Small Study Reports Neoadjuvant PD-1 Blockade Yields 100% Clinical Complete Response Rate in Locally Advanced Mismatch Repair–Deficient Rectal Cancer

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In a small study of patients with locally advanced mismatch repair–deficient (dMMR) rectal cancer, treatment with the anti–PD-1 agent dostarlimab-gxly alone led to a clinical complete response rate of 100%. The findings of this study from Memorial Sloan Kettering Cancer Center (MSK) were reported by Melissa Amy Lumish, MD, at the 2022 ASCO Gastrointestinal Cancers Symposium.1

“We observed an unprecedented clinical response rate of 100% among the first 11 patients who completed treatment with 6 months of the anti–PD-1 agent alone. This strategy may uniquely allow patients to avoid chemoradiation and surgery with reduced morbidity…. We think this represents a potential new paradigm for the treatment of mismatch repair–deficient rectal cancer,” Dr. Lumish said.

Total neoadjuvant therapy is a standard approach for all patients diagnosed with clinical stage II or III rectal cancer. This includes neoadjuvant fluorouracil and oxaliplatin-based chemotherapy and chemoradiation, with subsequent endoscopic and radiographic evaluation, followed by total mesorectal excision. To avoid toxicity and morbidity related to surgery, patients achieving a clinical complete response are often now offered the option of nonoperative management. Investigators from MSK were instrumental in advancing the nonoperative approach a few years ago.

We observed an unprecedented clinical response rate of 100% among the first 11 patients who completed treatment with 6 months of the anti–PD-1 agent alone.
— Melissa Amy Lumish, MD

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Study Rationale

Dr. Lumish described the rationale for using an anti–PD-1 agent in this patient population, noting that dMMR characterizes 5% to 10% of all rectal cancers and that metastatic dMMR colorectal cancer is responsive to immune checkpoint blockade. Most patients with rectal cancer and dMMR tumors have Lynch syndrome: young patients of child-bearing potential for whom avoidance of surgery would be desirable. Colorectal dMMR tumors have a reduced likelihood of responding to fluorouracil alone and an increased likelihood of experiencing disease progression on neoadjuvant chemotherapy, she said.

“Though we know metastatic dMMR colorectal cancer is responsive to immune checkpoint blockade, it’s not been thoroughly studied in the neoadjuvant setting, which is the idea behind our ongoing study,” she explained. “We have replaced neoadjuvant chemotherapy with anti–PD-1 given over a period of 6 months.”

About the Phase II Trial

The single-arm prospective phase II study will ultimately enroll 30 patients with clinical stage II and III dMMR rectal cancer. The population now includes 16 patients, 11 of whom have completed all anti–PD-1 therapy. The tumor stage is T3 or T4 in 75% and T1 or T2 in 25%. All but 1 patient has lymph node–positive disease, and 8 of 14 have Lynch syndrome. “You can see we did not artificially select for patients with low-risk tumors,” she noted.

Patients are treated with dostarlimab at 500 mg every 3 weeks for nine cycles and undergo imaging and endoscopic evaluation at baseline, 6 weeks, 3 months, and 6 months. Patients achieving a clinical complete response at the end of treatment have the option of nonoperative management, whereas those with residual disease are reevaluated after chemotherapy and radiation, following with nonoperative management if warranted.

The primary objective is overall response rate to PD-1 blockade as well as clinical complete response at 12 months after completion of PD-1 blockade or pathologic complete response with or without chemoradiation. Clinical complete response is defined as endoscopic plus radiographic complete response.

Clinical Complete Responses in 100%

Of the 11 patients who have completed the full 6 months of anti–PD-1 therapy, 11 (100%) have achieved clinical complete responses. Notably, all 11 patients have achieved both endoscopic and radiographic complete responses. For two patients, treatment is ongoing; one has achieved an endoscopic and radiographic complete clinical response before the end of treatment. None of the 11 complete responders has required chemoradiation or surgery, and they are undergoing surveillance, Dr. Lumish reported. She also acknowledged that the durability of these responses requires further long-term follow-up. 

DISCLOSURE: Dr. Lumish reported no conflicts of interest.


1. Lumish MA, Cohen JL, Stadler ZK, et al: PD-1 blockade alone for mismatch repair deficient locally advanced rectal cancer. 2022 Gastrointestinal Cancers Symposium. Abstract 16. Presented January 22, 2022.


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