Examining Impact of Crossover in the TRANSFORM Study of CAR T in LBCL

Nathan M. Denlinger, DO, MS

Assistant Professor

Division of Hematology

The Ohio State University College of Medicine

Columbus, OH

Targeted Oncology^TM: Can you describe the TRANSFORM study (NCT03575351) of chimeric antigen receptor (CAR) T-cell therapy and how it compared with the ZUMA-7 study (NCT03391466)?

Nathan M. Denlinger, DO, MS: Lisocabtagene maraleucel [liso-cel; Breyanzi] was approved multiple years after axicabtagene ciloleucel [axi-cel; Yescarta] was. It's a similar study but had some pretty key differences. It was liso-cel vs standard-of-care [SOC] in relapsed large B-cell lymphoma [LBCL] for patients who relapsed within 1 year. There were a fewspecific differences [from ZUMA-7]. They allowed for secondary central nervous system [CNS] lymphoma. The other study didn't, so there was a few patients on [TRANSFORM] with that. They didn't require a minimum absolute lymphocyte count.

This trial allowed bridging therapy. That's critical, because liso-cel take takes longer to make. For whatever reason, it takes about 28 days. That's what our average have been. They have a manufacturing method where they separate the CD4 and the CD8 component and give you an equal amount of each. It might help the product in some ways…but it does add some time. Some studies have shown that no bridging is better than bridging, but it depends on disease burden and things like that. If they responded to bridging, that probably helped them.

In this study’s SOC cohort, crossover was allowed. Patients could cross over at cycle 3. If you have patients who are not responding, they're allowed to get liso-cel. It was an equipoise ethics–type [design]. After we saw the axi-cel study and some of the other data, I don't think they felt comfortable with not allowing [it], so crossover was the way to go. But that affected the end points.

What were the key efficacy outcomes of TRANSFORM?

Event-free survival [EFS] had dramatic differences. The median was 29.5 months vs 2.4 months for liso-cel vs SOC, so it turned out pretty good.¹[In ZUMA-7], the median EFS on axi-cel was 10.8 months, and [in TRANSFORM] the median EFS on liso-cel was 29.5 months.^1,2 You can't compare those two. The studies were different, so you might say liso-cel had this longer EFS rate, but there are differences in the study, so we hesitate to say liso-cel has better EFS.

[Patients receiving] liso-cel had excellent overall response rates [ORR] of 87%. The complete response [CR] rate was 74%. Median duration of response was not reached. Median progression-free survival was not reached and 36-month progression-free survival rate was 51%.

Importantly, 62% of the patients in the SOC arm crossed over and got liso-cel. So how many patients made it to transplant? Not that many. They were automatically sent to get liso-cel; 60% of those patients got liso-cel. It's remarkable that it beat it that dramatically when 60% of those patients got liso-cel anyways, it was just one line later.

What was the overall survival (OS) outcome and how was this affected by crossover?

OS did not reach statistical significance; the confidence interval didn't quite get there [HR, 0.757; 95% CI, 0.481-1.191]. People think a big portion of that is from the crossover component. If you don't let them ever get the good therapy, then they aren’t going to do so well. With axi-cel, patients were not allowed to get that good therapy for a while, so that [affects] the outcomes. Ethically, we can’t design a trial like that if you know CAR T-cell therapy is that much better.

It was found that if you adjust for crossover from SOC to liso-cel, then the difference becomes apparent.² If you take out the crossover component and just look at those 40% of patients who didn't crossover, it has a much improved OS, which makes sense [stratified HR, 0.415; 95% CI, 0.251-0.686]. But that is one reason. We have people in different camps saying that axi-cel has this real statistical benefit in the trials. Then you have other people saying, is that the case or not? We probably need some data to look at it.

How did the patients who crossed over to receive liso-cel respond?

[Looking at] the subgroup analysis, it was important for us to have this crossover group, because it prevented us seeing those OS differences…but ended up being important to our understanding of where CAR T-cell therapy fits in with prior lines of therapy, because 62% of patients from SOC went in and got liso-cel, except that they had 2 rounds of chemotherapy right beforehand. That is the only difference. The patient populations were very similar in all other regards. They had less chemotherapy-sensitive disease; it didn't work. But otherwise, the main difference is that they had 2 rounds of chemotherapy beforehand, so you have a control here looking at what happens with second-line therapy. That's the liso-cel arm.

The crossover group did significantly worse than the second-line cohort. The ORR in the crossover group was 62% with liso-cel vs 87% in that second-line group. The CR rate was 53% in the crossover group vs 74%. The median EFS was 5.9 months vs 33.9 months. This speaks to us that even a few rounds of chemotherapy [leading to a] delay…is what causes patients to do worse. 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.

DISCLOSURES: There were no known relevant disclosures.

REFERENCES:

1. Kamdar MK, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study. J Clin Oncol. 2024;42(suppl 16):7013. doi:10.1200/JCO.2024.42.16_suppl.701

2. Westin JR, Oluwole OO, Kersten MJ, et al; ZUMA-7 Investigators; Kite Members. Survival with axicabtagene ciloleucel in large b-cell lymphoma. N Engl J Med. 2023;389(2):148-157. doi:10.1056/NEJMoa2301665

3. Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023;141(14):1675-1684. doi:10.1182/blood.2022018730