Genetic sequencing approaches to cancer clinical trials

Cancer is far from a single disease: there are more than 200 separate subtypes known, with considerable genetic variability. The genetic landscape of a tumour is at least as important as its original location with regards to response to treatments and evaluation in the wrong patient cohorts can lead to unnecessary failures. Identifying the molecular causes of a tumour enables a specific molecular pathway to be targeted hopefully leading to a greater response. For example, in papillary RCC patients MET mutations have been linked to a greater likelihood of responding to foretinib (Chouieri et al., 2013).

Most cancer treatments are established following a traditional clinical trial where new drugs are assessed in patients with the same type of tumour (Figure 1). Advanced understanding and technology have led to the development of targeted treatment clinical trials: umbrella and basket clinical trials use genetic and molecular data to assess targeted treatments in the right patient cohorts. Individual patients with a remarkable response in a standard trial can provide genetic information to form the basis of future targeted trials: everolimus did not reach the endpoint in trials for bladder and thyroid cancer, but the best responders were found to have mutations in the mTOR pathway (Iyer et al., 2012, Wagle et al.,  2014, Wagle et al., 2014b) identifying a patient cohort for future trials.

Traditionalfig

Umbrella trials also assess drug effectiveness on an individual tumour type. However, tumour genotyping subsequently subdivides patients based on mutation to assess appropriate targeted treatments (Figure 2). The trialled drugs may be assessed for different types of tumours with the same mutation within this trial or as part of a separate trial.

Umbrella fig

The BATTLE umbrella trial assessed four treatments on non-small cell lung cancer (NSCLC) patients using an adaptive randomisation approach (Kim et al., 2011) with patients assigned to the mutation-specific treatment group proving most beneficial. The CUSTOM umbrella trial attempted to analyse the effectiveness of five targeted therapies on NSCLC, small cell lung cancer or thymic malignancies patient cohorts (Lopez-Chavez et al., 2015). Only two of the 15 trial arms enrolled a sufficient number of patients highlighting a limitation of umbrella trials due to the rare nature of some mutations in certain tumours.

In comparison, basket trials are histology-independent with treatment arms based on shared mutations (Figure 3). Treatment cohorts can therefore be more inclusive of rare mutations. Basket trials can assess multiple drugs efficiencies in multiple patient cohorts in parallel. The response can be assessed for the whole cohort or for individual histologies to allow for tissue-specific effects.

Basket fig

The upcoming NCI-MATCH basket trial will screen up to 3000 tumour biopsies and recruit 800-1000 patients, including rare cancer patients, for small cohort studies based on mutation and targeted drugs. There are currently 20 different arms based on genetic mutation and tumour histology and over 40 different drugs have been pledged from numerous pharmaceutical industries.

Large, multi-armed umbrella and basket trials require an adaptive design to exclude ineffective drugs and include new drugs based on new knowledge or different mutations. Regular assessment of treatment arms enables greater enrolment to those performing better and rapid closer of less successful treatments. They also require good infrastructure for rapid tumour genotyping and patient enrolment, and good links with industry to provide the wide range of therapeutics required.

Although BHD is a monogenic disease caused by mutations in the tumour suppressor folliculin (FLCN), patients show phenotypic variation in renal tumour histology suggesting the involvement of other genes and pathways. As more is determined about renal tumourigenesis in BHD additional targetable pathways may be uncovered. The use of umbrella or basket trials would be better suited to assessing drug effectiveness in the limited number of BHD, and related disease, patients than standard clinical trials.

Success of genotyping trials depends on strong links between the target and the therapy. Targeted tumours must rely on the specific mutated pathway for growth and treatments must effectively block this pathway – something which may require combinatorial treatments. Greater understanding of molecular drivers in tumours will therefore enable the development of more successful targeted treatments for a range of cancers.

Further reviews of umbrella and basket trials can be found in Menis et al 2014 and Redig, Jänne 2015.

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