The European Medicines Agency (EMA) has validated GSK’s Type II Variation for a potential new indication for dostarlimab (Jemperli®), a programmed death receptor-1 (PD-1)-blocking antibody that binds to the PD-1 receptor and blocks its interaction with the PD-1 ligands PD-L1 and PD-L2, [1] in combination with chemotherapy (carboplatin-paclitaxel) for the treatment of adult patients with a type of gynecological cancer known as mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer.

Following the EMA’s Committee for Medicinal Products for Human Use will begin the formal review process to make a recommendation to the European Commission regarding marketing authorization for the potential new indication.

Mansoor Raza Mirza, MD, Chief Oncologist, Copenhagen University Hospital, Denmark and RUBY principal investigator.

Unmet medical need
Found in the inner lining of the uterus, known as the endometrium, endometrial cancer is the most common gynecologic cancer in developed countries, with approximately 417,000 new cases reported each year worldwide. [2] Incidence rates of endometrial cancer are expected to rise by almost 40% by 2040. [3][4] Approximately 15-20% of patients with endometrial cancer will be diagnosed with advanced disease at the time of diagnosis.[5]

Risk factors are related to excessive unopposed exposure of the endometrium to estrogen, including unopposed estrogen therapy, early menarche, late menopause, tamoxifen therapy, nulliparity, infertility or failure to ovulate, and polycystic ovary syndrome. In addition, risk factors also include increasing age, obesity, hypertension, diabetes mellitus, and hereditary nonpolyposis colorectal cancer. [3]

Regulatory submission
The regulatory submission is based on the interim results of the RUBY/ENGOT-EN6/GOG3031/NSGO phase 3 trial [NCT03981796]. The trial met its primary endpoint of investigator-assessed progression-free survival (PFS), showing a statistically significant and clinically meaningful benefit versus placebo plus chemotherapy in patients treated with dostarlimab plus carboplatin-paclitaxel in the dMMR/MSI-H population.

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In addition, the safety and tolerability profile of dostarlimab in combination with carboplatin-paclitaxel was generally consistent with the known safety profiles of the individual agents. The results, presented on March 27, 2023 at a European Society for Medical Oncology (ESMO) Virtual Plenary and the Society of Gynecologic Oncology Annual Meeting (April 25 – 28, 2023; Tampa Florida) and simultaneously published in The New England Journal of Medicine (NEJM), showed a statistically significant and clinically meaningful improvement in progression free survival (PFS) for dostarlimab plus carboplatin-paclitaxel in the mismatch repair deficient (dMMR)/micro-satellite instability-high (MSI-H) patient population (n=118) and in the overall population (n=494) versus placebo plus chemotherapy.[5]

The study results also demonstrated a significant reduction in risk of disease progression or death in patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer in the dostarlimab plus chemotherapy treatment arm compared to the placebo plus chemotherapy treatment arm.

“Clinical practice has been waiting decades for a meaningful advancement in the standard of care for primary advanced or recurrent endometrial cancer. The results from the RUBY clinical trial, especially given the difficult-to-treat histologies included in the trial, demonstrate support for a new treatment standard with the addition of dostarlimab to current standard-of-care chemotherapy,” observed Mansoor Raza Mirza, MD, Chief Oncologist, Copenhagen University Hospital, Denmark and RUBY principal investigator.

Additionally, at this first interim analysis, there was a clinically meaningful overall survival (OS) trend in the overall population among patients receiving dostarlimab plus chemotherapy followed by dostarlimab. The analysis was done at 33% maturity and statistical significance was not reached. OS follow-up continues and further analysis is planned.

Safety and tolerability
The safety and tolerability profile of dostarlimab in combination with carboplatin-paclitaxel in the RUBY phase 3 trial was generally consistent with the known safety profiles of the individual agents.

The most common (>45%) treatment-emergent adverse events (TEAEs) in both treatment arms in the dMMR/MSI-H and overall populations were nausea, alopecia and fatigue, as well as anaemia in the placebo plus chemotherapy arm in the dMMR/MSI-H population.

Severe and serious TEAEs were approximately 10% higher in the dostarlimab plus carboplatin-paclitaxel arm compared with the placebo plus carboplatin-paclitaxel arm in the overall population. The nature and types of immune-related adverse events (irAEs) in the dostarlimab plus chemotherapy safety profile were consistent with the mechanism of action of dostarlimab and similar to those reported for other PD-(L)1 inhibitors. In the overall population, 38.2% of participants in the dostarlimab plus carboplatin-paclitaxel arm and 15.4% of participants in the placebo plus carboplatin-paclitaxel arm had irAEs assessed by the investigator as related to dostarlimab or placebo, respectively.

The most frequently reported dostarlimab-related irAE categories were endocrinopathies (15.8% dostarlimab-related versus 3.3% placebo-related) and skin adverse reactions (14.1% dostarlimab-related versus 3.7% placebo-related).

Discontinuation of dostarlimab or placebo due to a TEAE occurred in 17.4% of patients in the dostarlimab plus chemotherapy treatment arm and 9.3% of patients in the placebo plus chemotherapy treatment arm in the overall population.

Accelerating Submission
“New treatment options are urgently needed for patients with primary advanced or recurrent endometrial cancer. With this initial filing, we are accelerating the submission of a potential new indication for dostarlimab in the patient population that demonstrated the strongest treatment effect in the RUBY phase III trial,” said Hesham Abdullah, Senior Vice President, Global Head of Oncology Development, GSK.

“These patients currently face significant unmet medical needs, and this combination could change the treatment paradigm for this condition. The RUBY phase III trial continues to follow patients for the dual-primary endpoint of overall survival in the intent-to-treat population,” Abdullah added.

GSK expects US regulatory filing review based on the RUBY phase III trial results to occur in the first half of 2023.

Current Indication 
Dostarlimab is indicated as monotherapy for treating adult patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen.

In the United States, dostarlimabis is approved for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by a US FDA-approved companion diagnostic test (VENTANA MMR RxDx assay), that has progressed on or following a prior platinum-containing regimen in any setting and are not candidates for curative surgery or radiation.

Dostarlimabis also indicated in the United States for patients with dMMR recurrent or advanced solid tumors, as determined by a U.S. Food and drug Administration (FDA-) approved test, that have progressed on or following prior treatment and have no satisfactory alternative treatment options. The latter indication is approved in the United States under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication in solid tumors may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

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Note: * Dostarlimab was original discovered by AnaptysBio and licensed to TESARO under a collaboration and exclusive license agreement signed in March 2014. This collaboration has resulted in three monospecific antibody therapies that have progressed into the clinic. These are: Jemperli (GSK4057190), a PD-1 antagonist; cobolimab, (GSK4069889), a TIM-3 antagonist; and GSK4074386, a LAG-3 antagonist. Under the terms of the agreement, GSK is responsible for the ongoing research, development, commercialization, and manufacturing of each of these agents. GSK acquired TESARO in 2018.

Clinical trial
A Study to Evaluate Dostarlimab Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Participants With Recurrent or Primary Advanced Endometrial Cancer (RUBY) – NCT03981796

Highlights of Prescribing Information
Dostarlimab (Jemperli®; GSK) [Prescribing Information]
Dostarlimab (Jemperli®; GSK) [EMA Reference Information]

Reference
[1] Laken H, Kehry M, Mcneeley P, et al. Identification and characterization of TSR-042, a novel anti-human PD-1 therapeutic antibody. European Journal of Cancer. 2016;69,S102. doi:10.1016/s0959-8049(16)32902-1.
[2] Faizan U, Muppidi V. Uterine Cancer. [Updated 2022 Sep 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Online. Last accessed on April 25, 2023.
[3] Braun MM, Overbeek-Wager EA, Grumbo RJ. Diagnosis and Management of Endometrial Cancer. Am Fam Physician. 2016 Mar 15;93(6):468-74. PMID: 26977831.
[4] International Research on Cancer. Global Cancer Observatory. Cancer Tomorrow. Online. Last accessed on July 13, 2022.
[5] Mirza MR, Chase DM, Slomovitz BM, dePont Christensen R, Novák Z, Black D, Gilbert L, Sharma S, Valabrega G, Landrum LM, Hanker LC, Stuckey A, Boere I, Gold MA, Auranen A, Pothuri B, Cibula D, McCourt C, Raspagliesi F, Shahin MS, Gill SE, Monk BJ, Buscema J, Herzog TJ, Copeland LJ, Tian M, He Z, Stevens S, Zografos E, Coleman RL, Powell MA; RUBY Investigators. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med. 2023 Mar 27. doi: 10.1056/NEJMoa2216334. Epub ahead of print. PMID: 36972026.

Featured image: Scientists working together in a R&D laboratory at GSK’s Stevenage site in the United Kingdom. Photo courtesy: © 2001-2023 GSK plc. Used with permission.

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