Long-Term Data in Frontline RCC Raise More Questions Than Answers

At the American Society of Clinical Oncology (ASCO) annual meeting, researchers reported long-term updates from various phase III trials on first-line treatment options for advanced and metastatic clear cell renal cell carcinoma (RCC).

In this exclusive MedPage Today video, Naomi B. Haas, MD, director of the Prostate and Kidney Cancer Program at the Hospital of the University of Pennsylvania in Philadelphia, discusses the questions these trial results present for physicians.

Following is a transcript of her remarks:

There were some long-term results presented for two of the largest clinical trials in front-line renal cell carcinoma. The first one was axitinib [Inlyta] and pembrolizumab [Keytruda] versus sunitinib [Sutent], and it was a long-term survival of outcome for those patients. And the second notable study was the CLEAR study, which was lenvatinib [Lenvima] and pembrolizumab versus lenvatinib and everolimus [Afinitor] versus sunitinib. And specifically the attention was the long-term follow-up with the lenvatinib plus pembrolizumab arm versus sunitinib.

And what was interesting in those trials was that, when it came to the overall survival, well the durable response rates in both of those trials did not appear to measure up to what was notable in CheckMate-214, which was the ipilimumab [Yervoy] plus nivolumab [Opdivo] trial versus sunitinib.

The other notable presentation in the oral abstracts was the CONTACT trial, which was asking the question of: in patients who had previously received PD-1 therapy or PD-L1 therapy, is offering those patients a PD-L1 therapy, retreating them as a second-line or third-line therapy, does that have a beneficial outcome? And what that trial showed was that there really was not any difference between cabozantinib [Cabometyx] and atezolizumab [Tecentriq] versus cabozantinib.

In the first study, the main question is really important for patients, and that is — patients and physicians — if you are starting to treat a patient with front-line therapy, which of the four therapies do you use? Do you use an IO [immunotherapy]/IO combination? Do you use an IO/VEGF [vascular endothelial growth factor] combination? And I think that it really depends on the patient.

So if a patient has intermediate or poor risk IMDC [International Metastatic RCC Database Consortium] criteria disease and they are reasonably stable, my choice would be ipilimumab and nivolumab in that population, because that regimen has the best chance of patients eventually being able to come off of treatment and have a durable response. However, we’re also faced with patients who have rapidly progressive disease, and given that the median time to response is about 3 months, some patients don’t have 3 months to wait for a response.

And so in that patient population, it’s still very reasonable to use a VEGF-R receptor tyrosine kinase inhibitor with an immune checkpoint inhibitor. However, I think that we need to do a lot more work in trying to figure out how we can render more of both of those populations free of disease or to have a really robust response.

As far as the CONTACT study, I think the big question was really, is a PD-L1 inhibitor as good as a PD-1 inhibitor? The trial used atezolizumab, and atezolizumab has not shown a benefit to overall survival in any of the RCC trials. And so would the answer be different if we wait for the results of the tivozanib [Fotivda]/nivolumab trial? And I think it remains to be seen.

Patients really like to be on immune checkpoint therapies. So as far as my own practice, I think it really depends on whether a patient is having just a little bit of progression in a couple of isolated areas or whether their disease overall is progressing. I’m still very much a fan to consider offering an immune checkpoint inhibitor later, but I think that we will have more results about that later. And the other issue that came up was just because the immune checkpoint inhibitors bind to the immune receptors for a very long period of time, and these trials often were transitioning patients who were progressing right onto a second-line inhibitor, would it make more sense to study this just in the population that had a good response and then recurred later. Similar to what we see in melanoma.