Final overall survival and new ctDNA analysis in MET-driven advanced papillary renal cancer (CALYPSO)

Abstract

Background: Phase II data from the CALYPSO study (NCT02819596) has shown activity for durvalumab (PD-L1 inhibitor) plus savolitinib (MET inhibitor) (D+S) in MET-driven advanced papillary renal cancer (aPRC), resulting in the ongoing randomised phase III study, SAMETA (NCT03091192). Here we present the final efficacy and new ctDNA analysis. Methods: The aPRC cohort was a single arm study of D+S in both untreated and previously treated disease. Efficacy endpoints include response rates (RR) as per RECIST 1.1, progression-free survival (PFS) and overall survival (OS). PD-L1, TMB and MET status were analysed. Safety was assessed via CTC criteria. FoundationOne CDx was used to profile tissue in 41 patients. Plasma was collected for ctDNA analysis (FoundationOne Tracker analysis; n=21) at baseline (pre-treatment) and sequential time points on treatment. MET mutations were also tracked using F1 Tracker following identification by the F1CDx assay. Results: At 41 months follow-up, the RR in the Intention to Treat (ITT) aPRC population (n=41) was 34% (95% CI, 20-51) and 59% (95% CI, 33-82) in MET-driven patients (n=17). The median PFS was 8.4 months (95% CI, 3.0-13.9) in the ITT population and 16.7 months (95% CI, 5.1-31.4) in MET-driven patients. The median OS was 18.3 months (95% CI, 7.3-30.6) in the ITT population and 27.4 months (95% CI, 9.3-51.6) in MET-driven patients. The hazard ratio (HR) for PFS and OS in MET-driven vs non-MET-driven in PRC cohort was 0.36 (p=0.02) and 0.76 (p=0.43), respectively. 66% of patients were PD-L1+, and 32% were both MET-driven/PD-L1+. The PD-L1 biomarker did not enrich for responders. 27% patients had tissue TMB >median (2.52mut/Mb). TMB was not associated with outcome. 10/16 (63%) were ctDNA positive at baseline, which was associated with a shorter median OS of 7.3 vs 36.4 months (HR 3.91, p=0.02). The mean reduction in Variant Allele Frequency (VAF) was 43% with therapy. For patients with pre- and on-treatment ctDNA, those with CR/PR had ctDNA VAF reduction while those with SD/PD had ctDNA VAF increase (p=0.05). ctDNA clearance was associated with improved PFS (p=0.04). Only 2 patients had MET mutations tracked. ctDNA positivity did not correlate with MET alterations, PD-L1 status or the presence of visceral metastases. Conclusions: D+S continue to show impressive efficacy in MET driven tumors, supporting the ongoing SAMETA trial. ctDNA monitoring on therapy holds promise as a prognostic and potentially predictive tool in this setting. Clinical trial information: NCT02819596.