Choueiri Discusses Papillary RCC, Other Developments in Kidney Cancer

Toni Choueiri, MD

Toni Choueiri, MD

Although it is the second most common type of kidney cancer, papillary renal cell cancer (PRCC) is rare and its biology is relatively unknown; however, a subset of patients with PRCC have an alteration in the MET gene, which may be helpful in furthering the understanding of the disease, said Toni Choueiri, MD.

In a single-arm, biomarker-based phase II trial presented at the 2017 Genitourinary (GU) Cancers Symposium, patients with advanced PRCC were given savolitinib, a selective MET inhibitor. Savolitinib was generally well tolerated in MET-driven patients, and, according to Choueiri, and further clinical investigation is warranted.

“Hopefully, in the future, we will have a study, or will at least investigate this well-tolerated drug that doesn't have VEGF inhibitor toxicity—but in a population that has MET alterations,” said Choueiri.

OncLive: Could you prove an overview of your study on savolitinib?

In an interview with OncLive at the GU Symposium, Choueiri, clinical director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, senior physician, Dana-Farber Cancer Institute, discussed the study of savolitinib in PRCC as well as other exciting findings in RCC coming out of the meeting.Choueiri: This was the largest PRCC trial to date. We took over 100 patients with PRCC and gave them a drug called savolitinib. Savolitinib is a specific MET-only inhibitor, and has a safety profile that is pretty well tolerated. Why a MET inhibitor in papillary RCC? Well, there is data from several sources, including The Cancer Genome Atlas (TCGA).

This is a rare tumor—it’s really just a subset of RCC, but all that we've talked about in renal cell trials is clear cell. PRCC is the second most common type of RCC, but it is still very rare and we don't understand the biology. But, we understand a subset of patients harbor an alteration in the MET gene—MET mutation, MET amplification, and others.

Switching topics, where do you see older agents fitting in with the recent approvals of cabozantinib and nivolumab in kidney cancer?

There were prior studies and there is preclinical evidence—so, we treated all of the patients with foretinib (GSK1363089) with metastatic previously treated, or untreated patients with PRCC. The response rate was low in the total cohort, 8%, and the only responders were the ones that had MET alterations—if you have MET alteration the response rate was closer to 20%, if you don't, 0%. The progression-free survival (PFS) was significant—the tumor shrinkage, also significant if you have MET alteration.I think these drugs still have their place, sunitinib (Sutent) remains one of the first-line standards, like pazopanib (Votrient). And rightly so—it is used as the control arm of multiple phase III trials. We are learning more and more despite the nature of the retrospective studies, that sunitinib could be tailored based on tolerability. Pazopanib also is a frontline standard that is not inferior to sunitinib and could be better tolerated compared to the 4:2 standard schedule.

Everolimus (Afinitor) actually did lose in terms of a second-line clinical trial against cabozantinib, nivolumab and a combination with lenvatinib (Lenvima), so it is going to be pushed later on. I think there is emerging data on a subgroup of patients, probably in the 10% range or less, that do have mutation in TSC1, TSC2 and mTOR, where the responses and the benefit from everolimus could be really greater. So, if you have a patient with these alterations, especially with that becoming more mainstream to have genomic testing on the tumor, then you could think about later lines of a mTOR inhibitor.

Axitinib (Inlyta), interestingly, still also has a place, it’s a drug that is well tolerated and you can go up and down on the dose easily and it has a short half-life. I do think that does come in after the therapies that show survival like nivolumab and cabozantinib, as well as the combo of everolimus and lenvatinib. Interestingly, axitinib is moving in trials to the frontline setting with avelumab and pembrolizumab; so, axitinib may even be brought into the frontline.

What are some other interesting updates in RCC?

I do think that [these older agents] will still be a part of how we treat patients, maybe less so, but certainly they will remain part of kidney cancer care.There have been some recent studies looking at active surveillance and there’s a subset of patients where you can wait to start treatment—but this is not new.

We do also have data about circulating free DNA in patients with RCC. Interestingly enough, the alterations found were different than the one found by TCGA—p53, and others. So, it tells us that sometimes if you take a tumor at a different stage of evolution compared to a primary nephrectomy, you may find changes, so this could be dynamic changes in the tumor.

The other thing that I find interesting is 1 particular study from France where patients treated with a PD-1 inhibitor who were on antibiotic for whatever reason did not really respond well. There is significant preclinical data to show that altering the microbial with antibiotic may lead to altering the response to checkpoint-blockades.

Choueiri TK, Plimack ER, Arkenau H-T, et al. A single-arm biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer (PRCC). J Clin Oncol 35, 2017 (suppl 6S; abstract 436).

I also want to highlight work from a clinical trial on atezolizumab. So, this was, I believe, a late-breaking abstract, a randomized phase II study with 100 patients in each arm, 300 patients in the total study of sunitinib as control versus atezolizumab and a combination of atezolizumab plus bevacizumab (Avastin). The trial did not meet its primary endpoint for PFS and response rates were similar across subgroups. However, if you look at those patients, half of the population that are PD-L1 positive/PD-L1 enriched, you have a signal for response rate and a signal for PFS. What this does justify is an ongoing phase III trial of sunitinib versus the combination of a PD-L1 inhibitor and bevacizumab. So, a lot of data should come from this study, this is just preliminary information to look at overall survival later.