73 (PB063) - Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) - Phase 2 Study of MLN0128 (TAK-228) in Patients with Tumors with TSC1 or TSC2 Mutations: Sub-protocol EAY131-M

Abstract

Background: The NCI-MATCH trial was designed to assess the clinical efficacy of select targeted therapies in pts with specific mutations in a tumor agnostic fashion. Loss of function mutations in the tumor suppressor genes TSC1 and TSC2 have been shown to activate the mTORC1 pathway constitutively. TAK-228 is an orally available potent inhibitor of both TORC1 and TORC2 complexes. Subprotocol M is a phase 2 study to determine the effects of TAK-228 on pts whose tumors harbor TSC1 or TSC2 alterations. Materials and Methods: Patients with advanced metastatic solid tumors or lymphomas who progressed following at least 1 prior systemic therapy were accrued to NCI-MATCH for tumor molecular profiling, and those with functionally curated somatic TSC1 or TSC2 alterations were offered participation in sub-protocol M. Patients received TAK-228 3 mg daily for 28-day cycles until progression or intolerable toxicity. Results: 49 pts were enrolled on arm M with 4 pts deemed ineligible or never starting treatment, leaving 45 evaluable pts. The primary analysis includes 34 pts with centrally confirmed mutations (CM), 7 from the MATCH screening cohort assay and 27 from approved outside laboratories. Of the 34 CM pts, 17 were female (50%), median age 62 (22–87), 21 had received 3 or more lines of prior therapy (61.7%), all had ECOG PS 0-1. Tumor types included urothelial (4), renal (2), prostate (2), colorectal (6), pancreas (1), HCC (1), ovary (3), endometrial stromal sarcoma (2), cervical adenocarcinoma (1), TNBC (1), squamous lung (2), PEComa (2), spindle cell sarcoma (1), PNET (1), angiosarcoma of spleen (1), osteosarcoma (1), melanoma (1), and undifferentiated carcinoma (2). TSC2 alterations made up 17 of the CM pts and 25 of the evaluable pts. Of the 34 CM pts, there were 5 PR for a 14.7% ORR (90% CI 6.0%- 28.5%), 13 SD, 12 PD and 4 were unevaluable. The estimated 6-month PFS rate is 28.7% (90% CI 17.3%–47.5%) in CM pts. The five responders were endometrial stromal sarcoma (1), high grade angiosarcoma of the spleen (1), PNET (1), HCC (1), and renal clear cell carcinoma (1). 4/5 responders had TSC2 alterations. Two pts with squamous NSCLC had clinical benefit for greater than 6 mo. Most common emergent adverse events among the 45 evaluable pts included hyperglycemia, fatigue, nausea, anemia and diarrhea. Grade 3–4 treatment-related adverse events (TRAE) included creatinine increase (4), TTP (4), dysphagia (4), pruritis (4). No grade 5 TRAE were reported. Six pts came off study due to adverse events. Conclusions: While the primary endpoint of 6/34 (17.6% ORR) CM responses was not met, TAK-228 therapy had modest clinical activity in pts with various solid tumors exhibiting TSC1 or TSC2 alterations. The observation that 4/17 (23.5%) tumors harboring confirmed TSC2 alterations responded in this heavily pretreated population merits further investigation. NCT02465060. No conflict of interest.