Dostarlimab for the treatment of advanced endometrial cancer

ABSTRACT

Introduction

Between 20% and 30% of the endometrial cancers (EC) are associated with a deficiency of a mismatch repair (MMRd) protein or high microsatellite instability (MSI-H), characteristics that render the tumor more sensitive to immune checkpoint inhibitors. There is no standard treatment for advanced EC after progression to a platinum-containing regimen.

Areas covered

The phase I GARNET clinical trial assessed the safety, tolerability, and antitumor activity of anti-PD1 dostarlimab in patients with advanced solid tumors. The A1 cohort of this trial enrolled patients with MMRd or MSI-H recurrent or advanced EC who had previously received a platinum-containing regimen. The results of this cohort showed significant clinical activity, durable responses, and a favorable safety profile, without reducing quality of life. Based on these data, dostarlimab achieved accelerated approval.

Expert opinion

Although a randomized study has not yet been conducted, dostarlimab monotherapy should be the treatment of choice for patients with advanced MMRd EC in progression after a platinum-containing regimen. Selecting patients with EC for immune checkpoint inhibitors using the MMRd predictive biomarker could facilitate more efficient and sustainable health systems and avoid the use of more toxic combinations, leading to personalized medicine.

KEYWORDS:

• Advanced endometrial cancer
• dostarlimab
• immune checkpoint inhibitor

Article highlights

• The mismatch repair deficient (MMRd) subtype, which comprises 20%–30% of all endometrial cancers, is characterized by the loss of expression of at least one of the MMR proteins, which entails high microsatellite instability (MSI-H).

• Until the arrival of immune checkpoint inhibitors, there was no approved treatment after progression to a platinum-containing regimen. Doxorubicin, weekly paclitaxel and hormone therapy have been the most common options.

• Several phase I-II trials have shown that immune checkpoint inhibitors have relevant clinical activity in advanced MMRd endometrial cancer.

• The phase I GARNET clinical trial was designed to assess the safety, tolerability, and antitumor activity of dostarlimab, an anti-PD1 immune checkpoint inhibitor, in patients with advanced solid tumors.

• In the A1 cohort of the GARNET trial, which included patients with recurrent or advanced MMRd endometrial cancer who had previously undergone a platinum-containing regimen, dostarlimab was associated with clinically meaningful activity, durable responses, and a favorable safety profile.

• Dostarlimab has achieved accelerated approval for recurrent or advanced MMRd endometrial cancer, after progression to a platinum-containing regimen, and should be the preferred option for this indication.

Declaration of interest

A Redondo reports honoraria and advisory/consultancy (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, Lilly, and Amgen); research grant/funding to his institution (Eisai, PharmaMar, and Roche); travel/accommodation/expenses (AstraZeneca, Tesara: A GSK Company, PharmaMar, and Roche); and speakers bureau (MSD, AstraZeneca, Roche, GSK, Clovis, and PharmaMar), outside the submitted work. A Gallego reports honoraria (Clovis, MSD, AstraZeneca, GSK, PharmaMar, and Roche); and travel/accommodation/expenses (Merck Sharp & Dohme, PharmaMar, Roche, Eisai, Pfizer, Pierre-Fabre, and Tesaro: A GSK Company), outside the submitted work. M Mendiola reports honoraria (MSD, AstraZeneca and GSK); research grant/funding to her institution (Eisai and PharmaMar); and travel/accommodation/expenses (AstraZeneca, GSK, PharmaMar, Roche, and Pfizer), outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. GSK provided a scientific accuracy review at the request of the journal editor.

Additional information

Funding

This paper was not funded.