The US Food and Drug Administration (FDA) has accepted GSKs supplemental Biologics License Application (sBLA) for dostarlimab (Jemperli®; GSK), 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 for the treatment of adult patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer.

The FDA granted Priority Review for this application and assigned a Prescription Drug User Fee Act (PDUFA) action date of 23 September 2023. Dostarlimab also was recently granted Breakthrough Therapy designation for this potential new indication.

Patients with primary advanced or recurrent endometrial cancer continue to experience poor long-term outcomes, highlighting the pressing need to improve upon the existing standard of care.

If approved in this patient population, dostarlimab plus chemotherapy could represent the first meaningful frontline treatment advancement in decades for patients with primary advanced or recurrent endometrial cancer.

This potential new indication could redefine the treatment landscape for this underserved patient population with high unmet medical need. 

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Project Orbis
Under Project Orbis, an initiative from the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology products among international partners, the dostarlimab sBLA will be reviewed by health authorities in the US, Australia, Canada, Switzerland, Singapore and the United Kingdom.

This collaboration among international regulators may allow patients diagnosed with cancer to receive earlier access to products in other countries where there may be significant delays in regulatory submissions, regardless of whether the product has received FDA approval.

“We are excited about this initial filing for this potential new indication for dostarlimab in the patient population that demonstrated the strongest treatment effect in the phase 3 RUBY trial,” noted Hesham Abdullah, Senior Vice President, Global Head of Oncology Development at GSK.

“Long-term outcomes for patients with primary advanced or recurrent endometrial cancer remain poor, and there is an urgent need to evolve the current standard of care, which is platinum-based chemotherapy. We look forward to working with the FDA and other health authorities as they review this application,” Abdullah added.

Endometrial cancer
Endometrial cancer is the most common gynaecologic cancer in developed countries,[2] and there are about 60,000 new cases of endometrial cancer diagnosed every year in the US.[3] Approximately 15-20% of patients with endometrial cancer will be diagnosed with advanced disease at the time of diagnosis.[4][5]

An estimated 20-29% of all endometrial cancers are dMMR/MSI-H.[6] Chemotherapy used alone is the current standard of care for primary advanced or recurrent endometrial cancer, and many patients eventually experience disease progression.[7]

Currently, in endometrial cancer, dostarlimab is approved in the US as monotherapy in dMMR recurrent or advanced endometrial cancer that has progressed on or following a prior platinum-containing regimen. If the sBLA is approved, dostarlimab could potentially be indicated earlier in treatment in combination with platinum-containing chemotherapy for patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer.

RUBY
The sBLA is based on the pre-specified interim analysis results from Part 1 of the RUBY/ENGOT-EN6/GOG3031/NSGO phase 3 trial* (ClinicalTrials.gov identifier: NCT03981796)

The trial was designed to compare dostarlimab plus standard-of-care chemotherapy (carboplatin-paclitaxel) followed by dostarlimab compared to chemotherapy plus placebo followed by placebo in adult patients with primary advanced or recurrent endometrial cancer.

A statistically significant and clinically meaningful improvement in progression free survival (PFS) was observed for dostarlimab plus carboplatin-paclitaxel in the mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) population (n=118) and in the overall population (n=494) versus placebo plus chemotherapy. The separation of the lines in the Kaplan-Meier curve below illustrates the 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.

The trial met its primary endpoint of investigator-assessed progression-free survival (PFS), which demonstrated a statistically significant and clinically meaningful benefit in patients treated with dostarlimab plus carboplatin-paclitaxel in the dMMR/MSI-H population and in the overall population.** The data reflect a robust median duration of follow-up of ≥24.8 months.

The safety and tolerability analysis from RUBY showed a safety profile for dostarlimab and carboplatin-paclitaxel that was generally consistent with the known safety profiles of the individual agents.

These data were presented at the European Society for Medical Oncology (ESMO) Virtual Plenary and the Society of Gynecologic Oncology (SGO) Annual Meeting on 27 March 2023, and were simultaneously published in The New England Journal of Medicine.[8]

Part 1 of the RUBY trial continues to assess the dual-primary endpoint of overall survival (OS) in the intent-to-treat (ITT) population. At the first interim analysis in the ITT population, a clinically meaningful OS trend was observed among patients receiving dostarlimab plus chemotherapy followed by dostarlimab. The OS analysis was done at 33% maturity and statistical significance was not reached.

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

In April 2023, the European Medicines Agency (EMA) validated GSK’s marketing authorisation application for dostarlimab plus chemotherapy for the treatment of dMMR/MSI-H primary advanced or recurrent endometrial cancer.

Note:* RUBY is a two-part global, randomised, double-blind, multicentre phase III trial of patients with primary advanced or recurrent endometrial cancer. Part 1 is evaluating dostarlimab plus carboplatin-paclitaxel followed by dostarlimab versus carboplatin-paclitaxel plus placebo followed by placebo. Part 2 is evaluating dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib versus placebo plus carboplatin-paclitaxel followed by placebo. The dual-primary endpoints in Part 1 are investigator-assessed PFS based on the Response Evaluation Criteria in Solid Tumours v1.1 and overall survival (OS). The statistical analysis plan included pre-specified analyses of PFS in the dMMR/MSI-H and intent-to-treat (ITT) populations and OS in the overall population. Pre-specified exploratory analyses of PFS in the mismatch repair proficient (MMRp)/microsatellite stable (MSS) population and OS in the dMMR/MSI-H populations were also performed. RUBY Part 1 included a broad population, including histologies often excluded from clinical trials and had approximately 10% of patients with carcinosarcoma and 20% with serous carcinoma. In Part 2, the primary endpoint is investigator-assessed PFS. Secondary endpoints in Part 1 and Part 2 include PFS per blinded independent central review, overall response rate, duration of response, disease control rate, patient-reported outcomes, and safety and tolerability.

** The Ruby trial demonstrated  a 72% and 36% reduction in the risk of disease progression or death observed in the dMMR/MSI-H population and overall patient population, respectively.

Clinical trials
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]

References
[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 accesses on June 6, 2023.
[3] American Cancer Society. Key Statistics For Endometrial Cancer. February 14, 2023. Online. Last accesses on June 6, 2023 .
[4] Cerner Enviza CancerMPact® Patient Metrics 2022. CMP:CancerMPact® [Patient Metrics], Cerner Enviza. Online. Last accessed on June 6, 2023
[5] CancerMPact® [Treatment Architecture], Cerner Enviza. Online. Last accessed on June 6, 2023
[6] Cerner Enviza CancerMPact® [Treatment Architecture]. Online. Last accessed on June 6, 2023
[7] Halla K. Emerging Treatment Options for Advanced or Recurrent Endometrial Cancer. J Adv Pract Oncol. 2022 Jan;13(1):45-59. doi: 10.6004/jadpro.2022.13.1.4. Epub 2022 Feb 1. PMID: 35173988; PMCID: PMC8805805
[8] 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 Jun 8;388(23):2145-2158. doi: 10.1056/NEJMoa2216334. Epub 2023 Mar 27. PMID: 36972026.

Featured image: Team of scientists working in a GSK’s R&D laboratory at the company’s Stevenage (UK) site.  Photo courtesy: © 2016 – 2023 GSK. Used with permission.

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