A phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO).

Abstract

545 Background: Metastatic papillary renal cancer (PRC) has poor outcomes and there is need for new treatments. There is a strong rationale for investigating MET and PD-L1 inhibition in this disease. In this study, we investigate savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) together. Methods: This single arm phase I/II trial explored durvalumab and savolitinib at starting doses of 1500mg Q4W and 600mg OD respectively, with a 4wk savolitinib run-in. Treatment naïve or previously treated patients with metastatic PRC were included. Response rate (RR) (RECIST v1.1) was the primary endpoint. Progression free survival (PFS), tolerability (CTCAE v4) and overall survival were secondary endpoints. Biomarkers were explored from archived tissue. Results: Dose escalation work identified a dose of durvalumab of 1500mg Q4W and savolitinib 600mg OD to take forward to phase II. Between Jan 2017 and Jul 2018, 42 patients were enrolled at this dose. 1 patient did not receive study treatment. The following analyses were performed on the remaining 41 patients. 12% of patients did not receive the combination (3 PD, 1 death, 1 PS deterioration). The median follow up was 8.9 months (95% CI: 6.9-10.9 months). IMDC good, intermediate and poor risk disease occurred in 29% (n=12), 63% (n=26), and 7% (n=3) patients respectively. Overall RR was 27% (11/41), while median PFS was 3.3 months (95% CI: 1.5-NR months). RR and median PFS in the previously untreated cohort (N=28) were 29% (8/28) and 12.0 months (95% CI: 1.5-NR months) respectively. Grade 3/4 toxicity occurred in 15 patients. Discontinuation for toxicity occurred in 3 patients, all due to liver toxicities. Biomarker work including PD-L1 and MET expression will be included in the analysis. Conclusions: The combination of savolitinib and durvalumab appears safe and associated with clinical activity in PRC. Clinical trial information: NCT02819596.

SEOM clinical guideline for treatment of kidney cancer (2019)

“…Data from prospective studies are also available. In the CALYPSO phase I/II trial utilizing the combination of savolitinib and durvalumab a response rate of 27% was achieved in patients with papillary renal cell carcinoma (pRCC) [73]. Finally, in the cohort B of the KEYNOTE 427B trial, 165 patients with recurrent, or metastatic papillary (71%), chromophobe (13%), or unclassified (16%).…”

Advanced renal cell carcinoma (RCC) management: an expert panel recommendation from the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG)

“…For patients with intermediate-risk or poor-risk disease according to the IMDC score (Escudier et al 2007), independent of PD-L1 status, the panelists suggest treatment with a combination of nivolumab plus ipilimumab (an anti-PD-1 plus anti-CTLA-4 agents) or pembrolizumab plus axitinib, according to local access to therapies (recommendation level A) (Motzer et al 2018a, b;Powles et al 2019a, b). The CheckMate 214 study found that compared to sunitinib (50 mg) orally once daily for 4 weeks (over a 6-week cycle), immunotherapy combined with anti-PD1/CTLA4 agents resulted in significant improvements in the primary objectives of OS and objective response rate (ORR) and numerically progression-free survival in intermediate/poor-risk patients score in a primary analysis of 25.2 months and a follow-up analysis of 32.4 months (Motzer et al 2018a(Motzer et al , b, 2019a.…”

“…Still based on scientific evidence from the KEY-NOTE-426 study, the panelists recommend that patients with the good-risk disease, independent of PD-L1 status, should also be treated with the combination of immunotherapy plus TKI (pembrolizumab plus axitinib) (recommendation level A) (Powles et al 2019a, b).…”

First-Line Immune Checkpoint Inhibitor-Based Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review

“…The ORR was more pronounced in those with tumors that had a PD-L1 combined positive score (CPS) of ≥ 1% (35.3%) compared to a CPS < 1% (10.3%). A second single-arm phase I/II trial enrolled both treatmentnaïve and previously treated patients with papillary mRCC to receive combination therapy with savolitinib (a MET-targeting TKI) and durvalumab [24]. In the 28 treatment-naïve patients, the ORR was 29% and median PFS was 12 months (95% CI 1.5-NR).…”