Treatment of advanced stage
anaplastic lymphoma kinase (ALK) positive
non-small cell lung cancer (NSCLC) with ALK
tyrosine kinase inhibitors (TKIs) has been shown to be superior to standard
platinum-based
chemotherapy. However, secondary progress of disease frequently occurs under ALK inhibitor treatment. The clinical impact of re-biopsies for treatment decisions beyond secondary progress is, however, still under debate. Here, we report on two novel subsequent polyclonal on- and off-target resistance mutations in a patient with ALK-fused NSCLC under ALK inhibitor treatment. A 63-year-old male patient with an advanced stage EML4-ALK fused pulmonary
adenocarcinoma was initially successfully treated with the second-generation ALK inhibitor
alectinib and upon progressions subsequently with
brigatinib,
lorlatinib and chemoimmunotherapy (
CIT). Progress to
alectinib was associated with a so far undescribed ALK mutation (p.A1200_G1201delinsW) which was, however, tractable by
brigatinib. An off-target KRAS-mutation (p.Q61K) occurred in association with subsequent progression under second-line TKI treatment. Third-line
lorlatinib showed limited efficacy but chemoimmunotherapy resulted in disappearance of the KRAS mutant clone and clinical
tumor control for another eight months. In conclusion, we suggest molecular profiling of progressive
tumor disease also for ALK-positive NSCLC to personalize treatment in a subgroup of ALK-positive patients.