Dostarlimab (Jemperli), an anti–PD-1 monoclonal antibody, demonstrated a 100% clinical complete response rate among 14 patients with mismatch repair-deficient (dMMR) locally advanced rectal cancer, according to the results of a recent clinical trial.
Although this is an early study with a small number of patients, the late-breaking results were considered important enough to warrant a separate session at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, and were simultaneously published in the New England Journal of Medicine (N Engl J Med. 2022 June 5. Epub ahead of print).
“We observed 100% complete response in the first 14 consecutive patients,” said lead investigator Andrea Cercek, MD, Section Head, Colorectal Cancer, and Co-Director, Center for Young Onset Colorectal and Gastrointestinal Cancers, Memorial Sloan Kettering Cancer Center, New York City. “There has been no disease recurrence during the follow-up period. Longer follow-up is certainly required to establish the durability of this treatment.”
“These data provide the framework for immune-ablative therapies and highlight the clinical impact of biomarker-driven therapy in early-stage disease,” Dr Cercek continued. “Treatment of the tumor-agnostic dMMR population of early-stage disease has the potential to eliminate the need for chemotherapy, radiation, and surgery in 3% to 4% of all cancers. This has the potential to be translated rapidly into areas around the world without access to modern chemotherapy, radiation, and surgery.”
The standard of care for locally advanced rectal cancer is chemotherapy, radiation, and surgery. Recent studies suggest a benefit with neoadjuvant chemotherapy followed by chemoradiation and surgery, with pathologic complete responses in up to 25% of patients, but this approach is associated with potentially severe complications and toxicity.
Given the consequences of surgical resection of the rectum—which often requires a permanent colostomy—interest in organ-sparing, nonoperative treatment for rectal cancer has increased. Clinical complete response to neoadjuvant treatment as a surrogate marker for pathologic complete response offers patients a nonoperative option that leads to survival benefits similar to those reported with surgery.
Immune checkpoint blockade alone is highly effective as first-line treatment for patients with dMMR metastatic colorectal cancer, as well as for patients with treatment-refractory disease, with objective response rates of 33% to 55%, clinically significant duration of response, and prolonged overall survival.
The ongoing phase 2 trial is designed to evaluate single-agent immune checkpoint inhibition in the treatment of dMMR locally advanced rectal cancer. A preliminary report in January 2022 disclosed that the first 11 patients treated had complete responses. Planned enrollment is 30 patients with stage 2/3 dMMR rectal cancer.
The data presented at ASCO 2022 focused on the first 18 patients enrolled in the trial. Median age was 54 years, and 12 of the 18 patients were women. Fourteen patients had T3/4 tumors, and all but 1 patient had ≥1 involved lymph nodes. Ten of 17 evaluable patients had germline mutations, and all 18 patients had BRAFV600E wild-type tumors.
Among the first 14 patients, clinical complete response occurred at the 6-month follow-up in 12 patients, and 2 patients met criteria for complete response by 3 months. The 4 remaining patients had not reached clinical complete response at 6 months of follow-up, but 1 patient had already met criteria for clinical complete response.
Dr Cercek noted that treatment was well-tolerated, and no patients developed grade ≥3 adverse events.
Dostarlimab is currently approved by the FDA for recurrent or advanced dMMR endometrial cancer and has tissue-agnostic approval for recurrent/advanced dMMR solid tumors that have progressed on previous therapy and have no suitable alternatives.
The results are clinically meaningful but should not be considered practice changing at this point, given the small sample size and short follow-up, said invited discussant Kimmie Ng, MD, MPH, Associate Chief, Gastrointestinal Oncology; Director, Young-Onset Colorectal Cancer Center; and Co-Director, Colon and Rectal Cancer Center, Dana-Farber Cancer Institute, Boston. She did acknowledge that dostarlimab will probably be used off label after publication of these results.
“The only end point available right now is overall response, with no data on survival or other clinically relevant outcomes,” Dr Ng noted.
Ideally, unresolved issues about the treatment would be addressed in a randomized clinical trial to compare neoadjuvant dostarlimab with standard treatment, but it is difficult to accrue patients for this relatively rare malignancy. In the absence of data from a randomized clinical trial, more patients and longer follow-up on other clinically relevant end points, such as 3-year disease-free survival, overall survival, and organ preservation, are needed.
“More importantly, we need multi-institutional participation,” Dr Ng said. “We need to confirm the high clinical complete response rates and that the complex nonoperative management of rectal cancer can be replicated in all cancer care settings.”