LUGANO, Switzerland - Adding immunotherapy to standard chemotherapy for first-line treatment of advanced or first recurrence of endometrial cancer significantly improves progression-free survival (PFS) compared to chemotherapy alone, with a promising early indication of improved overall survival (OS). These clinically meaningful results from the Phase 3 RUBY trial (ENGOT-EN6-NSGO/GOG3031) are the first confirmation of the benefits of immunotherapy in this patient population, and were reported at the ESMO Virtual Plenary on 27 March 2023. (1)
“This is the biggest news for patients with endometrial cancer for more than 30 years,” said Principal Investigator, Dr Mansoor Mirza, Chief Oncologist, Rigshospitalet, Copenhagen University Hospital, Denmark. “These results have shown an unprecedented improvement in PFS as a result of adding immunotherapy to standard chemotherapy, especially in the 25% of patients with so-called ‘hot’ endometrial tumours that have deficient DNA mismatch repair mechanisms.”
Endometrial cancer is the sixth most common cancer in women worldwide, with over 400,000 new cases per year (2), and both incidence and mortality are increasing (3-4). Localised disease is curable with surgery, with a five-year survival rate of 96% (5). However, in advanced disease, five-year survival falls to 20% (5). Following identification of four molecular sub-groups of endometrial cancer (6), European and US guidelines now recommend testing for tumour DNA repair status for risk classification and potentially to help guide treatment and improve outcomes (7-8).
Commenting on the trial findings, Dr Ilaria Colombo, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland, explained that despite better understanding of this cancer, chemotherapy with carboplatin and paclitaxel remains standard treatment for advanced disease; although effective in nearly 50% of patients, most progress within a year.
“We urgently need better treatment strategies, and the results of this trial have shown a new standard of care for women with advanced or relapsed endometrial cancer. We now need to see the results of other trials using different types of immunotherapy, and also to find out the best duration of maintenance immunotherapy and whether immunotherapy is more effective than chemotherapy in patients with mismatch repair deficiency or microsatellite instability, or if it could be used without chemotherapy,” she said.
Colombo was particularly impressed that the benefits of adding the immunotherapy to chemotherapy in the current trial were maintained for at least two years. “In patients with tumours with mismatch repair or microsatellite instability, 61.4% were free from disease progression at two years compared with 15.7% in the group who had chemotherapy alone. There was also a clinical benefit in patients without these DNA repair deficiencies, though of smaller magnitude, and we still need to identify better treatment options for patients with mismatch proficient or microsatellite stable tumours, that represent about 70% of patients with advanced or recurrent endometrial cancer. The trend in overall survival benefit is also encouraging, but this needs to be confirmed with longer follow-up, taking into account that in the standard arm many patients received immunotherapy in subsequent lines of treatment,” she said.
Colombo pointed out that there were no unexpected safety issues with the combination of immunotherapy and chemotherapy, and there was evidence of improved quality of life for patients. “The beneficial effect on quality of life is important because we need to know that patients are not only living longer but that they are also living better, especially when we use maintenance therapy and patients remain on treatment for a long time,” said Colombo.
“These results mean that many more women can be cured of endometrial cancer than was previously possible, but there will still be patients who progress after immunotherapy, so we are starting the next wave of trials to see how best to help them,” remarked Mirza.
Further trials are investigating other immunotherapy combinations for advanced endometrial cancer, including triple therapy with chemotherapy, immunotherapy and a PARP inhibitor, and a comparison of immunotherapy with chemotherapy in patients with ‘hot’ tumours. Immunotherapy studies are also underway in patients with early-stage endometrial cancer.
Study results
Overall median PFS was 11.8 months in patients treated with the PD-1 (checkpoint) inhibitor, dostarlimab, and standard chemotherapy (carboplatin and paclitaxel), compared to 7.9 months in those treated with standard chemotherapy and placebo (hazard ratio [HR] 0.64; confidence interval [CI] 0.507-0.800, p<0.0001). In patients with ‘hot’ tumours with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), PFS could not be estimated in the immunotherapy+chemotherapy group because too few cancers progressed during the 25-month follow-up. In contrast, PFS was 7.7 months in the chemotherapy+placebo group (HR 0.28; CI 0.162-0.495, p<0.0001). An exploratory analysis of results in patients with ‘cold’ tumours that were mismatch repair proficient (MMRp) or microsatellite stable (MSS) showed PFS of 9.9 months and 7.9 months, respectively (HR 0.76; CI 0.592-0.981, NA).
“In the patients with ‘hot’ tumours who had the additional immunotherapy, the 72% benefit in PFS was much larger than the 50% we expected to see, and in those with ‘cold’ tumours we saw a moderate effect of immunotherapy on PFS. It may be that the chemotherapy damages the DNA repair mechanisms of these ‘cold’ tumours so that they become more susceptible to immunotherapy,” explained Mirza.
There was also an early trend in OS in favour of combination treatment. In the immunotherapy+chemotherapy group, 71.3% of patients were alive at 24 months compared to 56% in the chemotherapy+placebo group. Among those with ‘hot’ tumours, OS was 83.3% and 58.7% respectively. In those with ‘cold’ tumours, OS was 67.7% and 55.1% respectively.
Disclaimer
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References
- Abstract 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) presented by Mansoor Mirza during ESMO Virtual Plenary on 27 March 2023, at 18:30 CEST (12:30 ET) The results will also be presented later the same day at the Society of Gynecologic Oncology Congress in Tampa, Florida, USA (17:15 ET). In concomitance with this latter presentation there will be simultaneous publication of results in the New England Journal of Medicine.
- World Cancer Research Fund International. Endometrial cancer statistics, 2020.
- Lortet-Tieulent J, Ferlay J, Bray F, Jemal A. International Patterns and Trends in Endometrial Cancer Incidence, 1978-2013. J Natl Cancer Inst. 2018 Apr 1;110(4):354-361
- Rahib L, Smith BD, Aizenberg R et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014 Jun 1;74(11):2913-21
- American Cancer Society. 5-year relative survival rates for endometrial cancer.
- Talhouk A, McConechy MK, Leung S et al. Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer. 2017 Mar 1;123(5):802-813.
- Abu-Rustum NR, Yashar CM, Bradley K, et al. NCCN Guidelines. insights: uterine neoplasms, version 3.2021. J Natl Compr Canc Netw 2021;19:888–95.
- Oaknin A, Bosse TJ, Creutzberg CL et al; Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022 Sep;33(9):860-877.
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.
|
|
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 |
||
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 | |||
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.
Watch the abstract presentation on OncologyPRO.