Francesca Jackson-Spence, MBChB, Barts Cancer Institute, London, England, discusses final efficacy and ctDNA data from the CALYPSO trial, as presented at the 2025 American Society for Clinical Oncology (ASCO) Genitourinary Cancers Symposium. Results demonstrated that durvalumab plus savolitinib prolonged efficacy among patients with MET-driven advanced papillary renal cancer. 

Transcript: 

My name is Dr Francesca Jackson-Spence, I'm a doctor at Bart's Cancer Institute in London. I'm going to be talking about the final overall survival data and ctDNA analysis results for savolitinib in combination with durvalumab in advanced papillary renal cancer, as part of the CALYPSO study. 

The CALYPSO study is a phase 2 trial investigating savolitinib in combination with durvalumab in advanced papillary renal cancer. Forty-one patients were enrolled with advanced papillary renal cancer who all had measurable disease, some had had prior VEGF-targeted therapy, some had not. Savolitinib, a MET inhibitor, and durvalumab, an immune checkpoint inhibitor, were given together and treatment was until progression. The primary end point was confirmed response rate. The secondary end point of progression-free survival had been presented previously by Christina Suarez and the results have been published in the JCO [Journal of Clinical Oncology], but today I'll talk about the final overall survival results and the results of the ctDNA analysis. 

Previous data showed the confirmed response rate in the intention-to-treat papillary population was 32%, but interestingly, this increases to 53% in MET-driven tumors, and this resulted in a randomized phase 3 global study called SAMETA, which is ongoing. As part of this analysis, we used 4 types of biomarkers, ctDNA analysis was conducted using FoundationOne tracker, which is FoundationOne testing on the tissue, in combination with Natera ctDNA testing on the plasma time-points and 48% of our patient cohort was ctDNA-positive at baseline. MET status was defined as MET-driven, which doesn't just include MET alterations but also things like chromosome 7 gain and HGF amplification, and 41% of our patients were defined as MET-driven. PD-L1 analysis was assessed centrally using IC and TC staining and 66% of patients were PD-L1-positive. Tumor mutational burden [TMB] was also analyzed using FoundationOne and median TMB was low at 2.52 mutations per megabyte. 

We presented the final progression-free survival and overall survival, which was 6.5 months for progression-free survival, in the intention-to-treat cohort, and 18.3 months for overall survival and interestingly, these both increase from 6.5 to 13.9 months in the MET-driven tumors and from 18.3 months for overall survival to 27.4 months for overall survival in the MET-driven cohort. We also did an analysis using PD-L1 status and according to TMB status, but neither appeared relevant in determining outcomes. For the ctDNA analysis we started with 42 patients enrolled on the trial, 41 patients receiving the combination therapy of savolitinib with durvalumab and 21 patients with sufficient tissue and plasma time points to be included in the ctDNA analysis using FoundationOne tracker. The ctDNA analysis showed us that 48% of patients were ctDNA-positive at baseline, but only 1 patient had trackable MET alterations in the plasma. ctDNA positivity was associated with a lower likelihood of responding to therapy, with 89% of the non-responders being ctDNA-positive at baseline compared to just 22% of the responders, and there appeared to be no correlation with prior VEGF targeted therapy, MET status, or PD-L1 status. ctDNA status at baseline was prognostic for overall survival, we compared ctDNA-positive with ctDNA-negative. The median overall survival for a ctDNA-positive patient was 7.3 months, but this increases to 33 months in the ctDNA-negative patients. ctDNA clearance was also associated with better outcomes, however only 2 patients cleared their ctDNA. 

Overall, we hope that these results from the CALYPSO study will be validated in the larger randomized phase 3 study, SAMETA trial, which is now completed enrollment and we're very excited about this. SAMETA is a randomized study with 3 arms comparing savolitinib with durvalumab, sunitinib alone, or durvalumab monotherapy in MET-driven tumors only, so really investigating that MET subset. 

In conclusion, the phase 2 CALYPSO study shows savolitinib in combination with durvalumab has activity in papillary renal cancer. Tumor responses are enriched in the MET-driven group with a median overall survival of 27.4 months, responses are irrespective of PD-L1 and TMB status. ctDNA status at baseline may be a useful tool in papillary renal cancer and has prognostic value, 48% of patients with ctDNA-positive at baseline. Few patients had trackable MET alterations, and we hope that results will be validated in the SAMETA trial. Thank you.

Source: 

Jackson-Spence F, Larkin J, Patel P, et al. Final overall survival and new ctDNA analysis in MET-driven advanced papillary renal cancer (CALYPSO). Presented at 2025 ASCO Genitourinary Cancers Symposium. February 13-15, 2025; San Francisco, CA. Abstract 444