Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer

Simple Summary Lung cancer remains one of the most common and difficult cancers to treat. However, excellent progress in identifying the genetic causes of lung cancers has revealed many of the mutant proteins driving progression of this cancer. This in turn has led to development of new precision medicines that target these proteins providing significant improvement to patient outcomes. Unfortunately, this benefit tends to be relatively short-lived as the cancers develop resistance to these targeted agents. In this review, we look specifically at cancers driven by the EML4-ALK protein that is present in around 5% of lung cancer patients, occurring more frequently in young non-smokers. We consider the recent evidence for how resistance develops to current clinically approved targeted ALK inhibitors in these patients. Furthermore, we explore how additional research is revealing exciting alternative treatment options that may lead to a more sustained response and increased long-term survival for these patients. EML4-ALK is an oncogenic fusion protein that accounts for approximately 5% of NSCLC cases. Targeted inhibitors of ALK are the standard of care treatment, often leading to a good initial response. Sadly, some patients do not respond well, and most will develop resistance over time, emphasizing the need for alternative treatments. This review discusses recent advances in our understanding of the mechanisms behind EML4-ALK-driven NSCLC progression and the opportunities they present for alternative treatment options to ALK inhibitor monotherapy. Targeting ALK-dependent signalling pathways can overcome resistance that has developed due to mutations in the ALK catalytic domain, as well as through activation of bypass mechanisms that utilise the same pathways. We also consider evidence for polytherapy approaches that combine targeted inhibition of these pathways with ALK inhibitors. Lastly, we review combination approaches that use targeted inhibitors of ALK together with chemotherapy, radiotherapy or immunotherapy. Throughout this article, we highlight the importance of alternative breakpoints in the EML4 gene that result in the generation of distinct EML4-ALK variants with different biological and pathological properties and consider monotherapy and polytherapy approaches that may be selective to particular variants.