Find in Library

<i>Anaplastic lymphoma-kinase (ALK)</i>-rearranged non-small cell lung cancer (NSCLC) is prone to developing heterogeneous, only partly known mechanisms of resistance to ALK-tyrosine-kinase-inhibitors (ALK-TKIs). We present a case of a 38-year old male, who never smoked with disseminated <i>ALK</i>-rearranged (<i>EML4</i> (20) – <i>ALK</i> (20) fusion variant 2) lung adenocarcinoma, who received four sequentially different ALK-TKIs and two lines of chemotherapy in-between. We observed significant clinical benefit by the first three ALK-TKIs (Crizotinib, Ceritinib, Alectinib) and chemotherapy with Pemetrexed, resulting in overall survival over 3 years. Longitudinal assessment of progressions by rebiopsies from hepatic metastases showed different mechanisms of resistance to each ALK-TKI, including secondary <i>ALK</i>-mutations and the downstream p.V600E <i>BRAF</i>-mutation that had not been linked to second-generation ALK-TKIs before. Ultimately, in connection with terminal rapid progression and resistance to Alectinib and Lorlatinib, we identified phenotypical epithelial-mesenchymal transition (EMT) of newly occurred metastatic cells, a phenomenon not previously related to these two ALK-TKIs. This resistance heterogeneity suggests a continuously changing disease state. Sequential use of different generation’s ALK-TKIs and combination therapies may yield prolonged responses with satisfactory quality of life in patients with advanced <i>ALK</i>-positive NSCLC. However, the development of EMT is a major hurdle and may explain rapid disease progression and lack of response to continued ALK-inhibition.