MedPage Today brought together three expert leaders in the field of gynecologic cancers — moderator Susana Campos, MD, from the Dana-Farber Cancer Institute in Boston, is joined by Richard Penson, MBBS, of Mass General Cancer Center at Massachusetts General Hospital in Boston, and Elizabeth K. Lee, MD, also from the Dana-Farber Cancer Institute — for a virtual roundtable discussion.
This third of four exclusive episodes focuses on the clinical implications of the recent KEYNOTE-826 and KEYNOTE-A18 trials, as well as the INTERLACE study, and how they are changing practice in cervical cancer. You can watch other videos in this series here.
Following is a transcript of their remarks:
Campos: Now we’re going to move on to equally exciting, is the cervical cancer data. And at ASCO this year, there was an update on the KEYNOTE-826. Dr. Penson, you want to briefly review to us what the final word was on 826?
Penson: Yeah, so it is actually the first of the oral sessions at the gynecologic presentations at ASCO. And Brad Monk presented the final overall survival for two groups, the all-comers and the [PD-L1] combined positive score 1 or greater. And so hazard ratios almost exactly the same — 0.6, 0.63 — and statistically significant improvements. So for the all-comers, 9 months better overall survival. I mean that’s huge. So that really has redefined things.
And I think Krish Tewari gave the interpretation of the data afterwards and he sort of made the comment that we’d been so excited to move the field forward with [GOG] 204 with the addition of bevacizumab [Avastin] pushing survival beyond a year on average. And now we’re doing so much better. And the pembrolizumab [Keytruda] is more important than the bevacizumab, highly delicate tissues in a smoker, prior radiation. And you’re really worried about a fistula with bevacizumab. But pembrolizumab, you really want everybody to get.
Campos: Thank you for that review on KEYNOTE-826, basically changing the way we take care of patients with metastatic cervical cancer. KEYNOTE-826 showing both the progression-free and overall survival benefit with the use of carboplatin, paclitaxel, pembrolizumab, and bevacizumab in the appropriate basis.
But equally important and in terms of perhaps changing the landscape of how we treat patients with cervical cancer was the A18 study which utilized pembrolizumab earlier in patients with 1b/2, 2b, and stage 3 and 4 with the use of concurrent cisplatin with chemotherapy and pembrolizumab. Dr. Penson, would you like to review some of that for us?
Penson: Yeah, so Merck had announced in July that this was a positive study. And so it’s very exciting to see the benefit. This is upfront intention to cure, its progression-free [PFS] or recurrence-free survival. But it’s very exciting. It met its primary endpoint with a hazard ratio for PFS of 0.7. And at 2 years that means your chance of being disease-free went up from 57% to 68%.
And what was really impressive when Domenica Lorusso presented the data was this trend in favor of overall survival [OS]. So it’s not statistically significant, but there was a clear separation of the curves at about 20 months, hazard ratio of 0.73, an absolute 6% better chance of being alive at 2 years up from 81% to 87%. So really unequivocally a positive study.
And again, I think when the goal is cure, the regulatory authorities may require OS data, but this was a 1,060-patient study, but that data’s going to be coming soon. And particularly having had a negative study from durvalumab [Imfinzi], the CALLA study, it was fabulous to see a positive study.
Campos: Absolutely. And on that note, I mean going back and looking at the eligibility criteria for CALLA and looking at the eligibility criteria for A18, it wasn’t that much different, to be honest with you. And just, speculation of course, why do you think CALLA was negative and A18 was positive? Just out of curiosity.
Penson: Yeah, I mean before this year I would’ve said — and I actually was the data safety monitoring chair for CALLA — I would’ve said that targeting PD-L1 was less attractive, but DUO-O being positive and DUO-E being positive, I think we’re having better respect for that. Neuroendocrine tumors seemed to do really well with PD-L1 targeted immunotherapy.
The studies were different. CALLA had a less high-risk population of patients, and there was the international collaboration around studies. There’s Asian countries that give very different radiation therapy. There might be other reasons that CALLA was a negative study. This unequivocally — it was positive.
Campos: Indeed it was, it absolutely was. And another interesting study that actually kind of deviates from what we’d normally do in cervical cancer was the INTERLACE study, actually, which used a little bit of neoadjuvant therapy. I use that term loosely. Dr. Lee, would you take us on the INTERLACE study?
Lee: Yes, absolutely. So this was a very interesting study in cervical cancer patients in which this neoadjuvant chemotherapy was essentially weekly carboplatin and weekly Taxol [paclitaxel] for 6 weeks prior to receiving radiosensitizing cisplatin with radiation. And this was in comparison to cisplatin plus radiation was the other arm.
And the results of this study did actually meet its primary endpoint of PFS. There was overall, I believe there was actually a 9% improvement in the PFS rate for those receiving the neoadjuvant chemotherapy. And that actually did meet their primary endpoint and was statistically significant. On their premature interim OS analysis it also seemed to have a benefit compared to the standard chemoradiation arm as well. There was an 8% improvement in overall survival at 5 years.
And so overall this did make it to its primary endpoint. So I think this is a very thought-provoking study of exactly where and when to use. This study was administered across a number of different countries. I would say primarily enrolling patients in the U.K., but also including Mexico as well as India; I think there was one patient from Brazil. But I think that’s also very interesting in thinking about the settings, the resources that are available in terms of healthcare for cervical cancer patients.
Campos: Yeah, I mean it was an interesting and surprising study. It’s certainly not what we normally do in clinical practice, but I think we’ve all had patients that have very bulky locally advanced cervical cancer and it was a very truncated course of chemotherapy. It wasn’t as if it was a very elaborate, it was like 6 weeks and yet the results were positive. It would be interesting to see whether or not if you added a little pembrolizumab to that, what exactly your response would be in that regard.
But these really bulky cervical cancer patients that you want to give radiation therapy to, and yet the radiation field may be too large initially to actually proceed with radiation. So thought-provoking, to be honest with you. We often see patients internationally that come our way and this is indeed the case. Dr. Penson?
Penson: Yeah, I was going to say, I shared the platform with Mary McCormack back in the day when 204 was positive and she was presenting this study as really exciting. And I have to say Brad Monk and I were, Krish and Brad and I were a little bit disparaging. We sort of felt like all the Australian effort, all the neoadjuvant studies, the randomized trials, this was sort of like late and it was passe. And yet this is an absolute 8% improvement from 72% to 80% of people alive. That’s really impressive, hazard ratio of 0.61. Unequivocally positive study for PFS and overall survival.
And then to use Mary’s language, she said this is ready for adoption. So the lovely thing is we are expanding the armamentarium with different options. You can absolutely do this. This isn’t failed “outback” chemotherapy. This is an induction, Sue, as you said, a neoadjuvant, quick two cycles, 6 weeks, shrink tumor to get a better outcome — and gets a better outcome.
The message it delivered to me was the best treatment results in better outcomes, and we are now getting a luxury of different options and approaches that we can pursue in cervical cancer.