Moshe Ornstein, MD, MA, shares data from the KEYNOTE-426 clinical trial that set a new standard of care for treatment-naïve metastatic clear cell RCC.
Nizar Tannir, MD: I’m going to turn it over to Moshe. Moshe, the floor is yours. Take it away. Talk to us about the KEYNOTE-426 trial, and then later CheckMate 9ER.
Moshe Ornstein, MD, MA: I’ll present the results for the KEYNOTE-426 [clinical trial (NCT02853331)], which was axitinib and pembrolizumab in the frontline setting for advanced RCC [renal cell carcinoma]. What’s great about this trial is it was the first I/O [immuno-oncology]–TKI [tyrosine kinase inhibitor] combination approved in the frontline setting. At the time of approval, it set a new standard in the treatment of frontline metastatic RCC.
Key eligibility criteria included newly diagnosed or recurrent stage IV disease with some clear cell component. Obviously, it’s treatment-naive, so no prior systemic treatments. [There were] stratifications by IMDC [International Metastatic RCC Database Consortium] risk group and geographic region. Patients were randomized in a 1:1 fashion to receive pembrolizumab 200 mg IV [intravenously] every 3 weeks for up to 35 cycles, plus axitinib 5 mg orally twice daily, vs the control arm of sunitinib, much like we saw in the CLEAR trial (NCT02811861) and in the CheckMate 214 trial (NCT02231749), of 50 mg once daily for the first 4 weeks of each 6-week cycle.
I’d like to highlight a couple of things. First, pembrolizumab in this trial was for up to only 35 cycles, approximately 2 years, at which point the I/O of pembrolizumab was discontinued. The axitinib was at the traditional starting dose of 5 mg orally twice daily, although there was a provision to allow patients who were tolerating therapy to up-titrate to 7 mg and then higher. The dual primary end points were overall survival [OS] and PFS [progression-free survival] in the ITT [intention-to-treat] population. This is different from the CheckMate 214 trial of ipilimumab and nivolumab, which included all risks but the primary end points were for intermediate- and poor-risk patients.
The baseline characteristics, as one would expect, are fairly classic for a metastatic RCC clinic and what one would expect in a randomized phase 3 trial. The only thing that I’d like to highlight is that as we see all these different I/O-TKI combinations approved, we start to look for nuances and differences in the baseline characteristics. The one thing I would point out on this slide is that in KEYNOTE-426, pembrolizumab plus axitinib had a relatively high rate of patients with favorable-risk RCC. We classically think about a 20/60/20 breakdown in terms of percentages of favorable, intermediate, and poor risk, respectively. Here we saw close to 32% of patients included who had favorable-risk metastatic RCC, and only about 12% or 13% who had poor-risk metastatic RCC. The rest of the baseline characteristics were well balanced and fairly similar to the other trials.
Once again, we’re going to show the PFS and OS in the ITT population, because those were the dual primary end points. The median PFS for pembrolizumab and axitinib was 15.7 months vs 11.1 months for sunitinib, with a strong hazard ratio of 0.68. The median overall survival for the axitinib-pembrolizumab arm was 45.7 months vs 40 months in the sunitinib arm, with a hazard ratio of 0.73. What you’re seeing here throughout the presentation are some of the updated data, not necessarily the data that were found in the initial publication, and a strong preference in the randomized phase 3 for pembrolizumab and axitinib in terms of both median PFS and overall survival.
I’d like to highlight the response rates. The response rates favor axitinib-pembrolizumab: 60% objective response rate vs 40% in sunitinib. The CR [complete response] rate was also more than double in the study arm, 10% vs 4% for sunitinib. The primary disease progression rate in terms of PD [progressive disease] as response was 11% for axitinib and pembrolizumab vs 17% in patients receiving sunitinib.
As far as overall survival in the ITT population and by IMDC risk status, we’re looking at the hazard ratio. For the ITT population, it was 0.73. For patients with intermediate- and poor-risk disease, the hazard ratio for survival was 0.64. The hazard ratio in the favorable risk is 1.17, with a fairly wide confidence interval of 0.76 to 1.80.
Treatment-related adverse events [AEs] in KEYNOTE-426 were in many ways as expected. We saw high rates of any-grade treatment-related AEs. Grade 3 to 5 adverse events were similar in both arms, slightly higher in patients receiving the combination, which isn’t unexpected, as they were getting an I/O agent. [There were] low rates of death due to treatment in both arms. As Scott [Tykodi, MD, PhD] mentioned, one of the interesting adverse events seen at higher rates than expected was high rates of transaminitis with the combination of axitinib and pembrolizumab, especially relative to the other I/O-TKI regimens.
In summary, being the first approved I/O-TKI combination, there was superiority in the ITT population in terms of OS and PFS. It set a new standard of care for treatment-naive metastatic clear cell RCC when it was presented.
Transcript edited for clarity.