Background: Approved rapalogs inhibit mTORC1 and have limited activity in mRCC, possibly due to compensatory feedback loops. Sapanisertib addresses the incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2 with antitumour activity demonstrated in patients with mRCC. In this multicenter, single arm phase II trial, we evaluated the efficacy of sapanisertib in patients with mRCC progressing on standard therapies (NCT03097328). Methods: Eligible mRCC patients had an ECOG performance status of 0-2 and had progressed on standard therapies. Prior therapy with rapalogs (everolimus, temsirolimus) and variant RCC histologies were permitted. Patients had a baseline biopsy and received treatment with sapanisertib 30 mg by mouth weekly until unacceptable toxicity or disease progression. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. Results: We enrolled 38 mRCC patients (clear cell = 28; variant histology = 10) between August 2017 and November 2019. The majority had intermediate (76%) or poor risk (11%) by IMDC criteria. Twenty (53%) had received ≥ 3 lines of therapy; 13 (34%) patients received prior rapalogs. Median follow-up was 10.4 months (range 1-27.4) and median duration of therapy was 1.6 (range 0.3-13.8) months. ORR by central review was 2 of 38 (5.3% 90%CI: 1%-15.6%). 31.6% of all patients and 30.7% of those with prior rapalog exposure had some tumor shrinkage during course of treatment. Median progression free survival (PFS) was 2.5 months (95% CI 1.8,3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events (AEs) with no grade 4 or 5 toxicity reported; 6 patients (16%) required dose reduction and 4 (11%) discontinued therapy for AEs. Oncopanel tumor sequencing identified alterations in the mTOR pathway in 6 of 29 patients (MTOR n = 2, PTEN n = 3, TSC1 n = 1.) Reduced PTEN expression by immunohistochemistry was seen in 7 of 19 patients. There was no association between mTOR pathway mutations or PTEN loss and response to sapanisertib. Conclusions: In this study we demonstrate minimal activity of sapanisertib in patients with treatment refractory mRCC with no clear benefit among patients with mTOR/PTEN pathway alterations. Additional treatment strategies are needed for patients with refractory mRCC.