A New Standard of Care for Cervical Cancer: Assessing the KEYNOTE-A18 Study

ASCO Daily News

Dr. Linda Duska and Dr. Domenica Lorusso discuss the practice-changing results of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, which evaluated pembrolizumab plus chemoradiotherapy as treatment for previously untreated, high-risk, locally advanced cervical cancer.

TRANSCRIPT

Dr. Linda Duska: Hello, I'm Linda Duska, your guest host of the ASCO Daily News Podcast today. I'm a professor of obstetrics and gynecology and serve as the associate dean for clinical research at the University of Virginia School of Medicine.

On today's episode, we'll be discussing a new standard of care for previously untreated, high- risk locally advanced cervical cancer. This follows the ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, which I will be referring to as KEYNOTE-A18 for the rest of this podcast, which demonstrated that pembrolizumab plus chemoradiotherapy improved both progression-free and overall survival compared to chemoradiotherapy alone. I was a co-author of this study, and I'm delighted to be joined today by the study's lead investigator, Dr. Domenica Lorusso, for today's discussion. She is also a professor of obstetrics and gynecology. She's at Humanitas University Rosano and the director of the Gynecologic Oncology Unit at the Humanitas Hospital San Pio in Milan, Italy.

Our full disclosures are available in the transcript of this episode.

Dr. Lorusso, it's great to be speaking with you today.

Dr. Domenica Lorusso: Thank you, Linda. It's a great pleasure to be here. Thank you.

Dr. Linda Duska: So I was hoping you could start us out with some context on the challenges associated with treating patients with high-risk, locally advanced cervical cancer.

Dr. Domenica Lorusso: Yes. I have to make a disclosure because in my experience as a gynecologist, cervical cancer patients are the most difficult patients to treat. This is a tumor that involves young patients [who often have] small kids. This is a very symptomatic tumor. More than 50% of patients report pain. Sometimes the pain is difficult to control because there is an infiltration of the pelvic nerves and also a kind of vaginal discharge, so it's very difficult to treat the tumor. Since more than 25 years, we have the publication of 5 randomized trials that demonstrate that when we combine platinum chemotherapy to radiation treatment, we increase overall survival by 6%. This is the new standard of care – concurrent chemoradiation plus brachytherapy. This is a good standard of care because particularly modern, image-guided radiotherapy has reported to increase local control. And local control in cervical cancer translates to better overall survival. So modern radiotherapy actually is able to cure about 75% of patients. This is what we expect with chemoradiation right now.

Dr. Linda Duska: So what are the key takeaways of A18? This is a really exciting trial, and you've presented it a couple of times. Tell us what are the key takeaways that you want our listeners to know.

Dr. Domenica Lorusso: Linda, this is our trial. This is a trial that we did together. And you gave me the inspiration because you were running a randomized phase 2 trial exploring if the combination of pembrolizumab to concurrent chemoradiation was able to give signals of efficacy, but also was feasible in terms of toxicity. There were several clinical data suggesting that when we combine immunotherapy to radiotherapy, we can potentially increase the benefit of radiotherapy because there is a kind of synergistic effect between the two strategies. Radiotherapy works as a primer and immunotherapy works better. And you demonstrated that it was feasible to combine immunotherapy to concurrent chemoradiation.

And KEYNOTE-A18 was based on this preliminary data. We randomized about 1,060 patients to receive concurrent chemoradiation and brachytherapy or concurrent chemoradiation and brachytherapy in combination with pembrolizumab followed by pembrolizumab for about two years. Why two years? Because in more than 80% of cases, recurrence in this patient population occurred during the first two years. So the duration of treatment was based on the idea to provide protection to the patient during the maximum time of risk.

And the trial had the two primary endpoints, progression free and overall survival, and met both the endpoints, a significant 30% reduction in the risk of progression that was confirmed. At the 3-year follow up, the observation was even better, 0.68. So 32% reduction in the risk of progression. And more importantly, because this is a curative setting, 33% reduction in the risk of death was reported in the experimental arm when pembro was combined with chemoradiation.

Dr. Linda Duska: That's amazing. I wanted to ask you, a prior similar study called CALLA was negative. Why do you think A18 was positive?

Dr. Domenica Lorusso: Linda, there are several discussions about that. I had the possibility to discuss several times with the PI of CALLA, Brad Monk. The idea of Brad is that CALLA was negative because of using durvalumab instead of PD-1 inhibitor, which is pembrolizumab. I do not have exactly the same impression. My idea is that it's the kind of patient population enrolled. The patient population enrolled in KEYNOTE-A18 was really a high-risk population; 85% of that patient were node positive, where the definition of node positivity was at least 2 lymph nodes in the pelvis with a short diameter of 1.5. So, we are very confident this patient was node-positive, 55% at the grade 3 and 4 diseases. So this is really a high-risk population. I remember at the first presentation of CALLA, I was honored to discuss the CALLA trial when it was first presented at IGCS a few years ago. And when I received the forest plot of Calla, it was evident to me that in patients with stage III and node positive there was a signal of efficacy. And we have a huge number of patients with node positive. So in my opinion this is the reason why KEYNOTE-A18 is positive.

Dr. Linda Duska: Yeah, I agree with you. I've thought about it a lot and I think you're right about that. The INTERLACE trial results were recently published. How should we interpret these results in the context of A18?

Dr. Domenica Lorusso: So it's very difficult to compare the 2 trials. First of all, in terms of population. The population enrolled in INTERLACE is a low-risk, locally advanced but low risk population; 76% were stage II, 10% were stage I, 60% were node-negative patients. So, first of all, the population is completely different. Second is the type of radiotherapy that was provided. INTERLACE is a 10-year long trial, but in 10 years the quality and the technique of radiotherapy completely changed. Only 30% of patients in INTERLACE received what we call the modern image-guided brachytherapy, which is important because it provides local control and local control increases overall survival. And third, we read the paper. I'm not a methodologist, but there are some methodological biases in the paper. All the statistical design of the trial was based on PFS, but PFS was evaluated at physician description. And honestly, I never saw a trial that had no pre-specified timeline for radiological evaluation. It's very difficult to evaluate progression in cervical cancer because the fibrosis related to radiotherapy changes the anatomy in the pelvis. And I think that the radiological evaluation is important to address if the patient is progressing or not. Particularly, because the conclusion of CALLA is that the PFS was mainly in favor of distant metastasis. So really, it's difficult for me to understand how distant metastasis may be evaluated with the vagina visit.

So really, it's very difficult to compare the two trials, but I have some concerns. And also because of toxicity in the study, unfortunately 30% of patients did not complete concurrent chemoradiation because of residual toxicity due to induction chemotherapy. So I wanted to be sure in the context of modern radiotherapy, if really induction chemo adds something to modern radiotherapy.

Dr. Linda Duska: Well, I have two more questions for you. As we move immunotherapy into the front line, at least for these high risk locally advanced cervical cancer patients that were eligible for A18, what does that mean then for hopefully those few that develop recurrence in terms of second line therapy?

Dr. Domenica Lorusso: Well, Linda, this is a very important question. We do not have data about immuno after immuno, but I would not completely exclude this hypothesis because in KEYNOTE-A18, the patient received treatment for a well-defined time period. And for those patients not progressing during immunotherapy, I really guess if there is a space for the reintroduction of immunotherapy at the time of recurrence. In this moment we have 30% of patients in KEYNOTE-A18 in the control arm that receive immunotherapy after progression, but still we have 11% of patients that receive immunotherapy in combination with concurrent chemoradiation and then receive, again, immunotherapy in later line of therapy. I think we need to collect these data to capture some signals and for sure we have the new drug. We have antibody drug conjugate. The trials are ongoing exploring the role of antibody drug conjugate, particularly in immune pretreated patients. So I think this is a very interesting strategy.

Dr. Linda Duska: I was going to ask you, “What are the next steps,” but I think you already answered that question.

You talked about the second line. If you were going to redesign a study in the frontline, what would it look like?

Dr. Domenica Lorusso: Probably one question that I would like to answer – there are two questions in my opinion in KEYNOTE-A18 – one is induction immunotherapy. Linda, correct me if I'm wrong, you reported very interesting data about the immune landscape change when you use induction immunotherapy. And I think this is something that we need to explore in the future. And the second question is the duration of maintenance. Because, again, we decided for two years based only on the epidemiology of recurrence, but I guess if one year may be enough.

Dr. Linda Duska: I think this sequencing question is really important, that the induction immunotherapy was actually GY017. I can't take credit for that, but I think you're right. I think the sequencing question is really important. Whether you need the concurrent IO or not is an important question. And then to your point about the 2 years, the length of the need for maintenance therapy is a question that we don't know the answer to. So there are lots of really important questions we can continue to ask.

I want to thank you so much for sharing your valuable insights with us on the podcast today. You're always so thoughtful about this particular study and cervix cancer in general and also for your great work to advance the care for patients with GYN cancers.

Dr. Domenica Lorusso: Thank you, Linda. It's our work - we progress together.

Dr. Linda Duska: Yes. And we thank the patients as well. The over 1,000 patients that went on this trial during a pandemic. Right?

Dr. Domenica Lorusso: Absolutely. Without their generosity and their trust, we would not be able to do this trial.

Dr. Linda Duska: So we're very grateful to them and we thank our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you all.

Disclaimer:

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

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Disclosures: 

Dr. Linda Duska:

Consulting or Advisory Role: Regeneron, Inovio Pharmaceuticals, Merck, Ellipses Pharma

Research Funding (Inst.): GlaxoSmithKline, Millenium, Bristol-Myers Squibb, Aeterna Zentaris, Novartis, Abbvie, Tesaro, Cerulean Pharma, Aduro Biotech, Advaxis, Ludwig Institute for Cancer Research, Leap Therapeutics

Patents, Royalties, Other Intellectual Property: UptToDate, Editor, British Journal of Ob/Gyn

Dr. Domenica Lorusso:

Consulting or Advisory Role: PharmaMar, AstraZeneca, Clovis Oncology, GSK, MSD, Genmab, Seagen, Immunogen, Oncoinvest, Corcept, Sutro Biopharma, Novartis, Novocure, Daiichi Sankyo/Lilly

Speakers’ Bureau: AstraZeneca, Clovis, GSK, MSD, ImmunoGen, Seagen

Research Funding (Inst.): PharmMar, Clovis, GSK, MSD, AstraZeneca, Clovis Oncology, Genmab, Seagen, Immunogen, Incyte, Roche, Pharma&, Corcept Therapeutics, Alkermes

Travel, Accommodations, Expenses: AstraZeneca, Clovis, GSK, Menarini