Use of [18F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [18F]-FDG PET-predicted non-responders (AVATAXHER): an open-label, randomised phase 2 trial
Use of [18F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [18F]-FDG PET-predicted non-responders (AVATAXHER): an open-label, randomised phase 2 trial
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DOI：
10.1016/s1470-2045(14)70475-9
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发表时间：
2014-12-01
期刊：
影响因子：
51.1
通讯作者：
Berriolo-Riedinger, Alina
中科院分区：
文献类型：
--
作者：
Coudert, Bruno;Pierga, Jean-Yves;Berriolo-Riedinger, Alina
新辅助治疗后未达到病理学完全缓解的早期HER 2阳性乳腺癌患者需要一种有效且耐受性良好的治疗。AVATAXHER试验旨在通过PET早期预测病理学完全缓解，并研究贝伐单抗的加入是否可以提高不太可能对治疗有反应的患者中达到病理学完全缓解的患者比例。一项多中心II期研究，招募了来自法国26个肿瘤中心的早期HER 2阳性乳腺癌女性（≥ 18岁）。患者最初接受两个周期的新辅助多西他赛（100 mg/m2，静脉注射，每3周一次）+曲妥珠单抗（8 mg/kg，静脉注射，每3周一次，然后6 mg/kg，静脉注射，每3周一次，第二个疗程）。在第一个和第二个周期之前，进行[F-18]-氟脱氧葡萄糖（FDG）PET，并使用标准化摄取值的变化来预测每例患者的病理学完全缓解。PET预测为应答者的患者继续接受标准治疗。预测的无应答者被随机分配（2：1）接受4个周期的多西他赛（100 mg/m2，静脉注射，每3周一次）和曲妥珠单抗（6 mg/kg，静脉注射，每3周一次）+贝伐珠单抗（15 mg/kg，静脉注射，每3周一次; A组）或继续多西他赛+曲妥珠单抗单药治疗（B组）。随机化是开放标签的，并通过自适应最小化方法完成。尽管研究者和患者知道分组，但负责集中审查手术样本和淋巴结的解剖病理学家对治疗分配不知情。主要终点是根据Chevallier分类集中评估的病理学完全缓解。在意向治疗人群中进行疗效分析。本文中的安全性分析是对从第3周期开始接受至少一剂治疗的所有患者进行的。生存结果尚未成熟。本研究已在ClinicalTrials注册。gov（NCT 01142778）和EUDRACT（2009-013410-26）。结果在2010年5月19日至2012年10月1日期间，招募了152名患者用于该研究。10例患者随后被排除，意向治疗人群中留下142例患者。在这142名患者中，69名通过[F-18]-FDG PET预测为两个治疗周期后的治疗应答者。将73例预测无应答者随机分为A组（n= 48）和B组（n= 25）。在37例（53.6%，95% CI 41.2-65.7）PET应答者、A组21例（43.8%，29.5-58.8）和B组6例（24.0%，9.4-45.1）中观察到病理学完全应答。所有三组中3-4级不良事件的发生率相似。最常见的3-4级不良事件为中性粒细胞减少（PET应答者4例，A组5例，B组3例）、发热性中性粒细胞减少（分别为1例、3例和1例）和肌痛（分别为4例、0例和1例）。总体而言，15例患者报告了24起严重不良事件（PET应答者：67例患者中4例[6%]发生9起事件; A组：47例患者中10例[21%]发生14起事件; B组：25例患者中1例[4%]发生1起事件）。在HER 2阳性乳腺癌患者中，早期PET评估可以帮助识别新辅助多西他赛联合曲妥珠单抗治疗的无应答者。在这些患者中，添加贝伐珠单抗可增加达到病理学完全缓解的患者比例。PET的这种潜在的新作用和贝伐单抗在这种情况下的活性需要在更大的3期试验中得到证实。
Background An effective and well tolerated treatment is needed for patients with early HER2-positive breast cancer who do not achieve a pathological complete response after neoadjuvant therapy. The AVATAXHER trial aimed to predict pathological complete response early with the use of PET and to investigate whether the addition of bevacizumab could improve the proportion of patients achieving a pathological complete response in patients unlikely to respond to treatment.Methods AVATAXHER was a randomised, open-label, non-comparative, multicentre phase 2 study that enrolled women (>= 18 years of age) with early-stage HER2-positive breast cancer from 26 oncology centres in France. Patients initially received two cycles of neoadjuvant docetaxel (100 mg/m(2) intravenously every 3 weeks) plus trastuzumab (8 mg/kg intravenously every 3 weeks then 6 mg/kg intravenously every 3 weeks for the second course). Before the first and second cycles, [F-18]-fluorodeoxyglucose (FDG) PET was done and the change in standardised uptake value was used to predict pathological complete response in each patient. Patients who were predicted to be responders on PET continued to receive standard therapy. Predicted non-responders were randomly assigned (2: 1) to receive four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) and trastuzumab (6 mg/kg intravenously every 3 weeks) plus bevacizumab (15 mg/kg intravenously every 3 weeks; group A) or continue on docetaxel plus trastuzumab alone (group B). Randomisation was open label and was done by an adaptive minimisation method. Although investigators and patients were aware of group assignment, the anatomo-pathologist in charge of centralised review of surgical samples and lymph nodes was masked to treatment assignment. The primary endpoint was centrally assessed pathological complete response according to the Chevallier classifi cation. Efficacy analyses were done in the intention-to-treat population. Safety analyses in this Article were done on all patients who received at least one dose of treatment starting from cycle 3. Survival outcomes are not yet mature. This study is registered with ClinicalTrials. gov (NCT01142778) and EUDRACT (2009-013410-26).Findings Between May 19, 2010, and Oct 1, 2012, 152 patients were recruited for the study. Ten patients were subsequently excluded, leaving 142 patients in the intention-to-treat population. Of these 142 patients, 69 were predicted by [F-18]-FDG PET to be treatment responders after two cycles of treatment. The 73 predicted non-responders were randomly assigned to group A (n= 48) and group B (n= 25). Pathological complete responses were noted in 37 (53.6%, 95% CI 41.2-65.7) of the PET responders, 21 (43.8%, 29.5-58.8) of those in group A, and six (24.0%, 9.4-45.1) of those in group B. Incidences of grade 3-4 adverse events were similar in all three groups. The most common grade 3-4 adverse events were neutropenia (four in PET responders, five in group A, and three in group B), febrile neutropenia (one, three, and one, respectively), and myalgia (four, none, and one, respectively). Overall, 24 serious adverse events were reported in 15 patients (PET responders: nine events in four [6%] of 67 patients; group A: 14 events in ten [21%] of 47 patients; group B: one event in one [4%] of 25 patients). No deaths occurred during the study.Interpretation In patients with HER2-positive breast cancer, early PET assessment can help to identify non-responders to neoadjuvant docetaxel plus trastuzumab therapy. In these patients, the addition of bevacizumab can increase the proportion of patients achieving a pathological complete response. This potential new role for PET and the activity of bevacizumab in this setting need to be confirmed in larger phase 3 trials.