- The single arm phase II CALYPSO study evaluated the efficacy of MET inhibitor savolitinib combined with PD-L1 inhibitor durvalumab in MET-driven papillary renal cancer, a kidney cancer subtype with a poor prognosis and few treatment options available.
- Approximately 30% of patients with this disease present alterations in the MET gene that encodes a hepatocyte growth factor receptor. These mutations are implicated in disease progression and can also contribute to cancer drug resistance.
- Senior authored by Cristina Suárez and published in the Journal of Clinical Oncology, final results of this study show that patients with MET alterations had a median overall survival of 27.4 months versus 18.3 months in the global population.
- These data further support the ongoing phase III SAMETA trial which is investigating the efficacy of the savolitinib-durvalumab combination versus sunitinib and durvalumab monotherapy in MET-driven, unresectable and locally advanced or metastatic papillary renal cancer.
Advanced papillary renal cancer (PRC) has a poor prognosis with few treatments available. Approximately 30% of patients with this disease present alterations in the MET gene that encodes a hepatocyte growth factor receptor. Mutations in this gene occur in several tumor types and are implicated in disease progression and can also contribute to cancer drug resistance. While the association of MET mutations with the development of this kidney cancer subtype has been well described, the effect of specifically targeting this gene in renal cancer is less clear.
Aimed at identifying new and more potent treatment avenues for these patients, the phase II CALYPSO study assessed various drug combinations in patients with advanced renal cancer. In the PRC cohort, the final results of which are now published in the Journal of Clinical Oncology, the investigators assessed the efficacy of savolitinib (a MET inhibitor) combined with durvalumab (a PD-1 inhibitor).
“Here we report the final results of the metastatic papillary renal cancer cohort. Based on previous single arm studies showing that savolitinib monotherapy achieved response rates of 18% in patients with MET gene alterations, as well as promising preclinical data suggesting a positive interaction between MET and PD-L1 inhibition, this study included 41 patients with advanced PRC, 17 of which presented alterations in the MET gene,” explained Cristina Suárez, Group Leader of the Vall d’Hebron Institute of Oncology’s (VHIO) Genitourinary (non-prostate), Central Nervous System Tumors (CNS), Sarcomas, and Tumors of Unknown Origin, a Medical Oncologist at the Vall d’Hebron University Hospital, and senior author of the study.
MET-driven status was defined as chromosome 7 gain, MET amplification, MET kinase domain variations, or hepatocyte growth factor amplification, which expanded the clinical trial population given that all these alterations can be implicated in the progression of PRC and influence cancer drug resistance.
The median overall survival was 27.4 months in those patients with MET-driven tumors versus 18.3 months in the global population. A median progression-free survival of 13.9 months was observed in the patients with MET-driven status compared to 6.5 months in the global population.
Adverse events were in line with what was expected for these two drugs, with grade 3 or 4 adverse events occurring in 41% of patients.
Using liquid biopsy, the investigators also assessed the presence of tumor DNA fragments in blood (ctDNA) at the beginning of the study and during treatment. The presence of ctDNA in blood prior to treatment associates with a worse prognosis since patients with detectable ctDNA generally exhibit lower survival rates. When this biomarker disappears or decreases on treatment, outcomes significantly improve.
“These data reinforce the value of ctDNA as a powerful, non-invasive liquid biopsy tool for the real-time monitoring of the disease and evaluation of therapeutic effectiveness,” added Suárez.
“Our findings show that the savolitinib and durvalumab combination is tolerable and demonstrate promising activity in MET-altered tumors. To date, we lack clear biomarkers in renal cancer, and the results of this study point to MET as a potential biomarker. Results from the PRC cohort of this study support further investigations in MET-altered tumors. This drug combination is currently being evaluated in the ongoing phase III SAMETA trial in patients with MET-driven advanced or metastatic disease,” she concluded.
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Reference:
Jackson-Spence Francesca, Larkin James, Patel Poulam, Valderrama Begoña P., Rodriguez-Vida Alejo, Glen Hilary, Thistlethwaite Fiona C., Ralph Christy, Srinivasan Gopalakrishnan, Mendez-Vidal Maria Jose, Childress Merrida, Li Wenshu, Boyle Patrick, Gascó Amaya, Markovets Aleksandra, Hartmaier Ryan, Ackerman Charlotte, Szabados Bernadett E., Priyadarshini Garima, Jamal Fahmida, Powles Thomas, Suárez Cristina. CALYPSO: Final Results of Savolitinib and Durvalumab Combination in Metastatic Papillary Renal Cancer. Journal of Clinical Oncology. 2025. doi:10.1200/JCO-25-01840.
