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

Abstract

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,.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.

Efficacy of Immune Checkpoint Inhibitor Therapy in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer

“…Likewise, data related to the level of PD-L1 expression in this patient population are not consistent. PD-L1 expression (≥1%) has been reported ranging from 37.5 to 100% among patients with RET fusion-positive NSCLC [18,19,21,22,24,25]. In this study, the information about TMB and PD-L1 expression was summarized among those who had it measured within 15 days prior to or 60 days after the index diagnosis, and data were only available from 14 (TMB) and 13 (PD-L1) patients in the CGDB; TMB and PD-L1 are not reported in the GHD.…”

“…However, similar to the current state of evidence about efficacy of ICI-based therapies, the evidence regarding expression of PD-L1 is also mixed in patients with oncogene-driven NSCLC. Among various studies, the percentage of RET fusion-positive patients with NSCLC reporting ≥50% expression of PD-L1 were: 12.5% (n = 1/8) [22], 22% (n = 2/9) [24], 25% (n = 5/20) [25], 37.5% (n = 3/8) [18] and 70% (n = 7/10) [21]. Given the mixed evidence to date, very limited understanding exists about the role of ICI therapy for patients with RET fusion-positive NSCLC [3,16].…”

Is there any place for immune-checkpoint inhibitors in the treatment algorithm of fusion-driven non-small cell lung cancer?—a literature review

“…ROS1 positive tumors were poorly represented even in retrospective case series (27,47,48), preventing any conclusion about PD-L1 expression in this subgroup of patients. Importantly, ROS1 positive NSCLC shares with ALK-and RET-positive counterparts a lower TMB compared to wild type or EGFR-mutated adenocarcinomas (49).…”

“…Whether these results are applicable also to NSCLC remains uncertain. RET positive NSCLC presented significant PD-L1 expression in different case series (49,(55)(56)(57), with PD-L1 positive (TPS ≥1%) RET-rearranged tumors accounting for 40-50% of all cases. Conversely, median TMB was significantly lower in RET positive as compared to wild type NSCLC (49,56), but similar to that reported for ALK and ROS1 positive NSCLC (49).…”

Phase III Study of Selpercatinib Versus Chemotherapy ± pembrolizumab in Untreated RET Positive Non-Small-Cell Lung Cancer

“…Several studies have suggested that NSCLC patients with driver oncogenes may benefit less from chemotherapyimmunotherapy combinations and a recent multi-disciplinary roundtable discussion recommended that immune checkpoint inhibitors should be used after targeted therapies and chemotherapy [16]. However, it is not yet clear whether these observations extend to NSCLC patients with RET fusions as the reported data are variable [17][18][19]. Additional studies are needed to fully characterize the effect of chemotherapy-immunotherapy combinations in RET fusion-positive NSCLC patients.…”