Genomic alterations in key components of PI3K/mTOR pathway have been proposed as candidate predictive markers for rapalog therapy in renal cell carcinoma (RCC). We tested this hypothesis in patients from a randomized phase II trial of everolimus versus sunitinib.

Archival specimens collected at baseline were analyzed with targeted next-generation sequencing (NGS). Focus of interest were alterations in key PI3K pathway components. PTEN expression was assessed by IHC. Association between molecular findings and treatment outcomes was investigated; same associations were tested for 2 everolimus-treated trial cohorts in gastric and hepatocellular carcinoma (HCC).

Among 184 everolimus-treated patients with RCC with NGS data, mutation rates in genes of interest were 6% (), 4.4% (), and 8.2% (); 44% harbored alterations in ≥1 PI3K pathway component. For subjects with presence versus absence of mutations in , or progression-free survival (PFS) neither differed on univariate analysis (HR, 1.0; = 0.895) nor on multivariate testing stratified by MSKCC risk group and other established prognostic factors (HR, 1.1; = 0.806). Everolimus-treated patients with retained ( = 50) versus lost ( = 50) PTEN IHC expression had median PFS of 5.3 months versus 10.5 months (HR, 2.5; < 0.001). Such differences were not seen with sunitinib (10.9 months vs. 10.3 months; HR, 0.8; = 0.475). Molecular findings did not correlate with outcomes in gastric and HCC cohorts.

Association between mutation status for // and therapeutic outcome on everolimus was not confirmed. Clinically meaningful differences in PFS were seen based on PTEN expression by IHC, lost in >50% of patients.