GU Oncology Now recently spoke with Michael B. Atkins, MD, Deputy Director, Georgetown-Lombardi Comprehensive Cancer Center, William M. Scholl Professor and Vice-Chair Department of Oncology and Professor of Medicine, Georgetown University Medical Center, to discuss a study he was involved in called “Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-nave patients with advanced non-clear cell renal cell carcinoma.“
GU Oncology Now: Can you speak to us about this study – why, and how it was conducted?
Sure. So the study was a study of NIVO monotherapy followed by NIVO IPI boost in patients who either had disease progression or had stable disease for a year. And it’s frontline treatment for patients with metastatic kidney cancer. In 2020 at ASCO, I presented cohort A, which was the clear cell population. And at 2021, I presented the results from cohort B, which was the non-clear cell population.
What were the results of the study, and some key takeaways?
The background for this study was that we had a lot of data for NIVO monotherapy in the second line setting in patients with clear cell kidney cancer. There was FDA approval based on the CheckMate 025 trial. And there was a lot of data with NIVO IPI in the frontline setting for patients with kidney cancer. And there was FDA approval for NIVO IPI in the intermediate and poor risk population. However, there was little information available regarding the efficacy and toxicity of NIVO monotherapy in patients with treatment naive, kidney cancer, or clear cell kidney cancer, or patients with non-clear cell cancer. And so this study was launched to try to fill that knowledge gap. And as I mentioned, we had data presented in 2020 for the clear cell population, and the non-clear cell population, which was a smaller population, was presented in 2021.
We had 35 patients who were enrolled in the non-clear cell cohort. Nineteen of those had papillary kidney cancer, six had, I think was chromophobe cancer, and I think the remaining 10 or so had unclassified kidney cancer. And overall, we saw a response rate of about 13% for the patients, with five or six responses in the 35 patients. And virtually all of those responses were in patients who had either unclassified or sarcomatoid characteristics for their tumor. We saw a surprisingly low response rate of about 5% for patients with papillary cancer, which was considerably less than what was seen with pembro monotherapy in the KEYNOTE-427 study, which had a much larger patient population, had a 25% response rate in the papillary population. So the distinction between what we saw and what was seen with pembrolizumab in that patient population remains to be discerned.
And we looked at PD-L1 expression, and we saw no responses in the 18 patients who had low PD-L1 expression. So all the responses were confined to the group of patients who either had PD-L1 high expression in their tumors or a subset of patients where we weren’t able to do the assay, who we presume were also PD-L1 positive. And so that, I think, led us to conclude that NIVO monotherapy had disappointing activity in the non-clear cell population and that its use might be restricted to patients who add unclassified cancer, sarcomatoid components in their cancer, and PD-L1 expression.
Did the study have any limitations?
I think one of the limitations with this study overall was that we required a biopsy or surgery on a metastatic lesion within one year of enrollment. And we needed to have enough tissue, because it was a biomarker driven study, to be able to have 18 unstained slides for analysis. And so some patients couldn’t go on because of not having enough tissue or not being willing to undergo a second biopsy. And at the time of either disease progression or prolonged stable disease, when we were going to look at the IPI boosts, we required another biopsy, and so many patients, particularly in cohort A, the clear cell cohort, weren’t able to undergo those biopsies or had surprisingly no tumor in those biopsy specimens. And so only about 50% of patients in cohort A who were eligible for crossover to the IPI boost component actually did. And we saw a similar finding in the non-clear cell population where somewhere around 19 or so patients were eligible to crossover, but only 17 patients did so. And we saw essentially no activity in that population with the IPI boost.
Do you have any future research plans pertaining to this area?
Yeah, we have all this tissue collected. And as I mentioned before, this was a biomarker based study so we’re in the process of doing additional biomarker assays for the entire study. In the patients we were able to get fresh tumor biopsies, we’re looking at single cell RNA seek studies. We’re looking at bulk RNAC on the paraffin tumor tissues in both baseline metastatic lesions and in patients where we had primary tumors available, those baseline primary tumors, as well as at time of resistance. And we’re also looking at quantitative immunofluorescence for more than just PD-L1, with the hope of identifying populations who are responsive or better predictive biomarkers for who will respond to immunotherapy and who is resistant and needs a different type of therapy.
Any closing thoughts?
Only that in looking at cohort A, the clear cell population, I think there is where we saw a surprisingly high response rate in the favorable risk population, 50% response rate. No patients with progressive disease at 12 weeks, and 14 out of 15 patients having ongoing response in that favorable risk population. That there is a real role for PD-1 monotherapy in the favorable risk population that I think is as yet unrealized or unappreciated by the general community, and I think has [inaudible] the activity of anti PD-1 in the [inaudible] setting.