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

Journalist Andy Ngo Confirms He Was Chased and Beaten in Portland While Covering Antifa

Show Me

Swedish Parliament Committee Says Government Failed in Pandemic Handling

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded June 3, 2021 | Video: 48 Minutes 43 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded June 3, 2021 | Video: 48 Minutes 19 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded June 3, 2021 | Video: 48 Minutes 58 Seconds

Show Me

Jenna Ellis: ‘The Truth Is Always Going To Come Out’ | Video: 7 Minutes 39 Seconds

Show Me

June 2, 2021 | Nightly News Rebroadcast | Video: 50 Minutes 15 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded June 2, 2021 | Video: 48 Minutes 59 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded June 2, 2021 | Video: 48 Minutes 18 Seconds

Show Me

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

Show Me

Fauci Plays Word Games With The Meaning Of Gain of Function | Video: 7 Minutes 22 Seconds

Show Me

June 1, 2021 | Nightly News Rebroadcast | Video: 52 Minutes 45 Seconds

Show Me

Gun sales up 66 percent in California during pandemic: nonprofit

Show Me

Mexico report suggests child sex abuse ring at some schools

Show Me

Va. School District Suspends PE Teacher Who Opposed Transgender Policy. Now, He’s Fighting Back

Show Me

Cyberattack Hits World’s Largest Meat Processing Company JBS, Production Disrupted

Show Me

Moderna applies for full FDA approval of its COVID-19 vaccine

Show Me

Florida State University Settles Discrimination Lawsuit With Catholic Student for Almost $100,000

Show Me

Highly contagious Indian COVID variant spreading rapidly in the US

Show Me

Justices reject Johnson & Johnson appeal of $2B talc verdict

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded June 1, 2021 | Video: 48 Minutes 16 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded June 1, 2021 | Video: 48 Minutes 24 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded June 1, 2021 | Video: 48 Minutes 59 Seconds

Show Me

Apparently, They Knew It All Along | Democrats Decry Voting Machines & Specifically Call Out Georgia | “So much for cybersecurity 101” ~ Democrat Senator Ron Wyden | Video: 2 Minutes 15 Seconds

Show Me

May 31, 2021 | Nightly News Rebroadcast | Video: 49 Minutes 48 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded May 31, 2021 | Video: 46 Minutes 40 Seconds

Show Me

The Unknowns By Sharyl Attkisson | Video 2 Minutes 24 Seconds

Show Me

The dead we honor: Shakespeare for Memorial Day

Show Me

7,300 People Tune in to White House YouTube Channel to Watch 81 Million Vote Recipient Joe Biden Deliver Memorial Day Service Remarks

Show Me

A Personal Memorial Day Memory: Introducing Loyce Deen of Altus, Oklahoma

Show Me

Editorial: This Memorial Day spend time with a veteran and contemplate ways you can help

Show Me

Exclusive — Sen. Tom Cotton on Serving at Arlington Cemetery: If They Sacrificed Their Lives, We Can Sacrifice Time and Comfort for Them

Show Me

On Memorial Day, We Celebrate Such Men And Women Because They Lived

Show Me

28 shot, 2 fatally, over Memorial Day weekend in Chicago

Show Me

Exclusive — Rep. Brian Mast on Memorial Day: The Fallen Are ‘Sewn into the Fabric of America’

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded May 31, 2021 | Video: 46 Minutes 27 Seconds

Show Me

You Know If The Main Stream Media Calls Someone A Monster, They Must Have A True Inner Goodness and Heartfelt Love For America | “Memorial Day Flashback: Young Boy of Fallen Hero Shows President Trump His Father’s Grave” | Video: 48 Seconds

Show Me

“Justice Clarence Thomas: Created Equal” The Documentary That Recounts Thomas Leaving The Violent Left To A Place Of Peace, In His Own Words | Video: 2 Minutes 9 Seconds

Show Me

What Happened To Us On The American Left? | “Justice Clarence Thomas: The Left Is The Enemy Of Free Thought” | Video: 1 Minute 40 Seconds

Show Me

Bannon’s War Room | Saturday Edition Hour 1 | Recorded May 29, 2021 | Video: 48 Minutes 26 Seconds

Show Me