Genomic-driven trials: it’s time to be flexible

Rodrigo Dienstmann

Hospital Vall dʹHebron, Barcelona, Spain

The molecular landscape of cancer can be quite complicated. In recent years, it has become increasingly evident that the spectrum of genetic alterations is specific for each tumour type and each patient. But the targetability of genetic alterations isn’t black and white, instead it usually encompasses all shades of grey. “The move to genomically-driven trials is, therefore, an intelligent one that gives us the greatest chance of a patient responding to treatment, but only when the driver genetic alterations of the tumour can be potently targeted in humans.

In such cases we see substantial sensitivity to matched targeted therapies,” says Dienstmann.

"When uncertainties in the biomarker–drug co-development remain after early clinical trials, appropriate control populations in a genomic-driven trial are essential and help to clarify the predictive role of a genetic alteration."

The choice of genomic-driven trial design is guided by the prevalence and type of the biomarker(s) being tested in a given tumour type. Recently developments in trial design that are helping to progress genomic-driven oncology care include ‘basket trials’ that enrol patients that share the same mutation, regardless of the tumour site (also known as histology or tissue agnostic clinical trials), and ‘umbrella trials’, which enrol patients with multiple actionable genomic alterations and a single tumour type. “In the setting of rare genetic alterations detected across different tumours, a basket trial design enables researchers to gain further insight into potential targetability in the clinics,” points out Dienstmann. “However, there is the possibility of false-negative conclusions given the small number of patients with a particular tumour type.”

Umbrella trials are also not free from challenges and one major complexity is the need for parallel development of multiple biomarkers and drugs in the same study. “Genomically-driven trials with an adaptive design can potentially help us to overcome some barriers as they offer flexibility while the trial is ongoing. For example, analysis of efficacy and safety at predefined timepoints during the study may trigger a switch from monotherapy to combination therapy, a change in treatment dose, or it could instigate stopping one treatment arm, and this can have clear benefits to patients.” Furthermore, using a targeted therapy often instigates clonal evolution in the tumour and acquired resistance, which prompts the need to switch therapy. In some cases it is worthwhile, therefore, to follow the evolution of driver alterations over time and a valuable option for doing this is by using liquid biopsies.

"There is a need to develop study designs that are flexible and sufficiently adaptative in their inclusion criteria to maximise patient care opportunities while the trial is ongoing."

Given the rarity of most targetable genetic alterations, another major challenge in genomic-driven oncology care is the need for multi-institutional co-operative networks that facilitate data exchange and patient referral. Continued medical education on emerging predictive biomarkers is essential for managing the matching of patients to the most appropriate treatment. In this regard, networks also have the advantage of developing expertise, with the use of molecular tumour boards to discuss the results of genomic tests, which can help prioritise potential targets and assist patients to access trials.

“We must recognise that the benefits to patients of genome-driven trials can, perhaps, be overestimated,” warns Dienstmann. “The genetic alterations and treatments are still under investigation and our knowledge in this area continues to evolve and expand.”

Increased access to genomic-driven trials relies on guided molecular testing. Rooted in evidence-based information available to date, the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) framework has been created to rank molecular alterations as targets for precision medicine in an effort to help all relevant stakeholders to prioritise patients for matched therapies.

Despite the potential benefits of genome-driven oncology care, access to academic institutions where next-generation sequencing is performed in the scope of molecular pre-screening programmes remains limited. One major reason is that centralised molecular testing financed by clinical trial sponsors is uncommon and commercial tests are very expensive. Also, a lack of expertise may result in many patients failing to have access to next-generation sequencing.

“Sometimes, clinicians have not been properly educated on whom to recommend for molecular pre-screening at a given timepoint in the evolution of the disease and what test should be requested.”

Genomically-driven oncology care potentially offers benefits in terms of improving the efficacy of targeted therapies. “In the future, I am confident that information generated through personalised genomic testing will give insights into the most appropriate type of therapy—not only targeted drugs but also immunotherapies and chemotherapies—as well as the optimal combination or sequence of these.”