Pembrolizumab Plus Axitinib vs Sunitinib as First-Line Therapy for Advanced ccRCC

Dr. Pal: Welcome to PracticeUpdate. My name’s Monty Pal. I’m a Medical Oncologist at the City of Hope Comprehensive Cancer Center in Los Angeles. I’m delighted today, to have one of my dear friends and colleagues, Dr. Jun Gong joining me. He’s an expert in GI and GU cancers at the Cedars-Sinai Medical Center. And I had the pleasure of working with him at City of Hope for a period of time.

Well, we’re here to talk about updates on KEYNOTE-426. So, this is a trial that I think has really sort of played a role in shaping the front-line landscape for renal cell carcinoma. Can you just rehash for our audience the design of KEYNOTE-426?

Dr. Gong: Right. So, KEYNOTE-426 was a randomized phase III trial, enrolling patients who were untreated with metastatic clear cell RCC, randomizing them to the combination of axitinib and pembrolizumab, vs the then standard of care, which was sunitinib, in the first-line treatment. And what the study showed in the original results was that the combination of axitinib and pembrolizumab demonstrated a superior OS, PFS, and overall response rate benefit over sunitinib, irrespective of IMDC risk category.

Dr. Pal: Got it. And just as with all these other phase III trials, we’re seeing little trinkets of data falling out at subsequent meetings. At this year’s meeting, there was a presentation that really focused on some of the subsequent therapies in KEYNOTE-426. Can you tell us a little bit about that?

Dr. Gong: Yes. So, this was an updated analysis, with the median follow-up of 43 months. I think there were two key findings from this presentation. One of them being that the most common second-line therapy following progression to axitinib and pembrolizumab, vs sunitinib in this study, was a second-line VEGF-TKI. The second key finding was that there was a superior progression-free survival two, or PFS-2 benefit, with the combination of axitinib/pembrolizumab vs sunitinib in this setting.

Dr. Pal: Interesting. Interesting. I think those are brilliant takeaways. Just maybe round things out by giving us your perspective on front-line treatment. What are you treating most patients with in this setting, and why?

Dr. Gong: Yeah. I think it’s a very ongoing, controversial discussion, with so many first-line regimens happening today, and more in development. I think what we first looked at is a way to stratify patients: are they better candidates for VEGF-TKI plus IO combinations or dual IO/IO combinations? I think you have less evidence to support an IO/IO combination in favorable risk, but in the intermediate- and poor-risk categories, you certainly can consider an IO/IO combination. You do have higher response rates with VEGF-TKI and IO combinations. So, sometimes we like to think about patients who need more of an urgent response, or tumor debulking effect. You might want to consider a VEGF-TKI IO combination. And then among the VEGF-TKI IO combinations, I think, with breakthrough data from leaders just like you, we’ve had more granularity in choosing out some regimens.

For example, you’ve pioneered some great data on cabozantinib, and its activity with some bone tropism, as well as some activity in CNS penetration. So, I think these are smaller subsets where you can consider specific VEGF-TKI combinations, but I think we’re still waiting to tease out some more granularity on what the preferred first-line regimen is. I think, that’s where biomarkers will come in handy. Additionally, I think with follow-up data from studies like this, you also help to find out which combinations can derive some longer-term benefits, such as PFS-2, and these may ultimately help the clinicians select a little bit more and tailor to their patient what the first-line regimen should be.

Dr. Pal: Just brilliant. Jun, as always, great insights for our audience.