Savolitinib Showcases Encouraging Efficacy in MET-Driven Papillary RCC

Toni K. Choueiri, MD

Findings from the SAVOIR trial demonstrated encouraging efficacy and an improved safety profile with savolitinib over sunitinib (Sutent) in patients with MET-driven papillary renal cell carcinoma (RCC), according to Toni K. Choueiri, MD, who added that additional randomized trials are needed to further address the unmet needs in this population.

In the open-label, randomized, multicenter phase 3 trial, investigators sought to assess the efficacy of savolitinib in patients with MET-driven papillary RCC versus sunitinib, a small-molecule, multitargeted receptor tyrosine kinase inhibitor.

In the analysis, 60 patients with central confirmation of MET-driven tumors were randomized 1:1 to receive either 600 mg of savolitinib once daily (n = 33), 400 mg if they weighed 50 kg or under, or 50 mg of sunitinib once daily in 6-week cycles of 4-weeks-on and 2-weeks-off (n = 27).

Results presented during the 2020 ASCO Virtual Scientific Program showed that the median progression-free survival (PFS) was 7.0 months in the savolitinib arm and 5.6 months in the sunitinib arm. The hazard ratio (HR) was 0.71, favoring savolitinib. Moreover, the median overall survival (OS) was not calculated in the savolitinib arm versus 13.2 months in the sunitinib arm.

The overall response rate by blinded independent central review (BICR) was 27% with savolitinib versus just 7% with sunitinib. The disease control rates via BICR at 6 months with savolitinib versus sunitinib were 48% and 37%, respectively; at 12 months, the rates were 30% versus 22%, respectively. Notably, at the time of the data cutoff, no patients who responded to treatment in the savolitinib arm experienced disease progression versus 1 patient of 2 who responded to sunitinib.

With regard to safety, patients who received savolitinib experienced less grade 3 or higher adverse effects (AEs) than those given sunitinib, at 42% versus 81%, respectively. Common grade 3 or higher AEs with savolitinib included increased alanine aminotransferase, increased aspartate aminotransferase, and dyspnea.

In an interview with OncLive, Choueiri, the Jerome and Nancy Kohlberg Chair and professor of medicine at Harvard Medical School, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, discussed the data from the phase 3 SAVOIR trial with savolitinib in patients with MET-driven papillary RCC and future directions for the agent.

OncLive: Could you speak to the data that have been seen with savolitinib in papillary RCC?

Choueiri: Savolitinib is a specific and potent MET inhibitor that we assessed in this randomized trial against standard-of-care sunitinib, specifically in [patients with] advanced papillary RCC. Notably, non-clear cell RCC is the second most common histology, right after clear cell RCC. Since not much research is happening in this space, several unmet needs exist. Interestingly enough, approximately 30% to 40% of these patients have a MET pathway alteration; these patients have chromosome 7 trisomy, germline or somatic MET mutations or amplification, or the ligand for MET, FGF, could be amplified.

We originally conducted a phase 2 study with savolitinib. If a patient is MET dependent, meaning they have these abnormalities in their tumor, the response rate to savolitinib is 18% versus 0% if they do not.

Could you speak to the phase 3 SAVOIR trial?

Choueiri: We launched a phase 3 trial assessing savolitinib versus sunitinib in patients with MET dependent and MET-driven papillary RCC. The goal was to recruit and randomize 180 patients. Unfortunately, after 60 patients, we had to stop because the results of an ongoing epidemiological study did not show that MET alterations are predictive of sunitinib.

Even so, we presented data on the first 60 patients from this trial during the 2020 ASCO Virtual Scientific Program. We showed that the HR for PFS, the primary end point of the trial, was 0.71, favoring savolitinib. [Moreover, the HR for] OS was 0.5, again favoring savolitinib. The response rate was 9% with sunitinib and 27% with savolitinib.

Again, this study assessed a pure MET inhibitor against sunitinib, a nonspecific RTK inhibitor that targets VEGF receptors, along with others. Of course, we cannot draw many conclusions from this small study. However, it's intriguing and justifies continued exploration of savolitinib in future trials in patients with MET dependent papillary RCC. It should also be mentioned that overall, the toxicity profile of savolitinib appeared to be better than sunitinib.

What are some of the next steps for savolitinib?

We justified the use of savolitinib as a single agent in SAVOIR. We also know that immune checkpoint inhibitors can have activity as a single-agent therapy in papillary RCC; this was demonstrated in the KEYNOTE-427 trial, which was conducted by David F. McDermott, MD, of Beth Israel Deaconess Medical Center, and colleagues,as well as in other studies. It’s possible that we can combine savolitinib with acheckpoint inhibitor. We are looking at all possibilities carefully, but we are hoping for a randomized study that will address the unmet need in this space.

Could you speak to the prominence of MET as a biomarker in this patient population?

This is quite an interesting target, although not everyone responds; however, it's reasonable to stratify patients based on METalterations. What MET alteration drives the most [response]? Chromosome 7 alterations are much more common in a population that is MET-driven, but not by the particular alteration that we defined. Why does a MET-driven tumor only respond sometimes [to treatment]?

These are open questions, but it's interesting when you can narrow down on a pathway with a specific inhibitor and you can start seeing responses with very acceptable safety profiles. That truly sparks interest for precision medicine in papillary RCC.

Reference

Choueiri TK, Lee J, Cancel M, et al. SAVOIR: a phase III study of savolitinib versus sunitinib in patients with MET-driven papillary renal cell carcinoma. J Clin Oncol. 2020;38(suppl 15):5002. doi:10.1200/JCO.2020.38.15_suppl.5002