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

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

Pulmonary metastasectomy in renal cell carcinoma: Predictive and prognostic elements from paired histopathological analysis of primary tumors and respective metastases

“…This element is quite interesting in the light of the possible sensitivity of RCC harboring genetic alterations in the mTOR pathway from available mTOR inhibitors, offering the cue for therapeutic implications in this setting. [31][32][33][34] c-MET expression in RCC patients resulted in high prevalence in the literature (80% of cases in old retrospective studies on primary tumor) and the present study. The negative prognostic role of this biomarker is known, but no data have been provided for c-MET expression in metastatic tissues.…”

Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants

“…Interestingly, in addition to mutations in MYCN , we also noticed recurrent (although not frequent) mutations in three other genes in the MYC/MTOR regulatory network, i.e., MTOR , DYRK3 , and AMBRA1 ( Figure 4 ), which have not been reported as mutated in BCC. The MTOR missense/activating mutations identified in other cancers are considered biomarkers for therapy with mTOR pathway inhibitors ( 89 ).…”

Profile of basal cell carcinoma mutations and copy number alterations - focus on gene-associated noncoding variants

“…Interestingly, in addition to mutations in MYCN , we also noticed recurrent (although not frequent) mutations in three other genes in the MYC/MTOR regulatory network, i.e., MTOR , DYRK3 , and AMBRA1 (Fig 4), which have not been reported as mutated in BCC. The MTOR missense/activating mutations identified in other cancers are considered biomarkers for therapy with mTOR pathway inhibitors [72]).…”