Overall Survival in Patients with Endometrial Cancer Treated with Dostarlimab plus Carboplatin-Paclitaxel in the Randomized ENGOT-EN6/GOG-3031/RUBY Trial.
[en] [en] BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer. At the first interim analysis, the trial met one of its dual-primary endpoints with statistically significant progression-free survival benefits in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis.
PATIENTS AND METHODS: RUBY is a phase 3, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer who were randomly assigned (1:1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual-primary endpoint.
RESULTS: A total of 494 patients were randomized (245 in dostarlimab arm; 249 in placebo arm). In the overall population, with 51% maturity, RUBY met the dual-primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death (HR = 0.69; 95% CI, 0.54-0.89; P = 0.0020) in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32; 95% CI, 0.17-0.63; nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair proficient/microsatellite stable (MMRp/MSS) population (HR = 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis.
CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful overall survival benefit in the overall population of patients with primary advanced or recurrent endometrial cancer while demonstrating an acceptable safety profile.
Disciplines :
Oncology
Author, co-author :
Powell, M A; National Cancer Institute sponsored NRG Oncology, Washington University School of Medicine, St Louis, MO, USA
Bjørge, L; Haukeland University Hospital, Bergen, and University of Bergen, Bergen, Norway
Willmott, L; Arizona Oncology, Phoenix, AZ, USA
Novák, Z; Department of Gynecology, Hungarian National Institute of Oncology, Budapest, Hungary
Black, D; Willis-Knighton Cancer Center, Willis-Knighton Health System, Gynecologic Oncology Associates, Shreveport, LA, USA
Gilbert, L; Division of Gynecologic Oncology, McGill University Health Centre and the Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
Sharma, S; Department of Obstetrics/Gynecology, AMITA Health Adventist Medical Center, Hinsdale, IL, USA
Valabrega, G; Ordine Mauriziano Torino and University of Torino, Torino, Italy
Landrum, L M ; Indiana University Health & Simon Cancer Center, Indianapolis, IN, USA
Gropp-Meier, M; AGO Study Group, Wiesbaden, and Oberschwabenklinik, St. Elisabethen-Klinikum, Ravensburg, Germany
Stuckey, A; Women and Infants Hospital of Rhode Island, Providence, RI, USA
Boere, I; Department of Medical Oncology, Erasmus MC Cancer Centre, Rotterdam, The Netherlands
Gold, M A; Oklahoma Cancer Specialists and Research Institute, Tulsa, OK, USA
Segev, Y; Head of Gynecology Oncology Division, Department of Obstetrics and Gynaecology, Carmel Medical Center, Haifa, Israel
Gill, S E; St. Joseph's/Candler Gynecologic Oncology & Surgical Specialists, Candler Hospital, Savannah, GA, USA
Gennigens, Christine ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale
Sebastianelli, A; CHU de Québec-Université Laval, Quebec, Canada
Shahin, M S; Hanjani Institute for Gynecologic Oncology, Abington Hospital-Jefferson Health, Asplundh Cancer Pavilion, Sidney Kimmel Medical College of Thomas Jefferson University, Willow Grove, PA, USA
Pothuri, B; GOG Foundation and Departments of Obstetrics/Gynecology and Medicine, Division of Gynecologic Oncology, Laura & Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
Monk, B J; GOG Foundation, Florida Cancer Specialists and Research Institute, West Palm Beach, FL, USA
Buscema, J; Arizona Oncology, Tucson, AZ, USA
Coleman, R L; Texas Oncology, US Oncology Network, The Woodlands, TX, USA
Slomovitz, B M; Department of Gynecologic Oncology, Mount Sinai Medical Center, and the Department of Obstetrics and Gynecology, Florida International University, Miami Beach, FL, USA
Ring, K L; University of Virginia Health System, Charlottesville, VA, USA
Herzog, T J; University of Cincinnati Cancer Center, Department of Ob/Gyn, Division of Gynecologic Oncology, Cincinnati, OH, USA
Balas, M Marco; GSK, New York, NY, USA
Grimshaw, Ma ; GSK, London, UK
Stevens, S; GSK, London, UK
Lai, D W; GSK, Los Angeles, CA, USA
McCourt, C ; Division of Gynecologic Oncology, Washington University School of Medicine, Washington University in St Louis, St Louis, MO, USA
Mirza, M R; Rigshospitalet, Copenhagen University Hospital, Copenhagen, and Nordic Society of Gynaecologic Oncology-Clinical Trial Unit, Copenhagen, Denmark. Electronic address: mansoor@rh.regionh.dk
Overall Survival in Patients with Endometrial Cancer Treated with Dostarlimab plus Carboplatin-Paclitaxel in the Randomized ENGOT-EN6/GOG-3031/RUBY Trial.
Gu, B., Shang, X., Yan, M., et al. Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990-2019. Gynecol Oncol 161:2 (2021), 573–580.
Sung, H., Ferlay, J., Siegel, R.L., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:3 (2021), 209–249.
Siegel, R.L., Miller, K.D., Fuchs, H.E., Jemal, A., Cancer statistics, 2022. CA Cancer J Clin 72:1 (2022), 7–33.
Giaquinto, A.N., Broaddus, R.R., Jemal, A., Siegel, R.L., The changing landscape of gynecologic cancer mortality in the United States. Obstet Gynecol 139:3 (2022), 440–442.
Lu, K.H., Broaddus, R.R., Endometrial cancer. N Engl J Med 383:21 (2020), 2053–2064.
Kalampokas, E., Giannis, G., Kalampokas, T., et al. Current approaches to the management of patients with endometrial cancer. Cancers (Basel), 14(18), 2022, 4500.
Miller, D.S., Filiaci, V.L., Mannel, R.S., et al. Carboplatin and paclitaxel for advanced endometrial cancer: final overall survival and adverse event analysis of a phase III trial (NRG Oncology/GOG0209). J Clin Oncol 38:33 (2020), 3841–3850.
Sorbe, B., Andersson, H., Boman, K., et al. Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxel-long-term follow-up. Int J Gynecol Cancer 18:4 (2008), 803–808.
Oaknin, A., Pothuri, B., Gilbert, L., et al. Safety, efficacy, and biomarker analyses of dostarlimab in patients with endometrial cancer: interim results of the phase I GARNET study. Clin Cancer Res 29:22 (2023), 4564–4574.
Oaknin, A., Gilbert, L., Tinker, A.V., et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. J Immunother Cancer, 10(1), 2022, e003777.
O'Malley, D.M., Bariani, G.M., Cassier, P.A., et al. Pembrolizumab in patients with microsatellite instability–high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol 40:7 (2022), 752–761.
Makker, V., Colombo, N., Casado Herráez, A., et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med 386:5 (2022), 437–448.
Mirza, M.R., Chase, D.M., Slomovitz, B.M., et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med 388:23 (2023), 2145–2158.
Eskander, R.N., Sill, M.W., Beffa, L., et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med 388:23 (2023), 2159–2170.
Available at JEMPERLI. Prescribing information, 2023, GSK https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Jemperli/pdf/JEMPERLI-PI-MG.PDF. (Accessed 6 November 2023)
JEMPERLI. Product characteristics. GSK. Available at https://www.medicines.org.uk/emc/product/12669/smpc/print, 2023. (Accessed 3 November 2023)
GSK. Jemperli (dostarlimab for injection) plus carboplatin and paclitaxel approved in Canada as a treatment option for primary advanced or recurrent dMMR/MSI-H endometrial cancer. Available at https://ca.gsk.com/en-ca/media/press-releases/jemperli-dostarlimab-for-injection-plus-carboplatin-and-paclitaxel-approved-in-canada-as-a-treatment-option-for-primary-advanced-or-recurrent-dmmrmsi-h-endometrial-cancer/, 2023. (Accessed 29 November 2023)
GSK. GSK's Jemperli. (dostarlimab) plus chemotherapy approved as the first and only frontline immuno-oncology treatment in the European Union for dMMR/MSI-H primary advanced or recurrent endometrial cancer. Available at https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-as-the-first-and-only-frontline-immuno-oncology-treatment-in-the-european-union/, 2023. (Accessed 21 December 2023)
Fleming, G.F., Brunetto, V.L., Cella, D., et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 22:11 (2004), 2159–2166.
Lorusso, D., Ferrandina, G., Colombo, N., et al. Carboplatin-paclitaxel compared to carboplatin-paclitaxel-bevacizumab in advanced or recurrent endometrial cancer: MITO END-2 – a randomized phase II trial. Gynecol Oncol 155:3 (2019), 406–412.
Oaknin, A., Bosse, T.J., Creutzberg, C.L., et al. Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 33:9 (2022), 860–877.
Hamilton, C.A., Pothuri, B., Arend, R.C., et al. Endometrial cancer: a Society of Gynecologic Oncology evidence-based review and recommendations. Gynecol Oncol 160:3 (2021), 817–826.
Nomura, H., Aoki, D., Michimae, H., et al. Effect of taxane plus platinum regimens vs doxorubicin plus cisplatin as adjuvant chemotherapy for endometrial cancer at a high risk of progression: a randomized clinical trial. JAMA Oncol 5:6 (2019), 833–840.
Randall, M.E., Filiaci, V.L., Muss, H., et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 24:1 (2006), 36–44.
Homesley, H.D., Filiaci, V., Gibbons, S.K., et al. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Gynecol Oncol 112:3 (2009), 543–552.
Matei, D., Filiaci, V., Randall, M.E., et al. Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer. N Engl J Med 380:24 (2019), 2317–2326.
Joly, F., Ray-Coquard, I.L., Rubio, M.J., et al. Randomized phase III trial in MMR deficient (MMRd) endometrial cancer (EC) patients comparing chemotherapy (CT) alone versus dostarlimab in first line advanced/metastatic setting: DOMENICA study (GINECO-EN105b/ENGOT-en13 study). J Clin Oncol, 41(suppl 16), 2023, TPS5630.
Slomovitz, B.M., Cibula, D., Simsek, T., et al. KEYNOTE-C93/GOG-3064/ENGOT-en15: a phase 3, randomized, open-label study of first-line pembrolizumab versus platinum-doublet chemotherapy in mismatch repair deficient advanced or recurrent endometrial carcinoma. J Clin Oncol, 40(suppl 16), 2022, TPS5623.
