Resistance is all too often looming with targeted therapies

Donald Harvey, PharmD, Emory University School of Medicine, Atlanta, USA

In which ways is resistance being tackled in the setting of targeted agents?

Resistance is the biggest challenge across the landscape of different compounds such as the new RET or MET inhibitors. I think it is promising to look at the story of EGFR-activating mutations, as initially we had gefitinib and erlotinib but were unaware of how they actually worked until the mutation data evolved. Subsequently, more potent compounds were created that continue to extend the time of patients on these treatments through improved medicinal chemistry and superior target binding. For the newer agents such as KRAS^G12C inhibitors, we are seeing good results, but resistance is real and already emerging. Thus, strategies to prevent resistance from the outset are needed, such as engineering agents that can inhibit both likely resistance mechanisms and the primary target. My hope is that we might be able to head this problem off earlier rather than later by exploring circulating tumor cells and blood-based markers of potential resistance development in a given patient. Much effort and technology are being invested trying to improve the outcomes of these patients across different platforms of science and drug discovery.

How can the design of clinical trials in the lung cancer setting be optimized to better meet the demands of modern drug development?

We need to be able to identify patients early and effectively through broad-based genomic platforms that ideally include data sharing. These days, next generation sequencing is performed in all lung cancer patients at many centers, but the clinical picture of the individual patient might not be suitable for enrollment in a trial investigating a new agent. Therefore, data sharing and having rapid opening opportunities for trials is important, as well as getting trials out into the community. Many times, patients are identified in the community but are unable to come to larger centers for treatment on trials.

With respect to the scientific design of trials, the tight link between molecular biology and the drug allows us to work with lower numbers of patients and observations. When patients are preselected to respond, the development of that drug can be accelerated in a fashion that allows for phase II or other early data to provide the basis for approval. Regarding execution of a trial, many sites are necessary to identify patients worldwide if they represent a rare population or if the genetic abnormality shows low penetrance. Some of the recent successful drug development stories are based on worldwide enrollment. Spreading that out as widely as possible will be critical to rapid trial completion and earlier agent access.

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