Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors

Abstract

Purpose: Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space.

Methods: This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry.

Results: A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression.

Conclusion: Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Trial registration: ClinicalTrials.gov NCT04082572.

FIG 1.

Flow diagram. CR, complete response; PR, partial response; SD, stable disease.

FIG 2.

Waterfall plot of pathologic tumor regression in the primary tumor of resected specimens after neoadjuvant pembrolizumab (n = 15). Patients not depicted above (n = 2): one patient with CRC who underwent surgical resection at an outside facility (ypT4bN0) and one patient with endometrial adenocarcinoma (ypT1aN0) who could not be classified using the tumor regression grade systems used for GI malignancies. CRC, colorectal cancer.

FIG 3.

(A) Waterfall plot showing best overall radiographic responses to neoadjuvant pembrolizumab in resected and unresected patients (n = 33). (B) Spider plot of the change in sum of target lesion diameters from baseline over time for all evaluable patients, RECIST version 1.1 (n = 33). Lines are color-coded on the basis of best overall response. Dash lines represent patients who underwent surgical resection. (C) Swimmer plot showing endoscopic responses of evaluable luminal patients (n = 17). (D) Waterfall plot showing absolute change in highest VAF (%) at baseline before pembrolizumab and at 3 weeks after one cycle of pembrolizumab in patients with baseline positive ctDNA values. CR, complete response; ctDNA, circulating tumor DNA; pCR, pathologic complete response; PD, progressive disease; PR, partial response; SD, stable disease; VAF, variant allele frequency.

FIG 4.

Tumor microenvironment profiling using imaging mass cytometry. (A) Heatmap expression profiles of 14 final annotated clusters (merged from 50 metaclusters) determined by FlowSOM. Accompanying panels show clusters on UMAP and stacked bar plots as a proportion of total cells for NP and P. (B) Boxplots showing differences in abundances of immune cell types as a percentage of total number of cells. Each dot represents one unique region of interest (NP, n = 47 v P, n = 7; t-tests). B, B cells; Gran, granulocytic; Mac, macrophage; Mac_M2, macrophages with CD163⁺CD206⁺; Mono, monocytic; NI (I-IV), various nonimmune cells; NP, nonprogressors; P, progressors; Tc, CD8⁺ T cells; TcTOX, CD8⁺ T cells with TOX^hi; Treg, regulatory T cells.

FIG 5.

Spatial analysis of immune microenvironment. (A) Network visualization of all spatial relationships among 14 cell types for nonprogressors and progressors. Distance relationships among all cell types were calculated based on the mean of all of the shortest distances between one cell to another. Node sizes represent relative abundance of the cell types. Node colors represent major cell types. Edge width and length both represent the relative similarity of neighbors between the two cell types that the edge connects. (B) Representative images from imaging mass cytometry (scale bar: 100 μm). (C) Violin plots of comparing the distances from Tc to other immune cell types in NP and P (number of cell-cell distances: NP, n = 2,802-3,447 v P, n = 235-508; t-tests). CK + ECAD, pan-cytokeratin + e-cadherin; COL + SMA, collagen + alpha-smooth muscle actin; Gran, granulocytic; Lym, lymphoid; Mac, macrophage; Mac_M2, macrophages with CD163⁺CD206⁺; Mono, monocytic; Myl, myeloid; NI, nonimmune; NI (I-IV), various nonimmune cells; NP, nonprogressors; P, progressors; Tc, CD8⁺ T cells; TcTOX, CD8⁺ T cells with TOX^hi; Treg, regulatory T cells.