Biomarker Assessment and Related Treatment Decision-Making for Patients with Colorectal Cancer

Faculty

TARGET AUDIENCE
This program is intended for medical oncologists, hematology-oncology fellows, surgeons and other healthcare providers involved in the treatment of colorectal cancer.

LEARNING OBJECTIVES

• Develop an understanding of validated biomarkers of response in CRC, such as RAS mutations, microsatellite instability (MSI)/mismatch repair (MMR) deficiency, HER2 overexpression and BRAF V600E mutations, and consider the implications for molecular testing and clinical care.
• Optimize the use of neoadjuvant and adjuvant systemic therapy for patients with localized CRC, considering various clinical and biological factors such as age, performance status, disease stage, MSI/MMR status and the potential relevance of molecular residual disease.
• Formulate a plan to guide the selection and sequencing of therapy for patients with metastatic CRC (mCRC), accounting for tumor sidedness, biomarker profile, prior systemic therapy, symptomatology and personal goals of treatment.
• Evaluate the biological rationale for the use of immune checkpoint inhibitors in the treatment of MSI-high/MMR-deficient localized or advanced CRC, and counsel patients regarding evidence-based and guideline-endorsed therapy recommendations.
• Appreciate published and emerging research documenting the efficacy of BRAF/EGFR inhibition for newly diagnosed or relapsed/refractory mCRC with a BRAF V600E mutation, and optimally incorporate this therapeutic strategy into patient care.
• Recognize available data with HER2-targeted therapies for HER2-positive mCRC, and consider the current role of FDA-approved approaches.
• Apply available research to optimize the selection and sequencing of therapy for patients with mCRC and a KRAS G12C mutation, considering the implications of recent clinical trial findings and regulatory actions.
• Recall ongoing trials evaluating novel biomarker-directed agents and strategies for CRC, and use this information to appropriately refer patients for study participation.

ACCREDITATION STATEMENT
Research To Practice is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT
CME credit is no longer available for this issue

AMERICAN BOARD OF INTERNAL MEDICINE (ABIM) — MAINTENANCE OF CERTIFICATION (MOC)
CME credit is no longer available for this issue

AMERICAN BOARD OF SURGERY (ABS) — CONTINOUS CERTIFICATION (CC)
CME credit is no longer available for this issue

PRIVACY POLICY
Personal information and data sharing: Research To Practice aggregates deidentified user data for program-use analysis, program development, activity planning and site improvement. We may provide aggregate and deidentified data to third parties, including commercial supporters. We do not share or sell personally identifiable information to any unaffiliated third parties or commercial supporters. Please see our privacy policy at ResearchToPractice.com/Privacy-Policy for more information.

HOW TO USE THIS CME ACTIVITY
Video Program: This CME activity consists of a video component. To receive credit, the participant should review the CME information, watch the video, complete the post-test with a score of 80% or better and fill out the evaluation located at ResearchToPractice.com/ASCOGI25/CRC/Video/CME.

CONTENT VALIDATION AND DISCLOSURES
Research To Practice (RTP) is committed to providing its participants with high-quality, unbiased and state-of-the-art education and adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of an accredited continuing education activity, including faculty, planners, reviewers and others, are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant conflicts of interest have been mitigated prior to the commencement of this activity. In addition, all activity content is reviewed by RTP scientific staff and an external, independent physician reviewer for fair balance, scientific objectivity of studies referenced and patient care recommendations.

FACULTY — The following faculty reported relevant financial relationships with ineligible entities:

Arvind Dasari, MD, MS
Professor
Department of Gastrointestinal Medical Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas

Consulting Agreements: Bristol Myers Squibb, Exelixis Inc, Illumina, Lantheus, Personalis, Taiho Oncology Inc, Takeda Pharmaceuticals USA Inc; Contracted Research: Eisai Inc, Enterome, Guardant Health, Hutchison MediPharma, Natera Inc, NeoGenomics, Personalis, Taiho Oncology Inc, Xencor.

Van K Morris, MD
Associate Professor
Department of Gastrointestinal Medical Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas

Advisory Committees: AmMax Bio, Bristol Myers Squibb, Incyte Corporation, Pfizer Inc, Scandion Oncology; Contracted Research: AmMax Bio, Bicara Therapeutics, BioNTech SE, Bristol Myers Squibb, Pfizer Inc.

Jenny Seligmann, MBChB, PhD
Professor of Gastrointestinal Cancer
University of Leeds
Leeds, United Kingdom

Advisory Committees: Bristol Myers Squibb, GSK, Merck Serono, Nanobiotix, Sanofi, Servier Pharmaceuticals LLC; Contracted Research: GSK, Merck Serono, Pierre Fabre, Roche Diagnostics; Data and Safety Monitoring Boards/Committees: GSK; Speakers Bureaus: Bayer HealthCare Pharmaceuticals, GSK, Merck Serono, Servier Pharmaceuticals LLC.

Eric Van Cutsem, MD, PhD
Professor of Medicine
Digestive Oncology
University Hospitals Leuven
Leuven, Belgium

Advisory Committees: AbbVie Inc, Agenus Inc, ALX Oncology, Amgen Inc, Arcus Biosciences, Astellas, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, BeiGene Ltd, BioNTech SE, Boehringer Ingelheim Pharmaceuticals Inc, Bristol Myers Squibb, Cantargia AB (CANFOUR trial), Daiichi Sankyo Inc, Debiopharm, Eisai Inc, ElmediX, Galapagos NV, GSK, Hookipa Pharma Inc, Incyte Corporation, Ipsen Biopharmaceuticals Inc, Lilly, Merck KGaA, Mirati Therapeutics Inc, MSD, Nordic Pharma, Novartis, Pfizer Inc, Pierre Fabre, Roche Laboratories Inc, Seagen Inc, Servier Pharmaceuticals LLC, Simcere, Taiho Oncology Inc, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation; Nonrelevant Financial Relationships: Bexon Clinical Consulting.

MODERATOR
Christopher Lieu, MD
Professor of Medicine
Associate Director for Clinical Research
Co-Director, GI Medical Oncology
University of Colorado Cancer Center
Aurora, Colorado

Consulting Agreements: Amgen Inc, Pfizer Inc; Contracted Research: Genentech, a member of the Roche Group, Sanofi.

RESEARCH TO PRACTICE CME PLANNING COMMITTEE MEMBERS, STAFF AND REVIEWERS — Planners, scientific staff and independent reviewers for Research To Practice have no relevant conflicts of interest to disclose.

These educational activities contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. Research To Practice does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

These activities are supported by educational grants from GSK, Natera Inc, and Pfizer Inc.

Release date: February 2025
Expiration date: February 2026

After completing the post-test, learners may download and review the answers here in order to identify further areas of study.

Dr Dasari

Dasari A et al. ctDNA applications and integration in colorectal cancer: An NCI Colon and rectal-anal task forces whitepaper. Nat Rev Clin Oncol 2020;17(12):757-70. Abstract

Kasi PM et al. Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): Interim analysis of BESPOKE CRC study. Gastrointestinal Cancers Symposium 2024;Abstract 9.

Maddalena G et al. INTERCEPT program of circulating tumor DNA (ctDNA) testing for minimal residual disease (MRD) in colorectal cancer (CRC): Results from a prospective clinical cohort. ASCO Gastrointestinal Cancers Symposium 2024;Abstract 27.

Nakamura Y et al. ctDNA-based molecular residual disease and survival in resectable colorectal cancer. Nat Med 2024;30(11):3272-83. Abstract

Phan TG, Croucher PI. The dormant cancer cell life cycle. Nat Rev Cancer 2020;20(7):398-411. Abstract

Taieb J et al. Combined analyses of ctDNA and Immunoscore in stage III colon cancer patients: A post hoc analysis of the IDEA-France and -Greece trials. ESMO Gastrointestinal Oncology 2024;Abstract 7MO.

Tie J et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: Overall survival and updated 5-year results from the randomized DYNAMIC trial. ASCO 2024;Abstract 108.

Tie J et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med 2022;386(24):2261-72. Abstract

Yukami H et al. Circulating tumor DNA (ctDNA) dynamics in patients with colorectal cancer (CRC) with molecular residual disease: Updated analysis from GALAXY study in the CIRCULATE-JAPAN. Gastrointestinal Cancers Symposium 2024;Abstract 6.

 

Dr Morris

André T et al. Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer. N Engl J Med 2024;391(21):2014-26. Abstract

André T et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383(23):2207-18. Abstract

Kopetz S et al. BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. Gastrointestinal Cancers Symposium 2025;Abstract 16.

Kopetz S et al. Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial. Nat Med 2024;30(11):3261-71. Abstract

Kopetz S et al. Encorafenib, binimetinib, and cetuximab in BRAFV600E-mutated colorectal cancer. N Engl J Med 2019;381(17):1632-43. Abstract

Pan K et al. Phase I/II trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAF^V600E metastatic colorectal cancer following progression on prior BRAF+EGFR targeted therapies. Gastrointestinal Cancers Symposium 2025;Abstract 182.

Shiu K-K et al. Pembrolizumab versus chemotherapy in microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): 5-year follow-up of the randomized phase III KEYNOTE-177 study. ESMO 2023;Abstract LBA32.

Tabernero J et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: Updated survival results and subgroup analyses from the BEACON study. J Clin Oncol 2021;39(4):273-84. Abstract

Tian J et al. Combined PD-1, BRAF and MEK inhibition in BRAF^V600E colorectal cancer: A phase 2 trial. Nat Med 2023;29(2):458-66. Abstract

Van Cutsem E et al. ANCHOR CRC: Results from a single-arm, phase II study of encorafenib plus binimetinib and cetuximab in previously untreated BRAF^V600E-mutant metastatic colorectal cancer. J Clin Oncol 2023;41(14):2628-37. Abstract

 

Dr Seligman

André T et al. Final overall survival for the phase III KN177 study: Pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). ASCO 2021;Abstract 3500.

Cercek A et al. Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. ASCO 2024;Abstract LBA3512.

Cercek A et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022;386(25):2363-76. Abstract

Cervantes A et al. Metastatic colorectal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34(1):10-32. Abstract

Chalabi M et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26(4):566-76. Abstract

Diaz LA Jr et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): Final analysis of a randomised, open-label, phase 3 study. Lancet Oncol 2022;23(5):659-70. Abstract

Elez E et al. SEAMARK: Phase II study of first-line encorafenib and cetuximab plus pembrolizumab for MSI-H/dMMR BRAF V600E-mutant mCRC. Future Oncol 2024;20(11):653-63. Abstract

Sinicrope FA et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient mismatch repair (ATOMIC, Alliance A021502). ASCO 2019;Abstract e15169.

 

Prof Van Cutsem

Raghav K et al. Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): Primary results from a multicentre, randomised, phase 2 trial. Lancet Oncol 2024;25(9):1147-62. Abstract

Rha SY et al. Zanidatamab (zani) + chemotherapy (CT) in first-line (1L) human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic colorectal cancer (mCRC). ESMO 2024;Abstract 516MO.

Sartore-Bianchi A et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): A proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17(6):738-46. Abstract

Siena S et al. HER2-related biomarkers predict clinical outcomes with trastuzumab deruxtecan treatment in patients with HER2-expressing metastatic colorectal cancer: Biomarker analyses of DESTINY-CRC01. Nat Commun 2024;15(1):10213. Abstract

Siena S et al. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): A multicentre, open-label, phase 2 trial. Lancet Oncol 2021;22(6):779-89. Abstract

Siena S et al. Breaking barriers in HER2+ cancers. C Cancer Cell 2020;38(3):317-9. Abstract

Strickler JH et al. Final results of a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC (MOUNTAINEER). ASCO 2024;Abstract 3509.

Strickler JH et al. MOUNTAINEER-03 phase III study design: First-line mFOLFOX6 + tucatinib + trastuzumab for HER2+ metastatic colorectal cancer. Future Oncol 2024:1-9. Abstract

Strickler JH et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): A multicentre, open-label, phase 2 study. Lancet Oncol 2023;24(5):496-508. Abstract

Yoshino T et al. Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Nat Commun 2023;14(1):3332. Abstract

 

Dr Lieu

Fakih MG et al. Overall survival (OS) of phase 3 CodeBreaK 300 study of sotorasib plus panitumumab (soto+pani) versus investigator’s choice of therapy for KRASG12C-mutated metastatic colorectal cancer (mCRC). ASCO 2024;Abstract LBA3510.

Fakih MG et al.Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl J Med 2023;389(23):2125-39. Abstract

Fakih MG et al. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): A prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol 2022;23(1):115-24. Abstract

Hong DS et al. Sotorasib (soto) plus panitumumab (Pmab) and FOLFIRI for previously treated KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreaK 101 phase 1b safety and efficacy. ASCO 2023;Abstract 3513.

Ji J et al. Targeting KRAS^G12C-mutated advanced colorectal cancer: Research and clinical developments. Onco Targets Ther 2022:15:747-56. Abstract

Kopetz S et al. KRYSTAL-1: Pooled phase 1/2 efficacy and safety of adagrasib (MRTX849) in combination with cetuximab in patients with metastatic colorectal cancer (CRC) harboring a KRAS^G12C mutation. AACR 2024;Abstract CT013.

Ottaiano A et al. KRAS p.G12C mutation in metastatic colorectal cancer: Prognostic implications and advancements in targeted therapies. Cancers 2023;15(14):3579. Abstract

Qunaj L et al. Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer. Front Oncol 2023:13;1252516. Abstract

Ryan MB et al. KRAS^G12C-independent feedback activation of wild-type RAS constrains KRAS^G12C inhibitor efficacy. Cell Rep 2022;39(12):110993. Abstract

Sacher A et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med 2023;389(8):710-21. Abstract

Siena S et al. Sotorasib (soto), panitumumab (pani) and FOLFIRI in the first-line (1L) setting for KRAS G12C–mutated metastatic colorectal cancer (mCRC): Safety and efficacy analysis from the phase Ib CodeBreaK 101 study. ESMO 2024;Abstract 505O.

Weiss J et al. KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. ESMO 2021;Abstract LBA6.

Yaeger R et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. Cancer Discov 2024;14(6):982-93. Abstract

Yaeger R et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med 2023;388(1):44-54. Abstract