42-Month Follow-up of KEYNOTE-426, Pembrolizumab plus Axitinib First-Line Treatment for Advanced Renal Cell Carcinoma - Thomas Powles

August 18, 2021

Alicia Morgans engages with Thomas Powles to discuss the 42-month follow-up data from the KEYNOTE-426 study, a phase 3 randomized trial examining the efficacy of axitinib and pembrolizumab versus sunitinib for metastatic kidney cancer. Dr. Powles elaborates on the study's results, which indicate that the combination therapy has been effective, particularly in terms of progression-free survival (PFS), but that the hazard ratio has drifted down to 0.73 from its initial 0.53. He stresses that while the data set becomes more robust over time, determining which patients will most benefit from the VEGF-TKI immune therapy remains a challenge. Drs. Morgans and Powles both emphasize the need for further research and support systems to translate clinical trial efficacy into everyday clinical effectiveness. They caution against making cross-trial comparisons at this stage, underscoring that the long-term outcomes of various regimens are still undetermined. 


Thomas Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology, Lead for Solid Tumour Research at Barts Cancer Institute, Director of Barts Cancer Institute, London, United Kingdom

Alicia Morgans, MD, MPH, GU Medical Oncologist, Dana Farber Cancer Institute, Boston, MA

Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans, and I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the US. I am so excited to have here with me today, a good friend and colleague, Professor Thomas Powles, who is the Director of the Barts Cancer Center and Professor of Urology Cancer at the Barts Cancer Institute in London, in the UK. Thank you so much for being here with me today, Dr. Powles.

Thomas Powles:
Thank you for inviting me.

Alicia Morgans:
Wonderful. I wanted to talk with you a little bit about a presentation at ASCO 2021, where we really heard the updates from the 42-month follow-up of KEYNOTE-426. Can you share with us a little bit about this?

Thomas Powles:
Yes. The study is a randomized phase 3 study. It is a kidney cancer frontline metastatic study. It tests the combination of axitinib and pembrolizumab versus sunitinib. You'll be aware, the first data cut happened after only 12.3 months. The hazard ratio for survival at that point was 0.53, which was the lowest survival hazard ratio we had seen in kidney cancer. It remains that, actually, and we showed response rates that were 60%, which was unprecedentedly high. And remember sunitinib at about 30%, ipi-nivo at about 40%. PFS of 15 months, which is much longer than we've seen before. And since then there has been a series of salami cuts of these data to see how we get on and whether or not we can maintain those results, because it was the first VEGF immune combination. People followed it carefully because there is an assumption that there are more similarities than differences between those immune VEGF combinations.

The question is, what do those data look like? I think the key issue is, from a landmark analysis perspective and from a survival perspective, the data looks as good as other data for combinations in the setting. The hazard ratio has drifted down and is currently at 0.73 from 0.53. I guess it suggests a couple of things. Number one is the data set becomes more robust as it goes on, but also it is clear that the combination of VEGF immune therapy is really important for those patients who are in harm's way immediately and have rapidly progressive disease. I think that VEGF-TKI immune therapy is important for that group of patients.

One of the challenges is we don't really know who they are. We don't know which patients are going to progress on ipi-nivo, we don't know which patients can be salvaged by giving VEGF immune. We've got some data, in fact, from some of the other trials looking at immune and angiogenic type signatures, but they are not ready for prime time yet.

And so, the toxicity profile is what one would expect. Of course, that hasn't changed. It's manageable. It is more difficult to give combination therapy than single-agent therapy. That's the reality. So, sunitinib is relatively straightforward. There are additional challenges and there are really important educational pieces around this. From the back of the room, I think what you can say from a PFS perspective is the original PFS advantage was statistically significant, which was not the case for ipi-nivo. The ipi-nivo curve wasn't so great at the start, and it has now plateaued. The VEGF-TKI immune curves got off to a better start and they are coming down, and they're now probably joining where ipi-nivo was. I don't think you can currently say there are huge differences between the two, but we don't know, in the fullness of time, whether or not that CTLA-4 component is important in maintaining that response. We don't really know that yet and we won't for probably a couple of years in reality, which is an important issue because it means we have to continue to do this work with these drugs.

The question I get asked most commonly is, is this the best VEGF-TKI regimen? And the answer is no, it's not. It's not the best. It looks very similar to the other VEGF-TKI immune regimens, and each one of the three regimens has a particular advantage and each one of the three has a disadvantage. I won't rehearse them for you now. So, what I am saying to people is, "Pick one and use it well," and I've been saying that consistently. I think that I'm getting a bit older now, one of my experiences from the VEGF-TKI story was we spent much too much time talking about whether pazopanib and sunitinib were better, where actually there were more similarities than differences between them as well.

And during that debate, we didn't talk enough about the best way of giving the drugs. Do the patients have CNS support? Is there a 24-hour hotline number? Does the patient have a patient group to speak to, to share their challenges with? Does the clinical team have a track record of treating these patients? These are all more important issues, in my perspective, in my opinion. And so, that summarizes that piece.

Can we currently say that these datasets show us that axi-pembro is better than ipi-nivo? No, we can't show that, that doesn't show that, and we shouldn't be doing that cross-trial comparison. I still think it's fair to say, at this point, that the VEGF-TKI immune combination has a high response rate, but better early PFS data. I still think it's fair to say that the long-term outcome associated with these different regimens has not yet been determined, and comparing the two remains premature. I think it is reasonable to say the axi-pembro dataset looks as robust as any other set that's available to us. And this sets the scene for the other drugs, which I'm sure will show similar effects.

Alicia Morgans:
Well, thank you so much for talking that through, and I think it is important really to clarify that, of course, we're not advocating for cross-trial comparisons, but really just demonstrating, I think, with this long-term outcome data, that this remains a very viable combination that is highly effective for our patients. But there's always work to be done in terms of biomarker selection, of course, and in supporting patients, because really, to make that jump between efficacy in a clinical trial and effectiveness in our actual clinical populations, we need to provide patients, their families, and our clinical teams with the supports necessary to effectively and safely give these drugs on a daily basis each day when we see patients in the clinic.

Thank you so much for sharing these updated data with us and for putting them in context. We always appreciate your expertise.

Thomas Powles:
Thank you.