Treatment with Jemperli (dostarlimab-gxly) has received a breakthrough therapy designation (BTD) from the Food and Drug Administration (FDA) for patients with locally advanced mismatch repair deficient (dMMR), microsatellite instability-high (MSI-H) rectal cancer, according to a press release from GSK plc. Notably, this marks the second regulatory designation for the agent in locally advanced dMMR/MSI-H rectal cancer, coming on the heels of the Fast Track designation for the same patient population in January 2023.
The press release goes on to state that a BTD is meant to expedite the development and review of drugs with the potential to treat a serious condition, for which preliminary clinical evidence may indicate substantial improvement over currently available therapy.
“Today’s designation, which is based on the unprecedented 100% clinical complete response rate of [Jemperli] 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 [Jemperli] in this patient population,” stated Hesham Abdullah, senior vice president of Global Head Oncology, R&D, at GSK.
Glossary
Breakthrough Therapy Designation: a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).
Clinical Complete Response Rate: the percentage of patients in a clinical trial who show no detectable signs of cancer based on clinical assessments.
Fast Track Designation: a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier.
Microsatellite instability-high: a condition in which cancer cells have a high number of mutations in microsatellites, which are short, repeated DNA sequences.
Mismatch Repair Deficienta: a condition where cells have mutations in genes that correct DNA copying errors. This results in an accumulation of DNA mutations that can lead to cancer.
Rectal cancer starts in the rectum, the final section of the large intestine, and is often categorized as colorectal cancer, the third most commonly diagnosed cancer in the world. Notably, it is estimated that approximately 46,220 people are given a rectal cancer diagnosis each year in the United States, 5% to 10% of which are classified as dMMR/ MSI-H, which means that these cancers contain abnormalities that affect the proper repair of DNA when copied in a cell. Tumors with the MMR biomarker — which has been shown to predict response to immune checkpoint blockade with PD-1 therapy — are most commonly found in solid tumors such as endometrial, colorectal and other gastrointestinal cancers.
To combat unmet needs within this at-risk patient population, the PD-1-blocking antibody Jemperli is being investigated in a robust clinical trial program both alone and in combination with other therapies for gynecologic, colorectal and lung cancers. This proves an important task to undertake, as Jemperli is not approved anywhere in the world for the frontline treatment of locally advanced dMMR/MSI-H rectal cancer.
Understanding the BTD and Other Designations of Jemperli
Preliminary clinical evidence from the ongoing phase 2, GSK-supported collaborative study with Memorial Sloan Kettering Cancer Center, in New York, New York, supported the FDA's decision to grant BTD. Data from this collaborative clinical trial resulted in a 100% clinical complete response rate in all patients enrolled (42) who had completed treatment with Jemperli. Clinical complete response rate was defined as no evidence of tumors as assessed by magnetic resonance imaging, endoscopy, PET scan and digital rectal exam.
A sustained clinical complete response with a median follow-up of 26.3 months was observed in the first 24 patients evaluated, according to the news release. Regarding safety, the safety and tolerability profile of the agent was also noted to be generally consistent with the known safety profile of the agent and no side effects of grade 3 or higher were reported in this trial.
Presently the investigative agent is indicated in combination with carboplatin and paclitaxel, followed by Jemperli as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial cancer in the United States, including patients with mismatch repair proficient/microsatellite stable and dMMR/MSI-H tumors. Moreover, Jemperli is also approved in the United States by the FDA for the single-agent treatment of adult patients with dMMR recurrent or advanced endometrial cancer that has progressed on or after prior platinum-containing treatment in any setting and are not candidates for curative surgery or radiation.
In the United States, Jemperli is indicated for dMMR recurrent or advanced solid tumors as well that have progressed on or following prior treatment and who have no satisfactory alternative treatment options. This specific indication received an accelerated approval for patients in the United States based on tumor response rate and durability of response, though continued approval is contingent upon verification and description of clinical benefit in a confirmatory trial.
Presently, the collaborative phase 2 trial is continuing to evaluate patients. Following up on the trial with Memorial Sloan Kettering, an ongoing phase 2 registrational AZUR-1 trial aims to confirm the findings of this supported study in locally advanced dMMR/MSI-H rectal cancer.
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