Written by: Dr. Jerome Goldschmidt Jr, MD
Sponsored by Takeda
The treatment landscape for metastatic colorectal cancer (mCRC) has seen considerable evolution over the past two decades. Early therapeutic strategies focused on a handful of chemotherapy agents, with incremental progress in survival seen through the addition of targeted therapies like VEGF and EGFR inhibitors. However, while these agents offered modest improvements, they also brought additional toxicity. More recent advancements, particularly in molecular diagnostics, have ushered in a new era of precision medicine, enabling a better understanding of genetic mutations and the tailoring of treatments. This article examines the key advancements in mCRC management, including immunotherapies, targeted therapies, and chemotherapy agents, and how these innovations are transforming the treatment landscape for this complex disease.
For almost two decades mCRC management has revolved around the use of a handful of drugs: 5-fluorouracil (5-FU), leucovorin, oxaliplatin and irinotecan. Additions to the chemotherapy backbones of FOLFOX and FOLFIRI with the VEGF and EGF receptor inhibitors were the first big innovation in the early 2000s. In retrospect, the benefit of adding these targeted agents to the chemotherapy backbone added on average 2-3 months to overall survival with additional toxicity. It took another few years to discover that EGFR blockers were only effective in ~40% of patients with the discovery of mutated KRAS, BRAF and NRAS. To date, biomarkers pointing to the benefit from VEGF inhibition have proven elusive.
This brings us to newer agents which are now interwoven into the tapestry of more modern molecular diagnostics. Molecular diagnostics have changed some of the paradigms in which mCRC patients are treated currently. These agents can be summarized as follows:
Immunotherapies:
Approximately 15% of CRC patients will be classified as having unstable microsatellites. What this means in practical terms are the addition of repeating, multiple CpG islands in the genome of the malignant colonocytes due to inappropriate mismatch repair mechanisms. A little under half of these MSI high patients will have germline mutations in mismatch repair genes like MLH1, MSH2, MSH6 or PMS2 and often present at an earlier age with CRC as part of the “Lynch Syndrome.” More than half of MSI patients will have acquired this genotype through an apparent random methylation of one of these genes which is more common in cells as they senesce. POLE and POLD1 mutations are another family of mutations involving DNA repair that are implicated in the formation of colorectal cancers. These tumors usually have high tumor mutational burden yet are microsatellite stable. The mismatch repair deficient or MSI high colon cancers as well as the POLE and POLD1 mutants are exquisitely sensitive to immune checkpoint inhibitors.1 First line therapies with single agent pembrolizumab and combination ipilimumab/nivolumab are now standard of care.
Targeted therapies:
HER2 directed therapy has long been employed in the more proximal GI tract. HER2 overexpression has been seen in fewer colorectal cancers. Patients will derive benefit with a trastuzumab backbone and the addition of either pertuzumab, tucatinib or lapatinib. The ADC fam-trastuzumab deruxetecan may be employed upon progression.2
The BRAF inhibitor encorafenib and others have long been a staple in the management of melanoma. In CRC, encorafenib is paired with either of the EGFR blockers, panitumumab or cetuximab to extend the usefulness of these antibodies in what would otherwise be a resistant tumor to EGFR blockade.
KRAS G12C is the most commonly mutated form of the KRAS family and has been found to be safely inhibited with two newer agents, sotorasib and adagrasib. Analogous to encorafenib, they must be paired with one of the EGFR blockers approved in mCRC to overcome resistance to these antibodies.
Chemotherapy:
Trifluridine and tipiracil combination by itself or paired with bevacizumab is approved for third line therapy. Modest improvements in overall survival have been seen. It appears to be agnostic in its mechanism of action as it targets DNA synthesis much like its relatives 5FU and capecitabine. Neutropenia appears to be its dose limiting toxicity.
VEGF inhibitors:
Fruquintinib is a novel oral small-molecule tyrosine kinase inhibitor that selectively targets vascular endothelial growth factor receptors (VEGFR-1, -2, and -3). Its mechanism of action involves the inhibition of VEGF-induced phosphorylation of these receptors, which leads to reduced endothelial cell proliferation, migration, and survival, ultimately inhibiting tumor angiogenesis, and promoting tumor cell death. Approved by the FDA on November 8, 2023 for use in adult patients with refractory metastatic colorectal cancer (mCRC), fruquintinib is indicated for those who have previously undergone treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as anti-VEGF and anti-EGFR therapies if RAS wild-type.3
Clinical trials, including FRESCO and FRESCO-2, demonstrated significant improvements in overall survival rates; patients receiving fruquintinib had a median overall survival of 7.4 months compared to 4.8 months for placebo recipients in the FRESCO-2 trial.4 The recommended dosage is 5 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity occurs.5 Common adverse effects include hypertension, palmar-plantar erythrodysesthesia, and proteinuria. This drug represents a critical advancement in the therapeutic landscape for mCRC, particularly in patients who have exhausted other treatment options.
Regorafenib has stood alone for many years as the sole agent in this space. Inhibiting VEGF is the main mechanism of action of this TKI with regards to suppressing colon tumors. It is often used as third line and beyond with only modest benefit. Noteworthy are its significant toxicities at full dose and often requires a ramp up phase to achieve tolerance of the dreaded hand foot syndrome associated with it.
The management of mCRC has made substantial advancements with the introduction of molecular diagnostics and targeted therapies. While the combination of chemotherapy agents and targeted therapies initially provided incremental survival benefits, newer innovations, such as immunotherapies and precision-targeted treatments, are offering more personalized and effective options for patients. However, challenges remain in determining the optimal use of these therapies, managing associated toxicities, and identifying the right biomarkers for treatment selection. As research continues to evolve, the future of mCRC treatment looks increasingly promising, with the potential for even greater advancements in patient outcomes.
Information regarding the studies:
FRESCO – https://jamanetwork.com/journals/jama/fullarticle/2685988
FRESCO2 – https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00772-9/abstract
References
- Ambrosini M, et al. Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer. Ann Oncol. 2023;35(7):643-655.
- Strickler JH, Cercek A, Siena S, André T, Ng K, Van Cutsem E, 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
- S. Food and Drug Administration. FDA approves fruquintinib for metastatic colorectal cancer. FDA website. Published November 8, 2023. Accessed January 31, 2025.
- Xu RH, Muro K, Morita S, et al. FRESCO-2: A Phase III trial of fruquintinib in patients with refractory metastatic colorectal cancer. Ann Oncol. 2023;34(6):779-787.
- Abernero J, et al. Fruquintinib: An oral inhibitor of VEGFR for the treatment of metastatic colorectal cancer. Clin Cancer Res. 2023;29(4):1025-1033.
