Reference Detail

Ref Type

Journal Article

PMID

(33727259)

Authors

Adib E, Klonowska K, Giannikou K, Do KT, Pruitt-Thompson S, Bhushan K, Milstein MI, Hedglin J, Kargus KE, Sholl LM, Tsuji J, Hyman DM, Sisk A, Shapiro GI, Vargas HA, Harding JJ, Voss MH, Iyer G, Kwiatkowski DJ

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	27	14	2021 07 15	3845-3853	Clin Cancer Res

URL

Abstract Text

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 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.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.Everolimus therapy had a disappointing ORR (7%) in this pan-cancer, mutation-selected, basket study.See related commentary by Kato and Cohen, p. 3807.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
SMARCA4	F1142L	missense	unknown	SMARCA4 F1142L lies within the C-terminal helicase domain of the Smarca4 protein (UniProt.org). F1142L has been identified in the scientific literature (PMID: 33727259), but has not been biochemically characterized and therefore, its effect on Smarca4 protein function is unknown (PubMed, May 2024).
TSC2	G1604C	missense	unknown	TSC2 G1604C lies within the Rap-GAP domain of the Tsc2 protein (UniProt.org). G1604C has been identified in sequencing studies (PMID: 33727259), but has not been biochemically characterized and therefore, its effect on Tsc2 protein function is unknown (PubMed, May 2024).
TSC2	P1675R	missense	unknown	TSC2 P1675R lies within the Rap-GAP domain of the Tsc2 protein (UniProt.org). P1675R has been identified in sequencing studies (PMID: 33727259), but has not been biochemically characterized and therefore, its effect on Tsc2 protein function is unknown (PubMed, May 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TSC1 inact mut	Advanced Solid Tumor	no benefit	Everolimus	Phase II	Actionable	In a Phase II trial, Afinitor (everolimus) treatment resulted in limited activity with an objective response rate of 7% (2/30, 2 partial responses), stable disease in an additional 40% (12/30), a clinical benefit rate of 13% (4/30), a median progression-free survival of 2.3 months, and a median overall survival of 7.3 months in patients with advanced solid tumors harboring inactivating TSC1 or TSC2 mutations or activating MTOR mutations (PMID: 33727259; NCT02201212).	33727259
TSC2 inact mut	Advanced Solid Tumor	no benefit	Everolimus	Phase II	Actionable	In a Phase II trial, Afinitor (everolimus) treatment resulted in limited activity with an objective response rate of 7% (2/30, 2 partial responses), stable disease in an additional 40% (12/30), a clinical benefit rate of 13% (4/30), a median progression-free survival of 2.3 months, and a median overall survival of 7.3 months in patients with advanced solid tumors harboring inactivating TSC1 or TSC2 mutations or activating MTOR mutations (PMID: 33727259; NCT02201212).	33727259