CMTM6 expression in M2 macrophages is a potential predictor of PD-1/PD-L1 inhibitor response in colorectal cancer

Abstract Background CMTM6 is a novel key regulator of PD-L1. High expression of both CMTM6 and PD-L1 may predict the benefit of PD-1 axis blockade in lung cancer. We aimed to investigate the expression pattern of CMTM6 between mismatch repair-defective (dMMR) and mismatch repair-proficient (pMMR) colorectal cancer (CRC) tissues and assess its correlation with the response to PD-1/PD-L1 pathway blockade. Methods Immunohistochemistry (IHC) was used to analyze CMTM6 and PD-L1 expression and immune cell density in dMMR/pMMR CRC. Quantitative multiplex immunofluorescence (IF) was performed to detect CMTM6, PD-L1, CD4, CD8, CD68 and CD163 expression in CRC patients treated with PD-1/PD-L1 inhibitors. Result IHC analysis showed that CMTM6 and PD-L1 were both expressed in tumor cells (TCs) and invasion front immune cells (ICs). CMTM6 and PD-L1 expression and CD4+, CD8+, CD68+ or CD163+ cell density were significantly higher in dMMR CRC patients than in pMMR CRC patients. CMTM6 expression was positively correlated with PD-L1 expression and CD163+ M2 macrophage density in dMMR CRC. IF analysis showed that the coexpression rate of CMTM6/PD-L1 and the expression rate of CMTM6 in CD8+ T cells and CD163+ M2 macrophages were significantly increased in the group that exhibited clinical benefit. CMTM6 expression in M2 macrophages was identified as the best biomarker for predicting the responsiveness to PD-1/PD-L1 inhibitors. Conclusions CMTM6 expression in M2 macrophages may predict the PD-1/PD-L1 inhibitor response rate in CRC patients more accurately than dMMR/microsatellite instability-high (MSI-H) status. It can also identify pMMR CRC patients who could benefit from PD-1/PD-L1 inhibitors.

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641 Spatially organized multicellular immune hubs in MMRd and MMRp colorectal cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.641 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A670-A670

Author(s):

Jonathan Chen ◽

Karin Pelka ◽

Matan Hofree ◽

Marios Giannakis ◽

Genevieve Boland ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Mismatch Repair ◽

Molecular Mechanisms ◽

Immune Cell ◽

Single Cells ◽

Large Set ◽

Colon Tissue

BackgroundImmune responses to cancer are highly variable, with DNA mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. Almost all tumors are infiltrated with immune cells, but the types of immune responses and their effects on tumor growth, metastasis and death, vary greatly between different cancers and individual tumors. Which of the numerous cell subsets in a tumor contribute to the response, how their interactions are regulated, and how they are spatially organized within tumors remains poorly understood.MethodsTo understand the rules governing these varied responses, we transcriptionally profiled 371,223 single cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd treatment-naive patients. We developed a systematic approach to discover cell types, their underlying gene programs, and cellular communities based on single cell RNA-seq (scRNAseq) profiles and applied it to study the distinguishing features of human MMRd and MMRp colorectal cancer. Cellular communities discovered from this analysis were spatially mapped in tissue sections using multiplex RNA in situ hybridization microscopy.ResultsTo understand the basis for differential immune responses in CRC, we first determined and compared the immune cell composition of MMRd and MMRp CRC and normal colon tissue, finding dramatic remodeling between tumor and normal tissue and between MMRd and MMRp tumors, particularly within the myeloid, T cell, and stromal compartments. Among the clusters enriched in MMRd tumors were activated CXCL13+ CD8 T cells. Importantly, gene program co-variation analysis revealed multicellular networks. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage, and an MMRd-enriched immune hub within the tumor, with activated IFNG+ and CXCL13+ T cells together with malignant and myeloid cells expressing T-cell-attracting chemokines (figure 1).ConclusionsOur study provides a rich dataset of cellular states, gene programs and their transformations in tumors across a relatively large cohort of patients with colorectal cancer. Our predictions of several multicellular hubs based on co-variation of gene expression programs, and subsequent spatial localization of two major immune-malignant hubs, organizes a large set of cell states and programs into a smaller number of coordinated networks of cells and processes. Understanding the molecular mechanisms underlying these hubs, and studying their temporal and spatial regulation upon treatment will be critical for advancing cancer therapy.Ethics ApprovalThis study was approved by the DF-HCC institutional review board (protocols 03-189 and 02-240).Abstract 641 Figure 1A coordinated network of CXCL13+ T cells with myeloid and malignant cells expressing ISGs. Image shows a portion of formalin-fixed paraffin-embedded tissue from an MMRd CRC specimen stained with multiplex RNA ISH / IF for PanCK-IF, CD3E-ISH, CXCL10/CXCL11-ISH, CXCL13-ISH, and IFNG-ISH. Note IFNG+ and CXCL13+ cells in proximity to cells expressing the chemokines CXCL10/CXCL11

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Establishment and Validation of a Genetic Label Associated With M2 Macrophage Infiltration to Predict Survival in Colon Cancer Patients and Assist Immunotherapy

10.21203/rs.3.rs-712255/v1 ◽

2021 ◽

Author(s):

Boyang Xu ◽

Ziqi Peng ◽

Guanyu Yan ◽

Ningning Wang ◽

Moye Chen ◽

...

Keyword(s):

Colon Cancer ◽

Microsatellite Instability ◽

Cancer Patients ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Macrophage Infiltration ◽

M2 Macrophage ◽

High Morbidity ◽

M2 Macrophages ◽

Hub Genes

Abstract Background: Colon cancer is a kind of malignant tumor with high morbidity and mortality. Researchers have tried to interpret it from different perspectives and divide it into different subtypes in order to achieve individualized treatment. With the rise of immunotherapy, its value in the field of tumor has initially emerged. Based on the above background, from the perspective of immune infiltration, this study classified colon cancer according to the infiltration of M2 macrophages in patients with colon cancer and further explored it.Methods: Cibersort was used to analyze the level of immune cell infiltration in colon cancer patients in the TCGA database. WGCNA, Consensus Clustering analysis, Lasso analysis, and univariate KM analysis were used to screen and verify the hub genes associated with M2 macrophages. PCA was used to establish the M2 macrophage-related score—M2I Score. The correlation between M2I Score and somatic cell variation and microsatellite instability were analysed. Furthermore the correlation between M2 macrophage score and differences in immunotherapy sensitivity was also explored. Results: M2 macrophage infiltration was associated with poor prognosis. Four hub genes (ANKS4B, CTSD, TIMP1, and ZNF703) were selected as the progression-related genes associated with M2 macrophages. A stable and accurate M2I Score for M2 macrophages used in COAD was constructed based on four hub genes. M2I Score was positively correlated with tumor mutation load (TMB). The M2I Score of MSI-H group was higher than that of MSI-L group and MSS group. Combine with the TCIA database, we concluded that patients with a high M2I Score were more sensitive to PD-1 inhibitors and PD-1 inhibitors combined with CTLA-4 inhibitors. The low rating group may have better efficacy without immune checkpoint inhibitors or with CTLA4 inhibitors alone.Conclusion: Four prognostic hub genes associated with M2 macrophages were screened to establish the M2I Score and divided the patients into two subgroups: high M2I Score group and low M2I Score group. TMB, microsatellite instability and sensitivity to immunotherapy were higher in the high-rated group. PD-1 inhibitors or PD-1 combined with CTLA-4 inhibitors are preferred for patients in the high-rated group who are more sensitive to immunotherapy.

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First Case Report of a Dramatic Radiographic Response to a Checkpoint Inhibitor in a Patient With Proficient Mismatch Repair Gene Expressing Metastatic Colorectal Cancer

JCO Precision Oncology ◽

10.1200/po.16.00005 ◽

2017 ◽

pp. 1-4 ◽

Cited By ~ 2

Author(s):

Steven Sorscher ◽

Jamie Resnick ◽

Michael Goodman

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Mismatch Repair ◽

Response Rate ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

The United States ◽

Mismatch Repair Gene ◽

Repair Gene ◽

First Case

Metastatic colorectal cancer (mCRC) remains the second most common cause of cancer death in the United States, and therapeutic options are limited. Recently, the checkpoint inhibitor pembrolizumab was given the Food and Drug Administration breakthrough therapy designation for the treatment of patients with mCRC whose tumors demonstrate deficient mismatch repair gene (dMMR) expression (as evidenced by microsatellite instability–high [MSI-H]). The designation was based on a phase II study showing that in patients with dMMR, an objective response rate of 40% was seen, whereas in patients with proficient mismatch repair gene mCRCs, the response rate was 0%. To our knowledge, this is the first case of a patient with a proficient mismatch repair gene mCRC whose tumor demonstrated a dramatic response to a checkpoint inhibitor. Because this patient’s tumor harbored amplification of both the PD-L1 and PD-L2 genes, the observed response was consistent with the presumed mechanism of action of checkpoint inhibitors. Checkpoint inhibitors are thought to activate a cytotoxic immune response that has been inhibited through tumor expression of PD-L1 and PD-L2. Given this result, dMMR in mCRC may not be the only predictor of responsiveness to checkpoint inhibition. As in non–small-cell lung cancer, PD-L1 or PD-L2 expression (or perhaps gene amplification) may also be predictors of checkpoint inhibitor efficacy.

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Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00991-2 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Senlin Zhao ◽

Yushuai Mi ◽

Bingjie Guan ◽

Binbin Zheng ◽

Ping Wei ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Molecular Mechanisms ◽

Macrophage Polarization ◽

In Vitro Assays ◽

Luciferase Reporter ◽

M2 Macrophage ◽

M2 Macrophages ◽

Premetastatic Niche ◽

Niche Formation

Abstract Background Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. Methods Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. Results In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. Conclusions These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.

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A Study of the Correlation Between M2 Macrophages and Lymph Node Metastasis of Colorectal Cancer

10.21203/rs.3.rs-136192/v1 ◽

2020 ◽

Author(s):

Yanping Wang ◽

Jikun Wang ◽

Jinhao Liu ◽

Zuoxiu Shi ◽

Yanlei Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Lymph Node ◽

Lymph Node Metastasis ◽

Lymph Nodes ◽

Comprehensive Treatment ◽

M2 Macrophage ◽

M2 Macrophages ◽

Metastatic Lymph Nodes ◽

Node Metastasis ◽

Metastatic Lymph

Abstract Background: Lymph node metastasis is a major prognostic factor of colorectal cancer and an important indicator for individualized treatment. M2 macrophages play a key role in carcinogenesis and tumor development, not only enhancing invasiveness, but also promoting lymph node metastasis. The purpose of this study was to investigate the effect of CD163-positive M2 macrophages on lymph node metastasis in colorectal cancer.Methods: Postoperative lymph node tissues were obtained from 120 patients with colorectal cancer who underwent radical surgery in the First Affiliated Hospital of Jinzhou Medical University between December 2019 and May 2020. We detected the expression of the CD163 protein in lymph nodes by immunohistochemistry. Furthermore, the relationship between M2 macrophages identified by this marker and lymph node metastasis were analyzed using the independent sample T-test and Chi-square test.Results: M2 macrophages were increased not only in metastatic lymph nodes, but also in non-metastatic lymph nodes adjacent to the cancer. The M2 macrophage count was higher in patients with macro-metastases than in those with micro-metastases.Conclusions: M2 macrophages represent an important factor for the promotion of lymph node metastasis in colorectal cancer, and may be a potential marker for its prediction. This may offer a new target for the comprehensive treatment of colorectal cancer.

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Spatial analysis of tumor immune microenvironment (TIME) in patients treated with Bintrafusp alfa.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3070 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3070-3070

Author(s):

Houssein Abdul Sater ◽

Jeffrey Robinson ◽

Julius Strauss ◽

Margaret Elena Gatti-Mays ◽

Jason Redman ◽

...

Keyword(s):

T Cell ◽

Immune Cell ◽

Nk Cell ◽

Cd8 T Cell ◽

Tumor Control ◽

M2 Macrophage ◽

M2 Macrophages ◽

M1 Macrophages ◽

Linear Discriminant ◽

Number Of Patients

3070 Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII receptor (TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In preclinical models, bintrafusp alfa treatment promoted CD8+ T cell and NK cell activation, and both immune cell (IC) populations were required for optimal bintrafusp alfa mediated tumor control. However, the effect of bintrafusp alfa on TIME in humans has not been reported. Methods: In this unplanned interim analysis of a biomarker expansion cohort (NCT 02517398), patients (pts) with advanced non-small cell lung cancer (NSCLC) underwent paired biopsies (bx) before and on treatment with bintrafusp alfa (~ 50 days apart). The objective was to evaluate frequency and localization of tumor infiltrated ICs by IHC. Out of 12 pts, 7 had matched (Pre vs Post) tumor-containing specimens sufficient for multiplex immunofluorescence (MxIF) analysis of TIME. Four pts were excluded as Post bx histology for 3/12 [2 PR (partial response), 1 SD (stable disease)] was negative for tumor (necrosis or fibrosis) and 1/12 did not have a Post bx performed. Results: TIME study shows CD8 T cell infiltrates were increased in Post compared to Pre bx (median 161 vs 62/mm²; interquartile range [IQR] 65–396/mm² vs 31–135/mm²; p = 0·04). While M2 macrophages were also increased (median 800 vs 367/mm²; IQR 776–1131/mm² vs 171–831/mm²; p = 0·04), the ratio of M1/M2 was reversed in pts with SD (↑) compared to pts with PD (↓). Other ICs such as CD4, T-regs, NK cells and M1 macrophages were not changed. On average compared to baseline, M2 macrophages were > 2 fold closer to every other IC in pts with PD, but > 2 fold further from any IC in pts with SD. Tregs were relatively closer to other IC in PD pts. Linear Discriminant Analysis was also performed and results indicate that differential IC densities (mainly M1 macrophages and CD4 T cells) do perform as classifiers between long ( > 5 months) and short ( < 5 months) term responses. Conclusions: This study suggests that bintrafusp alfa not only can enhance intratumoral effector IC infiltrates (CD8) but also has a modulating effect on the spatial distribution of both M1/M2 macrophages within the NSCLC TIME. The differential proximity of M2 macrophages to other IC infiltrates and changes in M1/M2 ratios in association with response suggests that an M1/M2 macrophage balance is directly involved in response and/or resistance to bintrafusp alfa. Given the limited number of patients in this cohort, we intend to study effects of bintrafusp alfa in a larger cohort of patients. Clinical trial information: 02517398 .

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First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study

Journal of Clinical Oncology ◽

10.1200/jco.21.01015 ◽

2021 ◽

Author(s):

Heinz-Josef Lenz ◽

Eric Van Cutsem ◽

Maria Luisa Limon ◽

Ka Yeung Mark Wong ◽

Alain Hendlisz ◽

...

Keyword(s):

Colorectal Cancer ◽

Adverse Events ◽

Mismatch Repair ◽

Clinical Benefit ◽

Objective Response Rate ◽

Low Dose ◽

Response Rate ◽

Objective Response ◽

First Line

PURPOSE Nivolumab received US Food and Drug Administration approval as a single agent or in combination with ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on CheckMate 142. Presented are results of nivolumab plus low-dose ipilimumab in the first-line therapy cohort from the phase II CheckMate 142 study. PATIENTS AND METHODS Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression. The primary end point was objective response rate (investigator assessment; RECIST v1.1). RESULTS Median age of treated patients was 66 years (N = 45). Median follow-up was 29.0 months. Objective response rate and disease control rate were 69% (95% CI, 53 to 82) and 84% (95% CI, 70.5 to 93.5), respectively, with 13% complete response rate. Median duration of response was not reached; 74% of responders had ongoing responses at data cutoff. Median progression-free survival and median overall survival were not reached with minimum follow-up of 24.2 months (24-month rates, 74% and 79%, respectively). Clinical benefit was observed regardless of baseline demographic and tumor characteristics, including BRAF or KRAS mutation status. In a post hoc analysis, of 14 patients who discontinued treatment and did not receive subsequent therapy, 10 remained progression-free. Patient-reported outcomes were stable over the treatment period. Grade 3-4 treatment-related adverse events occurred in 22% of patients; 13% discontinued because of any-grade treatment-related adverse events. CONCLUSION Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR mCRC. Based on these promising data, randomized studies are warranted.

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Tumor Microenvironment Immune Response in Pancreatic Ductal Adenocarcinoma Patients Treated With Neoadjuvant Therapy

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djaa073 ◽

2020 ◽

Cited By ~ 1

Author(s):

Theodoros Michelakos ◽

Lei Cai ◽

Vincenzo Villani ◽

Francesco Sabbatino ◽

Filippos Kontos ◽

...

Keyword(s):

Immune Response ◽

Tumor Microenvironment ◽

Pancreatic Ductal Adenocarcinoma ◽

Neoadjuvant Therapy ◽

Cell Density ◽

Antitumor Immune Response ◽

Ductal Adenocarcinoma ◽

M2 Macrophage ◽

Macrophage Density ◽

Cd8 Cell

Abstract Background Neoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC. Methods Clinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD4+, FoxP3+, CD8+, granzyme B+ cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided. Results Two hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II expression was lowest in photon and highest in proton patients (P = .02). The FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (P < .001). FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory (FoxP3+) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival. Conclusions Neoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8+ cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients’ antitumor immune response.

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Combined prognostic value of CD274 (PD-L1)/PDCDI (PD-1) expression and immune cell infiltration in colorectal cancer as per mismatch repair status

Modern Pathology ◽

10.1038/s41379-019-0219-7 ◽

2019 ◽

Vol 32 (6) ◽

pp. 866-883 ◽

Cited By ~ 9

Author(s):

Maarit Ahtiainen ◽

Erkki-Ville Wirta ◽

Teijo Kuopio ◽

Toni Seppälä ◽

Juha Rantala ◽

...

Keyword(s):

Colorectal Cancer ◽

Mismatch Repair ◽

Prognostic Value ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Mismatch Repair Status

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Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164

Journal of Clinical Oncology ◽

10.1200/jco.19.02107 ◽

2020 ◽

Vol 38 (1) ◽

pp. 11-19 ◽

Cited By ~ 81

Author(s):

Dung T. Le ◽

Tae Won Kim ◽

Eric Van Cutsem ◽

Ravit Geva ◽

Dirk Jäger ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Growth Factor ◽

Mismatch Repair ◽

Response Rate ◽

Objective Response ◽

Open Label ◽

Open Label Study ◽

Label Study ◽

Duration Of Response

PURPOSE KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) colorectal cancer (CRC). METHODS This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti–vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A. CONCLUSION Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

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