An update on pharmacotherapies for colorectal cancer: 2023 and beyond

ABSTRACT

Introduction

Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide. The treatment of metastatic colorectal cancer (mCRC) is difficult, and mCRC has a survival rate of only 13–17% compared with 70–90% in locoregional CRC. There is ongoing research effort on pharmacotherapy for CRC to improve the treatment outcome.

Areas covered

We reviewed the current literature and ongoing clinical trials on CRC pharmacotherapy, with a focus on targeted therapy based on the results of genetic testing. The pharmacotherapies covered in this article include novel agents targeting EGFR and EGFR-related pathways, agents targeting the VEGF pathway, immunotherapy options depending on the MMR/MSI status, and new therapies targeting genetic fusions such as NTRK. We also briefly discuss the value of next-generation sequencing (NGS) in treatment selection and response monitoring.

Expert opinion

We advocate for the early and routine use of NGS to genetically characterize CRC to assist with pharmacotherapy selection. Targeted therapy is a promising field of ongoing research and improves CRC treatment outcome.

KEYWORDS:

• Colorectal cancer
• dMMR/MSI
• EGFR
• immunotherapy
• metastatic colorectal cancer
• next-generation sequencing
• pMMR/MSS
• targeted therapy

Article highlights

• CRC with extended-RAS mutations can be treated with a new targeted therapy.

• CRC with BRAF^V600E mutation can be treated with encorafenib combined with either cetuximab or panitumumab in a non-first-line setting. Study is underway to investigate the role of targeted therapy in neoadjuvant setting.

• CRC with HER2 amplification or expression can be targeted with either dual HER2 blockade or ADC containing a HER2-targeting antibody.

• Anti-VEGF agents improve patient outcome in subsequent-line therapy even if the patient has progressed through prior anti-VEGF therapy.

• pMMR/MSS CRC responds poorly to immunotherapy, but there is ongoing research effort in priming the tumor micro-environment to make it more responsive.

• NGS is reliable, has high-throughput, and can identify previously unknown genetic changes. Ct-DNA sequencing captures intratumoral and temporal heterogeneity and can be used for post-treatment surveillance.

Declaration of interest

A B Benson III has the following declaration of interests: Research in 2023 for the following companies: AbbVie, Inc., Amgen, Cardiff Oncology, Elevar Therapeutics, INC, ITM Solucin, Janssen, Merck Sharp and Dohme LLC, Pfizer, ST Pharm CO. Ltd, The Nathan Cummings Foundation, Xenor; 2022: AbbVie, Inc., Apexigen, Array BioPharma, Artemida, Bristol-Myers Squibb Company, ITM, Elevar Therapeutics, INC, Merck Sharp and Dohme LLC, Natera, Pfizer, ST Pharm CO. Ltd, Samsung Bioepis, The Nathan Cummings Foundation, Therabionic, and Cardiff Oncology. A B Bension III also declares doing some Consulting in 2023–2022 for the following: AIM ImmunoTech, Amgen, Array BioPharma, Artemida, Asperigen, Astrellas DMC, Aveo, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb DMC, Clarivate, Envision, GSK, Halio, Hutchmed (Synapse), Janssen, Mirati, Mirati Therapeutics, Natera, Novartis DMC, Nuvation Bio, Pfizer, Replimune, Samsung Bioepis, Terumo, Therabionic, Tempus, Tukysa, and Xencor.

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

A reviewer on this manuscript has disclosed being a Co-Founder at Precision Biosensors Inc. Consultancy and having Advisory Board relationships with Elicio (scientific advisory board member/shares/stock ownership); ConsultancyAadvisory Board fees from Guardant Health, Natera, Foundation Medicine, Illumina, BostonGene, Merck/MSD Oncology, Tempus, Bayer, Lilly, Delcath Systems, IPBA, QED Therapeutics, Boston Healthcare Associates, Servier, Taiho Oncology, Exact Sciences, Daiichi Sankyo/AstraZeneca, Eisai, Saga Diagnostics, Neogenomics, Do More Diagnostics AS, and Seattle Genetics.

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

Additional information

Funding

This paper received no funding.