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.

Fig 1.. Everolimus activity in a pan-cancer cohort.

A. Distribution of primary cancer sites for 30 patients on this trial. Abbreviations: UC – urothelial carcinoma. B. Best recorded change in target lesions from baseline by RECIST v1.1. Twenty-two patients (out of thirty) are shown as eight patients did not have follow up data because they were off study by the 8-week follow-up. The bar color refers to the primary cancer site; the pattern refers to the gene with mutation. Patients marked with an asterisk (*) were considered to have progressive disease despite reduction in size of target lesions due to appearance of a new site of disease †: Liver – TSC1 mutation, ‡: Bladder – TSC1 mutation. Abbreviations: UC – urothelial carcinoma. C. Relative change in RECIST measurements in patients with objective response data. PR: partial response, SD: stable disease, PD: progressive disease, CB: clinical benefit. Mutations are shown for those with PR or CB.

Fig 2.. Map of pathogenic somatic variants in TSC1/TSC2.

A. The location of mutations at each nucleotide position in TSC1 (upper panel) and TSC2 (lower panel) is indicated by a lollipop. The color of the lollipop indicates the type of mutation according to the legend in (B). The size of lollipops corresponds to response to everolimus; small – no CB; medium – CB but not PR; large – PR. Two large deletions in TSC2 are indicated at the bottom, with dashed line indicating extension of the deletion to the adjacent PKD1 gene. B. Pie charts summarizing relative numbers of different mutation types seen in TSC1 and TSC2.

Fig 3.. Co-mutation plot of all variants.

SNVs/indels, LOH/biallelic inactivation events for TSC1 and TSC2, two-copy deletions, and amplification events are shown for cancer genes in the OncoKB and/or CGC databases, for which at least 10% of subjects had an event. For TSC1 and TSC2, only inactivating mutations are shown with indication of subclonal mutation. Clinical benefit was defined as PR: partial response, or stable disease at 22w with minimal reduction (SD22w); SD - stable disease, PD - progressive disease, and OUT - subject drop-out. Tumor mutation burden (TMB) for each patient is shown at top as nonsynonymous SNVs/indels per megabase of targeted capture genomic region. TMB is shown only for patients with Tumor-Normal paired WES analysis; patients with no WES available (results of MPS targeted assay only) are indicated with an asterisk. Abbreviations: UTUC – upper tract urothelial carcinoma.