局部晚期非人乳头瘤病毒 (HPV) 头颈癌 (HNC) 患者的预后不良。使用顺铂或抗表皮生长因子受体 (EGFR) 抗体的放化疗 (CRT) 可改善 III 期至 IV 期 HNC 患者的总生存期 (OS)，临床前数据表明，小分子酪氨酸激酶抑制剂双 EGFR 和 ERBB2（以前称为HER2 或 HER2/neu) 抑制剂可能比抗 EGFR 抗体治疗 HNC 更有效。 探讨在放射加顺铂的基础上添加拉帕替尼（EGFR 和 HER2 双重抑制剂）作为 III 期至 IV 期非 HPV HNC 的一线治疗是否可以改善无进展生存期 (PFS)。 这项多中心、2 期、双盲、安慰剂对照随机临床试验入组了 142 名具有 Zubrod 表现状态的 III 期至 IV 期口咽癌（p16 阴性）、喉癌和下咽癌患者2012 年 10 月 18 日至 2017 年 4 月 18 日期间，有 0 到 1 名符合预定血液化学标准的患者（中位随访时间为 4.1 年）。数据分析于 2020 年 12 月 1 日至 2020 年 12 月 4 日进行。患者被随机 (1:1) 接受 70 Gy（6 周）加 2 个周期的顺铂（每 3 周）加每天 1500 mg 的拉帕替尼（ CRT 加拉帕替尼）或安慰剂（CRT 加安慰剂）。主要终点是 PFS，需要 69 个事件。通过单边对数秩检验比较所有随机患者的臂间无进展生存率。次要终点包括 OS。在 142 名入组患者中，127 名（中位 [IQR] 年龄，58 [53-63] 岁；98 名 [77.2%] 男性）被随机分配； 63 为 CRT 加拉帕替尼，64 为 CRT 加安慰剂。最终分析并未表明 PFS（风险比，0.91；95% CI，0.56-1.46；P = .34）或 OS（风险比，1.06；95% CI，0.61-1.86；P = .58）有所改善。添加拉帕替尼。 3 至 4 级急性不良事件发生率无显着差异（CRT 加拉帕替尼组为 83.3% [95% CI, 73.9%-92.8%]，而 CRT 加安慰剂组为 79.7% [95% CI, 69.4%-89.9%]） ; P = .64) 或晚期不良事件发生率 (CRT 加拉帕替尼为 44.4% [95% CI, 30.2%-57.8%]，CRT 加安慰剂为 40.8% [95% CI, 27.1%-54.6%]；P = .84).在这项随机临床试验中，拉帕替尼双重 EGFR-ERBB2 抑制似乎并未增强 CRT 的益处。尽管该试验的结果表明，进行非 HPV HNC 特异性试验是可行的，但必须研究新的策略来改善这一预后不良人群的结果。ClinicalTrials.gov 标识符：NCT01711658。

Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC.To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS).This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020.Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo).The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS.Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84).In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis.ClinicalTrials.gov Identifier: NCT01711658.