74% for liso-cel patients, which was far superior to those on platinum based chemotherapy. The median duration of complete response was better for patients who achieved a CR on the liso-cel arm.

We saw an improved progression-free survival with a 60% reduction in risk of progression or death favoring liso-cel over standard of care, and we saw a trend in favor of an overall survival benefit with a numerically better overall survival in liso-cel, even though 2/3 of patients assigned to standard of care had crossed over as of the time of this analysis. As a result, we performed a supportive overall survival analysis using a 2-stage accelerated failure time model to adjust for the impact of crossover. When adjusting for the impact of crossover, we found a superior overall survival favoring liso-cel over a standard of care with a hazard ratio of 0.43. We found significant superiority in terms of event-free survival, complete response rate, and progression-free survival, as well as overall survival after adjusting for crossover favoring liso-cel over the historic standard therapy.

What do you think these data mean for the future of this space?

I think this is transformative therapy for the future of relapse large B-cell lymphoma. The majority of patients who relapse from large B-cell lymphoma relapse within 1 year of initial chemo immunotherapy, and that is the population that was included in our study. From my perspective, most patients who progress after frontline chemoimmunotherapy should receive a CAR T cell as their second-line treatment, rather than the historic standard of care of platinum-based chemotherapy followed by high-dose chemotherapy and autologous stem cell support.

There are now 2 CAR T cells fully FDA approved in this space, axicabtagene ciloleucel [axi-cel; Yescarta], and lisocabtagene maraleucel, both of which showed exciting efficacy in this space. We [recently] presented and performed a match adjusted indirect comparison between the TRANSFORM and the ZUMA-7 [NCT03391466] trials at [ASH], which matched for inclusion criteria and patient risk factors and found that the efficacy of liso-cel and axi-cel look quite comparable in the second-line setting for early relapsed or refractory large B-cell lymphoma, but that the safety profile significantly favors liso-cel with a dramatic reduction in incidence of cytokine release syndrome and neurologic toxicities with liso-cel compared with axi-cel. Ultimately, it is terrific to have not 1, but 2 highly effective CAR T-cell products available to maximize the likelihood of cure in second-line patients with large B-cell lymphomas.

REFERENCE:

Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial [published correction appears in Lancet. 2022 Jul 16;400(10347):160]. Lancet. 2022;399(10343):2294-2308. doi:10.1016/S0140-6736(22)00662-6