Expert Point of View: Christopher Willett, MD

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Christopher Willett, MD, Professor and Chair of the Department of Radiation Oncology at Duke University in Durham, North Carolina, shared his thoughts on the findings of the study by Lumish et al1 with The ASCO Post. He first noted the shift in recent years toward total neoadjuvant therapy in the management of clinical stage II and III rectal cancer. Traditional neoadjuvant management has long been radiation therapy with concurrent fluoropyrimidine (chemoradiation) or short-course radiation therapy followed by surgery and adjuvant chemotherapy. Total neoadjuvant therapy employs chemoradiation or short-course radiation therapy with induction or consolidation chemotherapy followed by surgery.

Total neoadjuvant therapy is an intensive therapy resulting in surgery following neoadjuvant therapy and is associated with acute and late toxicities, but it may free subsets of patients from requiring surgery, pointed out Dr. Willett. At a median follow-up of 2.1 years, Garcia-Aguilar et al reported, from a study of 158 patients, that 59% of those who achieved complete clinical responses after total neoadjuvant therapy were free of total mesorectal excision at 3 years.2 “These early study results are promising in that patients achieving a complete clinical response following total neoadjuvant therapy may not require surgery, may be cured, and importantly may also preserve organ function,” he explained.

Christopher Willett, MD

Christopher Willett, MD

Dr. Willett continued: “The phase II trial reported by Lumish et al at the 2022 ASCO Gastrointestinal Cancers Symposium examines a new treatment paradigm for patients with mismatch repair–deficient (dMMR) rectal cancer (5%–10% of patients), with the goals of both cure and organ preservation.1 This trial stems from the experience that PD-L1 blockade has emerged as a highly effective therapy for patients with dMMR advanced or metastatic colorectal cancer.”

In the landmark KEYNOTE-177 trial of 307 patients with previously untreated metastatic dMMR colorectal cancer, there was a statistically higher overall response rate (complete and partial) and median progression-free survival of 44% and 16.5 months respectively for patients receiving pembrolizumab vs 33% and 8.2 months, respectively, in patients treated with chemotherapy.3 Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months, Dr. Willett noted. 

‘Exciting but Preliminary’ Results

Based on these and other results, Lumish et al studied patients with dMMR clinical stage II and III rectal cancer treated with neoadjuvant PD-1 blockade alone. Patients received dostarlimab for nine cycles (3 months), with repeat imaging and endoscopy at 6 months. Those whose tumors demonstrated a complete clinical response were followed closely with endoscopy and magnetic resonance imaging. If there were patients who had residual disease after receiving dostarlimab, they would have been treated with chemoradiation. The complete clinical response rate of the first 11 patients on this trial was 100%.

“These results are exciting but preliminary, as total accrual (30 patients) to the study has not been completed, and longer follow-up is required to assess the durability of clinical response,” Dr. Willett commented. “It is worth recalling, however, the initial report by Nigro et al in 1974, which described a new paradigm of radiation therapy with fluorouracil and mitomycin for patients with anal cancer.4 In this report, all three patients with anal cancer experienced a complete clinical or pathologic response. These early results led to trials validating this paradigm as a curative therapy with organ preservation that remains the standard of care today.” 

DISCLOSURE: Dr. Willett has received honoraria from Cancer, UpToDate, and Oakstone CME.


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.

2. Garcia-Aguilar J, Patel S, Kim JK, et al: Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial. 2020 ASCO Virtual Scientific Program. Abstract 4008.

3. André T, Shiu KK, Kim TW, et al: Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 383:2207-2218, 2020.

4. Nigro ND, Vaitkevicius V, Considine B Jr: Combined therapy for cancer of the anal canal: A preliminary report. Dis Colon Rectum 17:354-356, 1974.


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