Efficacy of Savolitinib vs Sunitinib in Patients With MET-Driven Papillary Renal Cell Carcinoma: The SAVOIR Phase 3 Randomized Clinical Trial

Abstract

Importance: Papillary renal cell carcinoma (PRCC) is the most common type of non-clear cell RCC. Because some cases of PRCC are MET-driven, MET inhibition could be a targeted treatment approach. In previous studies, savolitinib (AZD6094, HMPL-504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in this patient group.

Objective: To determine whether savolitinib is a better treatment option for this patient population, vs standard of care, sunitinib.

Design, setting, and participants: The SAVOIR phase 3, open-label, randomized clinical trial was a multicenter study carried out in 32 centers in 7 countries between July 2017 and the data cutoff in August 2019. Overall, 360 to 450 patients were to be screened to randomize approximately 180 patients. Patients were adults with MET-driven (centrally confirmed), metastatic PRCC, with 1 or more measurable lesions. Exclusion criteria included prior receipt of sunitinib or MET inhibitor treatment. Overall, 254 patients were screened.

Interventions: Patients received 600 mg of savolitinib orally once daily (qd), or 50 mg of sunitinib orally qd for 4 weeks, followed by 2 weeks without treatment.

Main outcomes and measures: The primary end point was progression-free survival (PFS, assessed by investigator and confirmed by blinded independent central review). Secondary end points included overall survival (OS), objective response rate (ORR), duration of response, and safety/tolerability.

Results: At data cutoff, 60 patients were randomized (savolitinib n = 33; sunitinib n = 27); most patients had chromosome 7 gain (savolitinib, 30 [91%]; sunitinib, 26 [96%]) and no prior therapy (savolitinib, 28 [85%]; sunitinib, 25 [93%]). For savolitinib and sunitinib, 4 (12%) and 10 (37%) patients were women, and the median (range) age was 60 (23-78) and 65 (31-77) years, respectively. Following availability of external data on PFS with sunitinib in patients with MET-driven disease, study enrollment was closed. Progression-free survival, OS, and ORR were numerically greater with savolitinib vs sunitinib. Median PFS was not statistically different between the 2 groups: 7.0 months (95% CI, 2.8-not calculated) for savolitinib and 5.6 months (95% CI, 4.1-6.9) for sunitinib (hazard ratio [HR], 0.71; 95% CI, 0.37-1.36; P = .31). For savolitinib and sunitinib respectively, grade 3 or higher adverse events (AEs) were reported in 14 (42%) and 22 (81%) of patients and AE-related dose modifications in 10 (30%) and 20 (74%). After discontinuation, 12 (36%) and 5 (19%) of patients on savolitinib and sunitinib respectively, received subsequent anticancer therapy.

Conclusions and relevance: Although patient numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy vs sunitinib, with fewer grade 3 or higher AEs and dose modifications. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted.

Trial registration: ClinicalTrials.gov Identifier: NCT03091192.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Choueiri reports receiving research support (institutional and personal) from AstraZeneca, Alexion, Bayer, Bristol-Myers Squibb/ER Squibb and Sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, and Takeda; honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb and Sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OncLive, PeerView, and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, and Lilly; has had a consulting or advisory role for AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb and Sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, and Tempest; owns stock in Pionyr and Tempest; and has received travel, accommodations, and expenses in relation to consulting, advisory roles, or honoraria. Dr Heng reports consultancies with and honoraria from AstraZeneca, Pfizer, Novartis, BMS, Ipsen, Exelixis, and Merck. Dr Lee reports grants, personal fees, and other from Pfizer Korea and Ipsen Korea; personal fees and other from Janssen, Sanofi Aventis, Astellas Korea, and BMS Korea; and personal fees from Novartis Korea, outside the submitted work. Dr Verheijen is an employee of AstraZeneca and owns shares in AstraZeneca and Aduro Biotech. Dr Mellemgaard is an employee of AstraZeneca. Dr Ottesen is an employee of and owns shares in AstraZeneca. Dr Frigault is an employee, patent holder, and stock owner of AstraZeneca. Dr L’Hernault is an employee of and owns shares in AstraZeneca. Dr Szijgyarto is an employee of and owns shares in AstraZeneca, and reports receiving a long-term incentive as part of rewarding performance. Dr Signoretti reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, and Exelixis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, AACR, and NCI; and receives royalties from Biogenex. Dr Albiges reports research funding from Bristol-Myers Squibb; consultancy/advisory roles with Bristol-Myers Squibb, Novartis, Amgen, Ipsen, Roche, Pfizer, Merck, MSD, and AstraZeneca; and travel/accommodation expenses from Bristol-Myers Squibb and MSD. No other disclosures were reported.

Figures

Figure 1.. Patient Disposition

BICR indicates blinded independent central review. Two patients were included based on investigator’s assessment of papillary renal cell carcinoma subtype, which did not receive positive confirmation on ad hoc revision of histopathologic analysis, as per protocol. These patients remained in the analysis set (1 patient in each group).

Figure 2.. Kaplan-Meier Curves

BICR indicates blinded independent central review; HR, hazard ratio; NC, not calculated; OS, overall survival; PFS, progression-free survival.

Figure 3.. Target Lesion Size, Best Percentage Change Waterfall Plot by BICR In 27 Patients Treated With Savolitinib and 24 Treated With Sunitiniba

BICR indicates blinded independent central review. aNine patients (savolitinib n = 6; sunitinib n = 3) were not included in the target lesion size plot: no target lesions present at baseline that were selected as target lesions for the purpose of BICR assessment (n = 7: savolitinib n = 5, sunitinib n = 2); no postbaseline target lesion assessment captured (savolitinib n = 1; sunitinib n = 1).