ALK inhibitors, resistance development, clinical trials

Abstract

The treatment of advanced non-small-cell lung cancer (nsclc) has undergone a paradigm shift since the early 2000s. The identification of molecular subtypes of the disease, based on oncogenic drivers, has led to the development of personalized medicine and the ability to deliver molecularly targeted therapies to patients. In the 10 years that have elapsed since the discovery of the ALK gene in a patient with nsclc, several active drugs have moved rapidly from bench to bedside, and multiple others are currently in clinical trials. Those developments have led to important improvements in patient outcomes, while simultaneously raising key questions about the optimal treatment for ALK-positive nsclc. The inevitable emergence of resistance to alk-directed therapy is central to ongoing research and daily clinical practice for affected patients. In the present review, we highlight the current treatment landscape, the available and emerging clinical trials, and the evolving clinical decision-making in ALK-positive nsclc, with a focus on Canadian practice.

Keywords: alectinib; alk inhibitors; brigatinib; ceritinib; cns metastases; crizotinib; nsclc; resistance.

FIGURE 1

Current approach to managing ALK-positive non-small-cell lung cancer (NSCLC) in Canada. Crizotinib is still (for now) the standard first-line therapy for ALK-positive NSCLC. Distinct clinical patterns of resistance have been identified, highlighting the importance of multidisciplinary collaboration, particularly for patients with isolated central nervous system (CNS) progression. For patients with systemic progression, treatment with a next-generation ALK inhibitor is the standard of care. On subsequent progression, biopsy to determine molecular mechanisms of resistance is not routinely available and treatment is empirically selected. SRS = stereotactic radiosurgery.

FIGURE 2

Potential future management algorithm for ALK-positive non-small-cell lung cancer (NSCLC). Especially as next-generation ALK inhibitors become standard in first-line therapy, the need to understand the underlying mechanisms of resistance so as to direct subsequent therapy is accelerated. Further data from clinical studies, lower testing costs, and collaboration with pathologists and payers will potentially lead to molecular testing to characterize patients and optimize management.