Advances in Molecular Classification

James Fleck & Gustavo De Agostin: Anticancerweb 01 (12), 2019

Although a molecular classification has been proposed for colorectal cancer, its routine use requires additional validation. Currently, only three molecular parameters are used in the clinical decision-making process: DNA mismatch repair (MMR), RAS mutation (RAS-mut), and BRAF mutation (BRAF-mut). In early stages, a genetic signature showing deficient MMR (dMMR), expressing high number DNA replication errors (RER +) and high microsatellite instability (MSI-H) is associated with better prognosis than proficient form (pMMR) with low microsatellite instability (MSI-L). In metastatic disease, the role of MMR is less recognized and the prognostic and predictive importance of RAS and BRAF mutations prevail. In metastatic colorectal cancer (mCRC), K-RAS and N-RAS mutations are associated with a worse prognosis, making tumor cells refractory to cetuximab, an epidermal growth factor receptor (EGFR) blocker. The resistance can be easily explained since RAS-mut is located downstream in the EGFR-mediated signaling transduction pathway. In addition, BRAF-mut, particularly that occurring in codon V600 (BRAF V600E) is associated with significant prognostic deterioration, as it makes mCRR refractory to conventional therapeutic interventions. The median expected overall survival for a V600E BRAF-mut mCRC is only 11 months. In contrast to other metastatic tumor models (melanoma and non-small cell lung cancer), exclusive inhibition of BRAF V600E has not been very promising, considering undesirable positive feedback on EGFR expression. This microenvironmental compensatory mechanism for tumor cell resistance, provides translational support for the experimental combined use of a BRAF inhibitor and an anti-EGFR monoclonal antibody in the treatment of BRAF V600E mut mCRC. Phase I and II clinical studies support the additional use of a triple intervention, including a MEK inhibitor.

In October 2019, the New England Journal of Medicine published the prospective randomized trial BEACON CRC, in which 665 BRAF V600E-mut mCRC patients were randomly assigned (1: 1: 1) to three drug intervention arms, following progression in one or two previous treatment lines. The triple-blockade test arm was composed of the combination of encorafenib (BRAF inhibitor) + binimetinib (MEK inhibitor) + cetuximab (anti-EGFR monoclonal antibody). The double-blockade test arm consisted of the combination of encorafenib + cetuximab at the same doses and schedule as triple blockade. The control arm was treated with cetuximab + irinotecan or cetuximab + FOLFIRI at the investigator's discretion. The primary end point was overall survival obtained in triple blockade compared to the control arm. Secondary outcomes included double-blockade overall survival compared to that of the control arm, progression-free survival, duration of response, and safety observed in all arms. At the cut-off point of this interim analysis the median follow-up was 7.8 months. The median overall survival observed in the triple blockade arm was 9.0 months versus 5.4 months in the control arm, showing a significant reduction in the risk of death (HR = 0.52 P <0.001). The median survival observed in the double-blockade arm was 8.4 months, also reducing the risk of death compared to the control arm (HR = 0.60 P <0.001). Progression-free survival also favored the triple-blockade (4.3 months) and double-blockade (4.2 months) arms, compared to the control arm (1.5 months). The most common adverse reactions in the triple blockade arm were diarrhea, nausea, vomiting and acneiform dermatitis. The percentage of adverse events (Grade ≥ 3) was similar in the three study arms, ranging from 50% to 61%. Class-specific adverse reactions associated with MEK inhibitors (serous retinopathy and left ventricular dysfunction) reproduced rates previously reported in the literature and yielded to drug dose reduction or discontinuation. Headache, somatic pain, arthralgia and myalgia were the most commonly reported adverse events in the double blockade arm and the observed reduction in triple blockade is due to the ability of MEK inhibitors to mitigate the toxic effects associated with BRAF inhibition. The lack of statistical power, particularly in this interim analysis, does not allow direct comparison of triple blockade with double blockade, but both have better results than those observed in the control group. The BEACON CRC study reinforces the need for advances in the molecular classification of colorectal cancer.

References:

S. Kopetz, A. Grothey, R. Yaeger, E. Van Cutsem, et al: Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer, N Engl J Med 381: 1632-43, 2019

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