Breast Cancer Research Centre-WA, Perth & Curtin University, Nedlands, Australia.
Hospital Universitario Virgen del Rocío, Seville, Spain.
Breast. 2023 Feb;67:94-101. doi: 10.1016/j.breast.2022.12.003. Epub 2022 Dec 14.
Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies.
Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L.
563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed.
These complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective.
NCT02400476.
奈拉替尼是一种不可逆的泛 HER 酪氨酸激酶抑制剂，已被批准用于治疗 HER2 阳性早期和转移性乳腺癌。腹泻是最常见的副作用，也是早期停药的最常见原因。Ⅱ期 CONTROL 试验研究了止泻药预防或奈拉替尼剂量递增（DE）预防腹泻的效果。我们呈现了完整的研究结果，包括两种 DE 策略的最终数据。
完成曲妥珠单抗辅助治疗的患者接受奈拉替尼 240mg/天，持续 1 年。早期队列研究了强制性洛哌丁胺预防，然后是额外的布地奈德或考来替泊。最终队列评估了奈拉替尼在头 2（DE1）或 4 周（DE2）内的 DE。主要终点是≥3 级腹泻的发生率。使用 FACT-B 和 EQ-5D-5L 评估健康相关生活质量（HRQoL）。
563 名患者被纳入 6 个队列。所有策略均降低了≥3 级腹泻的发生率，DE1 组的发生率最低（DE1 为 13%；考来替泊+洛哌丁胺[CL]为 21%，DE2 为 27%；布地奈德+洛哌丁胺[BL]为 28%；洛哌丁胺[L]为 31%；考来替泊按需+洛哌丁胺[CL-PRN]为 33%）。与腹泻相关的停药发生较早，DE1 组最低（DE1 为 3%；CL 为 4%；DE2 为 6%；CL-PRN 为 8%；BL 为 11%；L 为 20%）。与历史对照相比，更多的患者按规定时间服用奈拉替尼。曲妥珠单抗和帕妥珠单抗的使用不影响≥3 级腹泻、腹泻相关停药或治疗持续时间的发生率。早期观察到 HRQoL 评分的短暂下降。
CONTROL 研究的这些完整结果表明，在治疗开始时进行积极的管理，可提高奈拉替尼的耐受性。奈拉替尼两周 DE 加按需使用洛哌丁胺尤其有效。
NCT02400476。
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