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

Author(s): 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.

Source: N Engl J Med 2022; 386:2363-2376 DOI: 10.1056/NEJMoa220144

Very impressive results that may change treatment-paradigm. However, number of patients treated, and duration of follow-up are significant issues here for early adoption.

ABSTRACT

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.

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.

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.).

Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial

There is hope for organ preservation in rectal preservation. I believe the good news is that waiting is not as harmful. Those who underwent surgery after regrowth almost had the same disease-free survival (DFS) as those who had surgery after treatment because of incomplete response. The use of CtDNA (not analyzed in the trial) may play an even a bigger role where you may not have to wait for clinical regrowth to have the surgery, but of course more trials are needed to see if this will have clinical benefit. (Is the positive or rising CtDNA enough reason to have surgery vs imaging recurrence?)
Still, this is an exciting new era that will see change in treating early-stage colorectal cancer, recall the immunotherapy results in patients who were MMR deficient.

Prospective Correlation of Magnetic Resonance Tumor Regression Grade With Pathologic Outcomes in Total Neoadjuvant Therapy for Rectal Adenocarcinoma

Tumor regression grade defined as the ratio between fibrosis and residual tumor, is routinely used to assess response to therapy and demonstrated to be an important predictor of patient’s outcome. In the era of TNT (total Neoadjuvant Therapy) this will help assess response to avoid surgery. It will be nice to add MRD testing in the blood as another tool.

Preoperative Treatment of Locally Advanced Rectal Cancer

Paradigm shift in rectal cancer therapy? Some may not need surgery, now some may not need radiotherapy.

Neoadjuvant Chemotherapy, Excision, and Observation for Early Rectal Cancer: The Phase II NEO Trial (CCTG CO.28) Primary End Point Results

Nice study showing a non-radiation approach to node-negative, earlier stage, low-lying rectal cancer, using FOLFOX/CAPEOX x 3 months followed by local excision for those with downstaging to T0/T1 disease. 79% of patients achieved organ preservation, and 2-year locoregional RFS was 90%. A good option for those who are not good candidates for radiation yet still want to avoid an APR-type surgery.