Perspectives on Treatment of Metastatic Colorectal Cancer with Immune Checkpoint Inhibitor Therapy

Abstract

Despite lengthening survival, death rates from metastatic colorectal cancer (CRC) remain unacceptably high, with a bright spot being the demonstration of durable responses in patients with CRC who have mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI-H) tumors and are treated with immune checkpoint inhibitor therapy. Nivolumab and pembrolizumab, as well as nivolumab in combination with low-dose ipilimumab-all checkpoint inhibitors-are currently approved by the U.S. Food and Drug Administration (FDA) for patients with MSI-H/dMMR metastatic CRC that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Nonetheless, there are a number of questions and considerations in the use of these checkpoint inhibitor therapies. Using a question-and-answer format, this review summarizes the scientific rationale for immune checkpoint inhibitor therapy in CRC, including the effects of tumor factors such as genetic aberrations and mutational load on the immune response, particularly in patients with MSI-H/dMMR disease. We discuss response patterns, response criteria, and immune-related adverse events using findings from published efficacy and safety data of immune checkpoint inhibitor therapy in metastatic CRC. We also discuss issues surrounding treatment sequencing, incorporating approved checkpoint inhibitors into the current treatment paradigm, and the multiple investigational strategies that may optimize immunotherapy for advanced CRC in the future, including novel combination therapies. IMPLICATIONS FOR PRACTICE: Colorectal cancer (CRC) is the third most common cancer in the U.S. Despite advances in chemotherapy, survival remains poor for patients with metastatic CRC. Certain immunotherapy agents have demonstrated long-lasting responses in previously treated patients with immune-responsive microsatellite instability-high/mismatch repair-deficient metastatic CRC, leading to U.S. Food and Drug Administration approval of the immune checkpoint inhibitors nivolumab (with or without low-dose ipilimumab) and pembrolizumab in this population. Combination therapy (e.g., nivolumab with low-dose ipilimumab) has demonstrated numerically higher response rates and improved long-term clinical benefit relative to anti-programmed death-1 monotherapy. Ongoing trials are evaluating immunotherapy in the broader CRC population and novel combinations to optimize immunotherapy for advanced CRC.

Keywords: Atezolizumab; Colorectal cancer; Immune checkpoint inhibitor; Ipilimumab; Nivolumab; Pembrolizumab.

Figure 1

Simplified NCCN Guidelines for Colon Cancer and Rectal Cancer treatment algorithm showing systemic therapy for metastatic colorectal cancer. All recommendations are category 2A (based on lower‐level evidence; there is uniform NCCN consensus that the intervention is appropriate) unless otherwise indicated. ^aNivolumab plus low‐dose ipilimumab is a category 2B recommendation in the first‐line setting (based on lower‐level evidence, there is NCCN consensus that the intervention is appropriate). Abbreviations: CRC, colorectal cancer; dMMR, mismatch repair deficient; EGFR, endothelial growth factor receptor; MMR, mismatch repair; MSI, microsatellite instability; MSI‐H, microsatellite instability‐high; NCCN, National Comprehensive Cancer Network; VEGF, vascular endothelial growth factor; WT, wild type. Source: Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer V.3.2018 and the NCCN Guidelines for Rectal Cancer V.3.2018. ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to http://nccn.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.