Current synthetic pharmacotherapy for treatment-resistant colorectal cancer: when urgent action is required

ABSTRACT

Introduction: Colorectal cancer (CRC) remains a global concern. Fourteen antineoplastics are approved for metastatic CRC (mCRC); however, the 5-year overall survival remains poor for the overwhelming majority of patients. Poor outcomes continue to highlight the critical need for therapeutic advancement.

Areas covered: mCRC represents a clinical and molecular complex malignancy with several treatment barriers. Prognostic and predictive factors have and continue to emerge anatomically, molecularly, and via patient-related factors. Herein, the authors review the current understanding and promising future directions amongst these different subtypes.

Expert opinion: CRC is largely considered a common cancer. Consequently, treatment approaches have been rather homogenous with systemic chemotherapy combinations. Of significance is the recent identification of targetable rare subsets of mCRC, notably for microsatellite instability-high (MSI-H) patients and for BRAF mutated patients. As a result, we are at the forefront of interpreting biological differences that provide targetable approaches and/or additional insight. To continue to do so, future clinical trial developments must focus on diverse subtypes of mCRC rather than all-encompassing mCRC proposals. Yet of greatest need is identifying options for RAS-mutated and microsatellite-stable mCRC patients. For the majority of these patients, we continue to seek novel innovative approaches to improve the overall survival of these patients.

KEYWORDS:

• Antineoplastic agents
• colorectal neoplasms
• immunotherapy
• molecular targeted therapy

Article highlights

• Despite the availability of 14 antineoplastic therapies, metastatic colorectal cancer (mCRC) continues to hold a poor 5-year survival rate.

• Emerging evidence reveals mCRC diversity comprising patient-related factors, anatomical tumor distinctions, and molecular classifications.

• Future challenges are predicted for early-age onset mCRC and primary tumor location distinctions along with the identification of aggressive and atypical metastatic sites resistant to standard of care therapy.

• Promising breakthroughs for rare mCRC entities (microsatellite-instability high/deficient mismatch repair (MSI-H/dMMR), BRAF^v600E mutant mCRC; human epidermal growth factor receptor-2 (HER2) + mCRC) are underway.

• Continued areas in need of attention are primary RAS mutations, RAS-wild type mCRC acquired anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody resistance, and continued immunotherapy-driven innovation for the bulk of mCRC.

• The key to advance mCRC care will be in focusing trial designs on diverse and distinct biological subtypes rather than mCRC as one entity.

This box summarizes key points contained in the article.

Declaration of interest

C Eng has received research grants from Genentech, Roche and Bristol-Myers Squibb. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.