Phase II Study of Vismodegib in Patients With SMO- or PTCH1 -Mutated Tumors: Results From the National Cancer Institute Molecular Analysis for Therapy Choice Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Trial (EAY131) Subprotocol T

PURPOSE The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) (EAY131, ClinicalTrials.gov identifier: NCT02465060 ) trial pairs patients with targeted therapies on the basis of tumor genomic alterations. Subprotocol T assessed vismodegib, a hedgehog pathway inhibitor, in patients with Patched-1 ( PTCH1 ) and Smoothened ( SMO ) alterations (excluding basal cell carcinoma). METHODS Eligible patients received oral vismodegib (150 mg daily) until progression or toxicity. The primary end point was objective response rate, with secondary end points including 6-month progression-free survival (PFS), survival, and predictive biomarkers. Optional plasma for cell-free DNA analysis was collected at enrollment, on treatment, and at progression. RESULTS From June 2016 to September 2020, 34 patients enrolled; 31 eligible patients (nine SMO , 22 PTCH1 ) received treatment, with 25 confirmed by the central NCI-MATCH assay (primary analysis cohort). Median age of the 31 eligible patients was 64 years, with 48.4% being women. Sixty-one percent received ≥3 previous therapies and 74% had multiple co-occurring mutations. Objective response rate was 8% (2/25 [90% CI, 1.4 to 23.1]) in the primary analysis cohort and 6.5% (2/31 [90% CI, 1.2 to 19]) overall. Partial responses occurred in soft tissue sarcoma ( PTCH1 ) and meningioma ( SMO ), with response durations of 19 and 9.23 months, respectively. Six-month PFS rates were similar (24%, 23.2%), with an identical median PFS of 1.8 months and median overall survival of 7.3 months for the analyzable and primary analysis patient cohorts. Four patients (12.9%) discontinued therapy because of adverse events. Common toxicities included grade 1-2 fatigue, anorexia, weight loss, alopecia, and dysgeusia. Four on-study deaths occurred, none treatment-related. CONCLUSION Vismodegib was well tolerated with mainly grade 1-2 toxicities, but it did not meet the primary end point. Select patients with specific SMO and PTCH1 alterations had notable responses, warranting further comprehensive molecular analyses to elucidate resistance mechanisms.