Molecular characterization of non-small-cell lung cancer (NSCLC) is essential to define the correct therapeutic algorithm in metastatic disease. Approximately 90% of epidermal growth factor receptor (EGFR) mutations are usually associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The remaining 10% defines a small, extremely heterogeneous subgroup of mutations, with a varied profile of sensitivity and response to target therapies.This retrospective observational study includes 47 patients affected by metastatic NSCLC harboring uncommon EGFR mutations (single or compound mutation). Patients were treated with EGFR-targeting TKIs or platinum-based chemotherapy as first-line treatment.Median OS resulted longer in the compound mutation group when compared to single rare mutations (33.6 vs 12 months; P = 0.473); a similar result was observed for PFS (16 vs 7.6 months; P = 0.281), although statistical significance was not reached. ORR, PFS and OS resulted similar for patients treated with first-line EGFR TKIs or chemotherapy. No difference in terms of PFS and OS was found according to the TKI administered.Compound mutations seem to be a good prognostic indicator for OS; they are also predictive of response to 1st and 2nd generation EGFR TKIs, as well as exon 19 insertions and mutations in codon 719 of exon 18. For mutations in exon 18 (not in codon 719) and exon 20 insertions, chemotherapy seems the most effective available option. The addition of immunotherapy to chemotherapy could change this approach in the next future.

非小细胞肺癌 (NSCLC) 的分子特征对于确定转移性疾病的正确治疗算法至关重要。大约 90% 的表皮生长因子受体 ( EGFR ) 突变通常与对 EGFR 酪氨酸激酶抑制剂 (TKI) 的敏感性有关。剩下的 10% 定义了一个小的、极其异质的突变亚组，具有不同的敏感性和对靶向治疗的反应。这项回顾性观察研究包括 47 名转移性非小细胞肺癌患者，携带不常见的EGFR突变（单个或复合突变）。患者接受 EGFR 靶向 TKI 或铂类化疗作为一线治疗。与单一罕见突变相比，复合突变组的中位 OS 更长（33.6 个月 vs 12 个月；P  = 0.473）；PFS 观察到了类似的结果（16 个月 vs 7.6 个月；P = 0.281），尽管没有达到统计显着性。接受一线 EGFR TKI 或化疗的患者的 ORR、PFS 和 OS 结果相似。根据给予的 TKI，在 PFS 和 OS 方面没有发现差异。复合突变似乎是 OS 的一个很好的预后指标。它们还可以预测对第一代和第二代 EGFR TKI 的反应，以及外显子 19 插入和外显子 18 的 719 密码子突变。对于外显子 18（不是密码子 719）和外显子 20 插入的突变，化疗似乎是最有效的可用选项。在化学疗法中加入免疫疗法可能会在未来改变这种方法。