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

Graham: Trump Could Make GOP Bigger and Stronger, or He Could Destroy It

Show Me

Manchin Says He’ll Continue to Back $11 Minimum Wage Hike

Show Me

Cuomo to Sign Bill Stripping His Emergency COVID-19 Powers

Show Me

Updates on CCP Virus: Michigan Makes Vaccines Available to the Homeless

Show Me

Dynamite Explosions at Army Base in Equatorial Guinea Kill at Least 15

Show Me

South Korea to Boost Funding for US Troops Under New Accord: State Department

Show Me

Key Players in Trial of Ex-Officer Charged in George Floyd’s Death

Show Me

GOP Pushes Bills to Allow Social Media Censorship Lawsuits

Show Me

Etna Keeps Up Its Spectacular Explosions; Ash Rains on Towns

Show Me

Trump Sends Legal Notices to RNC, NRCC, NRSC to Stop Using His Name and Likeness

Show Me

Yemen’s Houthis Fire Missiles, Drones at Saudi Oil Facilities

Show Me

US Will Do What’s Necessary to Defend Itself After Attack in Iraq, Austin Says

Show Me

Adverse Incident Reports Show 966 Deaths Following Vaccination for COVID-19 (Epoch Times)

Show Me

The Nation Speaks (March 6): Guardian Angel Seeks to Save NYC | Perfect Storm at Border | GA Tackles Election Reform

Show Me

Texas Launches Operation to Counter Growing Crisis at Southern Border

Show Me

Bannon’s War Room | Saturday Edition Hour 1 | Recorded March 6, 2021 | Video: 48 Minutes 52 Seconds

Show Me

Bannon’s War Room | Saturday Edition Hour 2 | Recorded March 6, 2021 | Video: 48 Minutes 17 Seconds

Show Me

March 5, 2021 | Nightly News Rebroadcast | Video: 55 Minutes 16 Seconds

Show Me

Naomi Wolf: We’ve Reached ‘Step Ten’ of the 10 Steps to Fascism

Show Me

As the Insurrection Narrative Crumbles, Democrats Cling to it More Desperately Than Ever

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded March 5, 2021 | Video: 48 Minutes 54 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded March 5, 2021 | Video: 48 Minutes 30 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded March 5, 2021 | Video: 48 Minutes 59 Seconds

Show Me

March 4, 2021 | Nightly News Rebroadcast | Video: 51 Minutes 24 Seconds

Show Me

President Donald J. Trump Speaks | Full CPAC 2021 Speech| Sunday February 28, 2021

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded March 4, 2021 | Video: 48 Minutes 50 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded March 4, 2021 | Video: 48 Minutes 45 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded March 4, 2021 | Video: 48 Minutes 59 Seconds

Show Me

Biden’s Live Feed Was Cut To Avoid Embarrassing Himself | Video: 15 Seconds

Show Me

March 3, 2021 | Nightly News Rebroadcast | Video: 52 Minutes 58 Seconds

Show Me

Green Run Update: Engineers Repair Valve for Mid-March Hot Fire Test

Show Me

March 2, 2021 | Nightly News Rebroadcast | Video: 52 Minutes 58 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded March 3, 2021 | Video: 48 Minutes 46 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded March 3, 2021 | Video: 48 Minutes 46 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded March 3, 2021 | Video: 48 Minutes 59 Seconds

Show Me

Biden’s Protection of Murderous Saudi Despots Shows the Hidden Reality of U.S. Foreign Policy

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded March 2, 2021 | Video: 48 Minutes 51 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded March 2, 2021 | Video: 48 Minutes 55 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded March 2, 2021 | Video: 48 Minutes 59 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded March 1, 2021 | Video: 48 Minutes 48 Seconds

Show Me