The phase 3 TRANSFORM trial has yielded compelling three-year follow-up data demonstrating the sustained efficacy of lisocabtagene maraleucel (liso-cel; Breyanzi) in patients with relapsed large B-cell lymphoma (LBCL), reinforcing its position as a preferred second-line therapy option.
The study compared liso-cel to standard-of-care (SOC) salvage chemotherapy followed by autologous stem cell transplantation (ASCT) in patients who relapsed within one year of initial treatment. Results showed a dramatic difference in event-free survival (EFS), with liso-cel achieving a median EFS of 29.5 months compared to just 2.4 months with standard therapy.
Key Efficacy Outcomes
Liso-cel demonstrated impressive efficacy metrics across multiple endpoints:
- 87% overall response rate (ORR)
- 74% complete response (CR) rate
- Median duration of response not reached
- Median progression-free survival (PFS) not reached
- 51% three-year PFS rate
These results are particularly noteworthy given that 62% of patients in the SOC arm eventually crossed over to receive liso-cel after failing standard therapy.
Impact of Crossover on Study Results
The TRANSFORM trial design allowed patients in the SOC arm to cross over and receive liso-cel after cycle 3 if they were not responding to standard therapy. This crossover component affected the overall survival (OS) analysis, which did not reach statistical significance (HR, 0.757; 95% CI, 0.481-1.191).
However, when researchers adjusted for crossover, the survival benefit became apparent with a stratified HR of 0.415 (95% CI, 0.251-0.686). This suggests that liso-cel provides a substantial survival advantage when the confounding effect of crossover is accounted for.
Dr. Nathan Denlinger, Assistant Professor in the Division of Hematology at The Ohio State University College of Medicine, noted, "It's remarkable that it beat it that dramatically when 60% of those patients got liso-cel anyways, it was just one line later."
Second-Line vs. Later-Line Therapy
One of the most significant findings from the TRANSFORM study was the difference in outcomes between patients who received liso-cel as second-line therapy versus those who crossed over after failing standard chemotherapy:
| Outcome | Second-Line Liso-Cel | Crossover Liso-Cel |
|---------|----------------------|-------------------|
| ORR | 87% | 62% |
| CR Rate | 74% | 53% |
| Median EFS | 33.9 months | 5.9 months |
These stark differences highlight the importance of early intervention with CAR T-cell therapy rather than attempting standard salvage chemotherapy first.
"This speaks to us that even a few rounds of chemotherapy leading to a delay is what causes patients to do worse," explained Dr. Denlinger. "I think that's why it was such a big game-changer. If you're in the second line and they're experiencing recurrence after less than a year, you must go to CAR T-cell therapy."
Comparing Liso-Cel and Axi-Cel
While the TRANSFORM trial evaluated liso-cel, the ZUMA-7 trial investigated axicabtagene ciloleucel (axi-cel; Yescarta) in a similar setting. Though direct comparisons between trials should be made cautiously due to differences in study design, some distinctions are notable:
-
Manufacturing Process: Liso-cel's manufacturing process separates CD4 and CD8 components and administers equal amounts of each, which may contribute to its efficacy profile but results in longer production times (approximately 28 days).
-
Safety Profile: Liso-cel demonstrated a more favorable toxicity profile with a 49% overall cytokine release syndrome (CRS) rate and very low rates of high-grade CRS. Neurologic events were also less common with liso-cel compared to axi-cel.
-
Bridging Therapy: The TRANSFORM trial allowed for bridging therapy, which is particularly important given liso-cel's longer manufacturing time.
Dr. Krish Patel, Director of Lymphoma Research at Sarah Cannon Research Institute, emphasized, "This is one of the exciting aspects of having two CAR T-cell therapies—to think about how that safety profile shapes our choices."
Real-World Applications
Experts note that real-world experience with both CAR T products aligns with what was observed in clinical trials, with the exception of vein-to-vein time. In practice, axi-cel typically has a faster turnaround time (approximately 14 days) compared to liso-cel.
Dr. Samuel Yamshon of Weill Cornell Medicine/New York Presbyterian explained, "For axi-cel these days, our average is about a 14-day turnaround. I had a patient recently who had a 10-day turnaround. That does sometimes change your thinking in terms of a patient who has aggressive lymphoma and just needs to get their cells as soon as possible."
Clinicians are also finding that CAR T-cell therapy can be successfully administered to a broader patient population than was included in clinical trials, including older patients and those with comorbidities such as heart failure or renal dysfunction.
"We are treating much sicker patients than are on the clinical trials," noted Dr. Denlinger. "Our own data are even more striking in the fact that we are seeing the same efficacy outcomes in terms of PFS and response rates with bad organ function, heart failure, or renal failure."
Clinical Implications
The TRANSFORM trial results, along with real-world experience, have several important implications for clinical practice:
-
CAR T-cell therapy should be considered early in the treatment course for patients with relapsed LBCL, particularly those who relapse within a year of initial therapy.
-
The choice between liso-cel and axi-cel may be guided by patient-specific factors, with liso-cel potentially preferred for older or frailer patients due to its more favorable toxicity profile, while axi-cel might be chosen when rapid treatment is essential.
-
Transplant ineligibility does not necessarily mean CAR T ineligibility, as the toxicity profiles differ significantly.
-
Improved management of CAR T-related toxicities has expanded the population of patients who can safely receive this therapy.
As Dr. Saurabh Dahiya of Stanford Medicine summarized, "The key message that we've been trying to communicate with our community colleagues is that if you're transplant-ineligible, that doesn't mean you are CAR T ineligible. The toxins are nonoverlapping."
The compelling efficacy data from the TRANSFORM trial, coupled with liso-cel's favorable safety profile, continue to strengthen the case for CAR T-cell therapy as a preferred second-line option for patients with relapsed LBCL, potentially offering a curative approach for this challenging disease.
