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Abstract：
HER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting.
HERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed RAS/BRAF wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1).
Thirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue.
HERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource.
2012-002128-33 and NCT03225937.
HERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed RAS/BRAF wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1).
Thirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue.
HERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource.
2012-002128-33 and NCT03225937.
摘要：
HER2是转移性结直肠癌（mCRC）的治疗靶点，正如使用曲妥珠单抗和拉帕替尼的关键HERACLES-A(HER2扩增结肠直肠癌增强分层)试验所证明的那样.HERACLES-B试验的目的是评估帕妥珠单抗和曲妥珠单抗-emtansine（T-DM1）组合在这种情况下的疗效。
HERACLES-B是单臂，第二阶段试验，在组织学证实的RAS/BRAF野生型和HER2+mCRC对标准治疗无效的患者中。根据HERACLES标准通过免疫组织化学和原位杂交评估HER2阳性。患者接受帕妥珠单抗（840mg静脉内负荷，然后每3周420mg静脉内）和T-DM1（每3周3.6mg/kg）治疗，直到疾病进展或毒性。主要和次要终点是客观缓解率（ORR）和无进展生存期（PFS）。Fleming/Hern设计（H0=ORR10%；α=0.05；功率=0.85），需要7/30的反应才能证明ORR≥30%(H1)。
31名患者,48%的患者有≥4行既往治疗，进行了治疗和评估。ORR为9.7％（95％CI：0至28），病情稳定（SD）为67.7％（95％CI：50至85）。OR/SD≥4个月与较高的HER2免疫组织化学评分(3+vs2+)相关(p=0.03)。中位PFS为4.1个月（95%CI：3.6至5.9）。在两名患者（血小板减少症）中观察到与药物相关的（G）3级不良事件；84％的周期中G≤2AE（n=296），主要是恶心和疲劳。
HERACLES-B试验未达到ORR的主要终点；然而，基于高度的疾病控制，PFS类似于其他抗HER2方案，低毒性,帕妥珠单抗联合T-DM1可被视为HER2+mCRC的潜在治疗资源.
2012-002128-33和NCT03225937。
HERACLES-B是单臂，第二阶段试验，在组织学证实的RAS/BRAF野生型和HER2+mCRC对标准治疗无效的患者中。根据HERACLES标准通过免疫组织化学和原位杂交评估HER2阳性。患者接受帕妥珠单抗（840mg静脉内负荷，然后每3周420mg静脉内）和T-DM1（每3周3.6mg/kg）治疗，直到疾病进展或毒性。主要和次要终点是客观缓解率（ORR）和无进展生存期（PFS）。Fleming/Hern设计（H0=ORR10%；α=0.05；功率=0.85），需要7/30的反应才能证明ORR≥30%(H1)。
31名患者,48%的患者有≥4行既往治疗，进行了治疗和评估。ORR为9.7％（95％CI：0至28），病情稳定（SD）为67.7％（95％CI：50至85）。OR/SD≥4个月与较高的HER2免疫组织化学评分(3+vs2+)相关(p=0.03)。中位PFS为4.1个月（95%CI：3.6至5.9）。在两名患者（血小板减少症）中观察到与药物相关的（G）3级不良事件；84％的周期中G≤2AE（n=296），主要是恶心和疲劳。
HERACLES-B试验未达到ORR的主要终点；然而，基于高度的疾病控制，PFS类似于其他抗HER2方案，低毒性,帕妥珠单抗联合T-DM1可被视为HER2+mCRC的潜在治疗资源.
2012-002128-33和NCT03225937。
