Medical College of Wisconsin, Milwaukee.
Department of Statistics, RTOG Foundation, Philadelphia, Pennsylvania.
JAMA Oncol. 2023 Nov 1;9(11):1565-1573. doi: 10.1001/jamaoncol.2023.3809.
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).
DESIGN, SETTING, AND PARTICIPANTS: 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.
重要性：局部晚期非人乳头瘤病毒（HPV）头颈部癌症（HNC）患者预后不良。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重 EGFR 和 ERBB2（前 HER2 或 HER2/neu）抑制剂在 HNC 中的疗效可能优于抗 EGFR 抗体治疗。
目的：研究在 III 期至 IV 期非 HPV HNC 的一线治疗中，添加 lapatinib（一种双重 EGFR 和 HER2 抑制剂）联合放疗加顺铂是否能改善无进展生存期（PFS）。
设计、地点和参与者：这项多中心、2 期、双盲、安慰剂对照随机临床试验纳入了 142 名 Zubrod 体能状态为 0 至 1 分、接受过预定义血液化学标准评估的 III 期至 IV 期口咽（p16 阴性）、喉和下咽癌患者，从 2012 年 10 月 18 日至 2017 年 4 月 18 日入组（中位随访时间 4.1 年）。数据分析于 2020 年 12 月 1 日至 12 月 4 日进行。
干预：患者被随机（1:1）分为 70 Gy（6 周）加 2 个周期顺铂（每 3 周）加每天 1500mg lapatinib（CRT 加 lapatinib）或安慰剂（CRT 加安慰剂）。
主要终点和测量：主要终点是 PFS，需要 69 个事件。通过单侧对数秩检验比较所有随机患者的无进展生存率。次要终点包括 OS。
结果：在纳入的 142 名患者中，127 名（中位[IQR]年龄，58[53-63]岁；98[77.2%]为男性）被随机分组；63 名患者接受 CRT 加 lapatinib，64 名患者接受 CRT 加安慰剂。最终分析并未提示 lapatinib 的添加可改善 PFS（风险比，0.91；95%CI，0.56-1.46；P=0.34）或 OS（风险比，1.06；95%CI，0.61-1.86；P=0.58）。3 至 4 级急性不良事件发生率（CRT 加 lapatinib 组为 83.3%[95%CI，73.9%-92.8%]，CRT 加安慰剂组为 79.7%[95%CI，69.4%-89.9%]；P=0.64）或晚期不良事件发生率（CRT 加 lapatinib 组为 44.4%[95%CI，30.2%-57.8%]，CRT 加安慰剂组为 40.8%[95%CI，27.1%-54.6%]；P=0.84）无显著差异。
结论和相关性：在这项随机临床试验中，lapatinib 对双重 EGFR-ERBB2 的抑制似乎并没有增强 CRT 的疗效。尽管该试验的结果表明，招募 HPV 特异性 HNC 特定试验的可行性，但必须研究新的策略来改善这一预后不良人群的预后。
试验注册：ClinicalTrials.gov 标识符：NCT01711658。
