Impact of next generation TKI and co-occurring mutations in ALK-positive NSCLC patients: Results of the Network Genomic Medicine

Abstract

Background: Anaplastic lymphoma kinase (ALK) gene rearrangements define amolecular subtype of 3-4% of non-small-cell lung cancer (NSCLC), highly sensitive to therapy with ALK-directed tyrosine kinase inhibitors (TKI). Genetic heterogeneity of ALK-positive lung cancer patients (pts) is poorly characterized due to the lack of multiplex diagnostics results besides conventional FISH diagnostics. The Network Genomic Medicine (NGM) performs next generation sequencing (NGS) based diagnostics on a central platform in Cologne for advanced lung cancer pts in Germany. Methods: The NGS panel used inNGM consists of 17 genes covering potentially targetable aberrations and is run on an Illumina (MySeq) platform. In 2016, we have started retrospective evaluation of ALK-positiveNGM pts with available clinical data from the time period before and after NGS implementation. In particular, we have focused on ALK-positive NSCLC pts treated with chemotherapy, crizotinib and next generations TKI. Furthermore, we have analyzed the impact of co-occurring mutations: their frequency, significance and impact on overall survival. Results: We have analyzed 289 ALK-positive pts with eligible clinical data. Cooccurring mutations were detected in 31% of these pts. The most frequent coalteration was mutated TP53 in 23% of the ALK-positive patients. Regardless of the treatment regime, pts without co-occurring mutations seem to have a better overall survival (OS) with 37 versus (vs.) 15 month in pts with co-mutations (p=0.038). TP53 co-mutated pts show an OS of 10 month (p=0.004). Likewise, next generation TKI treatment exerts a highly positive impact on overall survival compared to chemotherapy and crizotinib treatment: 50 vs. 11 vs. 31 month (p>0.0001). Conclusions: While the first NGM evaluation in 2013 already showed a survival benefit of pts with activating genetic aberrations in EGFR and ALK, our current evaluation shows the heterogeneity of ALK-positive lung cancer pts and, for the first time to our knowledge, the impact of co-occurring mutations in these pts cohort. This work provides evidence for the efficacy of sequential ALK inhibitor treatment using next generation inhibitors and underlines the relevance of multiplex genotyping.