【生产企业】：阿斯利康和第一三共株式会社（Daiichi Sankyo）
【规格】：100mg/瓶
【商标】：ENHERTU
【英文名称】：fam-trastuzumab deruxtecan-nxki
【性状】：静脉注射用白色至黄白色的冻干粉末
【贮藏】：2°C至8°C（36°F至46°F）的温度下冷藏。不要冻结或震荡。
 

【注射用ENHERTU适应症和用途】
ENHERTU是一种针对HER2的抗体和拓扑异构酶抑制剂的偶联物，适用于治疗无法切除或转移性HER2阳性乳腺癌的成年患者，这些患者已在转移环境中接受了两种或多种先前的基于抗HER2的治疗方案。
 

【注射用ENHERTU剂量和给药方法】
■不要用曲妥珠单抗或曲妥珠单抗-美坦新偶联物替代ENHERTU。
■ENHERTU的推荐剂量为5.4 mg / kg，每3周一次（21天周期）静脉滴注，直至疾病进展或出现不可接受的毒性。
■第一次输液
●输液时间在90分钟以上。
■后续输液
●如果先前的输注耐受性良好，则输液时间在30分钟以上。
●如果患者出现与输注相关的症状，请减慢或中断输注速度。
●如果发生严重的输注反应，请永久停用ENHERTU
■如果延迟或错过了计划的剂量，请尽快给药；不要等到下一个计划的周期。调整给药计划，以维持两次给药之间的3周间隔。以患者在最近一次输液中耐受的剂量和速率进行输液。

 
【注射用ENHERTU给药准备管理】
■为了防止用药错误，请检查药瓶标签，以确保准备和使用的药物是ENHERTU，而不是曲妥珠单抗或曲妥珠单抗-美坦新偶联物。
■静脉滴注前重新配制并进一步稀释ENHERTU。
■使用适当的无菌技术。
■ENHERTU是一种细胞毒性药物。遵循适用的特殊处理和处置程序。
使用：
■重配
1. 稀释前立即复溶。
2. 全剂量可能需要一个以上的小瓶。计算所需剂量（mg），重配的ENHERTU溶液的总体积以及所需的ENHERTU的小瓶数量
3. 用无菌注射器将5ml注射用的无菌水缓慢注入每100 mg小瓶，使最终浓度为20mg /mL。
4. 轻轻旋转小瓶直到完全溶解。不要摇晃。
5. 在给药前，无论何时，只要溶液和容器允许，应目视检查非肠道药物的颗粒物质和变色。溶液应该是透明的，无色到淡黄色。如果观察到可见的颗粒，或溶液混浊或变色，请不要使用。
6. 如果不立即使用，则将重新合成的ENHERTU小瓶在2°C到8°C(36°F到46°F)的冰箱中保存24小时，避免光照。不冻结。
7. 该产品不含防腐剂。冷藏24小时后丢弃未使用的ENHERTU。
■稀释
1. 用含有100毫升5%葡萄糖注射液的静脉输液袋稀释重配的ENHERTU的计算体积。不要使用氯化钠注射液。ENHERTU与由聚氯乙烯或聚烯烃(乙烯和聚丙烯的共聚物)制成的输液袋兼容。
2. 轻轻翻转输液袋，使溶液充分混合。不要摇晃。
3. 盖上输液袋，防止光线照射。
4. 如果不立即使用，则在室温下最多可存放4个小时（包括准备和输注），或者在2°C至8°C（36°F至46°F）的冰箱中保存24小时，并避免光照。不要冻结。
5. 丢弃小瓶中任何未使用的部分。
■管理
1. 如果将准备好的输注溶液冷藏保存（2°C至8°C [36°F至46°F]），则在给药前应使溶液达到室温。
2. 仅使用由聚烯烃或聚丁二烯和0.20或0.22微米在线聚醚砜（PES）或聚砜（PS）过滤器制成的输液器对ENHERTU进行静脉输注。请勿静脉推注或推注。
3. 请勿将ENHERTU与其他药物混合或通过同一静脉注射线使用其他药物。
 

【注射用ENHERTU药物过量】
无相关信息
 

【注射用ENHERTU禁忌症】
无
 

【注射用ENHERTU不良反应】
最常见的不良反应是间质性肺病/肺炎、中性粒细胞减少、左心室功能障碍等。
 

【注射用ENHERTU警告和注意事项】
■间质性肺疾病/肺炎：用ENHERTU治疗的患者可能发生严重、威胁生命或致命的间质性肺病（ILD），包括肺炎。建议患者立即报告咳嗽，呼吸困难，发烧和/或任何新的或恶化的呼吸道症状。监视患者ILD的体征和症状。及时调查ILD的证据。通过影像学检查评估疑似ILD的患者。考虑咨询肺科医生。对于无症状（1级）ILD，请考虑使用皮质类固醇治疗（例如，≥0.5mg / kg泼尼松龙或同等剂量）。保留ENHERTU直到恢复。如果出现症状性ILD（2级或更高），应立即开始皮质类固醇治疗（例如≥1 mg / kg泼尼松龙或同等剂量）。改善后，请逐渐减少（例如4周）。被诊断患有任何症状性（2级或更高）ILD的患者应永久停用ENHERTU。
■中性粒细胞减少症：用ENHERTU治疗的患者可能发生严重的中性粒细胞减少症，包括高热性中性粒细胞减少症。在开始使用ENHERTU之前和每次给药之前，按照临床指示监测全血细胞计数。 根据中性粒细胞减少症的严重程度，ENHERTU可能需要中断或降低剂量。
■左心室功能不全：接受ENHERTU治疗的患者发生左心功能不全的风险可能增加。包括ENHERTU在内的抗HER2治疗已观察到左心室射血分数（LVEF）降低。在开始ENHERTU之前和临床治疗期间应定期评估LVEF。 通过治疗中断来控制LVEF降低。 如果证实LVEF小于40％或从基线绝对下降大于20％，则永久终止ENHERTU。 症状性充血性心力衰竭（CHF）患者应永久停用ENHERTU。
■胚胎-胎儿毒性：根据其作用机理，ENHERTU对孕妇服用可引起胎儿伤害。在上市后的报告中，怀孕期间使用HER2定向抗体导致羊水过少的病例，表现为致命的肺发育不全，骨骼异常和新生儿死亡。根据其作用机理，ENHERTU的拓扑异构酶抑制剂成分DXd在施予孕妇时也可能引起胚胎对胎儿的伤害，因为它具有遗传毒性并靶向主动分裂的细胞。应告知患者胎儿的潜在危险。在开始ENHERTU之前，请验证具有生殖潜力的女性的怀孕状况。劝告有生殖潜能的女性在治疗期间以及最后一次使用ENHERTU后至少7个月内使用有效的避孕方法。建议具有生殖潜能的女性伴侣的男性患者在ENHERTU治疗期间以及最后一次ENHERTU给药后至少4个月内使用有效避孕方法。
■非临床毒理学现象：致癌性，诱变性，生育能力受损。尚未对fam-trastuzumab deruxtecan-nxki进行致癌性研究。
 

【注射用ENHERTU在特殊人群中使用】
■怀孕：根据其作用机理，ENHERTU对孕妇服用可引起胎儿伤害。没有关于孕妇使用ENHERTU的可用数据。在上市后的报告中，妊娠期间使用HER2定向抗体导致羊水过少的病例表现为致命的肺发育不全，骨骼异常和新生儿死亡。
■哺乳期：没有关于母乳中存在fam-trastuzumab deruxtecan-nxki，以及其对母乳喂养的孩子的影响或对母乳产量影响的数据。 由于母乳喂养的孩子可能会出现严重的不良反应，因此建议女性在进行ENHERTU治疗期间以及末次用药后7个月内不要母乳喂养。
■儿童：ENHERTU的安全性和有效性尚未在儿科患者中得到证实。
■老年：在接受ENHERTU 5.4 mg/kg治疗的234例her2阳性乳腺癌患者中，26%的患者年龄在65岁以上，5%的患者年龄在75岁以上。与年轻患者相比，年龄≥65岁的患者在疗效上没有总体差异。65岁以上患者(53%)的3-4级不良反应发生率高于年轻患者(42%)。
■肾功能不全：对于轻度或中度肾功能不全的患者，无需调整ENHERTU剂量。 没有严重肾功能不全患者的数据。
■肝功能不全：轻度或中度的患者，无需调整ENHERTU剂量。在中度肝功能不全的患者中，由于潜在的暴露增加，应密切监测与拓扑异构酶抑制剂DXd相关的毒性反应的增加。 严重肝功能不全的患者无可用数据。
 

【注射用ENHERTU作用机制】：
fam-trastuzumab deruxtecan-nxki是HER2定向的抗体-药物偶联物。 该抗体是人源化抗HER2 IgG1。 小分子DXd是拓扑异构酶I抑制剂，通过可裂解的接头与抗体连接。 与肿瘤细胞上的HER2结合后，fam-trastuzumab deruxtecan-nxki通过溶酶体酶进行内在化和细胞内接头裂解。 释放后，可透膜的DXd引起DNA损伤和凋亡细胞死亡。
 

【注射用ENHERTU患者资讯资料】
■告知患者严重或致命的ILD风险。 建议患者出现下列任何情况立即联系其医生：咳嗽，呼吸急促，发烧或其他新的或恶化的呼吸道症状。
■告知患者出现中性粒细胞减少症的风险，如果发烧，尤其是与任何感染迹象相关联，请立即联系其医生。
■告知患者出现左心室心功能不全的风险。建议患者出现下列任何情况立即联系其医生：新发或呼吸急促，咳嗽，疲劳，脚踝/腿肿胀，心悸，体重突然增加，头昏眼花，失去知觉。
■告知女性患者胎儿的潜在危险。建议女性患者出现已知或疑似怀孕情况立即联系其医生。告知有生殖潜力的女性在ENHERTU治疗期间以及最后一次给药后至少7个月内使用有效避孕方法。建议具有生殖潜能的女性伴侣的男性患者在ENHERTU治疗期间以及最后一次给药后至少4个月内使用有效的避孕药。
■告知妇女在治疗期间以及末次使用ENHERTU后7个月内不要母乳喂养。
■建议男性注意ENHERTU可能损害生育能力的生殖潜能。

【生产企业】：阿斯利康和第一三共株式会社（Daiichi Sankyo）
【规格】：100mg/瓶
【商标】：ENHERTU
【英文名称】：fam-trastuzumab deruxtecan-nxki
【性状】：静脉注射用白色至黄白色的冻干粉末
【贮藏】：2°C至8°C（36°F至46°F）的温度下冷藏。不要冻结或震荡。
 

【注射用ENHERTU适应症和用途】
ENHERTU是一种针对HER2的抗体和拓扑异构酶抑制剂的偶联物，适用于治疗无法切除或转移性HER2阳性乳腺癌的成年患者，这些患者已在转移环境中接受了两种或多种先前的基于抗HER2的治疗方案。
 

【注射用ENHERTU剂量和给药方法】
■不要用曲妥珠单抗或曲妥珠单抗-美坦新偶联物替代ENHERTU。
■ENHERTU的推荐剂量为5.4 mg / kg，每3周一次（21天周期）静脉滴注，直至疾病进展或出现不可接受的毒性。
■第一次输液
●输液时间在90分钟以上。
■后续输液
●如果先前的输注耐受性良好，则输液时间在30分钟以上。
●如果患者出现与输注相关的症状，请减慢或中断输注速度。
●如果发生严重的输注反应，请永久停用ENHERTU
■如果延迟或错过了计划的剂量，请尽快给药；不要等到下一个计划的周期。调整给药计划，以维持两次给药之间的3周间隔。以患者在最近一次输液中耐受的剂量和速率进行输液。

 
【注射用ENHERTU给药准备管理】
■为了防止用药错误，请检查药瓶标签，以确保准备和使用的药物是ENHERTU，而不是曲妥珠单抗或曲妥珠单抗-美坦新偶联物。
■静脉滴注前重新配制并进一步稀释ENHERTU。
■使用适当的无菌技术。
■ENHERTU是一种细胞毒性药物。遵循适用的特殊处理和处置程序。
使用：
■重配
1. 稀释前立即复溶。
2. 全剂量可能需要一个以上的小瓶。计算所需剂量（mg），重配的ENHERTU溶液的总体积以及所需的ENHERTU的小瓶数量
3. 用无菌注射器将5ml注射用的无菌水缓慢注入每100 mg小瓶，使最终浓度为20mg /mL。
4. 轻轻旋转小瓶直到完全溶解。不要摇晃。
5. 在给药前，无论何时，只要溶液和容器允许，应目视检查非肠道药物的颗粒物质和变色。溶液应该是透明的，无色到淡黄色。如果观察到可见的颗粒，或溶液混浊或变色，请不要使用。
6. 如果不立即使用，则将重新合成的ENHERTU小瓶在2°C到8°C(36°F到46°F)的冰箱中保存24小时，避免光照。不冻结。
7. 该产品不含防腐剂。冷藏24小时后丢弃未使用的ENHERTU。
■稀释
1. 用含有100毫升5%葡萄糖注射液的静脉输液袋稀释重配的ENHERTU的计算体积。不要使用氯化钠注射液。ENHERTU与由聚氯乙烯或聚烯烃(乙烯和聚丙烯的共聚物)制成的输液袋兼容。
2. 轻轻翻转输液袋，使溶液充分混合。不要摇晃。
3. 盖上输液袋，防止光线照射。
4. 如果不立即使用，则在室温下最多可存放4个小时（包括准备和输注），或者在2°C至8°C（36°F至46°F）的冰箱中保存24小时，并避免光照。不要冻结。
5. 丢弃小瓶中任何未使用的部分。
■管理
1. 如果将准备好的输注溶液冷藏保存（2°C至8°C [36°F至46°F]），则在给药前应使溶液达到室温。
2. 仅使用由聚烯烃或聚丁二烯和0.20或0.22微米在线聚醚砜（PES）或聚砜（PS）过滤器制成的输液器对ENHERTU进行静脉输注。请勿静脉推注或推注。
3. 请勿将ENHERTU与其他药物混合或通过同一静脉注射线使用其他药物。
 

【注射用ENHERTU药物过量】
无相关信息
 

【注射用ENHERTU禁忌症】
无
 

【注射用ENHERTU不良反应】
最常见的不良反应是间质性肺病/肺炎、中性粒细胞减少、左心室功能障碍等。
 

【注射用ENHERTU警告和注意事项】
■间质性肺疾病/肺炎：用ENHERTU治疗的患者可能发生严重、威胁生命或致命的间质性肺病（ILD），包括肺炎。建议患者立即报告咳嗽，呼吸困难，发烧和/或任何新的或恶化的呼吸道症状。监视患者ILD的体征和症状。及时调查ILD的证据。通过影像学检查评估疑似ILD的患者。考虑咨询肺科医生。对于无症状（1级）ILD，请考虑使用皮质类固醇治疗（例如，≥0.5mg / kg泼尼松龙或同等剂量）。保留ENHERTU直到恢复。如果出现症状性ILD（2级或更高），应立即开始皮质类固醇治疗（例如≥1 mg / kg泼尼松龙或同等剂量）。改善后，请逐渐减少（例如4周）。被诊断患有任何症状性（2级或更高）ILD的患者应永久停用ENHERTU。
■中性粒细胞减少症：用ENHERTU治疗的患者可能发生严重的中性粒细胞减少症，包括高热性中性粒细胞减少症。在开始使用ENHERTU之前和每次给药之前，按照临床指示监测全血细胞计数。 根据中性粒细胞减少症的严重程度，ENHERTU可能需要中断或降低剂量。
■左心室功能不全：接受ENHERTU治疗的患者发生左心功能不全的风险可能增加。包括ENHERTU在内的抗HER2治疗已观察到左心室射血分数（LVEF）降低。在开始ENHERTU之前和临床治疗期间应定期评估LVEF。 通过治疗中断来控制LVEF降低。 如果证实LVEF小于40％或从基线绝对下降大于20％，则永久终止ENHERTU。 症状性充血性心力衰竭（CHF）患者应永久停用ENHERTU。
■胚胎-胎儿毒性：根据其作用机理，ENHERTU对孕妇服用可引起胎儿伤害。在上市后的报告中，怀孕期间使用HER2定向抗体导致羊水过少的病例，表现为致命的肺发育不全，骨骼异常和新生儿死亡。根据其作用机理，ENHERTU的拓扑异构酶抑制剂成分DXd在施予孕妇时也可能引起胚胎对胎儿的伤害，因为它具有遗传毒性并靶向主动分裂的细胞。应告知患者胎儿的潜在危险。在开始ENHERTU之前，请验证具有生殖潜力的女性的怀孕状况。劝告有生殖潜能的女性在治疗期间以及最后一次使用ENHERTU后至少7个月内使用有效的避孕方法。建议具有生殖潜能的女性伴侣的男性患者在ENHERTU治疗期间以及最后一次ENHERTU给药后至少4个月内使用有效避孕方法。
■非临床毒理学现象：致癌性，诱变性，生育能力受损。尚未对fam-trastuzumab deruxtecan-nxki进行致癌性研究。
 

【注射用ENHERTU在特殊人群中使用】
■怀孕：根据其作用机理，ENHERTU对孕妇服用可引起胎儿伤害。没有关于孕妇使用ENHERTU的可用数据。在上市后的报告中，妊娠期间使用HER2定向抗体导致羊水过少的病例表现为致命的肺发育不全，骨骼异常和新生儿死亡。
■哺乳期：没有关于母乳中存在fam-trastuzumab deruxtecan-nxki，以及其对母乳喂养的孩子的影响或对母乳产量影响的数据。 由于母乳喂养的孩子可能会出现严重的不良反应，因此建议女性在进行ENHERTU治疗期间以及末次用药后7个月内不要母乳喂养。
■儿童：ENHERTU的安全性和有效性尚未在儿科患者中得到证实。
■老年：在接受ENHERTU 5.4 mg/kg治疗的234例her2阳性乳腺癌患者中，26%的患者年龄在65岁以上，5%的患者年龄在75岁以上。与年轻患者相比，年龄≥65岁的患者在疗效上没有总体差异。65岁以上患者(53%)的3-4级不良反应发生率高于年轻患者(42%)。
■肾功能不全：对于轻度或中度肾功能不全的患者，无需调整ENHERTU剂量。 没有严重肾功能不全患者的数据。
■肝功能不全：轻度或中度的患者，无需调整ENHERTU剂量。在中度肝功能不全的患者中，由于潜在的暴露增加，应密切监测与拓扑异构酶抑制剂DXd相关的毒性反应的增加。 严重肝功能不全的患者无可用数据。
 

【注射用ENHERTU作用机制】：
fam-trastuzumab deruxtecan-nxki是HER2定向的抗体-药物偶联物。 该抗体是人源化抗HER2 IgG1。 小分子DXd是拓扑异构酶I抑制剂，通过可裂解的接头与抗体连接。 与肿瘤细胞上的HER2结合后，fam-trastuzumab deruxtecan-nxki通过溶酶体酶进行内在化和细胞内接头裂解。 释放后，可透膜的DXd引起DNA损伤和凋亡细胞死亡。
 

【注射用ENHERTU患者资讯资料】
■告知患者严重或致命的ILD风险。 建议患者出现下列任何情况立即联系其医生：咳嗽，呼吸急促，发烧或其他新的或恶化的呼吸道症状。
■告知患者出现中性粒细胞减少症的风险，如果发烧，尤其是与任何感染迹象相关联，请立即联系其医生。
■告知患者出现左心室心功能不全的风险。建议患者出现下列任何情况立即联系其医生：新发或呼吸急促，咳嗽，疲劳，脚踝/腿肿胀，心悸，体重突然增加，头昏眼花，失去知觉。
■告知女性患者胎儿的潜在危险。建议女性患者出现已知或疑似怀孕情况立即联系其医生。告知有生殖潜力的女性在ENHERTU治疗期间以及最后一次给药后至少7个月内使用有效避孕方法。建议具有生殖潜能的女性伴侣的男性患者在ENHERTU治疗期间以及最后一次给药后至少4个月内使用有效的避孕药。
■告知妇女在治疗期间以及末次使用ENHERTU后7个月内不要母乳喂养。
■建议男性注意ENHERTU可能损害生育能力的生殖潜能。

Company: AstraZeneca and Daiichi Sankyo Company, Limited
Date of Approval: December 20, 2019
Treatment for: Breast Cancer

Enhertu (fam-trastuzumab deruxtecan-nxki) is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

20 December 2019 -- AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) today announced that the US Food and Drug Administration (FDA) has approved Enhertu® (fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu is a HER2-directed antibody-drug conjugate (ADC) and the FDA approval is based on the results of the registrational Phase II trial DESTINY-Breast01 of Enhertu (5.4 mg/kg) monotherapy in 184 female patients with HER2-positive metastatic breast cancer. All patients received prior trastuzumab, ado-trastuzumab emtansine, and 66% had prior pertuzumab.

The Phase II trial results showed a confirmed objective response rate of 60.3% (n=111; 95% CI: 52.9-67.4), including a 4.3% complete response rate (n=8) and a 56.0% partial response rate (n=103). A median duration of response of 14.8 months (95% CI: 13.8-16.9) was demonstrated as of August 1, 2019. In addition, a median progression-free survival of 16.4 months (95% CI: 12.7-not estimable), based upon a median duration of follow-up of 11.1 months, was recently presented at the San Antonio Breast Cancer Symposium and published online in The New England Journal of Medicine.

José Baselga, Executive Vice President, Oncology R&D, said: “Enhertu has shown impressive results in women with HER2-positive metastatic breast cancer, with the majority of women benefiting from treatment and the median duration of the response exceeding 14 months. With this first approval, we are proud to bring Enhertu to patients with high unmet need and we look forward to further exploring its potential in additional settings.”

Antoine Yver, Executive Vice President and Global Head, Oncology R&D, Daiichi Sankyo, said: “The approval of Enhertu underscores that this specifically engineered HER2-directed antibody-drug conjugate is delivering on its intent to establish an important new treatment for patients with HER2-positive metastatic breast cancer. Since the beginning of our clinical trial program four years ago, we have focused on the opportunity to transform the treatment landscape for patients with HER2-positive metastatic breast cancer, and we are extremely proud of how quickly we delivered Enhertu to patients in the US, as Enhertu represents one of the fastest-developed biologics in oncology.”

Enhertu is approved with a Boxed WARNING for Interstitial Lung Disease (ILD)/pneumonitis and Embryo-Fetal Toxicity. The safety of Enhertu has been evaluated in a pooled analysis from both the Phase II trial DESTINY-Breast01 and the earlier Phase I trial among a total of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of Enhertu (5.4mg/kg). ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients—two deaths previously reported in the Phase I trial and four deaths previously reported in the Phase II trial DESTINY-Breast01. Patients and physicians should be aware of ILD/pneumonitis and patients should be actively monitored for potential signs and symptoms. If ILD/pneumonitis is identified, it should be managed as per the FDA approved US Prescribing information. Management may require dose modification or treatment discontinuation and steroid treatment.

Enhertu can cause fetal harm when administered to a pregnant woman. The most common adverse reactions (frequency ≥20%) were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough and thrombocytopenia.

Enhertu will be available by prescription in the US within the coming weeks. AstraZeneca and Daiichi Sankyo are committed to ensuring that patients in the US who are prescribed Enhertu can access the medication and receive necessary financial support. Provider and patient support, reimbursement and distribution for Enhertu in the US will be accessible by visiting www.Enhertu4U.com or calling 1-833-Enhertu (1-833-364-3788).

Please visit www.Enhertu.com for full Prescribing Information, including Boxed WARNING, and Medication Guide.

Financial considerations
Following US approval, an amount of $125m is due from AstraZeneca to Daiichi Sankyo as the first milestone payment in HER2-positive breast cancer. Upon approval, this will be capitalized together with the upfront payment already made earlier in the year 2019.

Future sales of Enhertu in the US will be recognized by Daiichi Sankyo. AstraZeneca will report its share of gross profit margin from the sales in the US as collaboration revenue in the Company’s financial statements. For further details on the financial arrangements, please consult the announcement of the collaboration agreement from March 2019.

IMPORTANT SAFETY INFORMATION

Indication
Enhertu is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

· Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with Enhertu. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue Enhertu in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.

· Exposure to Enhertu during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications
None.

WARNINGS AND PRECAUTIONS
Interstitial Lung Disease / Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with Enhertu. In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with Enhertu, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with Enhertu. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt Enhertu until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue Enhertu. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg prednisolone or equivalent). Upon improvement, follow by gradual taper (e.g., 4 weeks).

Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with Enhertu. Of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received Enhertu, a decrease in neutrophil count was reported in 30% of patients and 16% had Grade 3 or 4 events. Median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients.

Monitor complete blood counts prior to initiation of Enhertu and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, Enhertu may require dose interruption or reduction. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt Enhertu until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt Enhertu until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt Enhertu until resolved. Reduce dose by one level.

Left Ventricular Dysfunction
Patients treated with Enhertu may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including Enhertu. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received Enhertu, two cases (0.9%) of asymptomatic LVEF decrease were reported. Treatment with Enhertu has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Assess LVEF prior to initiation of Enhertu and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue Enhertu if LVEF of <40% or absolute decrease from baseline of >20% is confirmed. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with Enhertu. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with Enhertu and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt Enhertu and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue Enhertu. If LVEF recovers to within 10% from baseline, resume treatment with Enhertu at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt Enhertu and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue Enhertu. Permanently discontinue Enhertu in patients with symptomatic congestive heart failure.

Embryo-Fetal Toxicity 
Enhertu can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of Enhertu. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of Enhertu. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Enhertu and for at least 4 months after the last dose of Enhertu.

Adverse Reactions
The safety of Enhertu was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of Enhertu 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. Enhertu was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving Enhertu. Serious adverse reactions in >1% of patients who received Enhertu were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

Enhertu was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with Enhertu. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with Enhertu. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common adverse reactions (frequency ≥20%) were nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (29%), diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia (20%).

Use in Specific Populations

· Pregnancy: Enhertu can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if Enhertu is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of Enhertu.

· Lactation: There are no data regarding the presence of Enhertu in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Enhertu and for 7 months after the last dose.

· Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of Enhertu. Contraception: Females: Enhertu can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Enhertu and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Enhertu and for at least 4 months following the last dose. Infertility: Enhertu may impair male reproductive function and fertility.

· Pediatric Use: Safety and effectiveness of Enhertu have not been established in pediatric patients.

· Geriatric Use: Of the 234 patients with HER2-positive breast cancer treated with Enhertu 5.4 mg/kg, 26% were ≥65 years and 5% were ≥75 years. No overall differences in efficacy were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (53%) as compared to younger patients (42%).

· Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.
Please see accompanying full Prescribing Information, including Boxed WARNING, and Medication Guide.

About HER2-Positive Breast Cancer

Approximately one in five breast cancers are HER2-positive. Despite recent improvements and approvals of new medicines, there remains significant clinical needs for patients with HER2-positive metastatic breast cancer. This disease remains incurable with patients eventually progressing after available treatment.

About HER2

HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells that is associated with aggressive disease and poorer prognosis in patients with breast cancer. To be considered HER2-positive, tumor cancer cells are usually tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). IHC test results are reported as: 0, IHC 1+, IHC 2+, or IHC 3+. A finding of IHC 3+ and/or FISH amplification is considered positive.

About DESTINY-Breast01

DESTINY-Breast01 is a registrational Phase II, single-arm open-label, global, multicenter, two-part trial evaluating the safety and efficacy of Enhertu in 184 female patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with ado-trastuzumab emtansine. The primary endpoint of the trial is objective response rate, as determined by independent central review. Secondary objectives include duration of response, disease control rate, clinical benefit rate, progression-free survival, overall survival and safety. Enrollment into DESTINY-Breast01 was completed in September 2018 with 184 patients at more than 100 sites globally.

About the Clinical Development Program

A comprehensive development program for fam-trastuzumab deruxtecan-nxki is underway globally with five pivotal trials in HER2-expressing metastatic breast and gastric cancers, including a trial in patients with metastatic breast cancer and low levels of HER2 expression (HER2-low). Phase II trials are underway for HER2-expressing advanced colorectal cancer, as well as metastatic non-squamous HER2-overexpressing or HER2-mutated non-small cell lung cancer. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

About Enhertu

Enhertu® (fam-trastuzumab deruxtecan-nxki) is the lead product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise and the most advanced program in AstraZeneca’s ADC scientific platform. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (“payload”) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

About the Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialize fam-trastuzumab deruxtecan-nxki as a potential new medicine worldwide, except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply.

Enhertu received Priority Review, Breakthrough Therapy Designation, and Fast Track Designation from the FDA for the treatment of select patients with HER2-positive metastatic breast cancer.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

Source: AstraZeneca

Posted: December 2019