Efficacy and Safety of Weekly Paclitaxel Plus Vistusertib vs Paclitaxel Alone in Patients With Platinum-Resistant Ovarian High-Grade Serous Carcinoma

Author:

Banerjee Susana12,Giannone Gaia3,Clamp Andrew R.4,Ennis Darren P.3,Glasspool Rosalind M.5,Herbertson Rebecca6,Krell Jonathan7,Riisnaes Ruth8,Mirza Hasan B.3,Cheng Zhao3,McDermott Jacqueline9,Green Clare10,Kristeleit Rebecca S.1112,George Angela1,Gourley Charlie13,Lewsley Liz-Anne14,Rai Debbie14,Banerji Udai8,Hinsley Samantha14,McNeish Iain A.37

Affiliation:

1. Gynaecology Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom

2. Division of Clinical Studies, Institute of Cancer Research, London, United Kingdom

3. Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, United Kingdom

4. The Christie NHS Foundation Trust and University of Manchester, Manchester, United Kingdom

5. Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom

6. Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, United Kingdom

7. Medical Oncology, Imperial College Healthcare NHS Trust, London, United Kingdom

8. Division of Cancer Therapeutics, Institute of Cancer Research, London, United Kingdom

9. Department of Histopathology, Imperial College Healthcare NHS Trust, London, United Kingdom

10. University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom

11. Research Department of Oncology, UCL Cancer Institute, University College London, London, United Kingdom

12. Now with Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom

13. Cancer Research UK Scotland Centre, University of Edinburgh, Edinburgh, United Kingdom

14. CRUK Glasgow Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom

Abstract

ImportancePatients 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.ObjectiveTo evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC.Design, Setting, and ParticipantsThis 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.InterventionsPatients 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 MeasuresThe 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.ResultsA 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 RelevanceIn 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.Trial Registrationisrctn.org Identifier: ISRCTN16426935

Publisher

American Medical Association (AMA)

Subject

Oncology,Cancer Research

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