‘Groundbreaking Option’ Approved for Rectal Cancer

The FDA on Monday granted accelerated approval to the PD-1 inhibitor dostarlimab (Jemperli) to help select patients with operable rectal cancer potentially avoid surgery.

The approval allows use in stage II/III patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) rectal cancer, a subgroup that represents about 3% of all locally advanced rectal cancers. Patients who achieve a complete response may be able to avoid the typical treatment paradigm for operable rectal cancer — chemotherapy, radiation, and surgery.

“Standard treatment for rectal cancer has major life-changing effects,” Angelo de Claro, MD, director of FDA’s Oncology Center of Excellence, said in a statement. “For certain types of rectal cancer, this approval represents a groundbreaking option that avoids surgery, radiation, and chemotherapy. This represents a significant benefit for patients and their families.”

Support for the approval came from the AZUR-1 trial, which showed that the vast majority of patients with dMMR/MSI-H rectal cancers and other solid tumors treated with dostarlimab had a complete response and were able to avoid surgery. At the time, principal investigator Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York City, said neoadjuvant PD-1 inhibition for dMMR/MSI-H cancers “could potentially eradicate the need for chemotherapy, radiation, and surgery in about 2% to 3% of all solid tumors.”

In an announcement from GSK, Cercek said, “The AZUR-1 results demonstrate the potential for a fundamentally different treatment approach in this biomarker-defined patient population, and today’s approval means MSI-H/dMMR patients can now access a licensed treatment tailored to the biology of their disease.”

Michael Sapienza, CEO of the Colorectal Cancer Alliance, added, “People facing rectal cancer are often thinking not only about treating their disease, but also worrying about what life will look like afterwards. The possibility of avoiding chemotherapy, radiation, and surgery represents a meaningful advance for patients and their families. Biomarker testing at diagnosis will be essential to identifying patients who may be eligible for this treatment and helping them understand their options.”

According to the company announcement, an exploratory analysis of AZUR-1 showed that 76% of evaluable patients had no evidence of cancer a year or more after treatment. After a median follow-up of more than 2 years, no recurrences have been reported.

As the long-term risk of relapse is unknown with dostarlimab in this setting, the labeling for the drug notes that the continued approval for this indication “may be contingent upon verification and description of clinical benefit in a confirmatory trial.”

In AZUR-1, most adverse events (AEs) were grade 1/2, the most common being fatigue (32% of patients), rash (22%), diarrhea (18%), and pruritus (17%). Grade 3 AEs consisted of one case each of diabetes, lung infection, hypothyroidism, encephalitis, and neutropenia. A single case of grade 4 febrile neutropenia also occurred. Prescribing information notes the potential for a variety of immune-mediated AEs.

In addition to the rectal cancer indication, dostarlimab has multiple approved indications in endometrial cancer and is approved for previously treated dMMR recurrent or advanced solid tumors.