Subtypes of EGFR- and HER2-Mutant Metastatic NSCLC Influence Response to Immune Checkpoint Inhibitors
Subtypes of EGFR- and HER2-Mutant Metastatic NSCLC Influence Response to Immune Checkpoint Inhibitors
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DOI：
10.1016/j.cllc.2020.12.015
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发表时间：
2021-07-30
影响因子：
3.6
通讯作者：
Sacher, Adrian G.
中科院分区：
文献类型：
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作者：
Lau, Sally C. M.;Fares, Aline Fusco;Sacher, Adrian G.
突变亚型对免疫检查点抑制剂（ICI）反应的影响存在争议。我们回顾并比较了EGFR和HER 2突变型非小细胞肺癌经ICIs治疗的结局差异。我们发现EGFR 20号外显子和HER 2突变与更好的缓解和无进展生存期相关，并得出结论，ICI是这些患者的重要治疗选择。简介：免疫检查点抑制剂（ICI）在EGFR突变的非小细胞肺癌（NSCLC）中的疗效较低，尽管偶尔有长期反应的报道。我们研究了HER 2和EGFR突变的NSCLC中突变亚型与ICI结局之间的关系。患者和方法：这项回顾性单中心研究分析了2013年至2019年期间接受至少1个周期ICI的EGFR和HER 2突变晚期NSCLC患者。患者特征、突变亚型和ICI结局。结果：48例晚期NSCLC患者中，14例（29%）有HER 2突变，34例（71%）有EGFR突变。EGFR突变包括16例（47%）19号外显子缺失、7例（21%）L 858 R、5例（15%）不常见和6例（18%）20号外显子插入。与EGFR致敏突变（ESM）相比，HER 2和EGFR 20号外显子突变与更好的缓解趋势（ESM、HER 2和EGFR 20号外显子分别为：11%、29%和50%; P = 0.07）和显著更好的疾病控制率（分别为18%、57%和67%; P = 0.008）相关。与ESM相比，HER 2突变（校正风险比，0.35; P = 0.02）和EGFR 20号外显子突变（校正风险比，0.37; P = 0.10趋势）也与PFS改善相关。程序性死亡配体1（PD-L1）表达仍然是PFS的独立预测因子（校正风险比，0.42; 95%置信区间，0.23-0.76; P = .004）。6个月PFS率分别为29%（HER 2）、33%（EGFR 20号外显子）和4%（ESM）。ICI在该人群中通常耐受良好。重要的是，在ICI后接受酪氨酸激酶抑制剂（TKI）作为下一线治疗的10例患者中未观察到免疫相关毒性。结论：HER 2和EGFR 20号外显子突变从ICI中获益更大，PFS与野生型历史二线/三线队列相当。鉴于目前尚无针对这些罕见突变的获批靶向疗法，ICI仍然是该基因组亚组的治疗选择。
The impact of mutation subtypes on response to immune checkpoint inhibitors (ICIs) is controversial. We reviewed and compared differences in outcomes of EGFR- and HER2-mutant non -small-cell lung cancer treated with ICIs. We found that mutations in EGFR exon 20 and HER2 are associated with better response and progression-free survival and conclude that ICIs constitute an important therapeutic option for these patients. Introduction: The efficacy of immune checkpoint inhibitors (ICIs) is low among EGFR-mutated non-small-cell lung cancer (NSCLC), although prolonged responses have occasionally been reported. We investigated the association between mutation subtypes and ICI outcomes among HER2- and EGFR-mutated NSCLC. Patients and Methods: This retrospective single-center study analyzed patients with EGFR- and HER2-mutated advanced NSCLC who received at least 1 cycle of ICI between 2013 and 2019. Patient characteristics, mutation subtype, and ICI outcomes. Results: Among 48 patients with advanced NSCLC, 14 (29%) had HER2 mutations and 34 (71%) had EGFR mutations. EGFR mutations included 16 (47%) exon 19 deletion, 7 (21%) L858R, 5 (15%) uncommon, and 6 (18%) exon 20 insertion. Compared to EGFR-sensitizing mutations (ESMs), HER2 and EGFR exon 20 mutations were associated with a trend toward better response (respectively, ESM, HER2, and EGFR exon 20: 11%, 29%, and 50%; P = .07) and significantly better disease control rates (respectively, 18%, 57%, and 67%; P = .008). Compared to ESM, HER2 mutations (adjusted hazard ratio, 0.35; P = .02) and EGFR exon 20 mutations (adjusted hazard ratio, 0.37; P = .10 trend) were also associated with improved PFS. Programmed death ligand 1 (PD-L1) expression remained an independent predictor of PFS (adjusted hazard ratio, 0.42; 95% confidence interval, 0.23-0.76; P = .004). The 6-month PFS rates were 29% (HER2), 33% (EGFR exon 20), and 4% (ESM). ICIs were generally well tolerated in this population. Importantly, no immune-related toxicity was observed in 10 patients who received a tyrosine kinase inhibitor (TKI) as the immediate next line treatment after ICI. Conclusion: HER2 and EGFR exon 20 mutations derive greater benefit from ICIs with comparable PFS to wild-type historical second/third-line unselected cohorts. ICIs remain a treatment option for this genomic subgroup, given the absence of approved targeted therapies for these rare mutations.