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

Top Scientists In The World Warned The Public Against Mass mRNA ‘Vaccination’ | 60 Percent Of Israel’s 514 Hospitalized Patients With SEVERE Covid-19 Symptoms Are Fully Vaccinated

Show Me

More Than Half of Israeli COVID-19 Patients Vaccinated as ‘Breakthrough Cases’ Rise

Show Me

Once Again, Despite Covid mRNA ‘Vaccination’ in UK Reaching 90% Of Population | “UK’s Covid cases rise again with 33,904 positive tests, marking a 15% week-on-week jump”

Show Me

Here Are The UK Covid-19 ‘Vaccination’ Numbers Reported By The BBC

Show Me

Texas Supreme Court sides with GOP, allowing arrest of absent House Democrats

Show Me

Stunning Poll Reveals Trump Would Win Election Held Today, as Nearly 1 in 10 Democrats ‘Regret’ Their 2020 Vote.

Show Me

Where’s Joe? Biden Hides at Camp David While Kabul Burns

Show Me

Jerusalem Is on Fire

Show Me

T-Mobile Says Data on Over 48 Million People Stolen by Hackers

Show Me

Taliban Tweets About Working Out and Eating Ice Cream Because This Situation Isn’t Absurd Enough

Show Me

Tyrannical Governments Always Practice Gun Control | “Taliban reportedly confiscating weapons from Afghan civilians”

Show Me

Man charged with attempted murder of two Chicago police officers after allegedly dragging one 40 feet with car

Show Me

‘Joe’s leading lambs to slaughter’: Trump tears into Biden for abandoning Afghans to the Taliban 

Show Me

Rubio Demands Biden Ban TikTok Over Chinese Communist Party Connection

Show Me

CDC Creates Center to Forecast Disease Outbreaks, Issue Warnings

Show Me

Biden administration urges COVID booster shots after 8 months

Show Me

Apple says researchers can vet its child safety features. It’s suing a startup that does just that.

Show Me

Governor Abbott Proves Once Again That The mRNA Covid Shot Does Not Prevent Infection, Incubation and Transmission Of Covid-19

Show Me

“Lasting immunity found after recovery from COVID-19” Without Any Vaccines | NIH

Show Me

Elon Musk says he supports COVID-19 vaccines after questioning safety

Show Me

‘I’M NOT AT RISK’ Elon Musk slams Bill Gates as a ‘knucklehead’ and ‘stupid person’ – and defends vow not to take coronavirus vaccine

Show Me

Covid-19 A Child Killer? Think again. | “Pediatric Flu Deaths During 2019-2020 Reach New High” by CDC

Show Me

Tennessee Seizes Thousands of Counterfeit COVID-19 Vaccination Cards Shipped From China

Show Me

COVID-19: China Owes the World $35 Trillion in Compensation

Show Me

Biden reps ‘most diabolical presidency and party, probably since slavery’: Mark Levin

Show Me

Taliban Enters Kabul, President and Diplomats Flee

Show Me

Don’t Call It ‘Breastfeeding’ When You Can Refer to It as ‘Parent’s Milk’

Show Me

Georgia Fulton County Elections Chief Ralph Jones Resigns – He Ran the Late Night Ballot Dump Operation in Atlanta

Show Me

Henry County Judge Surprises Many with New Ruling in Fulton County Mail-in Ballot Inspection Case

Show Me

What a Piece of Work – We Caught Him Again: Self-Described Colorado ‘Republican’ Matt Crane Caught at Dominion Party with Democrat Leaders and Eric Coomer

Show Me

To Many Americans, It’s Apparent That Fraud In Election 2020 Cost Donald J. Trump The Presidency | Video: 16 Minutes 29 Seconds

Show Me

Symposium Demonstrating How Donald Trump Won Election 2020 Attacked | Cyber Expert House Raided and Electronics Stolen | Mike Lindell Attacked At His Hotel | There Was A ‘Poison Pill’ Injected Into The Symposium Data

Show Me

Next Up, Vaccine Resistant COVID Lambda Variant From Central and South America, The 2022 Mid-Term Lock-down and Mail-In Ballot Variant

Show Me

Man Charged With Murdering 18-Year-Old 2 Days After Being Released From Prison Due To COVID-19: REPORT

Show Me

Former CBP Chief: Potentially 40K COVID-Positive Illegal Aliens Released into U.S. by Biden’s DHS

Show Me

EU Countries Making COVID-19 Vaccines Mandatory

Show Me

Los Angeles Councilmembers Introduce Motion to Ban Ghost Guns

Show Me

He Fits Right In With Biden’s Own Past | “Biden ATF nominee accused of racism, hiding statements from lawmakers”

Show Me

Delta Variant “Not a Game Changer,” says Dr. Martin Kulldorf | American Thought Leaders | Video: 10 Minutes 56 Seconds

Show Me

Antonella Marty: How Socialist, Communist Ideology Took Over Cuba, Latin America

Show Me