Including Polatuzumab Vedotin in First-Line DLBCL Treatment

The R-CHOP chemotherapy regimen — rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone — has been the standard first-line therapy in diffuse large B-cell lymphoma (DLBCL) for nearly two decades; however, nearly 40% of all DLBCL patients treated with R-CHOP will relapse or have primary refractory disease.

On April 19, the FDA approved the pola-R-CHP regimen, which replaces the vincristine in R-CHOP with the antibody-drug conjugate polatuzumab vedotin (Polivy) in frontline treatment. The approval was based on the POLARIX trial, updated results of which were recently presented at the American Society of Clinical Oncology (ASCO) annual meeting.

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 the first of four exclusive episodes focusing on the impact of the FDA approval and other potential frontline therapies.

Following is a transcript of their remarks:

Flinn: Hi, I’m Ian Flinn from the Sarah Cannon Research Institute. I’m joined by Caron Jacobson from the Dana-Farber Cancer Institute and Jason Westin from the MD Anderson Cancer Center. Today we’re going to do a roundup on large cell lymphoma from ASCO.

So Caron, maybe we’ll start with you. We’ve recently seen the approval of what is known as the POLARIX regimen, basically polatuzumab vedotin added to R-CHP — R-CHOP minus the vincristine. This was based on a large randomized phase III trial, and this just received FDA approval for patients with higher-risk IPI [International Prognostic Index] diffuse large B-cell lymphoma. So what’s your take on this trial? I mean the results were there was an improvement in progression-free survival, but not overall survival. Do you think you’re going to use this regimen? Do you think it’s a substantial improvement in our armamentarium for patients with large cell lymphoma?

Jacobson: Yeah. So, a) I think that for large B-cell lymphoma, it’s going to take much longer follow-up these days to see overall survival benefits because we have so many new therapies that are active in the relapsed setting. And so I’m not surprised that we don’t see an overall survival benefit. And I wouldn’t let that influence my decision whether to use this regimen.

I think a 6%-7% improvement in progression-free survival is not insignificant when you are thinking about what you’re saving those six to seven out of 100 patients. You’re saving them second-line therapy, whether it’s CAR [chimeric antigen receptor] T-cell therapy or salvage chemotherapy and an autologous stem cell transplant. And that’s meaningful to me. And so, I absolutely will adopt it into my clinic, especially given the fact that the safety profile for pola-R-CHP looks very, very comparable and similar to R-CHOP.

Now, of course, there’s going to be a difference in cost here, but again, to save seven out of 100 patients from second-line therapy, I think that’s meaningful. I think one of the interesting things that was seen in the post-hoc subgroup analysis is the demonstrably improved activity in non-GCB [germinal center B-cell] large cell lymphoma compared to GCB. And I do struggle a little bit about how to use that data because it’s a post-hoc analysis. The study was not powered to detect that. And other than the fact that CD79B plays a role in non-GCB lymphomas, I can’t really think of a reason why it would be better in one versus another. I don’t know, Jason or Ian, what you think.

Flinn: Well, I was going to ask Jason this question about the subgroup analysis, right? I mean, everyone wants to pick their favorite group about whether they would or would not use it. So Jason, would you use this broadly in patients, or just some of those high-risk patients?

Westin: I agree with everything that Dr. Jacobson said about how it is a step forward and it’s incremental, but it’s a positive phase III trial, and we’ve not had a lot of those in frontline large B-cell lymphoma. The subgroup analyses are problematic in that we like to look for little bits of information about which patient might be the ideal one. But as we know, those are not necessarily powered and they are sometimes influenced by small numbers that can make things look different.

The confidence intervals for some of the subgroups are on the right side of that line, so it’s possible that some of these could be real. But it’s always a bit of a note of caution to over-interpret and say it should be an elderly Asian man with GCB large B-cell lymphoma, and that’s the right poster child for … I’m not entirely sure that we can be conclusive on that, but as Dr. Jacobson mentioned, there’s not an increased toxicity. So it’s hard to make a counter-argument why you wouldn’t prefer this regimen in some of the subgroups that look like they might have had a better outcome.

What I’d say is that we hope we can do better than 6% or 7% improvement in progression-free survival, but for the time being, it’s a step forward from what we’ve had in the past, which has been R-CHOP.

Flinn: Can I follow up on that? What did you think about, there was an abstract at ASCO regarding a subgroup and the elderly and often a difficult group of people to treat. I mean, as you said, we don’t want to pick and choose perhaps on all these subgroups, but at least this was some good news, is that it held up in that patient population. Any thoughts about that?

Westin: Yeah, I think that was an intriguing abstract and certainly is useful for the practicing clinician. When we see these new great data come through and new approvals, it’s hard to know, does this apply to my normal patient in the clinic or are these Olympic athletes that were enrolled on a clinical trial? And seeing patients that are quote unquote elderly, and I think it was over age 70 in this abstract, was how they defined that, but patients who were advanced age often do have a harder time to tolerate intensive regimens. There didn’t appear to be any significant difference in the toxicity profile and the efficacy was also quite impressive.

So I think this is useful information to basically say this was not in a super-subselected group of patients. This looked more like the patients that we’ll see in our clinics next week, including those elderly patients that look like they can benefit from the addition of polatuzumab in place of vincristine.

Flinn: Great. And Caron, there was an abstract that added glofitamab to this regimen and basically it was not a huge number of patients, but there was 100% overall response rate. And everyone on the trial responded. The complete remission rates were pretty high, but again it’s a small group of patients. Is this where we’re going? Is this the next drug we’re going to add to this regimen or where do you see this going?

Jacobson: Yeah, so the complete response rate, I think, for the whole population was about 76.5% or 77%. Looked like it was a little bit better in the lowest-risk patients and the highest-risk patients, and the cohort with intermediate risk did a little bit less well, which again is probably just a small patient sample and sampling error. But obviously just based on response rates, not necessarily a significant improvement over pola-R-CHP, but I think the proof will be in the durability of response in the progression-free survival, which we have yet to see on this.

It did look like it was really reasonably well tolerated. So unlike other single-agent bispecific antibody studies, the glofit [glofitamab] came in in cycle two and patients had already gotten two cycles of pola-R-CHP. They were able to give two doses in cycle two and then give it once every cycle thereafter. And they saw only rates of CRS [cytokine release syndrome] of only about 13%, and they were largely low-grade and there were no ICANS [immune effector cell-associated neurotoxicity syndrome] on the study. So it looked like bringing glofit [glofitamab] in after a couple of cycles of pola-R-CHP actually mitigated some of the toxicities we see when we give these agents as single agents.

Flinn: Maybe that’s the way to get around having to admit patients in the future by this sort of debulking strategy, I guess you’d call it, and allowing this more easily to be given in the community, bispecifics that many of them require hospitalization right now.

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