Lenvatinib mesylate

过去的5年间，不可切除肝细胞癌的治疗取得了一定的进展。PD-L1抑制剂阿替利珠单抗联合VEGF抑制剂贝伐珠单抗、CTLA-4抑制剂tremelimumab联合PD-L1抑制剂度伐利尤单抗等策略，相继成为不可切除肝细胞癌的一线治疗策略，用药后患者中位总生存期（OS）为16~19个月。在现有疗法的基础上，如何持续改善肝细胞癌患者长期预后，是临床持续探索的方向。近日，《柳叶刀》（The Lancet）发表CheckMate 9DW试验预计划中期分析结果，表明在既往未接受治疗的不可切除肝细胞癌患者中，相比于TKIs单药治疗，PD-1抑制剂纳武利尤单抗联合CTLA-4抑制剂伊匹木单抗显著提高了中位OS（23.7个月 vs. 20.6个月），联合治疗使患者死亡风险降低了21%，未发现新的安全性问题。文章表示，研究结果支持纳武利尤单抗联合伊匹木单抗作为不可切除肝细胞癌一线治疗选择。截图来源：The LancetCheckMate 9DW试验是开放标签、随机、3期临床试验，纳入2020年1月6日至2021年11月8日，全球25个国家和地区的163家医疗中心晚期肝细胞癌成人患者668例。所有患者均满足以下条件：1）既往均未接受过系统性治疗；2）至少有一处未治疗病灶；3）Child–Pugh评分为5分或6分；4）东部肿瘤协作组体能状态评分为0分或1分。研究人员以1：1的随机比例分配患者接受以下任一治疗方式：联合治疗组（335例）：纳武利尤单抗（1 mg/kg）联合伊匹木单抗（3 mg/kg）治疗（每3周一次，最多4次），随后接受纳武利尤单抗单药（480 mg，每4周一次）治疗；单药治疗组（333例）：由研究者选择仑伐替尼（体重＜60 kg，8 mg/d；体重≥60 kg，12 mg/d）或索拉非尼单药治疗（400 mg，每日2次）；截至2024年1月31日，联合治疗组和单药治疗组分别有133例（40%）和224例（69%）的患者因疾病进展而停止治疗。中位随访时间为35.2个月，相比于单药治疗组，联合治疗组中位OS显著提高（23.7个月 vs. 20.6个月，HR=0.79，95%CI：0.65~0.96，P=0.018）。第24个月时，联合治疗组和单药治疗组OS率分别为49%和39%；第36个月时，两组OS率分别为38%和24%。在不同年龄、不同性别的亚组中，联合治疗组的OS都优于单药治疗组。▲单药治疗组（红色）和联合治疗组（蓝色）OS对比（图片来源：参考文献[1]）从上图可观察到，两组OS曲线早期有交叉，但随后两组曲线持续分离，且联合治疗组明显更具优势。两组生存曲线早期交叉的可能原因较多，如与研究无关的不良事件引起的死亡率不平衡、肿瘤免疫治疗可能存在延迟效应，而靶向治疗对肿瘤的生长和进展影响更为直接等。因此，对于既往未接受过系统性治疗的不可切除肝细胞癌患者，纳武利尤单抗联合伊匹木单抗可带来长期获益。联合治疗组确认的客观缓解率（ORR）也优于单药治疗组（36% vs. 13%，P＜0.0001）。联合治疗组和单药治疗组的中位缓解持续时间分别为30.4个月和12.9个月。治疗第24个月时，联合治疗组和单药治疗组分别有55%和35%的患者仍有缓解；治疗第36个月时，仅有联合治疗组有47%的患者仍有缓解。▲单药治疗组（红色）和联合治疗组（蓝色）持续缓解时间对比（图片来源：参考文献[1]）联合治疗组和单药治疗组中位无进展生存期（PFS）分别为9.1个月和9.2个月；18个月PFS率分别为34%和18%；24个月PFS率分别为28%和12%。安全性方面，联合治疗组和单药治疗组分别有84%和91%的患者发生任何级别的治疗相关不良事件，两组3或4级相关不良事件的发生率相似（41% vs. 42%），与此前报道的该方案相关安全性特征一致。总之，本次研究结果显示，对于既往未接受过系统性治疗的不可切除肝细胞癌，相较于TKIs靶向单药治疗，纳武利尤单抗联合伊匹木单抗的治疗方案可带来更好的生存获益，且这种获益在相关临床亚组中仍保持一致。点击文末“阅读原文/Read more”，即可访问The Lancet官网阅读完整论文。推荐阅读欢迎投稿：学术成果、前沿进展、临床干货等主题均可，点此了解投稿详情。参考资料[1] Thomas Yau, Peter R Galle, Thomas Decaens, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Published Online May 8, 2025. The Lancet. Doi：10.1016/ S0140-6736(25)00403免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医学新视点」微信公众号留言联系。如有其他合作需求，请联系wuxi_media@wuxiapptec.com分享，点赞，在看，传递医学新知

May 13, 2025 6:45 am ET New and updated data for MK-1084, an investigational KRAS G12C inhibitor, from the colorectal cancer and non-small cell lung cancer cohorts of the Phase 1 KANDLELIT-001 study will be presented Zilovertamab vedotin and sacituzumab tirumotecan data to highlight progress in Merck’s pipeline of innovative antibody-drug conjugates Follow-up data for KEYTRUDA ® (pembrolizumab) and WELIREG ® (belzutifan), as well as new and updated analyses for KEYTRUDA in earlier stages of cancer, add to the body of evidence supporting the role of these medicines RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced new research across more than 25 types of cancer and multiple treatment settings from the company’s broad and differentiated portfolio and pipeline will be showcased at the American Society of Clinical Oncology (ASCO) Annual Meeting (May 30–June 3). Data highlight Merck’s commitment to rapidly advance research across multiple tumor types and continue to build on its portfolio of established medicines. “The new data we are presenting at ASCO spotlight our commitment in oncology as we pioneer novel treatment approaches in our ongoing work to transform cancer care,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “Merck is fueling the next wave of innovation in cancer through research to help address significant unmet medical needs for even more patients.” Key data being presented on investigational candidates from Merck’s pipeline: First-time data from the colorectal cancer cohort of the Phase 1 KANDLELIT-001 study evaluating MK-1084, an investigational, oral selective KRAS G12C inhibitor, as monotherapy and in combination therapies for patients with KRAS G12C-mutated advanced colorectal cancer (Abstract #3508; Oral abstract session: Gastrointestinal cancer—colorectal and anal). 1 Additional data from the non-small cell lung cancer (NSCLC) cohorts of the Phase 1 KANDLELIT-001 study evaluating MK-1084 as monotherapy and in combination therapies for patients with KRAS G12C-mutated metastatic NSCLC (Abstract #8605; Poster session: Lung cancer—non-small cell metastatic). 1 First-time data from the Phase 2/3 waveLINE-003 study evaluating zilovertamab vedotin, an investigational antibody-drug conjugate (ADC) that targets receptor tyrosine kinase-like orphan receptor 1 (ROR1), plus standard of care as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (Abstract #7005; Oral abstract session: Hematologic malignancies—lymphoma and chronic lymphocytic leukemia). Data from the randomized Phase 2 OptiTROP-Lung03 study conducted in China, independently led by Kelun-Biotech, evaluating sacituzumab tirumotecan (sac-TMT), an investigational TROP2-directed ADC, as a treatment for patients with previously treated advanced EGFR-mutated NSCLC (Abstract #8507; Oral abstract session: Lung cancer—non-small cell metastatic). 2 Additionally, new or updated findings from Merck’s broad portfolio of cancer medicines will be presented, including longer-term results for KEYTRUDA ® (pembrolizumab), Merck’s anti-PD-1 therapy, and WELIREG ® (belzutifan), Merck’s oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, as well as findings in earlier stages of cancer. Key data being presented on existing medicines in Merck’s portfolio: Primary results from the first interim analysis of the Phase 3 ASCENT-04/KEYNOTE-D19 trial evaluating KEYTRUDA plus the TROP2-directed ADC sacituzumab govitecan-hziy for patients with previously untreated, locally advanced inoperable or metastatic triple-negative breast cancer will be featured as part of the ASCO press program (Abstract #LBA109; Oral abstract session: Breast cancer—metastatic). 3 Five-year follow-up results from the Phase 3 KEYNOTE-564 trial evaluating KEYTRUDA monotherapy as an adjuvant treatment for patients with renal cell carcinoma at increased risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions (Abstract #4514; Rapid oral abstract session: Genitourinary cancer—kidney and bladder). Five-year follow-up data from the Phase 2 LITESPARK-004 trial evaluating WELIREG as a treatment for von Hippel-Lindau (VHL) disease-associated tumors (Abstract #4507; Oral abstract session: Genitourinary cancer—kidney and bladder). Results from the Phase 1b TROPION-Lung02 trial evaluating KEYTRUDA plus the TROP2-directed ADC datopotamab deruxtecan, with or without platinum-based chemotherapy, as a first-line treatment for patients with advanced NSCLC (Abstract #8501; Oral abstract session: Lung cancer—non-small cell metastatic). 4 Data from the 4.5-year follow-up of the Phase 3 KEYNOTE-859 trial evaluating KEYTRUDA plus chemotherapy for the first-line treatment of advanced human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction adenocarcinoma (Abstract #4036; Poster session: Gastrointestinal cancer—gastroesophageal, pancreatic, and hepatobiliary). Final analysis results from the Phase 3 KEYNOTE-A18 trial evaluating KEYTRUDA in combination with concurrent chemoradiotherapy (CRT) as a treatment for patients with high-risk locally advanced cervical cancer (Abstract #LBA5504; Oral abstract session: Gynecologic cancer). 5 Exploratory efficacy analysis results from the Phase 3 KEYNOTE-689 trial evaluating KEYTRUDA as a neoadjuvant treatment for patients with resectable locally advanced head and neck squamous cell carcinoma, then continued as adjuvant treatment in combination with standard of care radiotherapy with or without cisplatin and then as a single agent (Abstract #6012; Rapid oral abstract session: Head and neck cancer). Merck investor event Merck will hold an Oncology Investor Event to coincide with the 2025 ASCO Annual Meeting on Monday, June 2, 2025, 6 p.m. CT, during which senior management will provide an update on the company’s oncology strategy and program. The event will take place in Chicago, Ill., and will be accessible via webcast. Investors, analysts, members of the media and the general public are invited to listen to a webcast of the presentation via this weblink . Details on abstracts listed above and additional key abstracts for Merck Breast cancer Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1-positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized Phase 3 ASCENT-04/KEYNOTE-D19 study. S. Tolaney. 3 Abstract #LBA109, Oral abstract session: Breast cancer—metastatic Sacituzumab tirumotecan (sac-TMT) as first-line treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): Initial results from the Phase II OptiTROP-Breast05 study. Y. Yin. 2 Abstract #1019, Rapid oral abstract session: Breast cancer—metastatic Gastrointestinal cancers The KRAS G12C inhibitor MK-1084 for KRAS G12C–mutated advanced colorectal cancer (CRC): Results from KANDLELIT-001. I. Ługowska. 1 Abstract #3508, Oral abstract session: Gastrointestinal cancer—colorectal and anal KEYNOTE-859: 4.5-year median follow-up of pembrolizumab plus chemotherapy for previously untreated advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. S. Rha. Abstract #4036, Poster session: Gastrointestinal cancer—gastroesophageal, pancreatic, and hepatobiliary Quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis of pembrolizumab (pembro) versus chemotherapy (chemo) in microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC) in the KEYNOTE-177 trial. E. Elez. Abstract #3631, Poster session: Gastrointestinal cancer—colorectal and anal Genitourinary cancers Five-year follow-up results from the Phase 3 KEYNOTE-564 study of adjuvant pembrolizumab (pembro) for the treatment of clear cell renal cell carcinoma (ccRCC). N. Haas. Abstract #4514, Rapid oral abstract session: Genitourinary cancer—kidney and bladder Hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan in von Hippel-Lindau (VHL) disease–associated neoplasms: 5-year follow-up of the phase 2 LITESPARK-004 study. V. Narayan. Abstract #4507, Oral abstract session: Genitourinary cancer—kidney and bladder Phase 1b/2 KEYNOTE-365 cohort I: Pembrolizumab (pembro) plus carboplatin and etoposide chemotherapy (chemo) or chemo alone for metastatic neuroendocrine prostate cancer (NEPC). G. Amsberg. Abstract #5059, Poster session: Genitourinary cancer—prostate, testicular, and penile Gynecologic cancers Pembrolizumab with chemoradiotherapy in patients with high-risk locally advanced cervical cancer: Final analysis results of the Phase 3, randomized, double-blind ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. L. Duska. 5 Abstract #LBA5504, Oral abstract session: Gynecologic cancer Head and neck cancer Neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Exploratory efficacy analyses of the Phase 3 KEYNOTE-689 study. D. Adkins. Abstract #6012, Rapid oral abstract session: Head and neck cancer Hematologic cancers WaveLINE-003: Phase 2/3 trial of zilovertamab vedotin plus standard of care in relapsed/refractory diffuse large B-cell lymphoma. P. Armand. Abstract #7005, Oral abstract session: Hematologic malignancies—lymphoma and chronic lymphocytic leukemia Lung cancer MK-1084 for KRAS G12C-mutated (mut) metastatic non–small-cell lung cancer (mNSCLC): Results from KANDLELIT-001. A. Sacher. 1 Abstract #8605, Poster session: Lung cancer—non-small cell metastatic Sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated advanced EGFR-mutated non-small cell lung cancer (NSCLC): Results from the randomized OptiTROP-Lung03 study. L. Zhang. 2 Abstract #8507, Oral abstract session: Lung cancer—non-small cell metastatic Patritumab deruxtecan (HER3-DXd) in resistant EGFR -mutated ( EGFR m) advanced non-small cell lung cancer (NSCLC) after a third-generation EGFR TKI: The Phase 3 HERTHENA-Lung02 study. T. Mok. 4 Abstract #8506, Oral abstract session: Lung cancer—non-small cell metastatic TROPION-Lung02: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC). B. Levy. 4 Abstract #8501, Oral abstract session: Lung cancer—non-small cell metastatic Sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated locally advanced or metastatic (LA/M) non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: Preliminary results from a Phase 2 study. L. Zhang. 2 Abstract #8615, Poster session: Lung cancer—non-small cell metastatic Sacituzumab tirumotecan (sac-TMT) in combination with tagitanlimab (anti-PD-L1) in first-line (1L) advanced non-small-cell lung cancer (NSCLC): Non-squamous cohort from the Phase II OptiTROP-Lung01 study. W. Fang. 2 Abstract #8529, Poster session: Lung cancer—non-small cell metastatic Melanoma and other skin cancers First-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in Chinese patients with unresectable or metastatic melanoma: Results from LEAP-003. J. Guo. 6 Abstract #9553, Poster session: Melanoma/skin cancers Multi-tumor Pembrolizumab monotherapy for melanoma or non-small cell lung cancer in India: Results of the Phase IV KEYNOTE-593 study. S. Limaye. Abstract #e21518, Publication only: Melanoma/skin cancers 1 In collaboration with Taiho Pharmaceutical Co. Ltd and Astex Pharmaceuticals (UK), a wholly owned subsidiary of Otsuka Pharmaceutical Co., Ltd 2 Led by Kelun-Biotech 3 In collaboration with Gilead 4 In collaboration with Daiichi Sankyo 5 In collaboration with the European Network for Gynaecological Oncology Trial (ENGOT) groups and the GOG Foundation, Inc. (GOG) 6 In collaboration with Eisai About Merck’s early-stage cancer clinical program Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is evaluating our portfolio of medicines and pipeline candidates in earlier disease states, with more than 30 ongoing registrational studies across multiple types of cancer. About KEYTRUDA ® (pembrolizumab) injection, 100 mg KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers. Selected KEYTRUDA ® (pembrolizumab) Indications in the U.S. Melanoma KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma. KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. Non-Small Cell Lung Cancer KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC. KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic. KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Head and Neck Squamous Cell Cancer KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test. Gastric Cancer KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. Cervical Cancer KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC. KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Triple-Negative Breast Cancer KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information. Selected Important Safety Information for KEYTRUDA Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients. Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution. Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution. Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA as a Single Agent KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients. KEYTRUDA With Axitinib KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event. Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypophysitis KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Thyroid Disorders KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism. Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Immune-Mediated Nephritis With Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti– PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection. Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatments and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT. Increased Mortality in Patients With Multiple Myeloma In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials. Embryofetal Toxicity Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose. Adverse Reactions In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%). In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054. In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%). In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%). In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%). In KEYNOTE-671, adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single-agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy. The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism. In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, serious adverse reactions occurred in 34% of 396 patients. The most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%). Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396 patients did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%). In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was administered as a single agent as adjuvant treatment, serious adverse reactions occurred in 14% of 290 patients. The most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of patients who received KEYTRUDA as a single agent, given as adjuvant treatment; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain (1%). Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred. In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%). In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%). In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism. In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each). In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%). In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%). In KEYNOTE-A39, when KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (21%). In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%). In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%). Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. In KEYNOTE-811, fatal adverse reactions occurred in 3 patients who received KEYTRUDA in combination with trastuzumab and CAPOX (capecitabine plus oxaliplatin) or FP (5-FU plus cisplatin) and included pneumonitis in 2 patients and hepatitis in 1 patient. KEYTRUDA was discontinued due to adverse reactions in 13% of 350 patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. Adverse reactions resulting in permanent discontinuation of KEYTRUDA in ≥1% of patients were pneumonitis (2.0%) and pneumonia (1.1%). In the KEYTRUDA arm vs placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA vs standard of care for diarrhea (53% vs 47%), rash (35% vs 28%), hypothyroidism (11% vs 5%), and pneumonia (11% vs 5%). In KEYNOTE-859, when KEYTRUDA was administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA, including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was permanently discontinued due to adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1.0%). The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%), and weight loss (20%). In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%). Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-A18, when KEYTRUDA was administered with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions occurred in 1.4% of 292 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 30% of patients; those ≥1% included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 7% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). For patients treated with KEYTRUDA in combination with CRT, the most common adverse reactions (≥10%) were nausea (56%), diarrhea (50%), vomiting (33%), urinary tract infection (32%), fatigue (26%), hypothyroidism (20%), constipation (18%), decreased appetite and weight loss (17% each), abdominal pain and pyrexia (12% each), hyperthyroidism, dysuria, rash (11% each), and pelvic pain (10%). In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each). KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%). For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%). In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%). In KEYNOTE-394, KEYTRUDA was discontinued due to adverse reactions in 13% of 299 patients with previously treated hepatocellular carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). The most common adverse reactions in patients receiving KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%), decreased appetite (15%), pruritus (12%), upper respiratory tract infection (11%), cough (11%), and hypothyroidism (10%). In KEYNOTE-966, when KEYTRUDA was administered in combination with gemcitabine and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%). In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in patients with MCC (n=105) were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%). In KEYNOTE-581, when KEYTRUDA was administered in combination with LENVIMA to patients with advanced renal cell carcinoma (n=352), fatal adverse reactions occurred in 4.3% of patients. Serious adverse reactions occurred in 51% of patients; the most common (≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension, myocardial infarction, pneumonitis, and vomiting (3% each), acute kidney injury, adrenal insufficiency, dyspnea, and pneumonia (2% each). Permanent discontinuation of KEYTRUDA, LENVIMA, or both due to an adverse reaction occurred in 37% of patients; 29% KEYTRUDA only, 26% LENVIMA only, and 13% both. The most common adverse reaction (≥2%) resulting in permanent discontinuation of KEYTRUDA, LENVIMA, or the combination were pneumonitis, myocardial infarction, hepatotoxicity, acute kidney injury, rash (3% each), and diarrhea (2%). The most common adverse reactions (≥20%) observed with KEYTRUDA in combination with LENVIMA were fatigue (63%), diarrhea (62%), musculoskeletal disorders (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), weight loss, dysphonia and proteinuria (30% each), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain and hemorrhagic events (27% each), vomiting (26%), constipation and hepatotoxicity (25% each), headache (23%), and acute kidney injury (21%). In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%). In KEYNOTE-868, when KEYTRUDA was administered in combination with chemotherapy (paclitaxel and carboplatin) to patients with advanced or recurrent endometrial carcinoma (n=382), serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy (n=377). Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%) and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone, with the exception of rash (33% all Grades; 2.9% Grades 3-4). In KEYNOTE-775, when KEYTRUDA was administered in combination with LENVIMA to patients with advanced endometrial carcinoma that was pMMR or not MSI-H (n=342), fatal adverse reactions occurred in 4.7% of patients. Serious adverse reactions occurred in 50% of these patients; the most common (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%). Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%). The most common adverse reactions for KEYTRUDA in combination with LENVIMA (reported in ≥20% patients) were hypothyroidism and hypertension (67% each), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), abdominal pain and weight loss (34% each), urinary tract infections (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar-plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%). In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%). Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose. Pediatric Use In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), leukopenia (30%), vomiting (29%), neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia (17%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Geriatric Use Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older. Additional Selected KEYTRUDA Indications in the U.S. Malignant Pleural Mesothelioma KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM). Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Urothelial Cancer KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma: who are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy, or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test. Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. Biliary Tract Cancer KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Endometrial Carcinoma KEYTRUDA, in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not MSI-H as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting are not candidates for curative surgery or radiation. KEYTRUDA, as a single agent, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Tumor Mutational Burden-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. Cutaneous Squamous Cell Carcinoma KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf . About LENVIMA ® (lenvatinib); available as 10 mg and 4 mg capsules LENVIMA, discovered and developed by Eisai, is an orally available multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, LENVIMA decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone. The combination of LENVIMA and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone. LENVIMA ® (lenvatinib) Indications in the U.S. For the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). In combination with pembrolizumab, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Selected Safety Information for LENVIMA Warnings and Precautions Hypertension. In differentiated thyroid cancer (DTC), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In advanced renal cell carcinoma (RCC), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In unresectable hepatocellular carcinoma (HCC), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC. Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity. Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials. Among patients receiving LENVIMA with KEYTRUDA, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%). Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Hepatotoxicity. Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients. 2% of patients discontinued LENVIMA due to hepatic encephalopathy and 1% discontinued due to hepatic failure. Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3). Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity. Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula. QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%. Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity. Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity. Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1,823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms. Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials. Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC. Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice. Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established. Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ. Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA. Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution. Embryo‐Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of LENVIMA during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose. Adverse Reactions In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%). In RCC, the most common adverse reactions (≥20%) observed in LENVIMA + KEYTRUDA-treated patients were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%), proteinuria (30%), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain (27%), hemorrhagic events (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with KEYTRUDA, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and KEYTRUDA. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of LENVIMA, KEYTRUDA, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% KEYTRUDA only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, KEYTRUDA, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA, KEYTRUDA, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with KEYTRUDA. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), vomiting (6%), increased ALT (5%), and increased amylase (5%). In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients. In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%). In endometrial carcinoma, the most common adverse reactions (≥20%) observed in LENVIMA + KEYTRUDA-treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar‐plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions among these patients occurred in 4.7% of those treated with LENVIMA and KEYTRUDA, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of these patients receiving LENVIMA and KEYTRUDA. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of these patients. The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%). Use in Specific Populations Because of the potential for serious adverse reactions in breastfed children, advise women to discontinue breastfeeding during treatment and for 1 week after last dose. LENVIMA may impair fertility in males and females of reproductive potential. No dose adjustment is recommended for patients with mild (creatinine clearance [CLcr] 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease. No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment. Please see Prescribing Information for LENVIMA (lenvatinib) at http://www.lenvima.com/pdfs/prescribing-information.pdf . About WELIREG ® (belzutifan) 40 mg tablets, for oral use Indications in the U.S. Certain von Hippel-Lindau (VHL) disease-associated tumors WELIREG (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. Advanced Renal Cell Carcinoma (RCC) WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) with a clear cell component following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Selected Safety Information for WELIREG Warning: Embryo-Fetal Toxicity Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective. Anemia WELIREG can cause severe anemia that can require blood transfusion. Monitor for anemia before initiation of, and periodically throughout, treatment. Transfuse patients as clinically indicated. For patients with hemoglobin <8 g/dL, withhold WELIREG until ≥8 g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then resume at a reduced dose or permanently discontinue WELIREG. In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established. In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced RCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received ESAs only, and 12% received both transfusion and ESAs. Hypoxia WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization. Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider. In LITESPARK-004, hypoxia occurred in 1.6% of patients. In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months). Embryo-Fetal Toxicity Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Adverse Reactions In LITESPARK-004, serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each). WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%). The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%). In LITESPARK-005, serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%). WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%) and hemorrhage (0.5%). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%). Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1.0%) were hypoxia (5%) and anemia (3.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (33%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%). Drug Interactions Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended. Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding. Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose. Females and Males of Reproductive Potential WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG. Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown. Pediatric Use Safety and effectiveness of WELIREG in pediatric patients under 18 years of age have not been established. Please see Prescribing Information, including information for the Boxed Warning about embryo-fetal toxicity, for WELIREG (belzutifan) at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf and Medication Guide for WELIREG at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_mg.pdf . About the Merck and Eisai strategic collaboration In March 2018, Eisai and Merck, known as MSD outside of the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA. Eisai and Merck are studying the KEYTRUDA plus LENVIMA combination through the LEAP ( LE nvatinib A nd P embrolizumab) clinical program across multiple clinical trials. About the Daiichi Sankyo and Merck collaboration Daiichi Sankyo and Merck entered into a global collaboration in October 2023 to jointly develop and commercialize patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug deruxtecan (R-DXd), except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply. In August 2024 , the global co-development and co-commercialization agreement was expanded to include gocatamig (MK-6070/DS3280), which the companies will jointly develop and commercialize worldwide, except in Japan where Merck will maintain exclusive rights. Merck will be solely responsible for manufacturing and supply for gocatamig. Merck’s focus on cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovation products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2024 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). Media Contacts: Julie Cunningham (617) 519-6264 Kristen Drake (908) 740-1679 Investor Contacts: Peter Dannenbaum (732) 594-1579 Steven Graziano (732) 594-1583 Source: Merck & Co., Inc.