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

‘They Beat His A** and I Recorded It’: Thugs Assault Cop While Bystanders Laugh

Show Me

Teyana Taylor Becomes First Black Woman To Be Named Maxim’s ‘Sexiest Woman Alive’

Show Me

More than 100 New Yorker and other Condè Nast employees protest outside Anna Wintour’s townhouse

Show Me

NYC condo sells for $157.5M — one block from homeless shelter

Show Me

Never-Before-Seen Records Reveal How Bezos, Musk, Other Top Billionaires Pay Almost Zilch in Income Taxes

Show Me

North Carolina County Shows How You Fight Back Against Woke Corporate Bullies

Show Me

Megyn Kelly: When Biden Called America A ‘Racist Country’ He ‘Had Someone Very Near’ In Mind After Hunter’s N-Word Texts Surfaced

Show Me

Canada Grapples With Anti-Muslim Bias After Family Killed in Truck Attack

Show Me

Hospital Suspends 178 Workers for Not Complying With COVID-19 Vaccine Mandate

Show Me

Editorial: When will California’s state of emergency stop being an emergency?

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded June 9, 2021 | Video: 48 Minutes 30 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded June 9, 2021 | Video: 48 Minutes 6 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded June 9, 2021 | Video: 48 Minutes 58 Seconds

Show Me

Man With Prior Sex Crime Conviction Sentenced To 29 Years For Enticing Boys To Send Sexually Explicit Images

Show Me

White House: Biden considers Manchin a friend despite latest policy break

Show Me

Netanyahu’s Likely Departure Is Not Easing the Fears of Palestinians

Show Me

The Enduring Myths of ‘Raiders of the Lost Ark’

Show Me

‘TRUE DAT N***A’: Hunter Biden Frequently Used Urban Slang In Texts With White Lawyer, Saved Meme Of His Dad Calling Barack Obama A ‘N***a’

Show Me

EXPLAINED: ‘Breaking the News’ Reveals Tricks the Media Use to Contort Every Story to Fit Their Agenda

Show Me

Alzheimer’s drug approved despite not one FDA adviser recommending it

Show Me

Inside Durham’s Investigation: Deep State Strikes Back | Truth Over News

Show Me

Epshteyn: 25% of Ballot Boxes in Maricopa Do Not Match

Show Me

June 8, 2021 | Nightly News Rebroadcast | Video: 45 Minutes 38 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded June 8, 2021 | Video: 48 Minutes 31 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded June 8, 2021 | Video: 48 Minutes 25 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded June 8, 2021 | Video: 48 Minutes 58 Seconds

Show Me

Big Tech Watches Tide Turning on Taxes After Its Years of Plenty

Show Me

Biden’s DOJ Vows to Stop Spying on Journalists Months After Placing Gag Order on New York Times

Show Me

AP wins 2 RFK Journalism Awards

Show Me

EXCLUSIVE As China plans new rules, global automakers move to store car data locally

Show Me

Black Conservative Gives Pro-America, Anti-Biden Speech That Will Have You Run Through a Wall

Show Me

Lightfoot’s Attorneys Promise To Clarify Policy That Denied Interviews To White Journalists

Show Me

More Latinos Bid ‘Adios’ to Democrats

Show Me

Microsoft Appears to Censor 1989 Tank Man Image

Show Me

Former Bush Press Secretary supports a Trump outsider party vs DC insider one

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded June 7, 2021 | Video: 48 Minutes 04 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded June 7, 2021 | Video: 48 Minutes 20 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded June 7, 2021 | Video: 48 Minutes 59 Seconds

Show Me

Microsoft Blocks Images of Tiananmen Square Protests on Massacre Anniversary

Show Me

The COVID-19 Pandemic Should End Science as an Institution. We Need Full Public Hearings

Show Me