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PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer

List of authors.
  • Andrea Cercek, M.D.,
  • Melissa Lumish, M.D.,
  • Jenna Sinopoli, N.P.,
  • Jill Weiss, B.A.,
  • Jinru Shia, M.D.,
  • Michelle Lamendola-Essel, D.H.Sc.,
  • Imane H. El Dika, M.D.,
  • Neil Segal, M.D.,
  • Marina Shcherba, M.D.,
  • Ryan Sugarman, M.D., Ph.D.,
  • Zsofia Stadler, M.D.,
  • Rona Yaeger, M.D.,
  • J. Joshua Smith, M.D., Ph.D.,
  • Benoit Rousseau, M.D., Ph.D.,
  • Guillem Argiles, M.D.,
  • Miteshkumar Patel, M.S.,
  • Avni Desai, M.D.,
  • Leonard B. Saltz, M.D.,
  • Maria Widmar, M.D.,
  • Krishna Iyer, M.D., Ph.D.,
  • Janie Zhang, M.D.,
  • Nicole Gianino, M.S.,
  • Christopher Crane, M.D.,
  • Paul B. Romesser, M.D.,
  • Emmanouil P. Pappou, M.D., Ph.D.,
  • Philip Paty, M.D.,
  • Julio Garcia-Aguilar, M.D.,
  • Mithat Gonen, Ph.D.,
  • Marc Gollub, M.D.,
  • Martin R. Weiser, M.D.,
  • Kurt A. Schalper, M.D., Ph.D.,
  • and Luis A. Diaz, Jr., M.D.



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.


Download a PDF of the Research Summary.

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.


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.


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; number, NCT04165772.)

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PD-1 Blockade in Locally Advanced Rectal Cancer

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Funding and Disclosures

Supported by the Simon and Eve Colin Foundation, GlaxoSmithKline, Stand Up to Cancer, Swim Across America, and the National Cancer Institute of the National Institutes of Health (awards R21CA252519 and NCI-P30CA008748).

Disclosure forms provided by the authors are available with the full text of this article at

This article was published on June 5, 2022, at

A data sharing statement provided by the authors is available with the full text of this article at

We thank the participating patients and their families; the study team; and Mary Lynne Hedley, Ph.D., Leon O. (Lonnie) Moulder, Jr., M.B.A., Martin Huber, M.D., and the team at Tesaro (now part of GlaxoSmithKline) for their initial support of this study.

Author Affiliations

From the Division of Solid Tumor Oncology (A.C., M.L., J. Sinopoli, J.W., M.L.-E., I.H.E.D., N.S., M.S., R.S., Z.S., R.Y., B.R., G.A., M.P., A.D., L.B.S., L.A.D.) and the Departments of Pathology (J. Shia), Surgery (J.J.S., M.W., E.P.P., P.P., J.G.-A., M.R.W.), Radiation Oncology (C.C., P.B.R.), Epidemiology and Biostatistics (M. Gonen), and Radiology (M. Gollub), Memorial Sloan Kettering Cancer Center, New York; and the Department of Pathology, Yale University School of Medicine, New Haven, CT (K.I., J.Z., N.G., K.A.S.).

Dr. Cercek can be contacted at or at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065. Dr. Diaz can be contacted at or at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065.