Salvage Therapy beyond Targeted Therapy in Lung Adenocarcinoma

Targeted therapy in lung adenocarcinoma has evolved rapidly over the last few years, especially in the application of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs). Although many patients with advanced EGFR-mutated or ALK-rearranged lung adenocarcinoma do benefit from treatment with a specific TKI, the duration of disease control is notoriously short. Different patterns of disease progression have been recognized that may require distinct treatment approaches. Isolated progressive disease in the central nervous system requires additional local therapy (radiotherapy or surgery) and an exploratory pulsatile regimen of TKI. Oligoprogressive disease at extracranial sites, representing resistant tumor clones in isolated lesions, requires local ablative therapy (radiotherapy or surgery) and continuation of the existing TKI. Multifocal progressive disease is a key therapeutic challenge to overcome because of widespread acquired resistance due to heterogeneous mechanisms. It is now known that EGFR TKI-acquired resistance is mostly (50-60%) due to a single resistance mutation in exon 20 (T790M) and occasionally (5-10%) due to c-MET amplification. On the contrary, the acquired resistance mechanisms to ALK TKI appear more diverse. Specific therapeutic strategies are being developed to overcome various acquired resistance mechanisms and may further improve the overall prognosis of advanced lung adenocarcinoma with actionable driver mutations.