New Data Confirm Survival Benefit of Pembrolizumab in Cervical Cancer

The addition of pembrolizumab (Keytruda) to chemotherapy with or without bevacizumab (Avastin) for the first-line treatment of patients with persistent, recurrent, or metastatic cervical cancer continues to result in significant survival benefits, according to a presentation at the recent American Society of Clinical Oncology (ASCO) annual meeting.

MedPage Today brought together three expert leaders in the field — moderator Susana Campos, MD, MPH, from the Dana-Farber Cancer Institute in Boston, is joined by Richard Penson, MBBS, of Mass General Cancer Center in Boston, and Elizabeth K. Lee, MD, also from the Dana-Farber Cancer Institute — for a virtual roundtable discussion. This second of four exclusive episodes focuses on the updated findings from the phase III KEYNOTE-826 trial.

Following is a transcript of their remarks:

Campos: Now we spent a good time talking about NRG-GY018 and RUBY01, the strengths, the weaknesses, the questions that we still have, the questions that will become after IO [immunotherapy]. This is only undoubtedly going to become more complicated as LEAP-001 enters our arena and also the DUO-E [study], but we don’t really have that data. So we’re going to actually move on to another topic at this point in time. But that’s been really a nice discussion on both NRG-018 and RUBY01.

Now, not to be undone, we had some great successes in uterine cancer, but also KEYNOTE-826 certainly was a very inviting presentation by Dr. Bradley Monk, who took us down the survival advantage of cervical cancer. Dr. Penson, could you review for us just very briefly -826 and the data that was presented at ASCO by Dr. Monk?

Penson: So, KEYNOTE-826 is a really fabulous randomized controlled trial, as you say, presented by Brad Monk. So this was in patients with persistent, recurrent, or metastatic cervical cancer. And it was cisplatin-paclitaxel with or without bevacizumab, but with the addition of pembrolizumab. And that was concurrent and then maintenance therapy, and it was for up to 35 cycles of therapy. It was done in 548 women. And this was the preplanned overall survival [analysis].

And there were really sort of two things that were sort of big take-home’s. So a very substantial improvement in overall survival. But the second thing that really took my eye was the complete response rate. So this is concurrent and maintenance therapy. And in the group which was really the sort of primary analysis, the PD-L1 combined positive score (CPS) greater than or equal to 1, the complete response rate increased from 14.5% to 25.6%.

And what was fascinating, because this is really an agent that is approved when you have a positive score, at least 1% of the cells staining for PD-L1, it was really all of them, all-comers was an improvement from 14% to 25%. And the ones you expect to respond most, PD-L1 CPS greater than or equal to 10, that was a 13% to 25% complete response rate.

So the tail on the curve, which is what we get excited about, are we truly making patients live for longer? That’s exciting, but maybe we’re starting to understand why that is. The concurrent use of immunotherapy as you’re killing cancer-releasing antigen, setting up an immune response for the best outcome. The increase in the number of CRs [complete responses] was so impressive, that felt like that was a large part of what was driving the immune response.

And so we have really changed from maintenance therapy with anti-angiogenics. And in this study bevacizumab did result in better survival and better response rates, better progression-free survival and better response rates. But it’s really a completely different setting when we’re trying to impact overall survival, truly how long people live. And the concurrent use of immunotherapy looks to be really important.

Campos: Absolutely. And maybe we could take it a little bit further, and you spoke about the bev [bevacizumab]. Now this is a four-drug regimen. Tell us when you avoid the bev because that is a consideration in some individuals.

Penson: So Krish Tewari presented data at last year’s ASCO and reminded people that bevacizumab in people who’ve had prior chemoradiation therapy had a fistula and perforation rate of about 9%. That is a big risk. And so one of the things that’s really improved outcomes in the last few decades is attention to the general care of patients. You get patients nutritionally ready, you get them nephrostomy if they have obstructive uropathy. You get them sort of like buffed-up ready for treatment.

But there is a high instance of in-field radiation complications and fistula may not be life-threatening like a large bowel perforation could be acutely, but it is one of the most miserable things to be living with. I can’t think of a tougher thing in terms of its impact on your quality of life.

And so selecting patients, and there are some predictors, for example, smoking and nutrition, there are some sort of quite helpful predictors, the more criteria for outcomes from GOG 240. But really bevacizumab, the sort of default, should be to include it.

I think the whole field of oncology is moving more to defining subsets so that we can be honest with patients about outcomes, but adding therapies that get better outcomes to patients.

Campos: No, understood and completely agree. In terms of the length of therapy, because often this is debated, how long do you continue the pembrolizumab in your patient population as maintenance?

Penson: Candidly, we don’t see that many patients with cervical cancer. I’ve now given a second dose of tisotumab [Tivdak], which I’ve been wanting to give these exciting new agents. So there remain too many barriers to access for patients with cervical cancer. Things are changing. Vaccination is exciting. But that 35 cycles, I would stick to the clinical trial-defined duration of treatment.

Campos: Yeah. And I’ll address Dr. Lee with this, in a very similar light to what we just talked about, uterine cancer, our focus is changing. We’re using immunotherapy in patients at a PD-L1 positive in the upfront setting. Patients recur. And again, to Dr. Lee, would you use immunotherapy as a second-line therapy in patients who’ve had prior IOs? And what considerations would you think about in that patient population?

Lee: That’s a really great question, and I wish we had better data in this setting. I think that unfortunately and fortunately that we have such rapidly evolving changes to our treatment practice that we don’t have a lot of good evidence one way or another.

I would say it depends on the timing of the recurrence. Let’s say they have recurred while they are on immune checkpoint inhibitor maintenance, in which case if I were to reach for another immunotherapy to treat the recurrence, I would not do it as single agent in thinking that the resistance mechanism, for example, to an anti-PD-1, would not respond to, again, another anti-PD-1. I would be thinking about combinations; for example, would you put an anti-CTLA-4? Would you add something like oral Cytoxan [cyclophosphamide], which can be a little bit more immunomodulatory in the tumor microenvironment?

I think the converse is that if you have a patient who’s completed their 35 cycles of pembrolizumab maintenance and they’re, for example, on active surveillance, at that point they have been disease free, off of really any therapy, and then they recur again, then I would consider whether resuming a single-agent immune checkpoint inhibitor could be done.

Campos: No, I think your point’s well taken. I think it’s going to be a very interesting time in terms of combinations of immunotherapy. Not at this present ASCO, but a year ago we heard about some very inviting data with tisotumab and pembrolizumab that’s still starting to evolve. And maybe some of the bispecifics that we’re looking at targeting PD-L1 and CTLA-4 that may be a very good contender in patients who’ve had prior immunotherapy. I think apart … yes, Richard.

Penson: No, I just wanted to augment what Dr. Lee said, that we have three patients who’ve done amazingly with ipi-nivo, ipilimumab [Yervoy]-nivolumab [Opdivo]. So I do think there are patients, I have two patients who have had like miracle responses to immunotherapy with cervical cancer when their CPS is more than 50%, which is one of those groups where you really hope that some miracle may happen. So I wanted to sort of like say that immunotherapy still is really exciting.

But one caveat is that people often forget that clinical trials are not so much designed to establish a new standard of care as to really sort of maximize the chance that your investigation arm is going to score. And we almost always design the duration of treatment around when we expect that progression.

So anti-angiogenics, 11-month progression-free survival in advanced or metastatic ovarian cancer, that sort of thing really determined the number of cycles of treatment. Immunotherapy just stretched it out with a lot of debate and no clear science behind those 35 cycles. Two years of PARP inhibitor was a tough tension between the risk of MDS [myelodysplastic syndrome], AML [acute myeloid leukemia], and covering that progression-free survival. And then it turns out superbly, that 44% reduction in the risk of death at 7 years in SOLO-1 with olaparib is just fantastic.

So 2 years might be enough, but people need to know that wasn’t science. That was a happy accident. And so these trials are designed to help clinicians do the best thing for their patient. And unfortunately, like when we apply for off-label treatment, we always need one or two studies to support that, and that is a bit of an active tension for clinicians. These things should inform what we do in patient-centered decisions.

Campos: No, agreed. And so we have KEYNOTE-826, an excellent study, changed the way we treat patients with advanced cervical cancer, metastatic cervical cancer.

I’ll just speak a little bit about what I think some of the limitations are in cervical cancer … that we focus on all these studies that focus on squamous, adenocarcinoma, adenosquamous. But we’re seeing a body of patients also with gastric-type cancers in cervical cancer. So I’d love to see some studies also dedicated to non-HPV-related diseases also. Because I don’t know about you guys, but we’re starting to see a lot more of these in our own clinical practice.

Click here to watch the other videos from this ASCO roundtable series on gynecologic cancers.

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