Pharmacotherapy for unresectable metastatic colorectal cancer

ABSTRACT

Introduction

Unresectable metastatic colorectal cancer (mCRC) has a poor prognosis. Emerging treatment paradigms have improved outcomes in selected unresectable mCRC cases. Recent therapeutic advancements are due in part to a shift in trial designs. By examining CRC as a heterogeneous group of various tumor subtypes, researchers have identified molecular distinctions that have led to promising targets.

Areas covered

Nineteen antineoplastic agents are included in the National Comprehensive Cancer Network guidelines for the palliative management of mCRC. However, not all patients will be candidates for each agent. New therapies for rare mCRC subtypes have emerged. Herein, the authors review these rare mCRC subtypes: microsatellite instability-high/deficient mismatch repair, BRAFV600E-mutant, and human epidermal growth factor receptor 2-positive tumors. Additionally, they provide an overview of unresectable mCRC management and future directions.

Expert opinion

Treatment in the majority of mCRC patients (RAS wild-type or RAS-mutant, microsatellite instability-stable or -low/mismatch repair-proficient, BRAFV600E wild-type, or HER2-negative) needs further advancement and remains an unmet need. The authors believe that the key to identifying more breakthroughs in these mCRC patients is to continue to differentiate their tumors molecularly and clinically.

KEYWORDS:

• Agents
• antineoplastic
• BRAFV600E mutant
• checkpoint inhibitors
• colorectal neoplasms
• human epidermal growth factor receptor 2
• microsatellite instability-high/deficient mismatch repair

Article highlights

• Unresectable metastatic colorectal cancer (mCRC) is treated systemically with palliative intent.

• Therapeutic advancement has led to breakthroughs in treatment of rare mCRC subtypes, but mCRC continues to have a poor 5-year survival rate.

• Immune checkpoint inhibition is now the frontline standard of care for microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) mCRC.

• Treatment with a BRAF inhibitor (encorafenib) combined with an epidermal growth factor receptor inhibitor (cetuximab or panitumumab) has been confirmed clinically to overcome resistance of mCRC to single-agent BRAF inhibition. Encorafenib plus cetuximab or panitumumab is currently the standard-of-care second-line therapy for BRAFV600E-mutant mCRC.

• The diverse portfolio of anti-human epidermal growth factor receptor 2 (HER2) agents for mCRC treatment has expanded. Currently, three anti-HER2 options are recommended for refractory HER-positive mCRC.

• Treatment in the majority of mCRC patients (RAS wild-type or RAS-mutant, microsatellite instability-stable or -low/mismatch repair-proficient, BRAFV600E wild-type, or HER2-negative) needs further advancement. Two novel discoveries in this area are novel RAS inhibitors that act on KRAS G12C mutations and rechallenge with anti-epidermal growth factor receptor monoclonal antibodies.

• The key to identifying more breakthroughs in treatment for the majority of mCRC cases is to continue to differentiate these tumors molecularly and clinically.

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript has not been funded.