FDA Grants Dostarlimab Breakthrough Therapy Designation in dMMR/MSI-H Rectal Cancer

• Breakthrough therapy designation (BTD) was granted to dostarlimab-gxly (Jemperli) from the FDA for the treatment of patients with locally advanced mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) rectal cancer.¹
• This marks dostarlimab’s second regulatory designation in locally advanced dMMR/MSI-H rectal cancer, following a fast track designation for these patients in January 2023.
• Dostarlimab is a programmed death receptor-1 (PD-1)-blocking antibody that has potential when given alone and in combination with standard of care for patients with currently limited treatment options.

The FDA has granted BTD to dostarlimab for the treatment of patients with locally advanced dMMR/MSI-H rectal cancer.¹

BTD seeks to accelerate the development and review of new agents that show the potential to treat serious conditions, supported by early clinical evidence that may suggest significant improvement vs currently existing treatments.

This BTD for dostarlimab marks the agent’s second regulatory designation in locally advanced dMMR/MSI-H rectal cancer, following fast track designation for the same patient population in January 2023.²

“Today’s designation, which is based on the unprecedented 100% clinical complete response rate of dostarlimab reported to date, supports a path to help change the treatment paradigm for patients with locally advanced dMMR/MSI-H rectal cancer, who face long-term adverse quality-of-life effects. Our registrational AZUR-1 trial is continuing to study dostarlimab in this patient population,” said Hesham Abdullah, senior vice president, global head oncology, research and development, GSK, in a press release.¹

Microscopic, photorealistic image of colorectal cancer cells - Generated with Adobe Firefly

About Dostarlimab in dMMR/MSI-H Rectal Cancer

The PD-1-blocking antibody binds to the PD-1 receptor and blocks its interaction with the PD-1 ligands PD-L1 and PD-L2. Dostarlimab shows potential for the treatment of patients who have limited treatment options when given alone and in combination with standard of care. The agent also shows promise as a combination therapy with future novel cancer treatments.

The FDA’s BTD is based on promising preliminary clinical evidence from an ongoing phase 2 collaborative study that is supported by GSK in partnership with Memorial Sloan Kettering Cancer Center. This trial focuses on frontline treatment for patients with locally advanced dMMR rectal cancer.

In the study, all 42 patients treated with dostarlimab achieved a 100% clinical complete response (cCR), which is defined as the absence of detectable tumors, assessed through advanced imaging methods, including magnetic resonance imaging, endoscopy, PET scans, and digital rectal exams. Among the first 24 patients evaluated, a sustained cCR was observed with a median follow-up of 26.3 months (95% CI, 12.4-50.5).

Safety and tolerability of dostarlimab in this study were consistent with the agent’s known profile, and no grade 3 or higher adverse events were reported. The trial continues to evaluate outcomes in enrolled patients.

In addition to this study, an ongoing, phase 2, registrational trial titled AZUR-1 is evaluating dostarlimab in locally advanced dMMR/MSI-H rectal cancer. The study aims to confirm the findings from the prior phase 2 trial.

While dostarlimab is not approved anywhere globally for the frontline treatment of patients with locally advanced dMMR/MSI-H rectal cancer, the agent is indicated in combination with carboplatin and paclitaxel, followed by dostarlimab as a single agent for the treatment of adult patients with primary advanced or recurrent endometrial cancer in the US. This includes patients with mismatch repair proficient/microsatellite stable and dMMR/MSI-H tumors.

The FDA also approved dostarlimab as a single agent for adult patients with dMMR recurrent or advanced endometrial cancer, as determined by a US FDA-approved test, that has progressed on or following a prior platinum-containing regimen in any setting and are not candidates for curative surgery or radiation. Also in the US, dostarlimab is approved for the treatment of patients with dMMR recurrent or advanced solid tumors, as determined by a US FDA-approved test. These patients must have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

REFERENCES:

1. Jemperli (dostarlimab) receives US FDA breakthrough therapy designation for locally advanced dMMR/MSI-H rectal cancer. News release. GSK plc. December 16, 2024. Accessed December 16, 2024. https://tinyurl.com/z5jes7ft

2. US FDA Advisory Committee votes in support of trials designed to evaluate Jemperli (dostarlimab-gxly) as a potential treatment for mismatch repair-deficient/microsatellite instability-high locally advanced rectal cancer. News release. GSK. February 9, 2023. Accessed December 16, 2024. https://tinyurl.com/ms5e64zt