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

Delta Cancels Over 100 Flights, Opens Some Middle Seats

Show Me

Forget your phony laptop excuses, Hunter Biden: Devine

Show Me

Fact Check: Major League Baseball Moves All-Star Game over Law that Expands Some Voting

Show Me

The Cabal, As Time Magazine Called Them, Are At It Again | “More Corporations, Including Google, Microsoft, and American Express Denounce Georgia’s Voter Integrity Law”

Show Me

Matt Gaetz’s Stirring Speech On The House Floor Hours After The January 6th Capitol Breach Finalized Putting A Target On His Back | Video: 4 Minutes 15 Seconds

Show Me

In rural Minnesota, where cops and community are familiar, Derek Chauvin trial looks different

Show Me

Vaccinations Rise, but Variants and Factory Mix-Up Present Hurdles

Show Me

Iowa governor signs bill allowing permitless purchase, carry of handguns

Show Me

Beijing Accelerating Timeline for Possible Invasion of Taiwan, Expert Warns

Show Me

Crowds gather at holy sites across Jerusalem for Easter as the country unlocks

Show Me

Commentary: History of Easter

Show Me

Why Is Jesus Still Wounded After His Resurrection?

Show Me

Hackers leak phone numbers and personal data from 533 MILLION Facebook users online 

Show Me

Facebook removes Capitol attack suspect’s page

Show Me

Virgil: The Great Reset Continues — Facebook’s New Imperial Order 

Show Me

Zuckerberg-Funded Group Spent over $30 Million in Texas in the 2020 Election

Show Me

Mark Zuckerberg’s cellphone number goes online after massive Facebook hack

Show Me

Facebook data on more than 500M accounts found online

Show Me

Clear Thinking on Elections from Clarence Thomas

Show Me

Psaki Doubles Down On Biden’s ‘Four Pinocchio’ Claim That Georgia Election Bill Ends Voting Hours Early

Show Me

Major League Baseball bends to bullies, endorses lies about Georgia voting law

Show Me

South Carolina Democrat Introduces Bill Banning Minors from Gender-Reassignment Surgery

Show Me

Sen Paul blasts libs for ‘implying that people of certain races are not able to comply with rules’

Show Me

Our Species Is Enduring Largest Uncontrolled Experiment Ever, We Shouldn’t Ignore Vanden Bossche’s Warning

Show Me

Democrat Leaders Welcome MLB All-Star Game to Their States: Georgia Election Law Saga

Show Me

Georgia governor on growing backlash to election reform law: ‘We are not backing down’

Show Me

Is Dominion Voting Systems The Only Platform In The History Of Technology To Be Beyond Hacking As Dominion CEO Claimed Under Oath During Election 2020 Testimony? | Mike Lindell’s Second Television Special In Response | Video: 55 Minutes 39 Seconds

Show Me

Will Joe Biden walk back these comments after son Hunter admits laptop ‘could’ be his?

Show Me

Hunter Biden was ‘smoking crack every 15 minutes,’ his memoir ‘Beautiful Things’ reveals

Show Me

GOP Senators Demand Intelligence Records on Hunter Biden’s Dealings with Chinese Energy Conglomerate

Show Me

NPR issues stunning mea culpa after claiming Hunter Biden laptop story was ‘discredited’ by intelligence

Show Me

NPR Issues Correction After Falsely Claiming US Intelligence ‘Discredited’ Hunter Biden Laptop Story

Show Me

Hunter Biden: Ukraine Laptop ‘Could’ Be His but Says He Possibly Hacked by Russians

Show Me

Hunter Biden admits infamous laptop could be his, throwing media narrative for a loop

Show Me

NPR issues major correction on Hunter Biden laptop, Hunter admits laptop could be his

Show Me

Hunter Biden will talk about drug intervention, notorious laptop in CBS interviews

Show Me

Hunter Biden says he doesn’t remember having sex with Lunden Roberts

Show Me

Hunter Biden Addresses Laptop Saga for the First Time

Show Me

Text messages that allegedly sparked fed probe into Matt Gaetz emerge

Show Me

Matt Gaetz’ Communications Director Resigns Amid Sexual Allegations Scandal

Show Me