生物标志物预测阿法替尼相较于甲氨蝶呤二线治疗复发性和/或转移性头颈部鳞癌患者可带来更好的临床结局。
Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer.
机构信息
Moores Cancer Center, University of California San Diego, La Jolla, USA;.
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan;; Department of Medical Oncology, University of Milan, Milan, Italy.
出版信息
Ann Oncol. 2017 Oct 1;28(10):2526-2532. doi: 10.1093/annonc/mdx344.
BACKGROUND
In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1.
PATIENTS AND METHODS
Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes.
RESULTS
Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35).
CONCLUSIONS
Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings.
CLINICAL TRIAL REGISTRATION
NCT01345682.
背景
在 III 期 LUX-Head & Neck 1（LUX-H&N1）试验中，二线阿法替尼与甲氨蝶呤相比，显著改善了复发性/转移性头颈部鳞状细胞癌（R/M HNSCC）患者的无进展生存期（PFS）。在此，我们评估了 LUX-H&N1 中预先指定的生物标志物与疗效结果的相关性。
患者和方法
接受过≥2 周期铂类化疗后进展的 R/M HNSCC 患者随机接受阿法替尼（40mg/天）或甲氨蝶呤（40mg/m2/周）治疗。研究入组时，自愿参加生物标志物分析的患者采集肿瘤/血清样本。使用组织微阵列芯和切片评估肿瘤生物标志物，包括 p16（所有肿瘤亚部位的预先指定亚组；EGFR、HER2、HER3、c-MET 和 PTEN）；使用 VeriStrat®测试评估血清蛋白。生物标志物与疗效结果相关。
结果
在 483 名随机患者中，326 名（67%）纳入生物标志物分析；基线特征与总体研究人群一致。在 p16 阴性[2.7 与 1.6 个月；HR 0.70（95%CI 0.50-0.97)]、EGFR 扩增[2.8 与 1.5 个月；HR 0.53（0.33-0.85)]、HER3 低表达[2.8 与 1.8 个月；HR 0.57（0.37-0.88)]和 PTEN 高表达[1.6 与 1.4 个月；HR 0.55（0.29-1.05)]肿瘤患者中，阿法替尼组的 PFS 更优。在 p16 阴性和 EGFR 扩增肿瘤的联合亚组中，阿法替尼也改善了 PFS[2.7 与 1.5 个月；HR 0.47（0.28-0.80)]，在 p16 阴性且 EGFR 治疗初治的患者中，PFS 也得到了改善[4.0 与 2.4 个月；HR 0.55（0.31-0.98)]。在 VeriStrat“良好”与“差”的阿法替尼治疗患者中，PFS 得到改善[2.7 与 1.5 个月；HR 0.71（0.49-0.94)]，但未观察到治疗交互作用。阿法替尼改善了肿瘤应答，与甲氨蝶呤相比，除了 p16 阳性疾病患者（n=35）。
结论
基于预先指定的肿瘤生物标志物（p16 阴性、EGFR 扩增、HER3 低表达、PTEN 高表达），确定了可能从阿法替尼治疗中获益更大的 HNSCC 患者亚组。需要进一步的研究来验证这些发现。
临床试验注册
NCT01345682。
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