Abstract
BackgroundRearranged 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.MethodsPatients 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).ResultsAmong 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).ConclusionsRET-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.
Highlights
Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs)
Study design and patients The study flow chart is shown in Supplementary figure 1. This retrospective observational study was performed at 13 centers in China and included patients who had a pathologic diagnosis of NSCLC of any age with RET rearrangement determined by at least one of the validated tests including fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and nextgeneration sequencing (NGS)
The most common concomitant mutations identified in RET-positive NSCLC were TP53 (38%) and SETD2 (9%, Fig. 1a, b)
Summary
Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). The dawn of the targeted therapy era saw the discovery of receptor tyrosine kinase RET fusion in 1–2% of nonsmall cell lung cancers (NSCLC) [1, 2] and proved it to be tumorigenic and targetable. Since more specific and potent TKIs targeting RET such as BLU-667 and LOXO-29 2[7,8,9] are currently not available for all of the patients, the common systemic treatment regimen includes multikinase inhibitors (MKIs), chemotherapy, and immune checkpoint inhibitors (ICIs). ICIs have been widely accepted, the outcomes of these treatment strategies in RET-altered patients have not currently been well compared, and the immuno-characteristics in those patients have not been well characterized in previous studies [16, 17]
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