Dual EGFR blockade with cetuximab and erlotinib combined with anti-VEGF antibody bevacizumab in advanced solid tumors: a phase 1 dose escalation triplet combination trial
Dual EGFR blockade with cetuximab and erlotinib combined with anti-VEGF antibody bevacizumab in advanced solid tumors: a phase 1 dose escalation triplet combination trial
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DOI：
10.1186/s40164-020-00159-1
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发表时间：
2020-04-20
影响因子：
10.9
通讯作者：
Falchook, Gerald
中科院分区：
文献类型：
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作者：
Subbiah, Vivek;Dumbrava, Ecaterina Ileana;Falchook, Gerald
背景血管生成和表皮生长因子（EGFR）通路的激活在肿瘤增殖和转移中起重要作用。在大多数实体瘤中，单独靶向血管生成或EGFR不能产生足够的肿瘤控制。克服内在和/或获得性耐药可能需要双重或三重治疗策略。在此，我们报告了EGFR单克隆抗体和EGFR酪氨酸激酶抑制剂联合抗VEGF抗体双重EGFR阻断治疗晚期实体瘤的安全性和可行性。方法我们进行了一项联合厄洛替尼、西妥昔单抗和贝伐单抗的I期研究。分析晚期或转移性实体瘤（不包括结直肠癌和非小细胞肺癌）患者的安全性、毒性特征和缓解。根据实体瘤缓解评价标准（RECIST 1.0）评价抗肿瘤活性。结果36例患者接受了不同剂量水平的治疗。入组的最常见肿瘤类型为宫颈癌（n = 10）、头颈部鳞状细胞癌（n = 10）和甲状腺滤泡癌（n = 4）。最常见的治疗相关≥ 2级不良事件为皮疹（56%）、低镁血症（17%）、瘙痒（11%）、腹泻（8%）和肿瘤相关出血（8%）。17/19例（89%）接受最大耐受剂量治疗的患者未出现治疗相关的剂量限制性毒性。24例可评估患者中有15例（63%）实现了疾病控制（疾病稳定>= 4个月（n = 14）和部分缓解（n = 1））。既往治疗线的中位数为3（范围1-10）。结论厄洛替尼、西妥昔单抗和贝伐珠单抗三联治疗耐受性良好，可使重度预治疗患者获益。在EGFR通路异常的患者中，未来的研究需要使用第二代或第三代EGFR酪氨酸激酶三联体组合。试用注册：ClinicalTrials.gov标识符：NCT 00543504。申办者：国家癌症研究所（NCI），MD安德森癌症中心
Background Angiogenesis and activation of the epidermal growth factor (EGFR) pathway play an essential role in tumor proliferation and metastasis. Targeting angiogenesis or EGFR alone does not yield adequate tumor control in most solid tumors. Overcoming intrinsic and/or acquired resistance may need a doublet or triplet therapy strategy. Herein, we report the safety and feasibility of dual EGFR blockade with EGFR monoclonal antibody and EGFR tyrosine kinase inhibitor combined with anti-VEGF antibody in advanced solid tumors. Methods We conducted a phase I study combining erlotinib, cetuximab, and bevacizumab. Patients with advanced or metastatic solid tumors (excluding colorectal and non-small cell lung cancers) were analyzed for safety, toxicity profile, and response. Anti-tumor activity was evaluated per response evaluation criteria in solid tumors (RECIST 1.0). Results Thirty-six patients received treatment on a range of dose-levels. The most frequent tumor types enrolled were cervical (n = 10), head and neck squamous cell (n = 10), and follicular thyroid (n = 4) cancers. The most common treatment-related grade >= 2 adverse events were rash (56%), hypomagnesemia (17%), pruritus (11%), diarrhea (8%), and tumor-related bleeding (8%). Seventeen of 19 patients (89%) treated at the maximum tolerated dose did not present treatment-related dose-limiting toxicity. Fifteen (63%) of the 24 evaluable patients achieved a disease control (stable disease >= 4 months (n = 14) and partial response (n = 1). The median number of prior lines of therapies was 3 (range 1-10). Conclusions The triplet combination of erlotinib, cetuximab, and bevacizumab was well tolerated, conferring clinical benefit in heavily pretreated patients. Future studies are warranted with second or third-generation EGFR tyrosine kinase triplet combinations in the EGFR pathway aberrant patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00543504. Sponsor(s): National Cancer Institute (NCI), MD Anderson Cancer Center