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Background  Rearranged during transfection ( RET ) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In  RET -rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared.    Methods  Patients diagnosed with NSCLCs with  RET  rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs).    Results  Among 129 patients with  RET -rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant  TP53  mutation appeared most frequently (20/53, 37.7%). Patients with concurrent  TP53  mutation ( n  = 15) had shorter overall survival than those without ( n  = 30; median, 18.4 months [95% CI, 8.6–39.1] vs 24.8 months [95% CI, 11.7–52.8];  P  < 0.05). Patients with lower peripheral blood TCR diversity ( n  = 5) had superior overall survival compared with those with higher diversity ( n  = 6; median, 18.4 months [95% CI, 16.9–19.9] vs 4.8 months [95% CI, 4.5–5.3];  P  = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10).    Conclusions   RET -rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent  TP53  mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.

journal of hematology and oncology

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study