ABSTRACT

Background

Antibodies against epidermal growth factor receptor (EGFR), panitumumab, a fully human monoclonal antibody, and cetuximab, a human/mouse chimeric monoclonal antibody, have shown clinical efficacy in metastatic colorectal cancer (mCRC). In the phase 3 noninferiority ASPECCT (ClinicalTrials.gov, NCT01001377) study, panitumumab was demonstrated to be noninferior to cetuximab and provided a similar overall survival benefit for patients with chemotherapy-refractory wild-type KRAS exon 2 mCRC. However, some patients eventually develop resistance to anti-EGFR therapy. EGFR p.S492R mutation was previously identified as conferring resistance to cetuximab, but not to panitumumab.

Methods

This biomarker study analyzed plasma samples from ASPECCT collected at both baseline and posttreatment.

Results

No EGFR p.S492R mutations were identified at baseline; however, after treatment the EGFR p.S492R mutation was detected in 1% of patients treated with panitumumab versus 16% of those treated with cetuximab, supporting that, in a large population, this mutation is more likely to be induced by cetuximab than by panitumumab. There were, however, no significant differences in progression-free survival or overall survival between patients who were wild-type compared with those with the S492R mutation within the cetuximab arm or the overall population.

Conclusions

These results may support targeting treatment to small patient subgroups based on the presence of emerging EGFR mutations and provide a molecular rationale for rechallenging with a different anti-EGFR agent in patients who develop resistance. Prospective studies are needed to evaluate the efficacy of panitumumab in the EGFR p.S492R mutant population.

中文翻译：

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表皮生长因子受体中 S492R 突变的频率：分析来自接受帕尼单抗或西妥昔单抗单药治疗的转移性结直肠癌患者的血浆 DNA

摘要

背景

针对表皮生长因子受体 (EGFR) 的抗体、全人源单克隆抗体帕尼单抗和人/小鼠嵌合单克隆抗体西妥昔单抗已在转移性结直肠癌 (mCRC) 中显示出临床疗效。在 3 期非劣效性 ASPECCT（ClinicalTrials.gov，NCT01001377）研究中，帕尼单抗被证明不劣于西妥昔单抗，并为化疗难治性野生型KRAS外显子 2 mCRC患者提供了相似的总体生存获益。然而，一些患者最终会对抗 EGFR 治疗产生耐药性。EGFR p.S492R 突变先前被确定为对西妥昔单抗产生耐药性，但对帕尼单抗没有。

方法

该生物标志物研究分析了在基线和治疗后收集的 ASPECCT 血浆样本。

结果

基线时未发现 EGFR p.S492R 突变；然而，治疗后，在接受帕尼单抗治疗的患者中有 1% 检测到 EGFR p.S492R 突变，而在接受西妥昔单抗治疗的患者中则为 16%，这支持在大量人群中，西妥昔单抗比帕尼单抗更可能诱导这种突变. 然而，与西妥昔单抗组或总体人群中具有 S492R 突变的患者相比，野生型患者的无进展生存期或总生存期没有显着差异。

结论

这些结果可能支持基于新出现的 EGFR 突变的存在对小患者亚组进行靶向治疗，并为在产生耐药性的患者中重新使用不同的抗 EGFR 药物提供分子基础。需要前瞻性研究来评估帕尼单抗在 EGFR p.S492R 突变人群中的疗效。