DNA alterations in papillary renal cancer.

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725 Background: The characterisation of DNA alternations in papillary renal cancer (PRC) is unclear. The CALYPSO trial (NCT02819596) prospectively evaluated combination therapy of savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) in PRC. The trial showed high response rates (RR) in the MET-driven population. Here we explore the relationship between MET, PD-L1 and TMB in these tumours and the relevance of other biomarkers including PIK3CA, PTEN and KRAS. Methods: FoundationOne analysis from 41 samples of PRC patients enrolled on the CALYPSO trial was performed. The relevance of co-positivity between MET/PD-L1 and MET/TMB as well as analysis of other DNA alterations such as PIK3CA, PTEN and KRAS was explored. Outcome parameters were correlated with RR, PFS and OS. Results: 41% of patients were MET-driven, 66% were PD-L1+ (vCPS≥1) and 3% were TMB >10mut/Mb. Further testing used TMB ≥ median (2.52mut/Mb) 32% of patients were both MET-driven and PD-L1+. 17% of patients were both MET-driven and TMB ≥ median. RR and survival outcomes for combinations are shown in the table. The overall RR in MET driven and non-MET-driven patients was 52.9% and 13%, respectively. The median PFS and OS in the MET-driven group was 12.0 months (95% CI: 2.9-19.4) and 27.4 months (95% CI: 9.3-not reached [NR]), respectively, compared to a median PFS and OS in the non-MET-driven group of 2.7 months (95% CI: 0.5-5.0) and 7.5 months (95% CI: 0.0-16.0), respectively. PIK3CA, PTEN and KRAS mutations occurred in 1, 4 and 2 patients, with RR of 0% (0/1), 25% (1/4) and 50% (1/2), in the PIK3CA, PTEN and KRAS groups, respectively. Conclusions: MET-driven papillary cancers have low mutational burden, but high PD-L1 expression. Small patient numbers limit definitive conclusions, but responses occur irrespective of the immune biomarkers investigated. Other DNA alterations are rare and did not appear to influence outcomes in this cohort. These data support the design of the SAMETA trial (NCT05043090), further investigating the savolitinib and durvalumab combination. [Table: see text]

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