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. 2024 Sep 28:16:17588359241277656.
doi: 10.1177/17588359241277656. eCollection 2024.

Safety of dostarlimab in combination with chemotherapy in patients with primary advanced or recurrent endometrial cancer in a phase III, randomized, placebo-controlled trial (ENGOT-EN6-NSGO/GOG-3031/RUBY)

Annika Auranen  1 , Matthew A Powell  2 , Vladyslav Sukhin  3 , Lisa M Landrum  4 , Graziana Ronzino  5 , Joseph Buscema  6 , Dirk Bauerschlag  7 , Roy Lalisang  8 , David Bender  9 , Lucy Gilbert  10 , Amy Armstrong  11 , Tamar Safra  12 , Nicole Nevadunsky  13 , Alexandra Sebastianelli  14 , Brian Slomovitz  15 , Kari Ring  16 , Robert Coleman  17 , Iwona Podzielinski  18 , Ashley Stuckey  19 , Michael Teneriello  20 , Sarah Gill  21 , Bhavana Pothuri  22 , Lyndsay Willmott  23 , Sudarshan Sharma  24 , Christine Dabrowski  25 , Grace Antony  26 , Shadi Stevens  26 , Mansoor Raza Mirza  27   28 , Evelyn Fleming  29
Affiliations

Safety of dostarlimab in combination with chemotherapy in patients with primary advanced or recurrent endometrial cancer in a phase III, randomized, placebo-controlled trial (ENGOT-EN6-NSGO/GOG-3031/RUBY)

Annika Auranen et al. Ther Adv Med Oncol. .

Abstract

Background: In Part 1 of the phase III RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer (EC), dostarlimab plus carboplatin-paclitaxel (CP) significantly improved progression-free survival and overall survival compared with CP alone. Limited safety data have been reported for the combination of immunotherapies plus chemotherapy in this setting.

Objectives: The objective of this analysis was to identify the occurrence of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) and to describe irAE management in Part 1 of the RUBY trial.

Design: RUBY is a phase III, randomized, double-blind, multicenter study of dostarlimab plus CP compared with CP alone in patients with primary advanced or recurrent EC.

Methods: Patients were randomized 1:1 to dostarlimab 500 mg, or placebo, plus CP every 3 weeks for 6 cycles, followed by dostarlimab 1000 mg, or placebo, every 6 weeks for up to 3 years. Adverse events (AEs) were assessed according to Common Terminology Criteria for Adverse Events, version 4.03.

Results: The safety population included 487 patients who received ⩾1 dose of treatment (241 dostarlimab plus CP; 246 placebo plus CP). Treatment-emergent AEs were experienced by 100% of patients in both arms. TRAEs occurred in 97.9% of the dostarlimab arm and 98.8% of the placebo arm.The most common TRAEs occurred at similar rates between arms and were mostly low grade. IrAEs occurred in 58.5% of patients in the dostarlimab arm and 37.0% of patients in the placebo arm. Dostarlimab- or placebo-related irAEs were reported in 40.7% of patients in the dostarlimab arm and 16.3% of the placebo arm.

Conclusion: The safety profile of dostarlimab plus CP was generally consistent with that of the individual components. Dostarlimab plus CP has a favorable benefit-risk profile and is a new standard of care for patients with primary advanced or recurrent EC.

Trial registration: NCT03981796.

Keywords: dostarlimab; dostarlimab plus chemotherapy; endometrial cancer; immune checkpoint inhibitor; safety.

Plain language summary

Safety of dostarlimab plus carboplatin-paclitaxel compared with carboplatin-paclitaxel in primary advanced or recurrent endometrial cancer For many years, patients with primary advanced or recurrent endometrial cancer were treated with chemotherapy, specifically with a combination of carboplatin and paclitaxel. Recently, new treatments called immune checkpoint inhibitors have been used to treat endometrial cancer. Dostarlimab, an immune checkpoint inhibitor, is being tested to treat many types of cancer, including endometrial cancer. In the RUBY trial, a combination of dostarlimab plus chemotherapy was compared with chemotherapy alone as treatment for primary advanced or recurrent endometrial cancer. Results showed that patients treated with dostarlimab plus chemotherapy had a lower risk of their cancer becoming worse and a lower risk of dying. Results in this article describe the safety of dostarlimab plus chemotherapy compared with chemotherapy alone. All patients in the RUBY trial experienced at least one adverse event (an undesired effect that happens while receiving treatment or shortly after stopping treatment); most were determined to be caused by the cancer treatments. No differences in the frequency of the overall cancer treatment-related adverse events were seen in patients who received dostarlimab plus chemotherapy compared with those patients who received chemotherapy alone. Some patients experienced an immune-related adverse event. These are a specific type of undesired effect that can occur when patients are treated with immune checkpoint inhibitors. Immune-related adverse events occurred more frequently in patients who received dostarlimab plus chemotherapy than in those who received chemotherapy alone. Physicians were generally able to treat the immune-related adverse events, and only a low percentage of patients discontinued treatment because they experienced an immune-related adverse event. The types of adverse events seen were similar to a combination of those seen in patients who received dostarlimab alone or patients who received chemotherapy alone as treatment for endometrial cancer. Dostarlimab plus chemotherapy is a new standard of care for patients with primary advanced or recurrent endometrial cancer.

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Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.Au. reports advisory board fees from GSK and MSD. M.A.P. reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, and Merck. J.B. reports honoraria from GSK. D.Ba. reports GSK study site funding for the RUBY trial; consulting fees from AstraZeneca, GSK, and MSD; participation on a data safety monitoring board or advisory board for AstraZeneca, GSK, and MSD; and leadership in the AGO study group. R.L. reports advisory board participation from Eisai and GSK. D.B. reports institutional grants from AbbVie, AstraZeneca, Clovis Oncology Inc., Genentech, MSD, and Tesaro. L.G. reports institutional grants from Alkermes, AstraZeneca, Corcept Therapeutics, Esperas, GOG Foundation, GSK, ImmunoGen, IMV, K-Group Beta, Merck Sharp & Dohme, Mersana Therapeutics, Novocure GmbH, OncoQuest Pharmaceuticals, Pfizer, Roche, Shattuck Labs, Sutro BioPharma Inc., and Tesaro; consulting fees from GSK and Merck; honoraria from GSK and Merck; travel support from EndomEra, GSK, Merck, and Zentalis; and participation on a data safety monitoring board or advisory board from CanariaBio, Corcept, Eisai, GSK, Immunogen, Kora Healthcare, and Merck, and Novocure. A.Se. reports honoraria from Eisai, GSK, Johnson & Johnson, and Merck and participation on a data safety monitoring board or advisory board from Eisai and GSK. B.S. reports consulting fees from Aadi Biosciences, AstraZeneca, BioNTech, Clovis Oncology, Eisai, Genentech, Genmab, Gilead, GSK, Incyte, Karyopharm, Merck, Novartis, Novocure, Regeneron, and Seagen and payment or honoraria from Seagen. R.C. reports grants or contracts from AstraZeneca, Clovis, Genelux, Genmab, Immunogen, Merck, and Roche/Genentech; consulting fees from AbbVie, Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, Novocure, Merck, OncoQuest, OncXerna, Regeneron, and Roche/Genentech; honoraria from AstraZeneca, Clovis, Merck, and Roche/Genentech; and participation on a data safety monitoring board or advisory board from Eisai/BMS and VBL Therapeutics. A.St. reports royalties as an UpToDate reviewer. B.P. reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Duality Bio, Eisai, Genentech/Roche, Karyopharm, Merck, Mersana, Seagen, Sutro Biopharma, Takeda Pharmaceuticals, Tesaro/GSK, Toray, and VBL Therapeutics; consulting fees from AstraZeneca, BioNtech, Clovis Oncology, Eisai, GOG Foundation, Lily, Merck, Mersana, SeaGen, Sutro Biopharma, Tesaro/GSK, Onconova, and Toray; and travel support from GSK and BioNtech. L.W. reports speakers’ bureau fees from Astra Zeneca, Eisai, Immunogen, Merck, and Seagen; and advisory board fees from AstraZeneca, Immunogen, and Seagen. M.R.M. reports consulting fees from AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, and Zailab; speakers’ bureau fees from AstraZeneca and GSK; research funding (to institution) from Apexigen, AstraZeneca, Deciphera (trial chair), GSK, and Ultimovacs; and personal financial interest in Karyopharm (stocks/shares, member of board of directors). A.Ar., E.F., G.R., I.P., K.R., L.M.L., M.T., N.N., S.G., S.Sh., T.S., and V.S. have nothing to report. G.A., C.D., and S.St. are GSK employees.

Figures

Figure 1.
Figure 1.
Enrollment and randomization of patients. CR, complete response; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.
Figure 2.
Figure 2.
Occurrence, onset, and duration of TRAEs. (a) Common TRAEs (⩾15% in either arm) by treatment period and grade. (b) Onset and duration of the most frequent TRAEs (occurring in ⩾30% of patients in either treatment arm) (safety analysis set). In panel B, n/N represents the number of patients with duration data over the number of patients with onset data. Patients with duration data had at least 1 day between the resolution of all events from the first course of the TRAE to the onset of a second course of the AE. Patients without duration data did not fit this criterion. The duration was defined as time from onset of any TRAE considered in this analysis to the first time the patient was free of any such AE. Median onset was the median time to onset of the first occurrence of the specified AE. AE, adverse event; CP, carboplatin–paclitaxel; irAE, immune-related AE; TRAE, treatment-related adverse event.
Figure 3.
Figure 3.
Occurrence, onset, and duration of dostarlimab- or placebo-related irAEs. (a) Most common dostarlimab- or placebo-related irAEs (occurring in ⩾5% of patients in either treatment arm) by treatment period and grade. (b) Onset and duration of the most frequent dostarlimab- or placebo-related irAEs (occurring in ⩾5% of patients in either treatment arm). IrAEs were defined as events from a predefined list occurring at grade 2 and above. In panel B, n/N represents the number of patients with duration data over the number of patients with onset data. Patients with duration data had at least 1 day between the resolution of all events from the first course of the irAE to the onset of a second course of the irAE. Patients without duration data did not fit this criterion. The duration was defined as time from onset of any irAE considered in this analysis to the first time the patient was free of any such irAE; a gap of at least 1 day between the resolution of all irAEs from the first course to the onset of second course was required. Median onset was the median time to onset of the first occurrence of the specified irAE. aTR irAE refers to dostarlimab- or placebo-related irAEs. AE, adverse event; ALT, alanine aminotransferase; CP, carboplatin–paclitaxel; irAE, immune-related adverse event; TR, treatment-related.
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