Efficacy and safety of weekly paclitaxel plus vistusertib vs paclitaxel alone in patients with platinum-resistant ovarian high-grade serous carcinoma: The OCTOPUS Multicenter, Phase 2, Randomized Clinical Trial
Banerjee, S. Giannone, G. Clamp, Andrew R Ennis, D. P. Glasspool, R. M. Herbertson, R. Krell, J. Riisnaes, R. Mirza, H. B. Cheng, Z.
Banerjee, S.
Giannone, G.
Clamp, Andrew R
Ennis, D. P.
Glasspool, R. M.
Herbertson, R.
Krell, J.
Riisnaes, R.
Mirza, H. B.
Cheng, Z.
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Abstract
Importance: Patients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity.
Objective: To evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC.
Design, setting, and participants: This phase 2, double-blind, placebo-controlled multicenter randomized clinical trial recruited patients from UK cancer centers between January 2016 and March 2018. Patients with PR-HGSC of ovarian, fallopian tube, or primary peritoneal origin and with measurable or evaluable disease (Response Evaluation Criteria in Solid Tumors version 1.1 and/or Gynecological Cancer Intergroup cancer antigen 125 criteria) were eligible. There were no restrictions on number of lines of prior therapy. Data analysis was performed from May 2019 to January 2022.
Interventions: Patients were randomized (1:1) to weekly paclitaxel (80 mg/m2 days 1, 8, and 15 of a 28-day cycle) plus oral vistusertib (50 mg twice daily) or placebo.
Main outcomes and measures: The primary end point was progression-free survival in the intention-to-treat population. Secondary end points included response rate, overall survival, and quality of life.
Results: A total of 140 patients (median [range] age, 63 [36-86] years; 17.9% with platinum-refractory disease; 53.6% with ≥3 prior therapies) were randomized. In the paclitaxel plus vistusertib vs paclitaxel plus placebo groups, there was no difference in progression-free survival (median, 4.5 vs 4.1 months; hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; 1-sided P = .18), overall survival (median, 9.7 vs 11.1 months; HR, 1.21; 80% CI, 0.91-1.60) or response rate (odds ratio, 0.86; 80% CI, 0.55-1.36). Grade 3 to 4 adverse events were 41.2% (weekly paclitaxel plus vistusertib) vs 36.7% (weekly paclitaxel plus placebo), and there was no difference in quality of life.
Conclusions and relevance: In this randomized clinical trial of weekly paclitaxel and dual mTORC1/2 inhibition in patients with PR-HGSC, vistusertib did not improve clinical activity of weekly paclitaxel.
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Date
2023
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Article
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Banerjee S, Giannone G, Clamp AR, Ennis DP, Glasspool RM, Herbertson R, et al. Efficacy and Safety of Weekly Paclitaxel Plus Vistusertib vs Paclitaxel Alone in Patients With Platinum-Resistant Ovarian High-Grade Serous Carcinoma: The OCTOPUS Multicenter, Phase 2, Randomized Clinical Trial. JAMA Oncol. 2023 Mar 16. PubMed PMID: 36928279. Pubmed Central PMCID: PMC10020933 grants from Lady Garden Foundation Charity, and personal fees from AstraZeneca during the conduct of the study; grants from GSK, personal fees from AstraZeneca, GSK, Amgen, Clovis, Eisai, Epsilogen, Immunogen, Mersana, MSD, Novartis, Novocure, OncXerna, Pfizer, Regeneron, Roche, Shattuck Labs, and Takeda outside the submitted work. Dr Giannone reported personal fees from Mylan, AccMed, and Polistudium outside the submitted work. Dr Clamp reported grants from AstraZeneca during the conduct of the study; grants from AstraZeneca and personal fees from AstraZeneca, MSD, Clovis Oncology, GSK, and Immunogen outside the submitted work. Dr Glasspool reported funding to support the trial activity from AstraZeneca and Cancer Research UK during the conduct of the study; personal fees from AstraZeneca (speaker and advisory board fees), personal fees from MSD (advisory board), grants from Clovis Oncology, personal fees from Clovis Oncology (speaker and advisory board fees), personal fees from GSK (speaker and advisory board fees), nonfinancial support from GSK (drug donation scheme), other from GSK (medical conference attendance), other from Novartis (fees to institution for a trial steering committee), grants from Boehringer Ingelheim and Lilly/Ignyta, and personal fees from Immunogen (advisory board) outside the submitted work. Dr Kristeleit reported personal fees from Celcuity during the conduct of the study; grants, personal fees, and nonfinancial support (conference attendance) from MSD; personal fees and nonfinancial support (conference attendance) from Clovis Oncology and GSK; personal fees from Basilea, Eisai, Seattle Genetics, AstraZeneca, and Shattuck Labs; and nonfinancial support from AstraZeneca (conference attendance) outside the submitted work. Dr George reported personal fees from AstraZeneca, GSK, and MSD and other from Roche NZ (research review support) outside the submitted work. Dr Gourley reported grants from AstraZeneca during the conduct of the study; grants paid to institution from AstraZeneca, MSD, GlaxoSmithKline, Clovis, BerGenBio, Novartis, Aprea, NuCana, and Medannexin and personal fees from AstraZeneca, MSD, GlaxoSmithKline, Clovis, Roche, NuCana, Chugai, Takeda, Verastem, Eisai, and COR2ED outside the submitted work; in addition, Dr Gourley had a patent for PCT/US2012/040805 issued. Dr Banerji reported other (advisory board) from Carrick Therapeutics, Pegasy, Boehringer Ingelheim, Idea Pharma (Janssen), and grants from Verastem, Carrick Therapeutics, Verastem, and Chugai outside the submitted work; and AstraZeneca funded the investigator-initiated trial of vistusertib in combination with paclitaxel. Dr McNeish reported grants from AstraZeneca (institutional), personal fees from AstraZeneca, Clovis Oncology, GSK, Roche, ScanCell, and Theolytics outside the submitted work. No other disclosures were reported. Epub 2023/03/18. eng.