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PD-1 Inhibition with Dostarlimab Led to Remission in All Patients with Mismatch Repair-Deficient Rectal Cancer

JHOP - August 2022 Vol 12, No 4 - ASCO Highlights

First-line treatment with dostarlimab-gxly (Jemperli), a PD-1 inhibitor, achieved complete responses (CRs) in 100% of a subset of patients with locally advanced mismatch repair-deficient (dMMR) rectal cancer, sparing them surgery, chemotherapy, and radiation, as of the latest follow-up.

The results of this prospective, phase 2 study were published in the New England Journal of Medicine1 and the updated, late-breaking results were presented at the 2022 ASCO meeting.

All 14 patients who were followed for at least 6 months had CRs, with no evidence of cancer on follow-up. Follow-up in the cohort ranged from 6 to 25 months, and none of the patients received another therapy. In addition, 4 other patients with limited follow-up had preliminary evidence of a response to the PD-1 inhibition, including 1 clinical CR.

The 6-month treatment course of dostarlimab was well-tolerated, and none of the patients had grade 3 or higher adverse events, said lead investigator Andrea Cercek, MD, Section Head, Colorectal Cancer, Memorial Sloan Kettering Cancer Center, New York City.

“We observed 100% complete response in the first 14 consecutive patients,” Dr Cercek said. “There has been no disease recurrence during the follow-up period. Longer follow-up is certainly required to establish the durability of this treatment.” This 100% response is unusual in cancer therapy and may provide new hope for a subset of patients using clearly defined targeted therapies.

“These data provide the framework for immune-ablative therapies and highlight the clinical impact of biomarker-driven therapy in early-stage disease,” she continued. “Treatment of the tumor-agnostic mismatch repair-deficiency population of early-stage disease has the potential to eliminate the need for chemotherapy, radiation, and surgery in 3% to 4% of all cancers.”

The standard of care for locally advanced rectal cancer is chemotherapy, radiation, and surgery. Recent studies suggest that neoadjuvant chemotherapy followed by chemoradiation and surgery has benefit, with pathologic CR in up to 25% of patients, but there can be potentially severe complications and toxicity.

Because surgical resection of the rectum often requires a permanent colostomy, interest in organ-sparing, nonsurgical treatment for rectal cancer has increased. Clinical CR to neoadjuvant treatment as a surrogate marker for pathologic CR offers patients a nonoperative option that leads to survival benefits that are similar to those observed with surgery.

Approximately 5% to 10% of rectal adenocarcinomas are dMMR and have a poor response to standard chemotherapy. Checkpoint inhibition has produced response rates of 33% to 55% in patients with metastatic dMMR colorectal cancer, and responses have often been durable, leading to prolonged overall survival.

This led the researchers of this phase 2 clinical trial to evaluate treatment with the immune checkpoint inhibitor, dostarlimab, in locally advanced dMMR rectal cancer. A preliminary report in January 2022 disclosed that the first 11 patients who received treatment in the trial had CRs. The planned study enrollment is 30 patients with stage II or III dMMR rectal cancer.

The data presented at the ASCO meeting focused on the first 18 patients who were enrolled in the study. A clinical CR occurred at the 6-month follow-up in 12 patients, and 2 additional patients met the criteria for CR by 3 months. The 4 remaining patients had not reached 6 months of follow-up, but 1 patient had already met the criteria for clinical CR.

Dostarlimab is FDA approved for the treatment of recurrent or advanced dMMR endometrial cancer and for tumor-agnostic recurrent or advanced dMMR solid tumors that have progressed after previous therapy in patients who have no suitable therapy alternatives.

Expert Commentary

The study results are clinically meaningful, but they should not be considered practice-changing at this point, with such a small sample size and short follow-up, said invited discussant Kimmie Ng, MD, MPH, Associate Chief, Division of Gastrointestinal Oncology, Dana-Farber Cancer Institute, Boston, MA. She did acknowledge that dostarlimab will probably be used off label after the publication of these results.

“The only end point available right now is overall response, with no data on survival or other clinically relevant outcomes,” she said.

Ideally, unresolved issues about dostarlimab would be addressed in a randomized clinical trial to compare neoadjuvant dostarlimab with standard-of-care treatment, but it is difficult to accrue patients with 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.

“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.”

  1. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N Engl J Med. 2022;386:2363-2376.
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