Memorial Sloan Kettering Cancer Center, New York, NY
Gopa Iyer , Dustin A. Deming , Michael J. Demeure , Noah Federman , Meredith McKean , Elizabeth Katherine Lee , Alexander I. Spira , David J. Kwiatkowski , Maen A. Hussein , Erlinda Maria Gordon , David G. Crockett , Kristen N. Ganjoo , Brian Schulte , Lee D. Cranmer , Li Ding , Anita N. Schmid , Willis H. Navarro , Jordi Rodon Ahnert
Background: nab-Sirolimus is a novel albumin-bound mTOR inhibitor (mTORi) approved in the US for adult patients with malignant PEComa. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with a broad variety of cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi class adverse events. Methods: PRECISION I (NCT05103358) will evaluate efficacy and safety of nab-sirolimus in patients with TSC1 (Arm A) and TSC2 (Arm B) alterations. Eligible patients are ≥12 y old and mTORi-naïve, possess malignant solid tumors with TSC1/TSC2 inactivating alterations (confirmed by central review of sequencing reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 will be given weekly intravenously over 30 min on Days 1 and 8 of each 21-d cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading next-generation sequencing vendors will expedite the identification of patients with qualifying TSC1/TSC2 mutations; study access will be facilitated through a just-in-time approach to trial location activation. Based on the prevalence of TSC1/TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric (Table). Clinical trial information: NCT05103358.
Tumor type | TSC1 Mutations, %a | TSC2 Mutations, %a | TSC1/TSC2 Combined, % |
---|---|---|---|
Bladder | 6.33 | 1.70 | 8.03 |
Hepatobiliary | 1.27 | 3.31 | 4.58 |
Endometrial | 2.10 | 1.22 | 3.32 |
Soft tissue sarcoma | 1.28 | 1.71 | 2.99 |
Ovarian | 1.85 | 0.92 | 2.77 |
Esophagogastric | 0.65 | 1.46 | 2.11 |
Colorectal carcinoma | 0.99 | 0.39 | 1.38 |
Pancreatic | 0.57 | - | 0.57 |
aThe proportion of patients with definite impact mutations (ie, mutations known to have a biological impact, including frameshift, nonsense, and splice-site mutations and deep deletions) derived from analysis of TCGA and cBioPortal by Gulati et al. Data on file.
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Abstract Disclosures
2024 ASCO Genitourinary Cancers Symposium
First Author: Gopa Iyer
2024 ASCO Gastrointestinal Cancers Symposium
First Author: Dustin A. Deming
2023 ASCO Gastrointestinal Cancers Symposium
First Author: Dustin A. Deming
2023 ASCO Genitourinary Cancers Symposium
First Author: Gopa Iyer