Brian Rini, MD, discusses the KEYNOTE-426 study and the promise of emerging combinations in renal cell carcinoma.
Brian Rini, MD
The ongoing phase III KEYNOTE-426 trial is investigating the safety and efficacy of the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) versus sunitinib (Sutent) alone in treatment-naive patients with advanced or metastatic renal cell carcinoma (RCC).
The study was launched after phase I results showed antitumor activity with the combination of the PD-1 inhibitor pembrolizumab and the VEGF inhibitor axitinib. The primary endpoints are progression-free survival and overall survival.
In an interview with OncLive, Brian Rini, MD, Cleveland Clinic, discussed the KEYNOTE-426 study and the promise of emerging combinations in RCC.Rini: In the field of kidney cancer, there are a lot of trials combining VEGF agents and immuno-oncology agents—that is one of the main facets of kidney cancer research right now. VEGF agents are the standard of care, immuno-oncology agents obviously are coming in and taking over a lot of cancers, including RCC. So, part of the rationale for the combination is that each drug by itself is active as monotherapy—VEGF agents, like axitinib, and checkpoint inhibitors, like pembrolizumab.
There is also some biologic rationale that VEGF inhibition may favorably alter the immunomodulatory environment, so basically allow immuno-oncology agents to work better. Preclinical mouse model data [that is] actually fairly compelling…has been around for a long time.
[Additionally] there was a trial of 52 previously untreated patients with RCC who received axitinib and pembrolizumab. This was reported by Dr Michael Atkins last fall, I believe. The results were really the best results that have ever been seen in kidney cancer, honestly. The repose rate was 71%, which is about 30% higher than what has ever been reported. Axitinib by itself is in the 30% to 40% range; pembrolizumab has not really been tested by itself in kidney cancer, but if it’s like nivolumab (Opdivo), it would probably be 20%.
[So] it is at least additive, if not more. Not a huge study, 52 patients—but not small, either. A reasonable-sized phase I/II study. Ninety-four percent of patients had tumor shrinkage—so almost everybody saw some effect, that is pretty good for this disease. The progression-free survival was in the 15-month range, but I am not sure if that was mature data, meaning a lot of patients had not progressed yet. That initial experience was reasonably safe, expected toxicities, and really, some impressive clinical data.
What that led to is a phase III trial and that is combination axitinib/pembrolizumab compared to sunitinib, which is the standard of care monotherapy in advanced kidney cancer. That trial is ongoing and accruing now. If the trial is positive, it becomes standard of care. Now, again, that is in the context of 3 or 4 other similar trials of a VEGF [inhibitor] plus an immuno-oncology agent. There is also a large trial of nivolumab and ipilimumab (Yervoy) compared to sunitinib, that will be the first to report in the next year or so. Although a different combination, among those 4 to 6 trials—unless they are all flatly negative—the standard of care is going to change. In a year or 2, people won't be getting a TKI as monotherapy, I’m sure of it.It has been tested in melanoma extensively, with data presented last year. It is clearly active in kidney cancer, there have been previous trials, but this is the first of the large phase III trials that will read out in the next 6 to 12 months.It is a pretty clean compound—it’s just a VEGF inhibitor. What I tell patients is hypertension, fatigue, and diarrhea. Hypertension is not a big deal, fatigue is there, but it is not as bad as say sunitinib—it is a different kind of fatigue, and then diarrhea tends to be the one that they deal with most chronically. Patients who I have on that drug long term, which is many patients, most have chronic diarrhea and we just deal with it. That is relevant to pembrolizumab, which also causes diarrhea. In that early trial, the tolerability seemed good.Yes. Clearly not all the combinations can get a lot of use as it is a fairly rare disease, which is good. So, it is going to be the combination that is the best tolerated, the most efficacious, and the most convenient for dosing. There will be competition among these regimens, just like there is among TKIs and certain TKIs rose to the top for various reasons. So, I assume the same will happen for these combinations.
The sequencing question is important, as well. After you have used one drug in each class, the question is what are you going to do next? And I don't know what the answer is. You can imagine the next wave of trials will be looking at those patients who failed this combination therapy, what do you do and what is active? Those [answers] will come in the future. This is just one of many trials that are out there to enroll patients on, and there are more coming. It's a good problem to have.