Phase 1b study of pan‐AKT inhibitor vevorisertib alone or with paclitaxel or fulvestrant in PIK3CA/AKT/PTEN‐mutated advanced solid tumors

Abstract

Background:In this first-in-human phase 1b study (ClinicalTrials.gov identifier NCT02761694) of advanced solid tumors with PIK3CA/AKT/PTEN mutations, the authors investigated the safety and efficacy of the pan-AKT inhibitor vevorisertib (MK-4440; ARQ 751) as monotherapy or with paclitaxel or fulvestrant. Methods: Patients with histologically confirmed, advanced or recurrent, PIK3CA/ AKT/PTEN-mutated solid tumors, measurable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status ≤1 received vevorisertib (dose range, 5-100 mg) alone or with paclitaxel 80 mg/m 2 or fulvestrant 500 mg. The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Of 78 patients enrolled, 58 received vevorisertib monotherapy, 10 received vevorisertib plus paclitaxel, and nine received vevorisertib plus fulvestrant. Doselimiting toxicity occurred in three patients (vevorisertib monotherapy, n = 2 [grade 3 pruritic and maculopapular rashes]; vevorisertib plus paclitaxel, n = 1 [grade 1 asthenia]). Across doses, treatment-related AEs occurred in 46 patients (79%) with vevorisertib monotherapy, in 10 patients (100%) with vevorisertib plus paclitaxel, and in nine patients (100%) with vevorisertib plus fulvestrant; and grade 3 treatment-related AEs occurred in 13 (22%), 7 (70%), and 3 (33%) patients, respectively. No grade 4/5 treatment-related AEs occurred. Maximum vevorisertib concentrations were reached 1-4 hours after dosing; the elimination half-life ranged 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.

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises

“…On the other hand, vevorisertib was evaluated in a Phase Ib study involving advanced solid tumors with PIK3CA/Akt/PTEN mutations, either as monotherapy or in combination with paclitaxel or fulvestrant. The trial results indicated a manageable safety profile and minimal to modest antitumor activity of vevorisertib, both alone and in combination with paclitaxel, in patients who had previously received treatment for advanced solid tumors with PIK3CA/Akt/PTEN mutations . Due to business reasons, the development of vevorisertib has been officially terminated (NCT02761694).…”

Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers

“…Vevorisertib (ARQ751) is another novel pan-AKT inhibitor that was investigated in preclinical studies as a single agent or in combination with sorafenib in hepatocellular carcinoma in cirrhotic rat models [215]. It was first evaluated in a phase Ib study as a single agent or in combination with paclitaxel or fulvestrant in PIK3CA/AKT/PTENmutated advanced solid tumors and demonstrated only modest clinical activity (5% in the monotherapy group and 20% ORR in the vevorisertib-paclitaxel group) [216].…”