Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
Southwest Oncology Group (SWOG) Statistical Center and Clinical Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Lancet Oncol. 2018 Jan;19(1):101-114. doi: 10.1016/S1470-2045(17)30694-0. Epub 2017 Nov 20.
EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive.
We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712).
Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9-39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75-1·12; p=0·40; median 5·4 months [95% CI 4·5-5·7] vs 4·8 months [3·9-5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83-1·04; p=0·22; median 10·9 months [95% CI 9·5-12·0] vs 9·2 months [8·7-10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36-0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46-1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78-1·40; p=0·77; and 1·02, 0·77-1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68-1·14; p=0·34; and 0·99, 0·78-1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85-1·17; p=0·97; and 1·03, 0·88-1·20; p=0·69; respectively). The most common grade 3-4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [<1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group.
Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation.
National Cancer Institute and Eli Lilly and Company.
表皮生长因子受体（EGFR）抗体已在晚期非小细胞肺癌（NSCLC）患者中显示出良好的疗效，尤其是具有鳞状细胞组织学特征的患者。我们假设 EGFR 拷贝数的荧光原位杂交（FISH）检测可以确定最有可能从这些药物联合化疗中获益的患者，因此我们旨在探索 EGFR FISH 阳性的晚期 NSCLC 患者接受西妥昔单抗联合化疗的疗效。
本研究在美国和墨西哥的 277 个研究中心进行，采用开放性、3 期 SWOG S0819 设计，入组的 EGFR FISH 阳性、未经治疗的Ⅳ期 NSCLC 患者 1313 例，按照 1:1 的比例随机分配至接受紫杉醇（200 mg/m2，每 21 天 1 次）联合卡铂（曲线下面积 6 按改良 Calvert 公式计算，每 21 天 1 次）或卡铂联合紫杉醇及贝伐珠单抗（15 mg/kg，每 21 天 1 次）治疗，联合治疗组（西妥昔单抗组）接受西妥昔单抗（负荷剂量后每周 250 mg/m2），对照组（贝伐珠单抗组）不接受西妥昔单抗治疗，分层因素包括贝伐珠单抗治疗、吸烟状况和 M 亚分期，采用动态平衡算法分组。主要研究终点为 EGFR FISH 阳性患者的无进展生存期和整个研究人群的总生存期。我们采用意向治疗原则进行临床结局分析，安全性结局分析包括至少接受 1 次研究药物治疗的患者。本研究在 ClinicalTrials.gov 注册，编号为 NCT00946712。
2009 年 8 月 13 日至 2014 年 5 月 30 日，共随机分配 1313 例患者至对照组（n=657，意向治疗人群中 277 例接受贝伐珠单抗治疗，380 例未接受贝伐珠单抗治疗）或西妥昔单抗组（n=656，意向治疗人群中 283 例接受贝伐珠单抗治疗，373 例未接受贝伐珠单抗治疗）。976 例患者可评估 EGFR FISH 状态，其中 400 例（41%）患者 EGFR FISH 阳性。最后一次随访时，仍存活的患者中位随访时间为 35.2 个月（22.939.9 个月）。在 EGFR FISH 阳性亚组中，西妥昔单抗组和对照组分别有 194 例和 198 例患者发生疾病进展，无进展生存期无显著差异（风险比[HR]0.92，95%CI 0.751.12；p=0.40；中位 5.4 个月[95%CI 4.55.7] vs 4.8 个月[3.95.5]）。在整个研究人群中，西妥昔单抗组和对照组分别有 570 例和 593 例患者死亡，总生存期也无显著差异（HR 0.93，95%CI 0.831.04；p=0.22；中位 10.9 个月[95%CI 9.512.0] vs 9.2 个月[8.710.3]）。在 EGFR FISH 阳性且具有鳞状细胞组织学特征的亚组中，西妥昔单抗组的总生存期显著长于对照组（HR 0.58，95%CI 0.360.86；p=0.0071），但该亚组的无进展生存期也无显著差异（HR 0.68，0.461.01；p=0.055）。具有 EGFR FISH 阴性且鳞状细胞组织学特征的患者（HR 1.04，95%CI 0.781.40；p=0.77）和无论 EGFR FISH 状态如何均具有非鳞状细胞组织学特征的患者（对于 EGFR FISH 阳性患者，HR 0.88，0.681.14；p=0.34；和 HR 0.99，0.781.27；p=0.96；对于 EGFR FISH 阴性患者，HR 1.00，0.851.17；p=0.97；和 HR 1.03，0.881.20；p=0.69），总生存期和无进展生存期也无显著差异。最常见的 3~4 级不良事件为中性粒细胞计数减少（西妥昔单抗组 210 例[37%]，对照组 158 例[25%]）、白细胞计数减少（西妥昔单抗组 103 例[16%]，对照组 74 例[20%]）、疲乏（西妥昔单抗组 81 例[13%]，对照组 74 例[20%]）和痤疮或皮疹（西妥昔单抗组 52 例[8%]，对照组 1 例[＜1%]）。西妥昔单抗组 9%（59 例）的患者和对照组 5%（31 例）的患者发生严重不良事件。西妥昔单抗组和对照组分别有 6%（32 例）和 2%（13 例）的患者死亡与治疗相关。
尽管本研究未达到主要终点，但 EGFR FISH 阳性的鳞状细胞癌患者的亚组分析结果令人鼓舞，支持在该亚组中进一步评估抗 EGFR 抗体。
美国国家癌症研究所和礼来公司。
