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Amazing Complete Response Rates With Dostarlimab in Locally Advanced MMRd Rectal Cancer

One of ASCO 2022’s most headline-grabbing presentations included results from the PD-1 inhibitor dostarlimab in patients with mismatch repair-deficient (MMRd) stage II and III rectal adenocarcinoma. The current standard of care for patients with locally advanced rectal cancer, regardless of MMR status, includes multimodal therapy, usually given as neoadjuvant chemotherapy, followed by chemoradiation (CRT) and surgery. Although this approach is effective and results in a pathologic complete response (pCR) in one-quarter of patients, it is commonly associated with impaired quality of life due to treatment complications and toxicity. Around 5 – 10% of patients have MMRd rectal adenocarcinoma, which is known to be less responsive to chemotherapy. Based on the benefits seen with PD-1 inhibitors in patients with metastatic MMRd colorectal cancer, the investigators from Memorial Sloan Kettering Cancer Center hypothesized that locally advanced MMRd rectal cancer may be sensitive to PD-1 checkpoint blockade and that its neoadjuvant use may impact the need for subsequent CRT and/or surgery.

They conducted a prospective phase 2 study, in which patients with locally advanced MMRd rectal cancer received dostarlimab every 3 weeks for 6 months (nine cycles) followed by standard CRT with capecitabine and surgery. Patients who achieved clinical CR (cCR) after completing dostarlimab therapy, determined by digital rectal exam, endoscopy and rectal magnetic resonance imaging (MRI) proceeded without CRT and surgery. They were closely monitored every 4 months. Early results from this study were presented in a special late-breaking abstract session by Andrea Cercek, MD (Memorial Sloan Kettering Cancer Center, New York, US) and were published simultaneously in the New England Journal of Medicine. Of 18 patients included by the time of presentation, the majority had bulky tumors with high tumor mutational burden, and 94% were node positive. The primary endpoints were overall response rate (ORR) to PD-1 blockade alone or with CRT, sustained cCR at 12 months after anti-PD-1 with/without CRT, or pathologic CR in patients who underwent surgery. Results from the first 14 consecutive MMRd patients were impressive, showing that all patients achieved cCR with dostarlimab alone. Importantly, during a median follow-up of 6.8 months, no patient required CRT or surgery, and no disease recurrence was observed. Four patients have been followed up for nearly 2 years. There were no grade 3/4 adverse events.

Dr. Cercek concluded that these findings “highlight the clinical impact of biomarker-driven therapy.” She added that in patients with early-stage MMRd cancer, CRT and surgery could potentially be eliminated in up to 3 – 4% of all cases. Discussant Kimmie Ng, MD, MPH (Dana-Farber Cancer Institute, Boston, US) found the findings both scientifically plausible and clinically meaningful, but not yet practice-changing. She noted that to change the standard of care, “We need a larger sample size, longer follow-up time, data on other clinically relevant endpoints, such as three-year disease-free survival and overall survival and organ preservation rates, and very importantly, multi-institutional participation.” She highlighted the importance of confirming that “high clinical complete response rates and the complex non-operative management of rectal cancer can be replicated in all cancer care settings.”

References:
Cercek A, et al. ASCO 2022: Abstract LBA5.
Cercek A, et al. N Engl J Med. Published online June 5, 2022.