Phase II Clinical Trial of Everolimus in a Pan-Cancer Cohort of Patients with mTOR Pathway Alterations.

Abstract

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 <i>TSC1</i>/<i>TSC2</i> or <i>MTOR</i> mutations. Patients with tumors with inactivating <i>TSC1</i>/<i>TSC2</i> or activating <i>MTOR</i> mutations identified in any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. Patients were treated with everolimus 10 mg 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. Between November 2015 and October 2018, 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Tumors harbored <i>TSC1</i> (13/30), <i>TSC2</i> (15/30), concurrent <i>TSC1</i> and <i>TSC2</i> (1/30), or <i>MTOR</i> (1/30) mutations. The most common treatment-related adverse event of any grade was mucositis (8/30, 27%); 1 patient had fatal pneumonitis. Partial responses were seen in 2 patients [7%; 95% confidence interval (CI), 1%-22%]. Median progression-free survival 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 2 patients with objective response, 1 had upper tract urothelial carcinoma with biallelic inactivation of <i>TSC1</i> and high tumor mutation burden, and the other had uterine carcinoma with biallelic <i>TSC2</i>-inactivating mutations and PEComa-like pathologic features. Everolimus therapy had a disappointing ORR (7%) in this pan-cancer, mutation-selected, basket study.<i>See related commentary by Kato and Cohen, p. 3807</i>.