FOCUS4: a new trial design for evaluation of targeted drugs in colorectal cancer?
Authors: Hans-Joachim Schmoll
Journal: The Lancet. Gastroenterology & hepatology (2017)

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 drugs1Loree JM Kopetz S Raghav KPS Current companion diagnostics in advanced colorectal cancer; getting a bigger and better piece of the pie.J Gastrointest Oncol. 2017; 8: 199-212Crossref PubMed Scopus (23) Google Scholar—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.2Pietrantonio F Vernieri C Siravegna G et al.Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer.Clin Cancer Res. 2017; 23: 2414-2422Crossref PubMed Scopus (125) Google Scholar 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 trial3Schmoll H Arnold D de Gramont A et al.MODUL – a multicentre randomised clinical trial of biomarker-driven therapy for the 1st-line maintenance treatment of metastatic colorectal cancer (MCRC): a signal-seeking approach.Ann Oncol. 2014; 25 (abstr 612TiP).: iv209Crossref Google Scholar—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). Richard Adams and co-investigators are to be congratulated in reporting the first results from the trial; they demonstrate that this innovative approach is at least feasible, and the statistical multiarm, multistage (MAMS) methodology used, with prespecified plans to stop or continue the trial based on progression-free survival events in the placebo arm, seems to work. However, this negative result raises several questions and considerations. First, induction chemotherapy was not the same for all patients, since it was not part of the protocol but left to the discretion of the investigator. In particular, although all patients are RAS/BRAF wild-type, only seven (22%) received an anti-EGFR antibody for induction chemotherapy, and only one of those seven had been retreated at progression (as planned) with the anti-EGFR antibody. The heterogeneity of induction and post-progression treatments, together with the low patient number, and the lack of follow-up data after re-induction, does not allow correlations to be drawn between outcomes and the type of induction chemotherapy. Therefore, for example, the hypothesis that AZD8931 might reduce secondary resistance to EGFR inhibitors such as cetuximab or panitumumab cannot be evaluated. Second, the low rate of previous exposure of the patients to an anti-EGFR antibody raises concerns regarding the FOCUS4 trial design, with induction treatment fixed only for duration, not for the type of induction (by contrast, all patients enrolled in MODUL are to receive the same induction treatment). In this case of cohort D, with patients mainly lacking previous exposure to an anti-EGFR antibody, one might have expected AZD8931 to have had some activity in terms of progression-free survival, given there was a low frequency of previous exposure to anti-EGFR antibodies and no proven resistance to cetuximab. However, this lack of activity is consistent with the negative results of two small phase 2 trials in HER2-positive breast cancer and of neratinib (a HER1, 2, and 4 tyrosine kinase inhibitor) in colorectal cancer.5Hyman DM, Piha-Paul S, Rodon J, et al. Neratinib in HER2-or HER3-mutant solid tumors: SUMMIT, a global, multi-histology, open-label, phase 2 'basket' study. AACR Annual Meeting; Washington, DC, USA; April 1–5, 2017; abstract CT001.Google Scholar Third, only a third of patients had restarted their induction therapy after progression under placebo or AZD8931 at the time of data collection; although the authors acknowledge that not all of the data for post-progression treatments was available at the time of writing, as many as two-thirds of patients may not have restarted on treatment that was previously effective. This in turn may have a negative effect on overall survival in those patients who are not restarted on their induction regimen. Fourth, the use of a placebo as the control, instead of active maintenance, may be of concern. It may be that, even if the previous induction therapy is restarted after progression, the total time to definitive progression is significantly shorter in the case of no active maintenance compared with active maintenance. Indeed, the observed median progression-free survival in both the placebo group and the experimental group is rather low compared with results from maintenance trials.6Goey KKH Bias SG van Tinteren H et al.Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study.Annals Oncol. 2017; 28: 2128-2134Crossref PubMed Scopus (45) Google Scholar For example, in a similar patient population and molecular subgroup of the CAIRO-3 maintenance trial,6Goey KKH Bias SG van Tinteren H et al.Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study.Annals Oncol. 2017; 28: 2128-2134Crossref PubMed Scopus (45) Google Scholar median progression-free survival was 5·2 months in the no maintenance control arm, and 8·8 months with active maintenance: considerably longer than in both groups in FOCUS4-D. Nevertheless, it remains unclear whether this has a relevant effect on survival in FOCUS4. Another question is specific for this type of trial: does the introduction of a specific (targeted) drug—in the absence of progression under an active chemotherapy—have an impact on the molecular biology of the tumour? For instance, could it induce collateral resistance, with potential consequences for the activity of standard salvage therapy? This has been observed at least for the EGFR/HER pathway,2Pietrantonio F Vernieri C Siravegna G et al.Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer.Clin Cancer Res. 2017; 23: 2414-2422Crossref PubMed Scopus (125) Google Scholar and is a matter that needs careful consideration. However, in FOCUS4 no data are currently available regarding the efficacy of reinduction with the same induction chemotherapy as well as salvage treatment; these questions should be addressed carefully in further analyses. Notwithstanding these concerns, the first data from the FOCUS4 trial are very interesting and important. Despite the lack of efficacy, they represent a developmental pathway that appears to be highly effective, that is able to reduce the number of patients needed and financial resources spent, and that can evaluate new drugs at an accelerated pace. However, more data from both FOCUS4 and MODUL are needed to provide further insight into this exciting approach to drug testing early in first-line treatment. H-JS co-developed and is a co-principal investigator in the MODUL trial, which is being run by Roche. Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRAS, and NRAS (FOCUS4-D): a phase 2–3 randomised trialThe MAMS trial design for FOCUS4 has shown efficiency and effectiveness in trial outcome delivery, informing the decision to proceed or stop clinical evaluation of a targeted treatment within a molecularly defined cohort of patients. The overarching FOCUS4 trial is now aiming to open a replacement arm in the cohort with all wild-type tumours. Full-Text PDF Open Access