Dostarlimab, known commercially as Jemperli, is an immunotherapy drug that has shown remarkable efficacy in treating certain rectal cancer cases. Its emergence offers a new avenue for patients with specific tumor characteristics, highlighting a shifting paradigm in oncology towards more targeted treatment strategies.
Understanding Rectal Cancer and Standard Approaches
Rectal cancer originates in the rectum, the final section of the large intestine before the anus. These tumors can be particularly challenging to treat due to their location within the narrow confines of the pelvis, which is rich in nerves and other organs. Traditional approaches for locally advanced rectal cancer often involve a multi-pronged strategy, typically including chemotherapy, radiation therapy, and surgery, sometimes referred to as total mesorectal excision (TME).
Patients undergoing these standard treatments frequently face difficult side effects that can significantly impact their quality of life. Radiation therapy to the pelvic area can lead to issues such as bowel, urinary, and sexual dysfunction, and in some cases, infertility. Surgery, while often effective in removing the tumor, can result in permanent changes like the need for an ostomy, where a portion of the bowel is redirected to an opening in the abdomen. Despite these intensive treatments, up to one-third of patients still experience distant metastasis, where the cancer spreads to other parts of the body.
Dostarlimab: A Novel Immunotherapy
Dostarlimab is a monoclonal antibody, a type of engineered protein designed to target specific substances in the body. It functions as an immunotherapy, which means it works by harnessing the body’s own immune system to fight cancer. Unlike traditional chemotherapy that directly attacks cancer cells, immunotherapy aims to empower the patient’s immune defenses.
This drug specifically operates as a PD-1 (Programmed Death-1) checkpoint inhibitor. PD-1 is a protein found on the surface of immune cells, particularly T-cells, and acts as a “brake” to prevent the immune system from attacking healthy cells. Cancer cells can sometimes exploit this pathway by expressing ligands (PD-L1 and PD-L2) that bind to PD-1, effectively deactivating the T-cells and allowing the tumor to evade immune detection and destruction. By blocking the interaction between PD-1 and its ligands, dostarlimab releases this immune system “brake,” allowing the T-cells to recognize and mount a more effective attack against the cancer cells. This mechanism is particularly effective in tumors with many genetic mutations, such as those with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H), as these mutations make the cancer cells more recognizable to the activated immune system.
The Landmark Clinical Trial
Dostarlimab gained prominence for its use in rectal cancer due to a clinical trial conducted at Memorial Sloan Kettering Cancer Center (MSK). This phase II study focused on patients with locally advanced rectal cancer characterized by mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H).
The trial administered dostarlimab as a single agent before any other treatments, with patients receiving 500 mg intravenously every three weeks for six months. All 42 patients who completed treatment achieved a 100% clinical complete response. A clinical complete response means that there was no detectable evidence of the tumor remaining, as confirmed by various assessments including MRI, endoscopy, PET scans, and digital rectal exams. The consistent disappearance of tumors in all participants was a significant finding. Long-term follow-up of the initial patients continues to show sustained responses, with the first 24 patients demonstrating a sustained clinical complete response at a median follow-up of 26.3 months.
Patient Eligibility, Considerations, and Outlook
Patient eligibility for dostarlimab in rectal cancer hinges on the presence of mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H) in their tumor. Testing for these genetic markers is therefore a necessary step before considering this treatment. Dostarlimab is administered intravenously, typically as an infusion.
As with all immunotherapies, there can be potential immune-related side effects, which occur when the activated immune system mistakenly attacks healthy tissues. These can range from fatigue and digestive problems (nausea, diarrhea, constipation) to less common but more serious inflammatory conditions affecting organs such as the lungs (pneumonitis), liver (hepatitis), intestines (colitis), or thyroid gland (thyroiditis). Regular monitoring and close communication with the healthcare team are important to manage these effects.
Dostarlimab is not yet a standard first-line treatment for all rectal cancers. However, it has received Breakthrough Therapy designation from the FDA for dMMR/MSI-H locally advanced rectal cancer, which expedites its development and review. Ongoing studies, such as the AZUR-1 trial, are further evaluating dostarlimab as a single therapy for this patient population, aiming to confirm these findings in a larger, multicenter setting. The success of dostarlimab in this specific group of rectal cancer patients highlights the growing importance of precision medicine and immunotherapy in oncology, pointing towards a future where cancer treatments are increasingly tailored to each patient’s tumor.