Second-Line CAR-T Improves Survival in Large B-Cell Lymphoma

Treatment with the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) resulted in significantly improved overall survival compared with the current standard of care among patients with early relapsed or refractory large B-cell lymphoma (LBCL), according to findings from the phase III ZUMA-7 trial, which were presented at the American Society of Clinical Oncology (ASCO) annual meeting and published concurrently in the New England Journal of Medicine.

MedPage Today brought together three expert leaders in the field: Moderator Ian Flinn, MD, PhD, from the Sarah Cannon Research Institute in Nashville, Tennessee, is joined by Caron A. Jacobson, MD, from the Dana-Farber Cancer Institute in Boston, and Jason Westin, MD, from the University of Texas MD Anderson Cancer Center in Houston, for a virtual roundtable discussion. This second of four exclusive episodes focuses on the overall survival data from the ZUMA-7 trial.

Following is a transcript of their remarks:

Flinn: Jason, you presented data on ZUMA-7, and of course this was groundbreaking news when it was first presented, showing a significant improvement in progression-free survival for those patients who received the axi-cel CAR-T compared to the standard of care. But you presented data on overall survival. Maybe you could walk us through that and your thoughts on it.

Westin: Absolutely, and Dr. Jacobson’s a treasured collaborator on that study and a co-author on the manuscript that was published, so giving her her due on this as well. But the update we presented at the ASCO 2023 meeting for ZUMA-7 is that we now have a statistically significant improvement in overall survival in second line. And that’s the first time in nearly 30 years since the Parma trial that showed that transplant was significantly improved over chemotherapy. It’s the first time we’ve shown that statistically significant improvement in overall survival.

So axi-cel had a hazard ratio of 0.726, with a statistically significant P value, despite the fact that a little bit more than half of the patients, 57% of the patients on the standard-of-care arm, actually received subsequent cellular immunotherapy, which was largely CAR T-cell therapy in the third- or later-line setting.

So with that effective strategy of try chemo first, save CAR T cell for later, we can now say that using second line axi-cel is superior to that approach. And I think that this, in my opinion at least, ends the debate about, is trying chemo to see if the patient responds and saving CAR T cell for a later day, I think that ends the debate and says that second-line CAR T cells are superior to the prior paradigm.

Flinn: I think it really must, I mean that, you’re right, there was a debate after the original presentations and even including the BELINDA data, which seemed to me answered that question. I mean, there was such a long delay and people got third-line therapy.

Caron, as Jason was saying, you’re an investigator on this trial and what sort of strategies have you adopted in your practice in order to get patients into the clinic early and to avoid some of the delays and the need for third-line therapy?

Jacobson: Yeah, this is a really important aspect of this approval in the second line because when patients were getting CAR T cell in the third line, we had a natural referral pattern, which was send patients in at the time of relapse. While you’re waiting to see if they respond to second-line chemotherapy, you could then encourage them based on their response to CAR-T versus auto transplant.

Now we have patients and we’re seeing a very high percentage of patients coming in with primary refractory disease with very rapidly progressive tumors and large burdens of disease. And it’s actually really challenging to get them in to be seen as an initial consult, get them insurance approval, and get the ball rolling for their CAR T cells, not to mention the time it takes to manufacture the CAR T cells.

So, in practice, what is happening is oftentimes there’s a phone consultation with the referring doctor to discuss the patient and even potentially get the patient started on some sort of pre-bridging therapy before they even come to see you in clinic. And then with a plan to give them a subsequent cycle of bridging therapy following T-cell collection.

I think that we have to think about a shift in our referral practice because of this approval. I think the high-risk patients in the frontline should come in during their initial chemoimmunotherapy. So patients with high IPIs [International Prognostic Index], patients with high-grade B-cell lymphoma, double-hit lymphomas, they should come into CAR T-cell treatment centers just for an initial consult, so that they’re already known to us, which makes it much, much easier to feed them into the CAR-T pipeline if and when they’re either primary refractory or early relapsing.

Flinn: You know, that sounds like a great strategy. So we’ve seen CAR T cells move from third line to second line, and then I know, Jason we’ll return to you, there’s now an effort to try to move them into frontline, right? For a high-risk patient population. Some of the questions around that, it’s like, how do you define a high-risk grouping that you would justify use of CAR T cells in? And maybe you could speak to, there’s currently a trial, I think it’s ZUMA-23, looking at this.

Westin: That’s exactly right. So we had a trial-in-progress poster at the ASCO meeting for ZUMA-23. Dr. Jacobson’s involved in that trial as well. And that is for frontline patients that have an IPI of 4 or 5. And so that’s how we’re defining it for that study, it’s just the highest-risk patients, IPI 4-5. And just like Dr. Jacobson just said for the second line, that’s a group that sometimes is difficult to enroll into trials because if their performance status is limited by definition of having an IPI of 5, that’s a group that’s historically underrepresented on clinical studies.

Also, these patients are often the ones that show up in your clinic and need to be admitted to the hospital to start chemotherapy in the next couple of days. They don’t often wait very well for review of eligibility or financial clearance or the other things that we put up as unintentional barriers to get the sickest patients onto our studies.

So this trial actually accounts for that by mandating patients to have one cycle of R [rituximab] chemotherapy prior to being eligible for the trial. So all patients going on the ZUMA-23 trial have that high IPI diagnosis and then get one cycle of R chemo and it’s agnostic as to what that one cycle is. And then they can be enrolled on the trial and randomized 1:1 either to receive standard chemotherapy, basically stay the course and finish out your planned six cycles of either R-CHOP or R-EPOCH, or to be randomized to the axi-cel arm where they’d undergo apheresis, get a second cycle of R chemo as effectively a bridge to keep the Q3-week intensity of therapy ongoing and then get axi-cel and then they’re done.

And this is a large phase III global trial up and running now to basically ask, can CAR T cell supplant frontline chemotherapy in that ultra-high-risk patient population?

Flinn: I mean, it will certainly be interesting to see the outcomes here, but I guess as we move earlier in the course of disease, that it does get hard statistically to have some of these positive outcomes, although clearly this is a rich population for that to happen.

Watch episode one: Including Polatuzumab Vedotin in First-Line DLBCL Treatment