FOCUS4: a new trial design for evaluation of targeted drugs in colorectal cancer?
Mené au Royaume-Uni sur 32 patients atteints d'un cancer colorectal de stade avancé ou métastatique sans mutation des gènes BRAF, PIK3CA, KRAS ou NRAS, cet essai de phase II/III évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité d'un composé appelé AZD8931, un inhibiteur de tyrosine kinase anti-EGFR, anti-HER2 et anti-HER3 dispensé par voie orale
The molecular phenotype of colorectal cancer is highly heterogeneous, with several molecularly defined subgroups that are of relevance for understanding the biological behaviour of the cancer and also the efficacy of drugs—for instance, RAS mutations occur in 45% of colorectal cancers, BRAF mutations in 9%, HER2 amplification in 4%, and PIK3CA mutations in 14%, among many others. This heterogeneity is also highly relevant for the design of new trials that require a more selective, economic, and rapid approach. An important issue in this context is the potential for multiple changes in the mutational profile during drug treatment; indeed, the molecular profile can even vary across different metastatic lesions in the same patient.
Therefore, there could be major differences in outcome if the investigational drug or combination of drugs is applied as first-line treatment rather than in later stages of the disease, as is traditionally done. A potentially appropriate place for an experimental drug to be tested is during the maintenance period after the end of induction therapy, where either no active maintenance or fluorouracil (or derivative thereof), with or without bevacizumab, is given.
Two trials—FOCUS4 in the UK, and the international MODUL trial—have introduced the concept of the umbrella trial design using an adaptive platform of several (flexible) cohorts to colorectal cancer, in which a single trial tests, in different cohorts, multiple targeted agents after induction therapy, during the maintenance phase, on the basis of the molecular aberrations present in the patients' tumours. FOCUS4 includes several cohorts for different molecular phenotypes, comparing new targeted agents versus placebo maintenance, and a “no biomarker” cohort comparing standard capecitabine versus placebo, acting as a standard control arm across the trial.
The first outcome data from the FOCUS4 trial are reported in The Lancet Gastroenterology & Hepatology: the results from cohort D, which included patients with colorectal cancers that were triple wild-type for RAS, BRAF, PIK3CA and had no PTEN loss. The drug being tested in this cohort was an oral pan-HER tyrosine kinase inhibitor, AZD8931, on the basis of preclinical and molecular data that showed that combined inhibition of EGFR (HER1), HER2, and HER3 might have the potential to lower the risk of de-novo resistance to EGFR targeted drugs. However, the drug failed to show any anti-tumour effect, with a preplanned interim analysis halting the trial after the enrolment of 32 patients, on the basis of a prespecified number of progression-free survival events occurring in the placebo group. Median progression-free survival was numerically, but not statistically, shorter in the AZD8931 group than in the placebo group (2·96 months vs 3·48 months).
The Lancet Gastroenterology & Hepatology , commentaire en libre accès, 2016