Yuan Yuan, Lee Jin Sun, Yost Susan E, Stiller Tracey, Blanchard M Suzette, Padam Simran, Katheria Vani, Kim Heeyoung, Sun Canlan, Tang Aileen, Martinez Norma, Patel Niki Dipesh, Sedrak Mina S, Waisman James, Li Daneng, Sanani Shamel, Presant Cary A, Mortimer Joanne
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States of America.
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States of America.
J Geriatr Oncol. 2021 Jun;12(5):752-758. doi: 10.1016/j.jgo.2021.02.020. Epub 2021 Mar 2.
The tolerability and efficacy of targeted therapy in older adults with cancer has not been adequately studied. Neratinib is a novel HER1, HER2, HER4 tyrosine kinase inhibitor that has recently been granted FDA approval for treatment of breast cancer. The major toxicity of neratinib is diarrhea, which affects up to 90% of patients. This phase II trial evaluates the safety and tolerability of neratinib in adults ≥60.
Patients aged 60 or older with histologically proven metastatic breast cancer and HER2 amplification (defined by ASCO/CAP guideline) or HER2/HER3 activating mutation were enrolled to receive neratinib at 240 mg daily in 28-day cycles. The association between tolerability, defined as dose reduction and number of completed courses, and log Cancer and Aging Research Group (CARG) toxicity risk score was assessed using a Student's t-test and linear regression, respectively. Response rate, progression free survival, and overall survival were also evaluated.
25 patients were enrolled with median age of 66 (range 60-79). Seventy-six percent of patients were white, 16% Asian, and 8% African-American. Seventy-six percent were patients with hormone receptor (HR) positive metastatic breast cancer (MBC) and 24% were patients with HR negative MBC. Median number of prior lines of metastatic therapy were 3 (range 0-11). 20/25 (80%) had worst grade toxicities ≥2. A total of 9/25 (36%) had grade 3 toxicities including 5/20 (20%) diarrhea, 2/20 (8%) vomiting, and 2/20 (8%) abdominal pain. There were no grade 4 or 5 toxicities. A total of 9/25 (36%) had dose reduction, and 2/25 (8%) discontinued therapy due to toxicity. The association between dose reductions and CARG toxicity score reached borderline statistical significance suggesting a trend with participants with higher CARG toxicity risk scores being more likely to require a dose modification (p = 0.054). 1/25 (4%) had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not assessed. Median progression free survival (PFS) was 2.6 months (95% CI [2.56-5.26]), and median overall survival (OS) was 17.4 months (95% CI [10.3, NA]).
Neratinib was safe in this population of older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer (BC). Higher CARG toxicity risk score may be associated with greater need for dose adjustments. Future studies are needed to confirm this finding.
针对老年癌症患者的靶向治疗的耐受性和疗效尚未得到充分研究。来那替尼是一种新型的HER1、HER2、HER4酪氨酸激酶抑制剂，最近已获得美国食品药品监督管理局（FDA）批准用于治疗乳腺癌。来那替尼的主要毒性是腹泻，高达90%的患者会受到影响。这项II期试验评估了来那替尼在60岁及以上成年人中的安全性和耐受性。
招募年龄在60岁及以上、经组织学证实为转移性乳腺癌且HER2扩增（根据美国临床肿瘤学会/美国病理学家学会[ASCO/CAP]指南定义）或HER2/HER3激活突变的患者，接受来那替尼治疗，剂量为每日240毫克，每28天为一个周期。分别使用学生t检验和线性回归评估耐受性（定义为剂量减少和完成疗程数）与癌症与衰老研究组（CARG）毒性风险评分之间的关联。还评估了缓解率、无进展生存期和总生存期。
共招募了25名患者，中位年龄为66岁（范围60 - 79岁）。76%的患者为白人，16%为亚洲人，8%为非裔美国人。76%为激素受体（HR）阳性转移性乳腺癌（MBC）患者，24%为HR阴性MBC患者。既往转移性治疗的中位疗程数为3（范围0 - 11）。20/25（80%）的患者出现≥2级的最严重毒性。共有9/25（36%）的患者出现3级毒性，包括5/20（20%）腹泻、2/20（8%）呕吐和2/20（8%）腹痛。无4级或5级毒性。共有9/25（36%）的患者进行了剂量减少，2/25（8%）因毒性而停止治疗。剂量减少与CARG毒性评分之间的关联达到了临界统计学意义，表明CARG毒性风险评分较高的参与者更有可能需要调整剂量（p = 0.054）。1/25（4%）的患者出现部分缓解，11/25（44%）病情稳定，12/25（48%）病情进展，1/25（4%）未进行评估。中位无进展生存期（PFS）为2.6个月（95%置信区间[2.56 - 5.26]），中位总生存期（OS）为17.4个月（95%置信区间[10.3，无可用数据]）。
来那替尼在这群HER2扩增或HER2/3突变的老年转移性乳腺癌（BC）患者中是安全的。较高的CARG毒性风险评分可能与更大的剂量调整需求相关。未来需要进一步研究来证实这一发现。
