PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer | The NEW ENGLAND JOURNAL Of MEDICINE

Authors: Andrea Cercek, M.D., Melissa Lumish, M.D. https://orcid.org/0000-0003-4173-5567, Jenna Sinopoli, N.P., Jill Weiss, B.A., Jinru Shia, M.D., MichelleLamendola-Essel, D.H.Sc., Imane H. El Dika, M.D., and Luis A. Diaz, Jr., M.D.

BACKGROUND

Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer.

METHODS

We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.
PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer

RESULTS

A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.

CONCLUSIONS

Mismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.)
Locally advanced rectal cancer is typically managed with multimodal therapy, including chemotherapy, radiation, and surgery. Current evidence supports a strategy involving the use of neoadjuvant therapy, in which induction chemotherapy with a fluoropyrimidine in combination with oxaliplatin is followed by chemoradiotherapy and then surgery.1-3 This approach results in a pathological complete response in up to a quarter of patients, but it is associated with marked complications and toxic effects — including bowel, urinary, and sexual dysfunction; infertility; and altered quality of life — in a substantial proportion of patients.4-6 In patients undergoing surgery, resection of the rectum is life-altering and often warrants a permanent diverting colostomy.6,7 Owing to the complications of surgery and the high frequency of pathological complete response, interest in organ-sparing nonoperative management is increasing. The use of clinical complete response that is achieved with neoadjuvant treatment as a surrogate for pathological complete response provides patients with a nonoperative option that results in a survival benefit that is similar to that in patients undergoing surgical resection.8-11
Approximately 5 to 10% of rectal adenocarcinomas are mismatch-repair deficient, and these tumors have been shown to respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy in locally advanced rectal cancer.12-14 Immune checkpoint blockade alone has been shown to be highly effective as first-line treatment for patients with mismatch repair–deficient metastatic colorectal cancer, as well as for patients with treatment-refractory disease, with objective response rates of 33 to 55%, clinically significant durability of response, and prolonged overall survival.15-17
On the basis of the benefits seen in the context of metastatic disease, we hypothesized that single-agent programmed death 1 (PD-1) blockade alone might be beneficial in mismatch repair–deficient, locally advanced rectal cancer. To test this hypothesis, we initiated a phase 2 study to investigate the overall response and frequency of sustained clinical complete response to neoadjuvant treatment with dostarlimab, a PD-1 inhibitor, in this patient population.

Skip The Scoop | Seek Understanding

Bannon’s War Room
Evening Edition
Recorded January 19, 2021

Show Me

‘Trump Was Right’ With Tougher Approach to China: Biden’s Top Diplomat Nominee

Show Me

President Trump’s Farewell Address to the Nation: Full Transcript

Show Me

The New Domestic War on Terror is Coming

Show Me

Trump Issues Executive Order Protecting Americans From ‘Overcriminalization’ by Regulations

Show Me

Trump Signs Executive Order to Protect US Against Security Threats From Drones

Show Me

Bannon’s War Room
Morning Edition Hour 1
Recorded January 18, 2021

Show Me

Bannon’s War Room
Morning Edition Hour 2
Recorded January 18, 2021

Show Me

Bannon’s War Room
Evening Edition
Recorded January 18, 2021

Show Me

Bannon’s War Room
Saturday Edition Hour 1
Recorded January 16, 2021

Show Me

Bannon’s War Room
Saturday Edition Hour 2
Recorded January 16, 2021

Show Me

Bannon’s War Room
Morning Edition Hour 1
Recorded January 15, 2021

Show Me

Bannon’s War Room
Morning Edition Hour 2
Recorded January 15, 2021

Show Me

Bannon’s War Room
Evening Edition
Recorded January 15, 2021

Show Me

War on Terror Brought Home – Ben and Glenn’s After Hours #4

Show Me

Prisão Preventiva e Abusos Judiciários: Lava Jato, Crivella, Oswaldo: com Augusto de Arruda Botelho – Aprofundando #3

Show Me

Violence in the Capitol, Dangers in the Aftermath

Show Me

True the Vote: Abrams’ Sister’s Ruling Wrong on Law, Clear Conflict

Show Me

Jupiter-Saturn Great Conjunction: Watch Best View Since Middle Ages!

Show Me

Since Election Night The Presidential Winner Has Been In Dispute

Show Me

Sky Watching Highlights for October 2020

Show Me

International Observe the Moon Night 2020

Show Me