(UroToday.com) Papillary renal cell carcinoma (RCC) may be classified into two histologic subtypes, type 1 and type 2. Type 1 papillary RCC is typically associated with MET pathway dysregulation, whereas type 2 papillary RCC is associated with sporadic gene mutations or germline mutations in fumarate hydratase2. The MET pathway is associated with tumor growth, angiogenesis, and promotion of metastases, as well as treatment resistance3. Thus, targeting the MET pathway may be effective for selected patients. In the phase II study of savolitinib for patients with advanced papillary RCC, 109 patients with papillary RCC were treated, of whom 40% were MET driven, as defined by chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. Patients with MET driven tumors had a median PFS of 6.2 months, compared with 1.4 months for MET independent tumors. This study seeks to answer whether Savolitinib can improve overall survival over Sunitinib in MET driven papillary RCC.
The study schema is shown above. In brief, patients with MET driven tumors (chromosome 7 gain, MET or HGF amplification or MET kinase mutation were randomized in a 1 to 1 ratio to either savolitinib 600 mg daily or sunitinib 50 mg daily in 4 week on/2 week off cycle.
254 patients were screened and only 60 patients met criteria, most due to lack of MET driven alterations (n=181). In terms of baseline characteristics of the 60 patients, the majority were white men with either IMDC intermediate/poor tumors. This was the first line of therapy for almost all patients. 
The trial did not meet its primary endpoint of improving progression-free survival. The median PFS was 7 months with savolitinib compared with 5.6 months with sunitinib, HR 0.71, P=0.313. 
Median overall survival has not yet been reached for patients on savolitinib and was 13.2 months for sunitinib, HR 0.51, P=0.110. In terms of objective responses, 27% of patients on savolitinib had an objective response, compared with 7% of patients on sunitinib. For the patients with an objective response on savolitinib, no patients have had progression. For the 2 patients with a PR on sunitinib, 1 has progressed. 3 of the responders on savolitinib have been followed for greater than 6 months now. 
In terms of safety, 42% of patients on savolitinib had a grade 3 or higher adverse events (AE), and 9% of patients discontinued treatment due to AEs. 81% of patients on sunitinib had a grade 3 or higher AE and 7% of patients have discontinued treatment due to AE. The most common AEs related to savolitinib was peripheral edema, elevated liver enzymes, and dyspnea.
This trial did not meet its primary endpoint of improving PFS with savolitinib compared with sunitinib. However, the adverse events profile shows that savolitinib may have been better tolerated than sunitinib with fewer grade 3/4 toxicity. Also, of the patients who had responded the savolitinib, the durability of response appears longer than sunitinib. This is a challenging population to study given that it is a fraction of patients with metastatic RCC - while this study only had 60 patients enrolled, it provides valuable data on Savolitinib in a biomarker selected cohort of patients with papillary RCC.
Presented by: Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary (GU) Oncology, Dana Farber Cancer Center, Boston, MA
Written by: Jason Zhu, MD, Medical Oncologist, Division of Genitourinary Cancers, Levine Cancer Institute, Twitter: @TheRealJasonZhu, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.
References:
- Brodziak A, Sobczuk P, Bartnik E, et al. Drug resistance in papillary RCC: from putative mechanisms to clinical practicalities. Nature Reviews Urology 2019;16:655-73.
- Klatte T, Pantuck AJ, Said JW, et al. Cytogenetic and molecular tumor profiling for type 1 and type 2 papillary renal cell carcinoma. Clinical Cancer Research 2009;15:1162-9.
- Choueiri TK, Plimack E, Arkenau H-T, et al. Biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer. Journal of Clinical Oncology 2017;35:2993-3001.