There has been a revolution in the treatment of NSCLC in that patients with specific oncogenetic alterations receive first-line therapies that target those abnormalities. This provides a tremendous opportunity for these individuals, as they can begin their treatment with targeted therapy that may control their cancer for months or even years. However, patients on targeted therapy do ultimately progress, at which point we have to make a number of determinations on how best to proceed.

The first—and most important—thing to think about is probably the next line of therapy, but it is also important to consider some of the mechanisms of resistance that might be in play. The expanding knowledge base that results from understanding the mechanisms of resistance to targeted therapy can actually lead to the development of new treatments or combinations. Take the third-generation EGFR tyrosine kinase inhibitor osimertinib, one of the most commonly administered targeted therapies in the frontline setting. A median progression-free survival of approximately 19 months has been reported with osimertinib in this setting, which was significantly longer than the progression-free survival reported with standard EGFR tyrosine kinase inhibitors, with a similar safety profile and lower rates of serious adverse events. Nonetheless, resistance develops, and there is a diverse array of mechanisms of resistance to osimertinib that can be observed, including MET amplifications, secondary mutations in EGFR, and even histologic transformation to small cell lung cancer (SCLC). By identifying particular resistance mechanisms in individual patients, we can consider investigative approaches using targeted therapies or combinations that may have an advantage in that context. For instance, we see studies that evaluate the combination of EGFR inhibitors with MET inhibitors for patients who have MET amplifications at the time of resistance. And, for patients who have SCLC transformation, studies can assess the efficacy of chemotherapy that is directed toward SCLC.

However, the majority of patients will not have a targetable mechanism of resistance at the time of progression. For these individuals, the optimal approach to next-line therapy will be chemotherapy with a platinum doublet. Such platinum-based regimens can be very effective second-line therapies for some of these patients.