Additive and Overlapping Adverse Effects of RCC Therapy

Transcript: Daniel J. George, MD: What about adverse effects, Joe? Did you catch anything on that?

Chung-Han Lee, MD, PhD: Yeah. I mean in terms of adverse effects, there were no new adverse effects that were unexpected adverse effects that we would see from this type of combination. You know we certainly saw adverse effects related to being on a TKI [tyrosine kinase inhibitor]. We certainly saw adverse effects from being on an IO [immuno-oncology] agent, but it didn’t seem as if there were additive or synergistic adverse effects that arose out of this type of combination. These are adverse effects a lot of us are quite familiar with, so it could be managed fairly reasonably.

Daniel J. George, MD: Speaking of managing adverse effects on a combination like this—especially when they’re kind of additive and overlapping—Nizar, how do you handle that? A lot of people are concerned—do we need new steroids for everybody with diarrhea? What’s you plan on this?

Nizar M. Tannir, MD, FACP: When we’re treating a patient with a combination of a checkpoint inhibitor and TKI, the way we address this is to stop the TKI if it’s a diarrhea. Axitinib has a very short half-life, 4 hours, as we know. If the diarrhea is caused by axitinib, within a day or 2 days the diarrhea will improve, and you can spare those patients the corticosteroids. Obviously if it’s TKI-driven hypertension, you can hold the TKI and continue with the checkpoint, pembrolizumab.

I want to just add to what Bob said. You know you summarized it beautifully in, I think, 1 minute or 2 minutes, this is really impressive. I think the message from KEYNOTE-426 was that the hazard ratio was really impressive—0.53. We haven’t seen a hazard ratio for OS [overall survival] that low. The 1-year probability of survival was 90% in the combination of pembrolizumab with axitinib and 78% with sunitinib, and I think that’s impressive.

If we look at the breakdown of the risk factors, the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk factors, about one-third in fact—32% of those patients on that trial—had favorable risk biopsy. That, in my opinion, is an important consideration, and it explains the long median PFS [progression-free survival] of 11 months with sunitinib and 15 with a combination. We need to really take that into account and remember those details to try to really explain the impressive results.

Dan, you mentioned the other phase III trial that was also presented—the subgroup analysis—at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] and then obviously the primary analysis was at ESMO [European Society for Medical Oncology] 2018 with JAVELIN Renal 101 phase III trial. Both have relatively short median follow-up of 12.8 months. I think we really need to see longer follow-up with these 2 trials to see the curve for PFS at the landmark analysis of, say, not just 12 months but 24 months, 30 months, and 36 months, to really see if we’re going to see a plateau for PFS and OS with these checkpoint inhibitors and TKI as combinations.

Chung-Han Lee, MD, PhD: Kind of adding to that, I think 1 of the things also to consider about these trials—especially for these large phase IIIs—is the geographic distribution of patients. Especially if we’re looking at OS type of analysis, what is their access to checkpoint inhibitors down the line?

Although the results of the KEYNOTE-426 trial are fairly impressive—showing very, very early OS benefit—there was a substantial population that was treated overseas in areas in which it’s less clear what their access to downstream checkpoint inhibitors may have been.

Nizar M. Tannir, MD, FACP: That’s very important.

Daniel J. George, MD: It’s a good point, but I’m glad you brought up this hazard ratio. This is really impressive. This was an interim analysis and hazard ratio of 0.5, which really makes a dramatic difference. And what it’s telling me is that these are the 1 in 5 patients who are dying by a year. Some of these patients, whether they have access or not, don’t have time to get to that second-line therapy. They’re running into medical complications and issues before they ever get there. We know that in the real-world practice, a lot of patients—even in the United States and other countries where there’s access to second-line therapy—never get there. If you don’t know this is a relatively symptomatic, intermediate, high-risk patient, you don’t know if they’re going to make it to second line, so use your best combination up front because you have the best chance of being alive at 1 year. I think that’s a pretty compelling argument.

Chung-Han Lee, MD, PhD: I definitely agree. I think that a lot of what the data really suggests is that we really do have to use whatever is the most effective up front, because people sometimes don’t make it to second-line therapy, and this is a real phenomenon that we have to keep in mind.

Nizar M. Tannir, MD, FACP: I mean, several studies have shown that only about 60% of patients go from first line to second line. I really think you need to treat your patients with the best therapy available up front, because 40% of them will not have a chance to get to second line.

Transcript Edited for Clarity