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Phase II Study of Pembrolizumab Plus Capecitabine and Bevacizumab for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer

ABSTRACT: Background: This study evaluated the safety, tolerability and preliminary efficacy of pembrolizumab in combination with capecitabine and bevacizumab in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Patients and Methods: Patients with MSS/pMMR mCRC with stable or progressive disease on prior fluoropyrimidine-based therapy received capecitabine 1000 mg/m2 by mouth twice daily days 1-14, bevacizumab 7.5 mg/kg day 1, and pembrolizumab 200 mg day 1 every 3 weeks. The primary endpoint was overall response rate by RECIST 1.1. Secondary endpoints were safety, duration of response, progression-free survival (PFS), and overall survival (OS). Results: Forty-four patients were enrolled between April 2018 and October 2021. Median follow up time was 9.3 months, while median time on treatment was 6 months. Overall response rate for 40 evaluable patients was 5% with median duration of response of 13.5 months. Median PFS was 4.1 months and median OS was 10.1 months. Grade ≥3 treatment-related adverse events occurred in 13 patients (30%); none were classified as immune-related. Grade 1-2 immune-related adverse events occurred in 8 patients (18%). Dose modifications occurred in 27 patients (61%), most commonly for palmar-plantar erythrodysesthesia. Single cell RNA sequencing on a subset of tumor biopsies demonstrated that the frequency of dendritic cells and tumor-infiltrating activated T cells correlated with time on treatment. Conclusions: The combination of pembrolizumab with capecitabine and bevacizumab was tolerable with an expected toxicity profile in MSS/pMMR mCRC patients. The overall response rate of 5% did not meet the prespecified target of ≥15%;, however, 55% patients remained on treatment >6 months.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307398 | GEO | 2026/08/23

REPOSITORIES: GEO

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Project description:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. Here, we assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Good response was associated with 12p12.1 copy number loss, even in patients with a KRAS mutation, while copy number gain in wild-type KRAS patients was correlated with a poor response. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good response. In wild-type KRAS patients, miRNA expression did not predict response in a multivariate model. Thus, assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of patients eligible for anti-EGFR therapy. Copy number detection was performed using NimbleScan and Nexus software Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 metastisized colorectal cancer patients in a phase III trial (CKTO 2005-02; ClinTrials.gov NCT00208546) of the Dutch Colorectal Cancer Group (DCCG), who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab.

Project description:Background. Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Patients and Methods. We profiled expession of 24526 genes by means of whole genome 24K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab+chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results. Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1+TFF2+MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p=0.007), but not in the Control set (ORR 36.4%, p=0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1+TFF2+MCM5) profile versus any other ALDH6A1+TFF2+MCM5 profile was 15 (p=0.018) in the Bevacizumab qPCR set but only 0.72 (p=0.63) in the Control set. The tumor expression profile of (KLF12-high+TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12+TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p=0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12+TFF2 expression profile was 2.92 (p=0.03) in the Validation and 1.29 (p=0.39) in the Control set. Conclusions. Our <three-stage> hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer. 18 tumor tissue samples were analysed, no replicates

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Phase II Study of Pembrolizumab Plus Capecitabine and Bevacizumab for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer

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