改善早期乳腺癌患者对奈拉替尼耐受性

　　奈拉替尼（又被误译为来那替尼）是人类表皮生长因子受体HER1、HER2、HER4酪氨酸激酶的不可逆抑制剂，根据ExteNET研究结果，先后被美国和欧盟批准用于HER2阳性早期乳腺癌术后患者的强化辅助治疗，可以显著减少曲妥珠单抗1年辅助治疗后的浸润病变或死亡风险。不过，由于ExteNET研究未强制采取腹泻预防措施，3级腹泻患者达40%，腹泻所致停药达17%。

　　2020年5月25日，欧洲肿瘤内科学会《肿瘤学报》在线发表美国德克萨斯大学MD安德森癌症中心、洛杉矶加利福尼亚大学、南阿拉巴马大学、圣路易斯华盛顿大学、旧金山加利福尼亚大学、圣露西港血液科肿瘤科协作组、匹兹堡大学医疗中心、圣巴纳巴斯医疗中心、雷德兰兹社区医院、东南地区医疗中心、罗格斯大学、科珀斯克里斯蒂海湾癌症中心、北密西西比医疗中心、美洲狮生物技术公司、澳大利亚基督复临安息日医院、科廷大学、西班牙塞维利亚大学、马德里大学、加拿大多伦多大学、麦吉尔大学的CONTROL研究报告，探讨了改善HER2阳性早期乳腺癌术后患者奈拉替尼强化辅助治疗所致腹泻毒性的若干策略。

NCT02400476: An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide (PUMA-NER-6201)

　　该国际多中心非盲定群二期临床研究于2015年2月25日～2019年10月21日从美国、加拿大、西班牙、澳大利亚的12家医院入组HER2阳性早期乳腺癌术后完成曲妥珠单抗辅助治疗患者501例，随机分为4组：

• 奈拉替尼＋洛哌丁胺组：137例

• 奈拉替尼＋布地奈德＋洛哌丁胺：64例

• 奈拉替尼＋考来替泊＋洛哌丁胺：136例

• 奈拉替尼＋考来替泊＋必要时洛哌丁胺：104例

• 奈拉替尼剂量递增＋必要时洛哌丁胺：60例

　　全部患者每天口服奈拉替尼240毫克连续1年，第1～28天或第1～56天或必要时口服洛哌丁胺（易蒙停）预防腹泻，主要研究终点为≥3级腹泻发生比例。

　　结果，治疗持续中位11个月期间未见4级腹泻，3级腹泻发生比例都低于ExteNET研究：

• ExteNET研究：40%

• 奈拉替尼＋洛哌丁胺：31%

• 奈拉替尼＋布地奈德＋洛哌丁胺：28%

• 奈拉替尼＋考来替泊＋洛哌丁胺：21%

• 奈拉替尼＋考来替泊＋必要时洛哌丁胺：32%

• 奈拉替尼剂量递增＋必要时洛哌丁胺：15%

　　全部患者3级腹泻发生次数中位1次，各组患者3级腹泻持续天数1.0～2.0天。大多数3级腹泻和腹泻相关停药发生于第1个月。

　　腹泻相关停药比例：

• ExteNET研究：17%

• 奈拉替尼＋洛哌丁胺：20%

• 奈拉替尼＋布地奈德＋洛哌丁胺：8%

• 奈拉替尼＋考来替泊＋洛哌丁胺：4%

• 奈拉替尼＋考来替泊＋必要时洛哌丁胺：8%

• 奈拉替尼剂量递增＋必要时洛哌丁胺：3%

　　健康相关生活质量评分下降幅度并未超过有临床意义的临界值。

　　因此，该研究结果表明，通过未雨绸缪地预防用药或剂量递增，能够改善奈拉替尼的耐受性，与ExteNET研究相比，奈拉替尼所致≥3级腹泻的发生比例、停药比例、持续天数较少，尤其奈拉替尼剂量递增策略，可以减少强制预防用药和不良反应，故积极的预防措施有助患者在推荐疗程内坚持服用奈拉替尼。

　　据悉，国家药品监督管理局已于2020年4月27日正式批准奈拉替尼进入中国内地市场，商品名：贺俪安，由美洲狮生物技术授权北海康成在大中华区独家开发和商业化。

相关链接

Ann Oncol. 2020 May 25. Online ahead of print.

Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: diarrheal toxicity in the CONTROL trial.

Barcenas CH, Hurvitz SA, Di Palma JA, Bose R, Chien AJ, Iannotti N, Marx G, Brufsky A, Litvak A, Ibrahim E, Alvarez RH, Ruiz-Borrego M, Chan N, Manalo Y, Kellum A, Trudeau M, Thirlwell M, Saenz JG, Hunt D, Bryce R, McCulloch L, Rugo HS, Tripathy D, Chan A; CONTROL Study Investigators.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA; University of California Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA; University of South Alabama College of Medicine, Mobile, AL, USA; Washington University School of Medicine, St Louis, MO, USA; University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA; Hematology Oncology Associates of the Treasure Coast, Port St. Lucie, FL, USA; Adventist Health Care, Wahroonga, Australia; Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA; Saint Barnabas Medical Center, Livingston, NJ, USA; Redlands Community Hospital, Redlands, CA, USA; Southeastern Regional Medical Center, Inc, Newnan, GA, USA; Hospital Universitario Virgen del Rocio, Sevilla, Spain; Rutger Cancer Institute of New Jersey, New Brunswick, NJ, USA; Coastal Bend Cancer Center, Corpus Christi, TX, USA; North Mississippi Medical Center Hematology and Oncology Clinic, Tupelo, MS, USA; Sunnybrook Research Institute, Toronto, ON, Canada; McGill University Health Centre, Montreal, Canada; Hospital Clínico San Carlos, Madrid, Spain; Puma Biotechnology Inc., Los Angeles, CA, USA; Breast Cancer Research Centre-WA & Curtin University, Perth, WA, Australia.

HIGHLIGHTS

• CONTROL trial investigated anti-diarrheal strategies including dose escalation in neratinib-treated patients with early HER2+ breast cancer

• Both preemptive prophylaxis and dose escalation reduced the rate, severity, and duration of grade ≥3 diarrhea compared with ExteNET

• Lower diarrhea-related discontinuations and dose reductions in multiple cohorts compared with ExteNET suggested improved tolerability

• Neratinib dose escalation is a particularly promising strategy as it eliminates mandatory prophylaxis and related side effects

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no anti-diarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability.

PATIENTS AND METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and neratinib dose escalation (DE; ongoing). The primary endpoint was the incidence of grade ≥3 diarrhea.

RESULTS: Final data for loperamide (L; n=137), budesonide + loperamide (BL; n=64), colestipol + loperamide (CL; n=136), and colestipol + as-needed loperamide (CL-PRN; n=104) cohorts, and interim data for DE (n=60; completed ≥6 cycles or discontinued; median duration 11 months) are available. No grade 4 diarrhea was observed. Grade 3 diarrhea rates were lower than ExteNET in all cohorts and lowest in DE (L 31%, BL 28%, CL 21%, CL-PRN 32%, DE 15%). Median number of grade 3 diarrhea episodes was 1; median duration per grade 3 episode was 1.0-2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL, 8%, CL 4%, CL-PRN 8%, DE 3%). Decreases in health-related quality of life did not cross the clinically important threshold.

CONCLUSIONS: Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period.

KEYWORDS: neratinib, tyrosine kinase inhibitor, HER2-positive breast cancer, diarrhea prophylaxis, quality of life

PMID: 32464281

DOI: 10.1016/j.annonc.2020.05.012