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. 2013 Dec 20;31(36):4562-8.
doi: 10.1200/JCO.2013.50.7905. Epub 2013 Nov 18.

Evaluating Many Treatments and Biomarkers in Oncology: A New Design

Free PMC article

Evaluating Many Treatments and Biomarkers in Oncology: A New Design

Richard Kaplan et al. J Clin Oncol. .
Free PMC article


There is a pressing need for more-efficient trial designs for biomarker-stratified clinical trials. We suggest a new approach to trial design that links novel treatment evaluation with the concurrent evaluation of a biomarker within a confirmatory phase II/III trial setting. We describe a new protocol using this approach in advanced colorectal cancer called FOCUS4. The protocol will ultimately answer three research questions for a number of treatments and biomarkers: (1) After a period of first-line chemotherapy, do targeted novel therapies provide signals of activity in different biomarker-defined populations? (2) If so, do these definitively improve outcomes? (3) Is evidence of activity restricted to the biomarker-defined groups? The protocol randomizes novel agents against placebo concurrently across a number of different biomarker-defined population-enriched cohorts: BRAF mutation; activated AKT pathway: PI3K mutation/absolute PTEN loss tumors; KRAS and NRAS mutations; and wild type at all the mentioned genes. Within each biomarker-defined population, the trial uses a multistaged approach with flexibility to adapt in response to planned interim analyses for lack of activity. FOCUS4 is the first test of a protocol that assigns all patients with metastatic colorectal cancer to one of a number of parallel population-enriched, biomarker-stratified randomized trials. Using this approach allows questions regarding efficacy and safety of multiple novel therapies to be answered in a relatively quick and efficient manner, while also allowing for the assessment of biomarkers to help target treatment.


Fig 1
Fig 1
Trial schema for FOCUS4. (*) The molecular cohorts are arranged in a hierarchy from left to right. For example, a patient with both a PIK3CA mutation and a KRAS mutation will be classified into the PIK3CA mutation cohort. CRC, colorectal cancer; EGFR, epidermal growth factor receptor; EREG, epiregulin; FFPE, formalin fixed, paraffin embedded; HER, human epidermal growth factor receptor; IHC, immunohistochemistry; MMR, mismatch repair; OS, overall survival; P, placebo; PFS, progression-free survival; Rx, treatment.

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