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

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. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).

Figure 1.. Evolution of Endoscopic and Radiographic Response in Representative Patients Treated with Dostarlimab.

Shown are the results of endoscopic evaluations, T2-weighted MRI of the rectum, and ¹⁸F-fluorodeoxyglucose–positron-emission tomography (FDG-PET) for two representative patients at baseline and at 3 months and 6 months. Panel A (Patient 2) shows an endoscopic complete response and a near-complete response on T2-weighted rectal MRI at 3 months and a clinical complete response at 6 months. Panel B (Patient 9) shows an endoscopic complete response and a radiographic complete response at 3 months. Arrows identify the tumor at each time point. Diffusion-weighted images of the rectum for these two patients are provided in Figure S2 in the Supplementary Appendix.

Figure 2.. Biopsy Specimens of the Rectum before and after PD-1 Blockade and Viable Tumor Cell Content.

Hematoxylin and eosin staining of representative biopsy specimens obtained at baseline (Panels A and B) shows examples of viable tumor cells (Panel A, asterisk) surrounded by necrosis (Panel A, arrow) and extensive necrosis and inflammation with scant viable tumor cells (Panel B). Staining of representative biopsy specimens obtained at 3 months after initiation of treatment (Panel C) shows the presence of acellular residual mucin pools (arrow). Also shown (Panel D) are the estimated percentages of viable tumor cells on pathological examination of specimens obtained before treatment (baseline), during treatment (6 weeks through 6 months), and during follow-up in 10 patients. PD-1 denotes programmed death 1.

Figure 3.. Immune Contexture Changes after PD-1 Blockade in Rectal Tumors and Mucosa.

Representative multicolor fluorescence images (Panel A) show tumor and normal epithelial cells that are positive for cytokeratin, programmed death ligand 1 (PD-L1) protein, CD8+ T lymphocytes, and CD20+ B lymphocytes in rectal biopsy samples that were obtained at baseline and after 6 weeks, 3 months, and 6 months of PD-1 blockade. Changes in the levels of PD-L1 protein (Panel B), CD8+ T lymphocytes (Panel C), and CD20+ B lymphocytes (Panel D) that were selectively measured in the total tissue areas, in the cytokeratin-positive tumor and normal epithelial cell areas (labeled as “epithelial”), and in the cytokeratin-negative stromal tissue compartment are shown across multiple biopsy time points before and after initiation of treatment. Also shown are the mean factor change ±SE (I bars) of each marker relative to baseline levels in each patient for whom tissue samples could be evaluated. In addition, mean ±SE (T bars) quantitative immunofluorescence (QIF) scores of PD-L1 protein (Panel B), CD8+ T lymphocytes (Panel C), and CD20+ B lymphocytes (Panel D) that were selectively measured in tumor and normal epithelial cells and in stromal cells in biopsy samples obtained at baseline, during treatment (week 6 through month 6), and after treatment are shown. The number of individual samples included in each group is indicated above each bar. P values were calculated with the use of the Mann–Whitney test. DAPI denotes 4′,6-diamidine-2-phenylindole.