Subject matter experts in lymphoma reflect on chimeric antigen receptor T-cell therapy clinical trial design.
Matthew Lunning, DO, FACP: I was reflecting on what Fred was saying and it made me think that if I were McFly and you were Doc and we hopped in the DeLorean and went back to when we were planning these 3 trials, would you design it differently? It seemed like potentially a missed opportunity along the way. ZUMA-7 [NCT03391466] was planned first, but then you’ve got TRANSFORM [NCT03575351] and BELINDA [NCT03570892], which inherently looked a little different in trial design. Do you think it was a missed opportunity? Or would you run the trials the same?
Frederick Locke, MD: I wasn’t involved in designing TRANSFORM or BELINDA. I met with Stephen Schuster earlier here at ASCO [American Society of Clinical Oncology annual meeting], and he made it clear that he didn’t design the BELINDA study and he would’ve designed it differently. He advised it to be designed differently and it changed over time. Certainly, that trial could have been designed differently. I already mentioned the multiple cycles of therapy. There were also some differences regarding whether it was called an event if there was yet to be a response. Some of those things made a difference.
But to answer your question, I was involved in the design of ZUMA-7 and it answered the question in my mind, which isn’t autologous transplant vs CAR T, but whether these therapies work in the second-line setting and whether we’re making an impact on patients. Clearly, that’s the case if you give 1 treatment and 40% or 41% of the patients remain in remission at 2 years vs go down another path and 16% of patients get that treatment and intended therapy and are in remission. To me, it answered that question. A lot of people would like to see a different question answered, which is whether CAR T is better than transplant for a patient. Who’s in partial response after second-line chemotherapy? We don’t know the answer to that. We work together in a BMTCN exercise to think of new trials, and that’s a trial that you could still do: You give second-line chemotherapy, and if you’re in a partial response, should you get transplant or CAR T? It would be tough to pull off and I still would prefer to give CAR T.
Matthew Lunning, DO, FACP: Yes, we have a missed opportunity. We should have stolen very good partial remission from our myeloma colleagues and tried to find out that definition, because I imagine it’s those patients who benefit from high-dose therapy and autologous stem-cell rescue, and very poor PRs [partial responses] who benefit from CAR T-cell therapy.
Leo Gordon, MD: I helped to design ZUMA-7, but the only difference I would have done was what I alluded to earlier. I wouldn’t have allowed people with only a PR to get there. As it turned out, it didn’t matter, because only 30% got there.
Frederick Locke, MD: I’d add that in ZUMA-7, it was investigator’s choice. It was the investigator’s analysis of the response, and it was their decision on whether to go forward with transplant. In some of the other studies, it was central review on the response. That maybe introduces some delays and choices, and from what I understand, maybe some differences of opinion about whether you should go to transplant.
Leo Gordon, MD: The other trial that’s worth mentioning when we’re talking about the second line is the PILOT study [NCT03483103] that presented, which is basically second line but for a group of patients who weren’t otherwise considered good candidates for transplant. It could have been recurrence 3 years later. It wasn’t within the first 12 months. The data were similar, with 80% response and [approximately] 50% complete response. It’s still short follow-up, but it looks like fairly durable responses.
Caron Jacobson, MD: Yes, I wished that the label would be second line for patients relapsing within the first 12 months or for patients who were transplant ineligible, because right now, we still have to give those patients a second line of therapy, which seems wasteful.
Leo Gordon, MD: The PDUFA [Prescription Drug User Fee Act] date is June 24, so we’ll see what they decide.
Frederick Locke, MD: Interesting.
Caron Jacobson, MD: And that isn’t randomized. That’s an open-label phase 2.
Leo Gordon, MD: That’s a phase 2 open-label.
Caron Jacobson, MD: You’re absolutely right that we needed to randomize against the strategy, because knowing so many people who get chemotherapy in the second line and don’t respond don’t make it to CAR T-cell therapy is an important end point. And it tells you that by making people go through 1 or 2 cycles of chemotherapy, you jeopardize their chance to get to a definitive therapy. I like the ZUMA-7 study. It answers the right question.
Matthew Lunning, DO, FACP: I just wish everybody would have been able to get the CAR T cell. They didn’t need to go to commercial, that they would have offered CAR T cell.
Frederick Locke, MD: I understand that sentiment, but I’d also point out that all 3 of the trials had almost the exact same percentage of patients who were randomized to standard of care and eventually got CAR T-cell therapy. ZUMA-7 didn’t allow crossover, and 55% of those patients still got CAR T-cell therapy. It’s about the same in the other studies, which did allow crossover.
Leo Gordon, MD: For TRANSFORM, the reason they didn’t is that wasn’t approved yet at the time. It wasn’t commercial. So they included that.
Transcript edited for clarity.