FDA Grants Breakthrough Therapy Designation to GSK's Jemperli for Advanced Rectal Cancer
Key Insights
The FDA granted Breakthrough Therapy Designation to GSK's Jemperli (dostarlimab) for locally advanced dMMR/MSI-H rectal cancer (search).
The designation was based on a Phase II trial showing a 100% clinical complete response rate in all 42 patients treated with dostarlimab.
Jemperli targets the PD-1 (search) receptor and aims to improve the immune system's ability to eradicate cancer cells without traditional treatments.
The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to Jemperli (dostarlimab-gxly), a PD-1 (search) blocking antibody developed by GlaxoSmithKline (GSK), for the treatment of patients with locally advanced mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) rectal cancer (search). This designation aims to expedite the development and review of Jemperli, offering hope for a less invasive treatment option for a subset of rectal cancer patients who often face long-term adverse effects from standard therapies. The decision was based on preliminary clinical evidence from an ongoing Phase II trial, which demonstrated an unprecedented 100% clinical complete response rate in all 42 patients who completed treatment with dostarlimab.
Clinical Trial Results
The Phase II trial, a collaborative effort between GSK and Memorial Sloan Kettering Cancer Center, evaluated dostarlimab as a monotherapy in patients with dMMR/MSI-H locally advanced rectal cancer (search). The results showed that all 42 patients who completed the treatment achieved a clinical complete response (cCR), defined as the absence of tumors as assessed by MRI, endoscopy, PET scan, and digital rectal exam. Furthermore, in 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). Importantly, the safety and tolerability profile of dostarlimab was consistent with its known safety profile, with no adverse events of grade 3 or higher reported.
Implications for Treatment Paradigm
The current standard of care for locally advanced dMMR/MSI-H rectal cancer (search) typically involves chemotherapy, radiation, and surgery, which can lead to significant long-term side effects, including bowel, urinary, and sexual dysfunction, as well as secondary cancers and infertility. Dostarlimab offers a potential alternative that could spare patients these life-altering consequences.
Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK, stated, "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 (search), who face long-term adverse quality-of-life effects. Our registrational AZUR-1 trial is continuing to study dostarlimab in this patient population."
About dMMR/MSI-H Rectal Cancer
Rectal cancer (search), a type of cancer that begins in the rectum, is often categorized within the broader group of colorectal cancers. Colorectal cancer is the third most commonly diagnosed cancer worldwide. In the United States, approximately 46,220 individuals are diagnosed with rectal cancer annually. Around 5-10% of these rectal cancers are dMMR/MSI-H, characterized by abnormalities affecting DNA repair. This deficiency has been shown to predict a positive response to immune checkpoint blockade with PD-1 (search) therapy.
Ongoing Research and Development
While dostarlimab is not yet approved for the frontline treatment of locally advanced dMMR/MSI-H rectal cancer (search), GSK is conducting the Phase II registrational AZUR-1 trial to confirm the findings of the initial collaborative study. Additionally, Jemperli is being investigated in various clinical trials, both as a monotherapy and in combination with other therapies, for gynecologic, colorectal, and lung cancers.
About Jemperli (dostarlimab)
Dostarlimab is a programmed death receptor-1 (PD-1 (search))-blocking antibody. In the US, Jemperli 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 (search). Jemperli is also approved as a single agent for adult patients with dMMR recurrent or advanced endometrial cancer, that has progressed on or following a prior platinum-containing regimen and are not candidates for curative surgery or radiation. Additionally, Jemperli is indicated in the US for patients with dMMR recurrent or advanced solid tumors, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options. The latter indication is approved in the US 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).