Purpose: This was a multicenter, histology-agnostic, single-arm prospective phase II trial of therapeutic activity of everolimus, an oral mTORC1 inhibitor, in patients with advanced solid tumors that harbored TSC1/TSC2 or MTOR mutations.
Experimental design: Patients with tumors with inactivating TSC1/TSC2 or activating MTOR mutations identified in any CLIA-certified laboratory were eligible. Patients were treated with everolimus 10mg once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Whole-exome sequencing was performed to identify co-occurring genomic alterations.
Results: Between 11/2015 and 10/2018, 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan-Kettering Cancer Center. Tumors harbored TSC1 (13/30), TSC2 (15/30), concurrent TSC1 and TSC2 (1/30) or MTOR (1/30) mutations. The most common treatment-related adverse event of any grade was mucositis (8/30, 27%); one patient had fatal pneumonitis. Partial responses were seen in two patients (7%, 95%CI: 1%-22%). Median progression-free survival (PFS) was 2.3 months (95%CI: 1.8-3.7 months) and median overall survival (OS) was 7.3 months (95%CI: 4.5-12.7 months). There was no clear association between other genomic alterations and response. Of the two patients with objective response, one had upper tract urothelial carcinoma with biallelic inactivation of TSC1 and high tumor mutation burden, the other had uterine carcinoma with biallelic TSC2 inactivating mutations and PEComa-like pathologic features.
Conclusions: Everolimus therapy had a disappointing objective response rate (7%) in this pan-cancer, mutation-selected, basket study.