Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib, alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation - ALK G1202R - increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.

Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.

PAPs showed a strong predilection for the peripheral pulmonary arteries. Multiplicity of PAPs can be seen in the settings of endocarditis and pulmonary metastatic disease. Most PAPs were not associated with a ground-glass halo. PAPs can be lethal but were often not suspected clinically and were underreported by radiologists.

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MIE proves its safety after neoadjuvant therapy because it leads to faster progression during the early postoperative period while reducing pulmonary complications. Open and MIE approaches appear equivalent with regards to perioperative oncologic outcomes after neoadjuvant therapy. Long-term outcomes need further validation.