Increasing impact of molecular classification

James Fleck: Anticancerweb 17 (09), 2019

Progressive use of drugs with complementary mechanisms of action has been responsible for increasing median overall survival in unresectable metastatic colorectal cancer (mCRC). Fluoropyrimidines (FP), which inhibit the enzyme thymidylate synthase (TS), have been used for over 40 years. Advances in folinic acid (FA) modulation have enabled the emergence of a ternary complex, prolonging inhibition of TS enzyme, which ultimately led to a historical gain in mCRC one-year survival rate (FP = 37% versus FP + FA = 47%). Pharmacokinetic studies have shown additional benefit in mCRC median overall survival when FA is combined with FP-protracted infusion (15.5 months), rather than bolus FP (14.25 months). The use of an oral fluoropyrimidine (capecitabine) showed lower toxicity and very similar median overall survival (13.3 months), making it a therapeutic alternative for underperforming or elderly mCRC patients. The addition of a third drug (irinotecan or oxaliplatin) to the dublet FP + FA provided additional gain in objective response rate and progression-free survival. The median overall survival of mCRC reached 16.2 months with the addition of oxaliplatin (FOLFOX) and 17.4 months when the dublet-associated drug was irinotecan (FOLFIRI). The use of FOLFOX or FOLFIRI in direct comparison trials with post-progression crossing-over showed equivalent median overall survival (respectively 20.6 months versus 21.5 months). The addition of bevacizumab (a humanized anti-VEGF monoclonal antibody) to the first line treatment of mCRC could eventually produce some improvement in results. However, the potential benefit might be partially offset by complications including high blood pressure, bleeding, intestinal perforation and thromboembolism. Currently, the upfront use of five drugs (FOLFOXIRI + bevacizumab) as first-line treatment for mCRC has reached a median overall survival of 27.6 months.

The progressive improvement in outcomes observed in mCRC treatment is based on a very heterogeneous population. More recently, several prognostic and predictive factors have begun to better guide therapeutic planning. Exploratory analyzes of the TRIBE trial show the prognostic importance of the RAS and BRAF mutations. In patients with mCRC treated with FOLFOXIRI + bevacizumab the median overall survival was 37.1 months for patients with both RAS and BRAF wild-type, decreasing to 25.6 months for patients expressing RAS mutation and reaching as low as 13.4 months for patients showing BRAF mutation. RAS phenotypic expression is also a predictive factor. EGFR inhibitors (cetuximab and panitumumab) have their therapeutic benefit restricted to wild-type RAS patients. Interestingly enough, the BRAF V600E mutation is generally mutually exclusive of the RAS mutation and is an isolated marker of poor prognosis. Recently, the BEACON study was designed to evaluate the treatment of mCRC expressing BRAF V600E mutation. BEACON is a prospective, randomized phase III trial and had its preliminary safety analysis published in the Journal of Clinical Oncology. Patients with mCRC expressing BRAF V600E mutation who had progressed after one or two previous treatment-lines were evaluated for triple therapy with encorafenib (BRAF inhibitor) + cetuximab with or without binimetinib (MEK inhibitor). In parallel, other predictive factors have been described. Mutations in DNA-mismatch repair (MMR) genes are present in 15-20% of sporadic colon cancer. The genetic signature of MMR-deficient tumors (dMMR) is characterized by a high number of DNA replication errors (RER +) and a high level of microsatellite instability (MSI). The dMMR expression in mCRC is usually associate with better response to immune checkpoint inhibitors. In addition, the complexity of guiding therapeutic decisions for mCRC is maximized by differences in embryonic development, cellular microenvironment, and unique immunogenic potential, leading to a worse prognosis in metastatic right colon cancer.

EGFR = Epidermal Growth Factor Receptor 

 

References:

Cremolini C, Antoniotti C, Lonardi S, et al. Updated results of TRIBE2, a phase III, randomized strategy study by GONO in the first- and second-line treatment of unresectable mCRC. J Clin Oncol 37, abs 3508, 2019 

Eric Van Cutsem, Sanne Huijberts, Axel Grothey, et al: Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients with BRAF V600E–Mutant Metastatic Colorectal Cancer: Safety Lead-In Results from the Phase III BEACON Colorectal Cancer Study, J Clin Oncol 37: 1460 – 1469, 2019