Savolitinib Plus Durvalumab in MET-Driven Papillary Renal Cell Carcinoma

Clinical Summary:

• Design/Context: The phase 2 CALYPSO trial evaluated savolitinib plus durvalumab in patients with metastatic papillary renal cell carcinoma. 
• Key Points: The combination showed higher response rates and improved survival outcomes in MET-driven disease, while PD-L1 and tumor mutational burden did not predict benefit.
• Clinical Relevance: MET status appears to be a key biomarker in papillary renal cell carcinoma, and ctDNA may emerge as a useful prognostic tool pending validation in phase 3 studies.

Francesca Jackson-Spence, MBChB, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom, discusses final results from the phase 2 CALYPSO study evaluating savolitinib plus durvalumab among patients with metastatic papillary renal cell carcinoma. 

Transcript:

Hello, my name is Dr Francesca Jackson-Spence, I’m a clinical research fellow and PhD candidate at Barts Cancer Institute, Queen Mary University of London, and I’m working under the supervision of Professor Tom Powles.

I’m going to talk today about the final results of the phase 2 CALYPSO study, which evaluated savolitinib plus durvalumab in metastatic papillary renal cancer. I’ll also discuss the results of the ctDNA analysis conducted within the trial.

Papillary renal cancer accounts for around 10 to 15 percent of all renal cancers and patients generally have poorer outcomes and fewer evidence-based treatments compared to those with clear cell kidney cancer. Targeting MET is of particular interest in papillary renal cancer. MET is a transmembrane receptor tyrosine kinase encoded on chromosome 7 and its ligand is hepatocyte growth factor. Approximately 30 to 40 percent of papillary renal cancers are MET-driven, meaning they have activation of the MET pathway through mechanisms such as chromosome 7 gain, MET gene amplification, MET kinase domain mutations, or amplification of the HGF ligand. This provides a strong biological rationale for combining selective MET inhibition, such as savolitinib, with immune checkpoint blockade, such as durvalumab.

Earlier results from the phase 2 CALYPSO study showed that this combination produced meaningful responses in patients with MET-driven papillary renal cancer. In our final analysis, with 41 months of follow-up, we observed the following: an overall response rate was 34% in the intention-to-treat population (ITT), increasing to 53% in MET-driven patients. The median duration of response in the ITT population was 11.3 months. Median progression-free survival was 6.5 months versus 13.9 months in MET-driven patients. Overall survival was also improved in the MET-driven population, at 27.4 months compared with 18.3 months in the overall population.

The key message is that this combination appears particularly active in patients with MET-driven papillary renal cancer, with higher response rates and longer progression-free and overall survival compared to non-MET-driven disease. 

We also evaluated tissue biomarkers, specifically PD-L1 expression and tumor mutational burden. In our cohort of 41 patients, 66% were PD-L1 positive and the median TMB was 2.5 mutations per megabase. However, neither PD-L1 nor TMB enriched for outcomes– this is consistent with broader renal cell carcinoma experience, where these biomarkers have been relatively unreliable, and again points toward MET status as the more relevant biomarker in this setting.

We also conducted a ctDNA analysis as part of the trial as there are limited data on the role of circulating tumor DNA in papillary renal cancer. We used the Signatera method, a tumor-informed approach, and tested patient samples at baseline, at predefined time points on treatment, and at progression.

Forty-eight percent of patients were ctDNA positive at baseline and response rates were higher in those who were ctDNA negative at baseline with response rates at 80% compared to 20% in ctDNA-positive patients. Baseline ctDNA positivity also correlated with shorter median overall survival of 7.3 months versus 33.3 months. ctDNA clearance and reductions in mean variant allele frequency were also associated with improved overall survival, although numbers were small, with only 2 patients achieving ctDNA clearance.

In terms of safety, no new safety signals were observed. The median duration of treatment was 3.9 months. We saw dose reductions and discontinuations due to toxicity occurring in 29% and 34% of patients, respectively, and 27% required dose reduction of savolitinib. The most common grade ≥3 treatment-related adverse events were edema and elevated liver enzymes. Overall, the regimen appears manageable with dose modification and appropriate monitoring.

Looking ahead, we hope that the results from the CALYPSO study will be validated in the randomized phase 3 SAMETA study, which is comparing savolitinib plus durvalumab versus durvalumab alone versus sunitinib in a 2:1:1 randomization. 

In MET-driven papillary renal cancer, savolitinib plus durvalumab delivers high response rates, prolonged progression-free survival, and encouraging overall survival, with a manageable safety profile. ctDNA appears promising as a dynamic prognostic tool in advanced papillary renal cancer, but its role remains exploratory and requires validation in prospective randomized phase 3 studies such as SAMETA before it can be implemented into routine practice.

Source: 

Jackson-Spence F, Larkin J, Patel P, et al. CALYPSO: Final results of savolitinib and durvalumab combination in metastatic papillary renal cancer. J Clin Oncol. Published online: March 20, 2026. doi:10.1200/JCO-25-01840