EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis.
EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis.
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DOI：
10.1158/1078-0432.ccr-15-3101
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发表时间：
2016-09-15
期刊：
影响因子：
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通讯作者：
Mino-Kenudson M
中科院分区：
文献类型：
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作者：
Gainor JF;Shaw AT;Sequist LV;Fu X;Azzoli CG;Piotrowska Z;Huynh TG;Zhao L;Fulton L;Schultz KR;Howe E;Farago AF;Sullivan RJ;Stone JR;Digumarthy S;Moran T;Hata AN;Yagi Y;Yeap BY;Engelman JA;Mino-Kenudson M
PD-1抑制剂是治疗非小细胞肺癌（NSCLC）的既定药物;然而，只有一部分患者获得临床获益。为了确定PD-1/PD-L1抑制剂在临床相关分子亚组中的活性，我们回顾性评价了EGFR突变型、ALK阳性和EGFR野生型/ALK阴性患者的缓解模式。我们确定了58例接受PD-1/PD-L1抑制剂治疗的患者。使用RECIST v1.1评估客观缓解率（ORR）。通过免疫组织化学评价PD-L1表达和CD 8+肿瘤浸润淋巴细胞（TIL）。在1/28例（3.6%）EGFR突变型或ALK阳性患者与7/30例（23.3%）EGFR野生型和ALK阴性/未知患者中观察到客观缓解（P = 0.053）。从不吸烟或轻度吸烟（≤10包年）者的ORR为4.2%，重度吸烟者为20.6%（P = 0.123）。在一个独立的晚期EGFR突变（N=68）和ALK阳性（N=27）患者队列中，分别在24%/16%/11%和63%/47%/26%的酪氨酸激酶抑制剂（TKI）前活检组织中观察到PD-L1表达，肿瘤细胞染色的临界值分别为≥ 1%、≥5%和≥50%。在TKI耐药前和耐药后活检的EGFR突变患者中（N=57），16例（28%）患者的PD-L1表达水平在耐药后发生变化。仅在1份治疗前（2.1%）和5份耐药（11.6%）EGFR突变体标本中观察到PD-L1同时表达（≥5%）和高水平CD 8 + TIL（≥2级），在任何ALK阳性、TKI治疗前或治疗后标本中均未观察到。携带EGFR突变或ALK重排的NSCLC与PD-1/PD-L1抑制剂的低ORR相关。肿瘤微环境中PD-L1和CD 8 + TIL的低并发表达率可能是这些临床观察结果的基础。
PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically-relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, ALK-positive, and EGFR wild-type/ALK-negative patients. We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORRs) were assessed using RECIST v1.1. PD-L1 expression and CD8+ tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry. Objective responses were observed in 1/28 (3.6%) EGFR-mutant or ALK-positive patients versus 7/30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- (≤10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced, EGFR-mutant (N=68) and ALK-positive (N=27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre-tyrosine kinase inhibitor (TKI) biopsies using cutoffs of ≥1%, ≥5% and ≥50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI resistant biopsies (N=57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (≥5%) and high levels of CD8+ TILs (grade ≥2) were observed in only 1 pre-treatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens, and was not observed in any ALK-positive, pre- or post-TKI specimens. NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8+ TILs within the tumor microenvironment may underlie these clinical observations.