Introduction | Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT

Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT · Introduction

Introduction

CC BY 4.0 · National Institute for Health and Care Research · approximately 7 min read

Background

Approximately 16,000 people die from colorectal cancer (CRC) in the UK every year, making it the second most common cause of cancer death in the UK and accounting for 10% of all cancer deaths in the country.1 Given that the concept of one treatment for all patients with a particular type of cancer has become outdated, the major challenge for oncologists is the identification of effective treatments for patients with CRC, given the limited benefits demonstrated of bevacizumab and cetuximab and the failure of multiple other agents in recent trials.2 To this end, the use of epidermal growth factor receptor (EGFR)-targeted therapy has highlighted the importance of BRAF, PIK3CA, KRAS and NRAS mutations for predicting a lack of response to EGFR-targeted therapy.3 However, there is also a need for a new approach to the design of clinical trials, allowing for the evaluation of multiple treatments in patients stratified based on biomarkers that are considered to be predictive of a treatment response.

The FOCUS4 trial was designed to enable the rapid identification of patients whose tumours could be characterised based on the presence of specific mutations or validated biomarkers that characterise biological subgroups. This trial was designed to characterise the tumours and stratify eligible patients into comparison subtrials, which, by being a component of a large national study, allow efficient adaptation of the biomarker eligibility criteria within the trial and enable the rapid accrual of patients, even those with the rare subtypes, such as those with the BRAF mutation, who account for only 8% of the population of patients with metastatic CRC.

The design of the FOCUS4 trial was considered to be efficient in that it exploited the concept of a population-enriched design, with the aim of evaluating multiple treatments and multiple biomarkers and, thereby, including most patients with a given type of cancer in the trial, irrespective of their biomarker categorisation. Each treatment was evaluated first in the cohort of patients for whom the biomarker was hypothesised to be predictive of response. If appropriate, the hypothesis of the predictive ability of the biomarker was subsequently tested by evaluating the agent in the biomarker-negative patients. It was not assumed that a treatment would work only in biomarker-positive patients, although it was assumed that a treatment that did not demonstrate efficacy in the selected or enriched cohort did not require further evaluation in a biomarker-negative patient population. This more efficient sequential testing approach had been favourably compared with other existing trial designs.4

The random assignment of each comparison with placebo within the biomarker-defined groups in the FOCUS4 trial design removed the potential bias of the prognostic effects of certain biomarker-defined groups. In addition, the FOCUS4 trial was adaptive in that random assignment to treatments that did not seem to be sufficiently active could be discontinued; new biomarkers and treatments could be introduced when warranted; and biomarkers could be refined as new information from within or outside the trial emerged.

The approach used in the FOCUS4 trial was driven by advances in the molecular understanding of CRC and the development of new targeted therapies, which demand the evaluation of these therapies in subsets of the CRC patient population that are mostly likely to derive benefit from the treatment. This need is evidenced by the failure of many classic trials to show benefit for new treatments in CRC,2 demonstrating the clear need for a new paradigm in the drive for progress.

Use of molecular classification in FOCUS4

In the FOCUS4 trial, patients were allocated to the comparison subtrials, which were initially defined by four specific molecular cohorts, with another cohort for patients whose cancer could not be classified into a specific molecular cohort. Cohorts could change as data became available during the trial.

The initial five molecular cohorts in the FOCUS4 trial, which were allocated to comparison subtrials referred to as FOCUS4-A, -B, -C, -D and -N, were as follows:

BRAF mutation (FOCUS4-A). BRAF mutations are more frequent in the presence of microsatellite instability (MSI) and arise more commonly in right-sided colon carcinomas and have a reasonably consistent gene expression signature.5 In the Medical Research Council (MRC) COntinuous or INtermittent (COIN) trial,6 8% of patients had BRAF mutations. Patients with this molecular classification and with normal platelets in the intermittent arm of the COIN trial had a median overall survival (OS) of 14.8 months and a median progression-free survival (PFS) in the interval off therapy of 3.1 months.
PIK3CA mutation or profound loss of phosphatase and tensin homologue (PTEN) expression (FOCUS4-B). These mutations lead to activation of the protein kinase B (AKT) signalling network, and approximately half of the patients also have KRAS mutations. In addition, approximately 10% of patients have a loss of PTEN expression by various mechanisms, including mutation, methylation silencing of the promoter and microRNA inhibition. The TCGA report7 has identified increased signalling through the insulin-like growth factor (IGF) receptor owing to amplification of IGF2 as an important additional driver within this pathway. PIK3CA mutations have been identified as one of the most common mutations in cancer and were identified in 13% of patients in the COIN trial.6 Patients with PIK3CA or PIK3R1 mutations or profound loss of PTEN expression account for approximately 20–30% of the CRC population and have activated AKT signalling. Patients with this molecular classification and with normal platelets in the intermittent arm of the COIN trial had a median OS of 16.9 months and a median PFS in the interval off therapy of 2.7 months. These figures were similar whether or not a KRAS/NRAS mutation was also present.
KRAS or NRAS mutation (FOCUS4-C). Expression profile analysis shows a variation in gene expression patterns in tumours with KRAS mutation, with signalling down the canonical RAS-RAF-MEK-ERK pathway dominating in about one-quarter, signalling through the PIK3-AKT-mTOR pathway in others and diverse signalling in other tumours.8 In the COIN trial,6 44% of patients exhibited either KRAS or NRAS mutations, rising to 52% of those who also exhibited PIK3CA mutation. Patients with this molecular classification and with normal platelets in the intermittent arm of the COIN trial6 had a median OS of 18.4 months and a median PFS in the interval off therapy of 3.0 months.
Wild type for all the above mutations (EGFR dependent) (FOCUS4-D). Patients with these tumours are wild type for BRAF, PIK3CA, KRAS and NRAS and do not have loss of PTEN, and include the subset of patients who respond best to EGFR-targeted monoclonal antibodies. In addition, mutations or amplification in human epidermal growth factor receptor (HER) 2 occur in around 5% and overexpression of HER3 in around 50% of these patients. In the COIN trial,6 42% of patients were free from all four above mutations. Patients with this molecular classification and with normal platelets in the intermittent arm of the COIN trial6 had a median OS of 19.1 months and a median PFS in the interval off treatment of 3.3 months. In the COIN-B trial,9 the equivalent figures were 20.0 months and 4.4 months, respectively, albeit with small patient numbers, indicating that prognosis is potentially good among such patients.
Non-stratified group (unclassified) (FOCUS4-N). Approximately 2% of patients with CRC have tumours that cannot be classified successfully; these patients were included in the non-stratified group. In addition, this cohort included those patients eligible for comparisons that were suspended between novel therapy evaluations or patients who chose not to participate in their specific molecular comparison for reasons such as distance to an experimental therapy centre. Once a patient entered a particular comparison subtrial, they could not enter another FOCUS4 comparison at another time.

The identification of novel biomarkers and their link to the selection of patients for specific therapy is a fast-moving field. Therefore, an essential feature of FOCUS4 was the capacity to introduce novel biomarkers once they had been sufficiently validated to identify newly characterised tumour subgroups for evaluation of therapies hypothesised to be effective in the identified patient subpopulations. Therefore, the FOCUS4 trial incorporated some accepted biomarkers (e.g. KRAS mutation), some biomarkers reaching consensus (e.g. BRAF mutation) and other biomarkers for which further development and refinement was required (e.g. PTEN, mRNA for epiregulin) but could be accomplished within the trial itself.

FOCUS4 was structured to provide an overarching recruitment and biomarker identification strategy, which was linked to a series of randomised comparison subtrials between novel and control treatments for the identified subpopulations. During the trial, some of these interventions could have been shown to lack sufficient activity and would be accordingly withdrawn and replaced by new agents or by new biomarker-defined groups.

Within the individual comparison subtrials for each molecular cohort, the novel therapy comparisons were double blind and placebo controlled where possible. However, patients in FOCUS4-N were allocated to either capecitabine or active monitoring; this was, therefore, an open-label, unblinded subtrial.

Aims and objectives

The primary objectives of the FOCUS4 trial were to answer the following research questions:

Clinical benefit . In the interval following standard first-line chemotherapy, do the proposed interventions improve PFS and eventually OS compared with a control group in the biomarker-defined cohorts?
Improvement in trial design and conduct. To understand better the challenges and efficiencies of conducting a large, molecularly stratified platform trial in metastatic CRC in the UK health-care system.

Attribution. Louise C Brown; David Fisher; Richard Adams; Jenny Seligmann; Matthew Seymour; Richard Kaplan et al. (2022). Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT. National Institute for Health and Care Research. Copyright © 2022 Brown et al. This work was produced by Brown et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited. Licensed under CC BY 4.0. NCBI Bookshelf NBK587971. CC BY 4.0. Original source ↗. Text reproduced from the Bookshelf XML without changing wording; figures, images and supplements are not reproduced.