Makker Vicky, Taylor Matthew H, Oaknin Ana, Casado Herraez Antonio, Orlowski Robert, Dutta Lea, Ren Min, Zale Melissa, O'Malley David M
Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Providence Cancer Institute, Portland, Oregon, USA.
Oncologist. 2021 Sep;26(9):e1599-e1608. doi: 10.1002/onco.13883. Epub 2021 Jul 30.
The combination of lenvatinib plus pembrolizumab has shown efficacy in treatment of advanced endometrial carcinoma (that is not microsatellite instability-high or mismatch repair deficient) following prior systemic therapy in any setting in the open-label, single-arm, phase Ib/II Study 111/KEYNOTE-146. With the exception of hypothyroidism, the safety profile of the combination was comparable to that of each monotherapy. Given the medical complexity and fragility of patients with endometrial carcinoma, further characterization of adverse reactions (ARs) associated with treatment will help health care professionals to optimize treatment with lenvatinib plus pembrolizumab combination therapy.
In Study 111/KEYNOTE-146, patients received lenvatinib at a starting dose of 20 mg orally once daily and pembrolizumab 200 mg intravenously every 3 weeks. Selected ARs (hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria) were chosen for detailed post hoc analyses.
Median times to first onset of the selected ARs in this analysis all occurred within the first 10 weeks of treatment. Of the selected ARs, grade ≥3 severity of fatigue, hypertension, and nausea occurred in ≥5% of patients. Overall incidence of hypothyroidism was 51%, primarily of grade 2 severity (46%). Most of the ARs assessed were managed with a combination of study drug dose modifications and concomitant medications.
No new safety signals were identified and the toxicity profile in this study was manageable with supportive medications, dose interruptions, and/or lenvatinib dose reductions. This analysis provides AR management guidance for patients with endometrial cancer receiving lenvatinib plus pembrolizumab combination therapy.
Lenvatinib plus pembrolizumab has shown efficacy in the treatment of patients with advanced endometrial carcinoma (that is, not microsatellite instability-high or mismatch repair deficient) following at least one prior systemic therapy in any setting. Patients may experience toxicity associated with this combination, including adverse reactions of hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria. These adverse reactions may be managed with a combination of concomitant supportive care medications and judicious lenvatinib dose modifications. This article provides context and guidance for the recognition and management of adverse reactions in patients receiving lenvatinib plus pembrolizumab.
在开放标签、单臂、Ib/II期111/KEYNOTE - 146研究中，乐伐替尼联合帕博利珠单抗已显示出对先前接受过任何系统性治疗的晚期子宫内膜癌（非微卫星高度不稳定或错配修复缺陷型）有效。除甲状腺功能减退外，该联合疗法的安全性与各单药疗法相当。鉴于子宫内膜癌患者的医疗复杂性和身体脆弱性，进一步明确与治疗相关的不良反应（ARs）将有助于医护人员优化乐伐替尼联合帕博利珠单抗的联合治疗方案。
在111/KEYNOTE - 146研究中，患者接受乐伐替尼起始剂量为每日口服一次20 mg，帕博利珠单抗每3周静脉注射200 mg。选择特定的ARs（高血压、疲劳、恶心/呕吐、腹泻、食欲减退/体重减轻、甲状腺功能减退、手足红斑感觉异常综合征、肌肉骨骼疼痛、口腔炎和蛋白尿）进行详细的事后分析。
本次分析中，所选ARs首次出现的中位时间均发生在治疗的前10周内。在所选ARs中，≥5%的患者出现了疲劳、高血压和恶心的≥3级严重程度反应。甲状腺功能减退的总体发生率为51%，主要为2级严重程度（46%）。大多数评估的ARs通过联合调整研究药物剂量和使用伴随药物进行处理。
未发现新的安全信号，本研究中的毒性情况可通过支持性药物、剂量中断和/或乐伐替尼剂量降低进行管理。该分析为接受乐伐替尼联合帕博利珠单抗治疗的子宫内膜癌患者提供了AR管理指导。
乐伐替尼联合帕博利珠单抗已显示出对在任何情况下至少接受过一次先前系统性治疗的晚期子宫内膜癌（即非微卫星高度不稳定或错配修复缺陷型）患者有效。患者可能会经历与该联合治疗相关的毒性，包括高血压、疲劳、恶心/呕吐、腹泻、食欲减退/体重减轻、甲状腺功能减退、手足红斑感觉异常综合征、肌肉骨骼疼痛、口腔炎和蛋白尿等不良反应。这些不良反应可通过联合使用支持性护理药物和谨慎调整乐伐替尼剂量进行处理。本文为识别和管理接受乐伐替尼联合帕博利珠单抗治疗患者的不良反应提供了背景和指导。
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