Phase II Clinical Trial of Everolimus in a Pan-Cancer Cohort of Patients with mTOR Pathway Alterations
Elio Adib, Katarzyna Klonowska, Krinio Giannikou, T. Khanh, Solida Pruitt-Thompson, Ketki Bhushan, Matthew I. Milstein, Jennifer Hedglin, Katherine E. Kargus, Lynette M. Sholl, Junko Tsuji, David M. Hyman, Anne Sisk, Geoffrey I. Shapiro, Hebert Alberto Vargas, James J. Harding, Martin H. Voss, Gopa Iyer, David J. Kwiatkowski
Abstract
Abstract 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. Patients and Methods: Patients with tumors with inactivating TSC1/TSC2 or activating MTOR 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. Results: Between November 2015 and October 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%); 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 TSC1 and high tumor mutation burden, and the other had uterine carcinoma with biallelic TSC2-inactivating mutations and PEComa-like pathologic features. Conclusions: Everolimus therapy had a disappointing ORR (7%) in this pan-cancer, mutation-selected, basket study. See related commentary by Kato and Cohen, p. 3807