The Evolving Role of CAR T Cell Therapy in Hematological Malignancies - Episode 13

Anticipation of ZUMA-7 Results


David Maloney, MD, PhD: We’re using these in second-line or third-line therapy right now. I know some of these studies are looking at lisocabtagene maraleucel in earlier lines, but we have some randomized phase III trials coming up.

Caron Jacobson, MD: Yes, the ZUMA-7 trial is looking at axicabtagene ciloleucel against standard of care in the second-line setting for patients who have either primary or refractory disease to an R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] regimen or who relapse within a year, which we know is a very high-risk group of patients who have a diminished long-term survival after autologous stem cell transplant. That’s been fully accrued, so we’re eagerly awaiting the results. But alluding to the discussion we had earlier, treating patients with decreased tumor volume and treating patients in earlier lines of therapy may lead to improved outcomes as well as improved T-cell fitness. And so, the bar that these trials have to beat is essentially long-term PFS [progression-free survival] of about 30% for this high-risk group of patients, and we’re already seeing that in the multiply refractory setting. I don’t have a crystal ball, but I’m optimistic that this is going to beat autotransplant in that setting.

Jason Westin, MD: I think we’re all optimistic that’s going to happen, and we’re eagerly anticipating the results of ZUMA-7. The difference in the ZUMA-7 trial versus the other trials is that ZUMA-7 does not allow for any bridging therapy for patients who are randomized to the CAR [chimeric antigen receptor] T-cell side. Again, we talked before about the relatively short manufacturing time, so that’s not likely a huge issue. But that’s one difference that will come out from this versus the other second-line studies, where the other trials did allow for randomized CAR T-cell patients to get bridging therapy as well as to potentially cross over if they had standard of care chemotherapy and didn’t respond.

David Maloney, MD, PhD: Yes, I think the other issue is that when we’re comparing against transplant, you have to remember a lot of people don’t make it to transplant. They fail before they even get there because they don’t have enough response of disease to get to transplant, which automatically makes them a candidate for standard of care, for which we have the 2 approved agents. I’d also like to point out that lisocabtagene maraleucel is being explored in the second-line setting for transplant-ineligible patients—so patients who can’t get a transplant.

Frederick Locke, MD: What does that mean?

David Maloney, MD, PhD: I know. We will have to decide what that means. Are we going to make autotransplant a historical procedure at this point for lymphoma?

Frederick Locke, MD: I think we need to see what these randomized trials show. But I would caution, let’s play it out. What if the randomized trials show that CAR T is better in the second-line setting? When patients relapse after CAR T, which is bound to happen, even if they have higher durable response rates in the second-line setting than in the refractory setting, we don’t know how to treat those patients. Should they be crossed back over to get autotransplant? Some centers are doing that in patients who are enrolled on this trial, and others are using different approaches, such as allogeneic transplant.

Max Topp, MD: I also would like to point out that the ZUMA-7 trial really was choosing patients who relapsed within 1 year. So autotransplant, to me, is still very valuable. We know that historically we can cure 60% of those patients. It’s not just going to disappear, but we have to look at the data very carefully. It really depends on if it’s 30%, or it’s 50%, or 70%. It’s a crystal ball. We don’t have the data yet.

Frederick Locke, MD: I would say though that we are, at least at our center, seeing a decreased number of autotransplants being performed. And with the approved CAR T-cell therapies, we know that a patient with a partial response [PR] going in to autotransplant has a worse outcome than a patient with a complete response going in to autotransplant. And some physicians are not enthusiastic about taking the patient to autotransplant with a partial response, knowing that CAR T-cell therapy is there.

David Maloney, MD, PhD: Well, that is a problem with these trials, right? Because the trials have pretty much insisted that if you have a PR you’re still a transplant candidate. Whereas many of the transplant centers, if you’re PET [positron emission tomography]-positive, we don’t want to treat those patients. I think that’s unfortunate. Most of the trials started off the other way, but the FDA essentially forced the trial design.

I want to move on, just for the last couple of seconds in this section. There are other lymphoma histologies. It’s not just diffuse large B-cell lymphoma or aggressive lymphomas. There are exciting results for mantle cell lymphoma and follicular lymphoma. What do people think about those results?

Max Topp, MD: I think the data for mantle cell lymphoma are very exciting. They’re looking to patients who are ibrutinib failures, for which we historically know those patients are doomed usually at just 4 or 6 months. That’s the most we can get out of those patients. And based on the abstract that I have read, this is really breakthrough therapy.

David Maloney, MD, PhD: Yes, I think we’re really excited about that. Also what is it, the ZUMA-5 trial, that is looking at follicular lymphoma?

Caron Jacobson, MD: In the ZUMA-5 trial, the follicular lymphoma arm is fully accrued. We are waiting to see whatever the FDA prescribed as the amount of follow-up the trial needs to have in order to see the results. But we know from work done in follicular lymphoma, the response rates are even better than what we see, and the complete response rates are even better than what we see in diffuse large B-cell lymphoma. At least with 2-year follow-up, there are very few relapses, or almost none. But of course with follicular lymphoma, 2-year data are not going to be enough to be practice-changing, I don’t think. This is a disease that has a very long natural history and oftentimes takes quite a long time to relapse. And so, I think we’re going to need to see more mature data for that. I think it’s a really exciting time for treating some of the indolent lymphomas.

David Maloney, MD, PhD: I think what we’re seeing is that when these new therapies get approved, they get approved in the relapsed/refractory setting and then they’re quickly going to start moving up. And I think the ZUMA-12 study is even looking now, after 2 cycles of therapy with PET-positive residual disease, at going directly to axicabtagene ciloleucel. These are really exciting studies that are going to change the therapy for lymphoma for many years to come. Thank you very much for your participation.

Transcript Edited for Clarity