Blohmer Jens-Uwe, Link Theresa, Reinisch Mattea, Just Marianne, Untch Michael, Stötzer Oliver, Fasching Peter A, Schneeweiss Andreas, Wimberger Pauline, Seiler Sabine, Huober Jens, Thill Marc, Jackisch Christian, Rhiem Kerstin, Solbach Christine, Hanusch Claus, Seither Fenja, Denkert Carsten, Engels Knut, Nekljudova Valentina, Loibl Sibylle
Charité Universitätsmedizin Berlin, Berlin, Germany.
Department of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany.
JAMA Oncol. 2022 Jul 1;8(7):1010-1018. doi: 10.1001/jamaoncol.2022.1059.
Adjuvant denosumab might improve disease-free survival in hormone receptor (HR)-positive primary breast cancer (BC). The optimal neoadjuvant nab-paclitaxel schedule in terms of efficacy and safety is unclear.
To determine whether adding denosumab to anthracycline/taxane-containing neoadjuvant chemotherapy (NACT) increases the pathological complete response (pCR) rate and which nab-paclitaxel schedule is more effective in the NACT setting.
DESIGN, SETTING, AND PARTICIPANTS: The GeparX was a multicenter, prospective, open-label, phase 2b, 2 × 2 randomized clinical trial conducted by GBG and AGO-B at 38 German sites between February 2017 and March 2019. The analysis data set was locked September 4, 2020; analysis was completed November 13, 2020. Patients had unilateral or bilateral primary BC, stage cT2-cT4a-d or cT1c, with either clinically node-positive or pathologically node-positive or HR-negative disease, or Ki-67 proliferation index greater than 20%, or ERBB2 (formerly HER2)-positive BC.
Patients were randomized to receive or not receive denosumab, 120 mg subcutaneously every 4 weeks for 6 cycles, and either nab-paclitaxel, 125 mg/m2 weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles (8 doses), followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m2 (every 2 weeks or every 3 weeks). Carboplatin was given in triple-negative BC (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in ERBB2-positive BC (ERBB2-positive substudy).
The primary outcome was pCR rates between arms for each randomization.
A total of 780 female (n = 779) and male (n = 1) patients (median [range] age, 49.0 [22-80] years) were randomized to the 4 treatment groups. The pCR (ypT0 ypN0) rate was 41.0% (90% CI, 37%-45%) with denosumab vs 42.8% (90% CI, 39%-47%) (P = .58) without denosumab, irrespective of BC subtype. Nab-paclitaxel weekly resulted in a significantly (significance level of α = .10) higher pCR rate of 44.9% (90% CI, 41%-49%) vs 39.0% (90% CI, 35%-43%) (P = .06) with nab-paclitaxel days 1 and 8 every 3 weeks. The pCR rates for nab-paclitaxel schedules in subgroups were only significantly different for TNBC (60.4% vs 50.0%; P = .06). Grade 3 to 4 toxic effects did not differ with or without denosumab. Nonhematologic toxic effects of grade 3 to 4 were higher with nab-paclitaxel weekly (33.7% vs 24.1%; P = .004).
In this randomized clinical trial, denosumab added to anthracycline/taxane-based NACT did not improve pCR rates. Nab-paclitaxel at a dosage of 125 mg/m2 weekly significantly increased the pCR rate compared with the days 1 and 8, every-3-weeks schedule overall and in TNBC, but generated higher toxicity.
ClinicalTrials.gov Identifier: NCT02682693.
辅助性地诺单抗可能会改善激素受体（HR）阳性原发性乳腺癌（BC）的无病生存期。含蒽环类/紫杉烷的新辅助化疗（NACT）在疗效和安全性方面的最佳白蛋白结合型紫杉醇方案尚不清楚。
确定在含蒽环类/紫杉烷的新辅助化疗中添加地诺单抗是否会提高病理完全缓解（pCR）率，以及哪种白蛋白结合型紫杉醇方案在NACT环境中更有效。
设计、设置和参与者：GeparX是一项由GBG和AGO-B在2017年2月至2019年3月期间在德国38个地点进行的多中心、前瞻性、开放标签、2b期、2×2随机临床试验。分析数据集于2020年9月4日锁定；分析于2020年11月13日完成。患者患有单侧或双侧原发性BC，cT2 - cT4a - d期或cT1c期，伴有临床淋巴结阳性或病理淋巴结阳性或HR阴性疾病，或Ki-67增殖指数大于20%，或ERBB2（原HER2）阳性BC。
患者被随机分配接受或不接受地诺单抗，每4周皮下注射120mg，共6个周期，以及白蛋白结合型紫杉醇，每周125mg/m²，共12周，或每3周第1天和第8天给药，共4个周期（8剂），随后进行4个周期的表柔比星/环磷酰胺，90/600mg/m²（每2周或每3周）。三阴性乳腺癌（TNBC）给予卡铂，ERBB2阳性BC（ERBB2阳性亚组研究）给予曲妥珠单抗生物类似药ABP980加帕妥珠单抗。
主要结局是每次随机分组时各治疗组之间的pCR率。
共有780名女性（n = 779）和1名男性（n = 1）患者（中位[范围]年龄，49.0[22 - 80]岁）被随机分配到4个治疗组。无论BC亚型如何，使用地诺单抗时pCR（ypT0 ypN0）率为41.0%（90%CI，37% - 45%），不使用地诺单抗时为42.8%（90%CI，39% - 47%）（P = .58）。与每3周第1天和第8天使用白蛋白结合型紫杉醇相比，每周使用白蛋白结合型紫杉醇导致pCR率显著（显著性水平α = .10）更高，分别为44.9%（90%CI，41% - 49%）和39.0%（90%CI，35% - 43%）（P = .06）。白蛋白结合型紫杉醇方案在亚组中的pCR率仅在TNBC中存在显著差异（60.4%对50.0%；P = .06）。3至4级毒性反应在使用或不使用地诺单抗时无差异。每周使用白蛋白结合型紫杉醇时3至4级非血液学毒性反应更高（33.7%对24.1%；P = .004）。
在这项随机临床试验中，在基于蒽环类/紫杉烷的NACT中添加地诺单抗并未提高pCR率。与每3周第1天和第8天给药方案相比，每周125mg/m²剂量的白蛋白结合型紫杉醇总体上和在TNBC中显著提高了pCR率，但产生了更高的毒性。
ClinicalTrials.gov标识符：NCT02682693。
