VP2-2023 – Dostarlimab+chemotherapy for the treatment of primary advanced or recurrent (A/R) endometrial cancer (EC): A placebo (PBO)-controlled randomised phase III trial (ENGOT-EN6-NSGO/GOG-3031/RUBY)
M.R. Mirza1, D. Chase2, B.M. Slomovitz3, R.D. Christensen4, Z. Novák5, D. Black6, L. Gilbert7, S. Sharma8, G. Valabrega9, L.M. Landrum10, L.C. Hanker11, A. Stuckey12, I.A. Boere13, M. Gold14, S.E. Gill15, B.J. Monk16, Z. He17, S. Stevens18, R.L. Coleman19, M.A. Powell20
1Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, and Nordic Society of Gynaecologic Oncology-Clinical Trial Unit, Copenhagen, Denmark; 2Affiliation at time of study: Arizona Center for Cancer Care, Creighton University School of Medicine Phoenix, AZ, USA, Current affiliation: Division of Gynecologic Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 3Department of Gynecologic Oncology, Mount Sinai Medical Center, and Department of Obstetrics and Gynecology, Florida International University, Miami Beach, FL, USA; 4Research Unit for General Practice, University of Southern Denmark, Institute of Public Health, Odense, Denmark; 5Department of Gynecology, Hungarian National Institute of Oncology, Budapest, Hungary; 6Department of Obstetrics and Gynecology, LSU Health Shreveport and Willis-Knighton Physician Network, Shreveport, LA, USA; 7Division of Gynecologic Oncology, McGill University Health Centre, Montreal, QC, Canada; 8Department of Obstetrics/Gynecology, AMITA Adventist Hinsdale Hospital, Hinsdale, IL, USA; 9Department of Oncology, University of Torino, AO Ordine Mauriziano, Turin, Italy; 10Department of Oncology, Indiana University Health and Simon Cancer Center, Indianapolis, IN, USA; 11Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; 12Department of Oncology, Women and Infants Hospital, Providence, RI, USA; 13Department of Medical Oncology, Erasmus MC Cancer Centre, Rotterdam, Netherlands; 14Department of Oncology, Oklahoma Cancer Specialists and Research Institute, Tulsa, OK, USA; 15Division of Gynecologic Oncology, Nancy N and JC Lewis Cancer and Research Pavilion, Savannah, GA, USA; 16Department of Gynecologic Oncology, HonorHealth Research Institute, University of Arizona College of Medicine, Phoenix, and Creighton University School of Medicine, Phoenix, AZ, USA; 17Department of Clinical Statistics, GSK, Philadelphia, PA, USA; 18Department of Clinical Development, GSK, London, UK; 19Department of Gynecologic Oncology, US Oncology Research, The Woodlands, TX, USA; 20Department of Gynecologic Oncology, National Cancer Institute sponsored NRG Oncology, Washington University School of Medicine, St. Louis, MO, USA
Background: Carboplatin-paclitaxel (CP) is standard of care (SOC) for first-line treatment of primary A/R EC; median OS is <3 yrs. Use of anti–PD-1s with chemo has improved outcomes in multiple tumour types. RUBY (NCT03981796) evaluated the efficacy and safety of the anti–PD-1 dostarlimab (D)+CP in A/R EC compared with CP alone.
Methods: RUBY is a phase III, global, randomised, double-blind, multicentre, PBO-controlled study. Pts with primary advanced stage III or IV or first recurrent EC were randomised 1:1 to receive dostarlimab 500 mg, or PBO, plus carboplatin AUC 5 and paclitaxel 175 mg/m2 Q3W (6 cycles), followed by dostarlimab 1000 mg, or PBO, monotherapy Q6W for up to 3 yrs. Primary endpoints were PFS by investigator assessment per RECIST v1.1 and OS. Graphical method was used for hypothesis testing of PFS in the dMMR/MSI-H population, then the overall population, and OS in the overall population. A prespecified exploratory analysis of PFS in MMR proficient (MMRp)/MS stable (MSS) pts was also performed. Safety was assessed.
Results: Of 494 pts randomised (245 D+CP; 249 PBO+CP), 23.9% had dMMR/MSI-H tumours (53 D+CP; 65 PBO+CP), 47.8% had recurrent disease; 18.6% and 33.6% had primary stage III and IV disease, respectively. PFS and OS results are presented in the table. Discontinuation of dostarlimab or PBO due to a TEAE occurred in 17.4% pts receiving D+CP and 9.3% pts receiving PBO+CP. The safety profile of D+CP was generally consistent with the safety profile of each drug.
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|
HR |
% Probability at 24 mo |
|
|
PFS |
dMMR/MSI-H |
||
|
D+CP |
0.28 |
61.4 |
|
|
PBO+CP |
15.7 |
||
|
Overall |
|||
|
D+CP |
0.64 |
36.1 |
|
|
PBO+CP |
18.1 |
||
|
MMRp/MSSa |
|||
|
D+CP |
0.76 |
28.4 |
|
|
PBO+CP |
18.8 |
||
|
OS |
Overallb |
||
|
D+CP |
0.64 |
71.3 |
|
|
PBO+CP |
56.0 |
||
|
dMMR/MSI-Hc |
|||
|
D+CP |
0.30 |
83.3 |
|
|
PBO+CP |
58.7 |
||
|
MMRp/MSSd |
|||
|
D+CP |
0.73 |
67.7 |
|
|
PBO+CP |
55.1 |
||
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aNo hypothesis testing of PFS in MMRp/MSS was planned. Maturity: b≈33%, c≈26%, d≈36%. eP-value ≤0.00177 required for statistical significance at this analysis |
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Conclusions: D+CP showed statistically significant and clinically meaningful PFS benefits in the dMMR/MSI-H and overall populations vs CP alone. A clinically relevant benefit in PFS was also observed in the MMRp/MSS population. An early trend toward improved OS was observed in all populations. The combination of dostarlimab+CP represents a new SOC for pts with newly diagnosed primary A/R EC.
Clinical trial identification: NCT03981796.
Editorial acknowledgement: Writing and editorial support, funded and coordinated by GSK (Waltham, MA, USA), was provided by Shannon Morgan-Pelosi, PhD, and Dena McWain of Ashfield MedComms, an Inizio company.
Legal entity responsible for the study: GSK.
Funding: GSK.
Disclosure: M.R. Mirza: Financial Interests, Personal, Advisory Board: AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, Zailab; Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK, Karyopharm; Financial Interests, Personal, Stocks/Shares: Karyopharm; Financial Interests, Institutional, Research Grant: GSK, AstraZeneca, Ultimovacs, Apexigen; Financial Interests, Institutional, Invited Speaker: Deciphera; Non-Financial Interests, Personal, Advisory Role: Ultimovacs, Apexigen.
D. Chase: Financial Interests, Personal, Advisory Board: GSK, AstraZeneca, Clovis, Genentech/Roche; Financial Interests, Personal, Advisory Role: GSK, AstraZeneca, Clovis, Genentech/Roche.
B.M. Slomovitz: Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis, Eisai, GSK, Genentech, Merck, ImmunoGen, Novocure; Financial Interests, Personal, Other, consultant: GOG Foundation; Non-Financial Interests, Personal, Invited Speaker: GOG Foundation.
R.D. Christensen: Financial Interests, Personal, Advisory Role: Nordic Society for Gynecologic Oncology, Karyopharm; Financial Interests, Personal, Advisory Board: Swiss GO Trial Group; Financial Interests, Personal, Stocks/Shares: Y-mAbs Therapeutics.
Z. Novák: Financial Interests, Personal, Advisory Board: Sofmedica, AstraZeneca, MSD, Richter Gedeon; Financial Interests, Personal, Other: Sofmedica, Preglem, AstraZeneca; Financial Interests, Personal, Officer: Hungarian Society of Gynecologic Oncology; Financial Interests, Personal, Stocks/Shares: Richter Gedeon.
D. Black: Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Personal, Member of the Board of Directors: GOG Partners Investigational Council.
L. Gilbert: Financial Interests, Institutional, Research Grant: Alkermes, AstraZeneca, Clovis, Esperas, IMV, ImmunoGen Inc, Karyopharm, Merck Sharp & Dohme, Mersana, Novocure GmbH, OncoQuest Pharmaceuticals, Pfizer, Roche, Tesaro; Financial Interests, Personal, Advisory Role: Merck, Alkermes, AstraZeneca, Eisai, Eisai-Merck, GSK.
G. Valabrega: Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Clovis Oncology, GSK, PharmaMar, Roche, Tesaro.
L.C. Hanker: Financial Interests, Personal, Advisory Board: Amgen, Roche, GSK, MSD, AstraZeneca.
A. Stuckey: Financial Interests, Personal, Other: UptoDate.
I.A. Boere: Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Advisory Board: AstraZeneca, GSK.
B.J. Monk: Financial Interests, Personal, Advisory Role: VBL, US Oncology Research, Sorrento, Regeneron, Pfizer, Myriad, Novocure, Novartis, Mersana, MacroGenics, Iovance, Karyopharm, ImmunoGen, Gradalis, GOG Foundation, Genmab/Seagen, EMD Merck, Elevar, Bayer, Aravive, Amgen, Akeso Bio, Agenus; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Speaker’s Bureau: Tesaro/GSK, Roche/Genentech, Merck, Easai, Clovis, AstraZeneca.
Z. He: Financial Interests, Personal, Full or part-time Employment: GSK.
S. Stevens: Financial Interests, Personal, Full or part-time Employment: GSK.
R.L. Coleman: Financial Interests, Personal, Advisory Board: AstraZeneca, Agenus, Alkermes, ImmunoGen, Roche/Genentech, GSK, Genmab/Seagen, Epsilogen, Myriad Genetics; Financial Interests, Personal, Invited Speaker: AstraZeneca, Genmab/Seagen; Non-Financial Interests, Personal, Principal Investigator: AbbVie, ImmunoGen, Roche/Genentech, Merck, Genmab, Clovis; Non-Financial Interests, Personal, Project Lead, MyLung Consortium: US Oncology Research.
M.A. Powell: Financial Interests, Personal, Advisory Role: GSK, Tesaro, Merck, Eisai, SeaGen, Clovis Oncology, AstraZeneca.
All other authors have declared no conflicts of interest.
