Phase 1b study of pan-AKT inhibitor vevorisertib alone or with paclitaxel or fulvestrant in PIK3CA/AKT/PTEN-mutated advanced solid tumors
Background: This phase 1b study (ClinicalTrials.gov identifier NCT02761694) marks the first exploration in humans of vevorisertib (MK-4440; ARQ 751), a pan-AKT inhibitor, for advanced solid tumors harboring PIK3CA/AKT/PTEN mutations. The study aimed to assess the safety and efficacy of vevorisertib as monotherapy and in combination with paclitaxel or fulvestrant.
Methods: Patients with confirmed histology of advanced or recurrent PIK3CA/AKT/PTEN-mutated solid tumors, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1, and Eastern Cooperative Oncology Group performance status ≤1 were enrolled. Vevorisertib was administered at doses ranging from 5 to 100 mg alone, or in combination with paclitaxel (80 mg/m2) or fulvestrant (500 mg). The primary endpoint was safety and tolerability, with secondary endpoints including pharmacokinetics and objective response rate by Response Evaluation Criteria in Solid Tumors, version 1.1.
Results: Among 78 enrolled patients, 58 received vevorisertib monotherapy, 10 received vevorisertib plus paclitaxel, and nine received vevorisertib plus fulvestrant. Dose-limiting toxicity occurred in three patients: two with vevorisertib monotherapy (grade 3 pruritic and maculopapular rashes) and one with vevorisertib plus paclitaxel (grade 1 asthenia). Treatment-related adverse events were reported in 46 patients (79%) with vevorisertib monotherapy, 10 patients (100%) with vevorisertib plus paclitaxel, and nine patients (100%) with vevorisertib plus fulvestrant; grade 3 treatment-related adverse events occurred in 13 (22%), seven (70%), and three (33%) patients, respectively. No grade 4/5 treatment-related adverse events were reported. Vevorisertib achieved maximum concentrations 1-4 hours post-dosing, with an elimination half-life ranging from 8.8 to 19.3 hours. The objective response rate was 5% with vevorisertib monotherapy (three partial responses), 20% with vevorisertib plus paclitaxel (two partial responses), and 0% with vevorisertib plus fulvestrant.
Conclusions: Vevorisertib, whether used alone or with paclitaxel or fulvestrant, demonstrated a manageable safety profile. Vevorisertib monotherapy and its combination with paclitaxel showed minimal to modest antitumor activity in patients with PIK3CA/AKT/PTEN-mutated advanced solid tumors.