1. Fuerst, Mark L.

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Neoadjuvant immunotherapy with dostarlimab for 6 months represents a promising new treatment for patients with Stage II to III mismatch repair (MMR)-deficient rectal cancer. The small study showed preoperative immunotherapy led to a 100 percent clinical complete response rate without the use of chemoradiation or surgery with responses that appear to be durable, suggesting that biomarker-driven immunotherapy alone may replace every component of standard of care for these patients.

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"We have treated a total of 14 patients to date, and 100 percent of them have had a clinical complete response to dostarlimab alone. We have not had to radiate anyone. And no one has gone to surgery," said Andrea Cercek, MD, Section Head of Colorectal Cancer at Memorial Sloan Kettering Cancer Center, as she presented the data at the 2022 American Society of Clinical Oncology Annual Meeting (Abstract LBA5).


The majority of patients achieved a clinical complete response at 6 months, with a few at 3 months, she noted. The median follow-up is 6.8 months. All patients remain disease-free. The study results were published June 5 in the New England Journal of Medicine (2022; doi: 10.1056/NEJMoa2201445).


Currently, locally advanced rectal cancer is treated with a combination of chemotherapy, radiation, and surgery. But this triple therapy often leads to life-altering consequences, including bowel and bladder dysfunction, sexual dysfunction, infertility, as well as a permanent stoma in up to 30 percent of patients.


MMR-deficient rectal cancer represents about 5-10 percent of all locally advanced rectal cancers and is relatively resistant to chemotherapy. Checkpoint blockade, however, is highly effective in MMR-deficient tumors, in particular in colorectal cancer in the metastatic setting, with complete response rates of about 10 percent.


The researchers designed a Phase II study including all patients at their center with locally advanced rectal cancer, therefore Stage II or III MMR-deficient disease. "We effectively swapped out chemotherapy and replaced it with the dostarlimab, which is a PD-1 monoclonal antibody," said Cercek. Patients received dostarlimab every 3 weeks for 6 months. At the completion of 6 months, they had a full evaluation, which included a rectal MRI, a PET CT, as well as an endoscopic examination.


To date, 18 patients, median age 54 years, have been accrued. The majority of patients had big, bulky tumors, 94 percent node-positive, all of them MSI-High. "So really, the standard of care for these patients would have very likely required all three modalities-so chemotherapy, radiation, and surgery," Cercek noted.


No Grade 3 or 4 adverse events were noted and no patients required chemotherapy, radiation, or surgery. No disease recurrence has been observed, although Cercek noted follow-up will be required to establish the durability of the treatment.


"We believe this data provides the framework for immunoablative therapies. It highlights the clinical impact of biomarker-driven therapy, in other words, of moving precision medicine into early-stage disease," Cercek stated. "The tumor-agnostic indication alone of MMR deficiency has the potential to eliminate definitive therapy with chemotherapy, radiation, and surgery in up to 3-4 percent of all cancers. And this is the potential to be translated rapidly into areas where access to modern chemotherapy and, more importantly, chemoradiation and surgery may not be available."


ASCO discussant Kimmie Ng, MD, MPH, Associate Chief of the Division of Gastrointestinal Oncology at Dana-Farber Cancer Institute, commented: "The 100 percent clinical complete response rate is unprecedented in rectal cancer, and the potential to decrease morbidity by eliminating pelvic chemoradiation and surgery for our patients is huge." Larger multicenter clinical trials with longer follow-up and disease-free survival and overall survival endpoints are needed, she said, adding that "it is going to be critical that we identify predictive biomarkers of pathologic complete response to help guide the treatments for our patients."


Moderator of the session, Mohamed Salem, MD, a gastrointestinal medical oncologist at the Levine Cancer Institute, told Oncology Times, "This is a key study. All patients had a complete clinical response, which is unheard of in rectal cancer. By achieving tumor regression, this is a chance to save patients from the toxicity or radiation and surgery. The challenge is long-term follow-up and to see whether we can ensure a pathological complete response."


Mark L. Fuerst is a contributing writer.