Supplementary Material for: Position Paper on the Value of Extended Adjuvant Therapy with Neratinib for Early HER2+/HR+ Breast Cancer

<b><i>Background:</i></b> In August 2018, neratinib – an oral, irreversible pan-HER-tyrosine-kinase inhibitor – was approved by the European Commission for the extended adjuvant treatment of adult patients with early-stage, hormone receptor-positive (HR+), HER2 overexpressed/amplified (HER2+) breast cancer who completed trastuzumab-based adjuvant therapy within the last year. Despite recent improvements in long-term outcome, there is still an unmet need to further reduce the risk of recurrence, especially in patients with poor response to neoadjuvant treatment. <b><i>Summary:</i></b> National and international guidelines included recommendations for using neratinib. Based on the health technology assessment for neratinib, the Federal Joint Committee (G-BA) in Germany has granted an added benefit for neratinib compared with the standard “watch and wait” strategies. Inclusion in the Reimbursement Code, however, was rejected by the Austrian social insurance companies in July 2020, and neratinib is now in the “No Box” for individual head physician reimbursement. <b><i>Key Messages:</i></b> We analysed the value of extended adjuvant therapy with neratinib in early HER2+/HR+ breast cancer based on current data and made recommendations for the evidence-based and economical use of neratinib in Austria. In particular, prognostic factors associated with an increased risk of recurrence following standard therapy are considered. Extended adjuvant therapy should be offered primarily to nodal-positive patients at surgery. For nodal-negative patients, neratinib therapy may be considered in case of large and/or inflammatory primary tumours (T3–4) without pathological complete response after neoadjuvant therapy. For all other patients, neratinib may be considered depending on additional risk factors on an individual basis that should be evaluated by interdisciplinary tumour conferences.

<b><i>背景：</i></b> 2018年8月，口服不可逆泛HER酪氨酸激酶抑制剂奈拉替尼（neratinib）获欧盟委员会批准，用于既往12个月内完成以曲妥珠单抗（trastuzumab）为基础辅助治疗的早期激素受体阳性（HR+）、HER2过表达/扩增（HER2+）乳腺癌成年患者的延长辅助治疗。尽管长期预后领域近年来已有进展，但仍存在未被满足的临床需求：需进一步降低复发风险，尤其针对新辅助治疗应答不佳的患者。<b><i>总结：</i></b> 多国及国际指南均纳入了奈拉替尼的使用推荐。基于奈拉替尼的卫生技术评估结果，德国联邦联合委员会（G-BA）认定奈拉替尼相较于标准"观察等待"策略具有额外临床获益。然而，奥地利社会保险机构于2020年7月否决了其纳入医保报销编码的申请，目前奈拉替尼已被列入医师个人报销的"No Box"范畴。<b><i>核心要点：</i></b> 本研究基于现有临床数据分析了奈拉替尼用于早期HER2+/HR+乳腺癌延长辅助治疗的价值，并针对奈拉替尼在奥地利的循证及经济化使用提出推荐意见，重点考量了标准治疗后复发风险升高的预后因素。延长辅助治疗应优先推荐给手术时存在淋巴结阳性的患者；对于淋巴结阴性患者，若新辅助治疗后未达到病理完全缓解，且存在大体积及/或炎性原发肿瘤（T3~4期），可考虑使用奈拉替尼治疗；对于其余患者，则需结合跨学科肿瘤委员会评估的个体化额外风险因素，酌情考虑奈拉替尼治疗。