Efficacy of Durvalumab Plus Savolitinib in MET-Driven Papillary Renal Cancer: Insights From CALYPSO

At the American Society of Clinical Oncology 2025 Genitourinary Cancers Symposium, the final efficacy analysis of the phase II CALYPSO study was presented along with a new ctDNA analysis from the study.

Previous data from the phase II CALYPSO study has demonstrated the efficacy of durvalumab in combination with MET inhibitor savolitinib in patients with MET-driven advanced papillary renal cancer (aPRC), leading to the ongoing phase III SAMETA study.

Durvalumab with savolitinib were studied in both untreated and previously treated patients. The primary endpoints of the study included response rates (RR) based on RECIST 1.1, progression-free survival (PFS), and overall survival (OS). PD-L1, TMB and MET status were also analyzed, and safety was determined using common toxicity criteria.

The study enrolled 41 patients in an intention-to-treat (ITT) cohort. Tumor tissue from each participant was analyzed using FoundationOne CDx, while plasma samples were collected for circulating tumor DNA (ctDNA) analysis via FoundationOne Tracker (n=21) at baseline (pre-treatment) and at multiple time points during therapy. MET mutations were tracked through F1 Tracker following their identification via F1CDx.

At 41 months follow-up, the RR in the ITT population was 34% (95% CI, 20-51), increasing to 59% (95% CI, 33-82) in 17 MET-driven patients. The median PFS was 8.4 months (95% CI, 3.0-13.9) in the overall 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 versus non-MET-driven patients in a PRC cohort was 0.36 (P=.02) and 0.76 (P=.43), respectively. PD-L1 expression was observed in 66% of patients, with 32% being both MET-driven and PD-L1-positive. However, PD-L1 status did not correlate with treatment response. Additionally, tumor mutational burden (TMB) above the median (2.52 mut/Mb) was observed in 27% of patients, but TMB was not associated with clinical outcomes.

Among 16 patients analyzed for ctDNA, 10 (63%) were ctDNA-positive at baseline. These patients experienced significantly shorter median OS (7.3 vs 36.4 months, HR 3.91, P=.02). On treatment, the mean reduction in variant allele frequency (VAF) was 43%. Patients who achieved complete or partial response showed a decrease in ctDNA VAF, whereas those with stable or progressive disease exhibited a VAF increase (P=.05).

ctDNA clearance was linked to improved PFS (P=.04). However, only two patients had MET mutations tracked, and ctDNA positivity did not correlate with MET alterations, PD-L1 status, or the presence of visceral metastases.

This final analysis of CALYPSO supports the ongoing SAMETA trial; the combination of durvalumab with savolitinib provides increased efficacy in MET-driven tumors. ctDNA monitoring on therapy acts as a promising prognostic and predictive tool in this setting.