Ongoing and evolving clinical trials enhancing future colorectal cancer treatment strategies

ABSTRACT

Introduction

Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (CRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF, and MSI status, and over the last few years, several promising new biomarkers have also been identified. Circulating tumor DNA has reshaped the prognosis of localized CRC. These genomic findings can guide treatment management to improve clinical outcomes.

Areas covered

Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory and metastatic CRC. In the localized stage, all clinical trials involving new approaches such as liquid biopsy or neoadjuvant immunotherapy are also discussed. Molecular alterations and targeted agents are described, and data from completed and ongoing studies with targeted therapy and immunotherapies are presented.

Expert opinion

The implementation of liquid biopsies in the localized CRC setting has reshaped management of this disease. The expanded use of biomarkers to guide CRC patients’ treatment has revealed a level of complexity arising from interactions between different biomarkers. Prevalence of most established targetable biomarkers is low; however, the number of identified biomarkers in CRC is increasing. Thus, metastatic CRC may ultimately be considered an umbrella diagnosis encompassing numerous rare disease subtypes.

KEYWORDS:

• BRAF
• KRAS-G12C
• HER2
• MSI
• targeted therapy
• liquid biopsy
• colorectal cancer

Article highlights

• Substantial therapeutic advances have been developed for colorectal cancer.

• In the localized setting, the implementation of liquid biopsies has enabled enhanced patient stratification, thus allowing novel clinical designs.

• In the metastatic setting, the development of NGS techniques has allowed the identification of several genomic alterations suitable for blockade with targeted agents.

• Several trials evaluating ctDNA in the non-metastatic scenario are testing drugs currently exclusive to the metastatic setting; e.g FOLFIRI (PEGASUS) and trifluridine-tipiracil (ALTAIR).

• Despite the fact that RAS mutations have been undruggable for many years, multiple KRAS-G12C inhibitors have demonstrated clinical activity, notably when combined with anti-EGFRs.

• The combination of encorafenib-cetuximab has substantially changed outcomes for BRAF-V600E-mutated patients.

• Pembrolizumab is the first non-chemotherapy treatment approved in the first-line setting for MSI metastatic CRC patients.

This box summarizes key points contained in the article.

Declaration of interest

J.R. declares to have received honoraria from Sanofi; and to have received travel and accommodations expenses from Amgen, Merck, Pierre-Fabre and Sanofi.

F.S. declares honoraria for advisory role, travel grants, research grants (past 5 years): Hoffman-La Roche, Sanofi Aventis, Amgen, Merck Serono, Servier, Bristol-Myers Squibb.

I.B. declares to have received honoraria from Sanofi; and to have received travel and accommodation expenses from Amgen, Merck, and Sanofi.

J.T. reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, DaiichiSankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharmaInternational, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, SotioBiotech, Taiho, Tessa Therapeutics and TheraMyc. And also educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER).

E.E. declares personal financial interests; they have received honoraria for advisory role, travel grants, research grants (past 5 years): Institutional financial interests, my institution received honoraria due to my investigator contribution in clinical trials from Hoffman-La Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi, Bayer. Array Biopharma, MSD, AbbVie, Amgen, GlaxoSmithKline, AstraZeneca, Merck Sharp & Dohme Corp., Bristol Myers Squibb, Novartis, Boehringer Ingelheim, Hoffman-La Roche, Medimmune, Pierre-Fabre, Sanofi Aventis.

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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Conflict of Interest

One referee receives honoraria from Amgen, Merck, Servier, Pierre Fabre, MSD, AstraZeneca, BMS, Bayer, and Roche. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded