Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greate

Abstract
Purpose
Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non–small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized.

Methods
We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed.

Results
We included 67 patients—38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation.

Conclusion
There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.

结果
我们纳入了67名患者–38名女性和29名男性; EGFR突变包括外显子19缺失(69%),L858R(25%)和其他(6%)。在最初的肺癌诊断中,58名患者患有NSCLC,9名患者具有从头SCLC或混合组织学。除了这9名患者外,所有患者在SCLC转化前都接受了一种或多种EGFR酪氨酸激酶抑制剂。转化的中位时间为17.8个月(95%CI,14.3至26.2个月)。转化后,铂 – 依托泊苷和紫杉烷均产生高反应率,但17名接受免疫治疗的患者均未出现反应。自诊断以来的中位总生存期为31.5个月(95%CI,24.8至41.3个月),而自SCLC转化时起的中位生存期为10.9个月(95%CI,8.0至13.7个月)。 59例患者在首次SCLC证据时进行了组织基因分型。所有人都保持了他们的创始人EGFR突变,并且19岁时患有先前EGFR T790M阳性的15人在转化时是T790野生型。其他复发突变包括TP53,Rb1和PIK3CA。在一些病例中鉴定出NSCLC克隆的重新出现。 CNS转移在转化后频繁发生。

结论
人们越来越认识到EGFR突变的NSCLC可以进行SCLC转化。我们证明这在诊断后平均发生在17.8个月,并且病例通常以Rb1,TP53和PIK3CA突变为特征。对铂 – 依托泊苷和紫杉烷的反应很常见,但检查点抑制剂没有产生反应。需要进一步调查以更好地阐明该组的最佳策略。

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