Reference Detail

Ref Type

PMID

Authors

Joseph W. Kim, Matthew I. Milowsky, Noah M. Hahn, David J. Kwiatkowski, Alicia K. Morgans, Nancy B. Davis, Leonard Joseph Appleman, Sumati Gupta, Primo "Lucky" N. Lara, Jean H. Hoffman-Censits, David I. Quinn, Yu Shyr, Patricia LoRusso, Jeffrey Sklar, Daniel Peter Petrylak

Title

Sapanisertib, a dual mTORC1/2 inhibitor, for TSC1- or TSC2-mutated metastatic urothelial carcinoma (mUC).

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology			2021

URL

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.6_suppl.431

Abstract Text

Background: A mammalian target of rapamycin (mTOR) inhibitor, everolimus, showed activity in patients with metastatic urothelial carcinoma (mUC) including an exceptional objective response in a patient with a deleterious TSC1 mutation. Sapanisertib is a potent inhibitor of mTOR complex 1 and 2. Here, we present the data from a phase II study of sapanisertib in patients with TSC1- or TSC2-mutated mUC. Methods: Eligible mUC patients with a TSC1 or TSC2 mutation received sapanisertib 3mg po daily on days 1 through 28 every 28 days. Primary endpoint was the overall response rate. Tumor samples were submitted for central confirmation of the mutation. A prescreening test for TSC1/2 mutation was available at a central lab for those with unknown mutational status. Results: Tumor samples from 41 patients were submitted for either prescreening (n=24) or confirmation (n=17). Of 24 prescreening patients, 4 (16%) had TSC1 mutation; 2 (8%) had TSC2 mutations. Of 17 confirmatory testing, 16 were confirmed by the central lab. Of 23 potentially eligible patients with a TSC1 or TSC2 mutation, 17 (14 TSC1 and 3 TSC2) were enrolled. Baseline characteristics of these 17 patients are shown. Four patients with TSC1- mutated mUC were deemed non-evaluable for response; two withdrew consent before starting sapanisertib to pursue an alternative therapy, and the other two withdrew consent with an adverse event before completing the first cycle. Of 13 evaluable patients, no objective response was observed. Although 4 patients had stable disease (SD) at their first restaging scan, none were confirmed to have SD with a subsequent scan. Median overall survival is 3.4 months. Four patients withdrew consent due to adverse event. Most common adverse events were hyperglycemia (80%), Cr elevation (53%) and AST increased (46.7%). No treatment-related death was observed. Conclusions: Sapanisertib did not result in any objective response in 13 patients with TSC1- or TSC2-mutated mUC. Given the lack of clinical activity, and problems with tolerance of sapanisertib, the trial was terminated early for futility. Future studies of an mTOR inhibitor or other targeted agent in the mTOR pathway should examine molecular alterations beyond TSC1 or TSC2.

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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	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TSC1 inact mut	transitional cell carcinoma	no benefit	Sapanisertib	Phase II	Actionable	In a Phase II trial, treatment with Sapanisertib (MLN0128) in metastatic urothelial carcinoma patients with either a TSC1 or TSC2 activating mutation (n=13) did not result in an objective response and led to a median overall survival of 3.4 months, and the trial was terminated early due to limited clinical activity and poor drug tolerability (Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021) 431-431; NCT03047213).	detail...
TSC2 inact mut	transitional cell carcinoma	no benefit	Sapanisertib	Phase II	Actionable	In a Phase II trial, treatment with Sapanisertib (MLN0128) in metastatic urothelial carcinoma patients with either a TSC1 or TSC2 activating mutation (n=13) did not result in an objective response and led to a median overall survival of 3.4 months, and the trial was terminated early due to limited clinical activity and poor drug tolerability (Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021) 431-431; NCT03047213).	detail...