Locally Advanced Head and Neck Squamous Cell Carcinoma

Merck & Co – known as MSD outside the US and Canada – has shared positive results from a late-stage study of its anti-PD-1 therapy in head and neck cancer. The phase 3 KEYNOTE-689 trial has been evaluating Keytruda (pembrolizumab) as a perioperative treatment for patients newly diagnosed with stage 3 or 4A, resected, locally advanced head and neck squamous cell carcinoma. The drug was given as a neoadjuvant therapy before surgery, then continued after surgery in combination with standard-of-care radiotherapy (with or without cisplatin) as an adjuvant therapy, and then as a maintenance therapy. Results from a pre-specified interim analysis demonstrated a statistically significant and clinically meaningful improvement in event-free survival for patients receiving the Keytruda regimen, meeting the study’s primary endpoint. A statistically significant improvement in major pathological response, a key secondary endpoint, was also shown for patients in the Keytruda arm compared with adjuvant radiotherapy alone, and the safety profile of Merck’s drug was consistent with that observed in previously reported studies. More than 58,450 new cases of head and neck cancer, which describes a number of different tumours that develop in or around the throat, larynx, nose, sinuses and mouth, are expected to be diagnosed in the US this year. Keytruda works by increasing the ability of the body’s immune system to help detect and fight tumour cells, and is already approved as a monotherapy and in combination regimens for certain patients with metastatic or unresectable, recurrent head and neck squamous cell carcinoma. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, outlined that KEYNOTE-689 “marks the first positive trial in two decades for patients with resected, locally advanced head and neck squamous cell carcinoma”. “These statistically significant and clinically meaningful findings have the potential to be practice-changing and continue to highlight the promising role of Keytruda for certain patients with earlier stages of disease,” she said. Beyond head and neck squamous cell carcinoma, Keytruda holds approvals to treat a wide range of cancers, including specific cases of breast cancer, cervical cancer, bladder cancer, biliary tract cancer, non-small cell lung cancer and renal cell carcinoma.

10月8日，默沙东宣布其抗PD-1疗法Keytruda（帕博利珠单抗）作为未经治疗、可切除的III期或IVA期局部晚期头颈部鳞状细胞癌（LA-HNSCC）患者的围手术期治疗方案的III期KEYNOTE-689研究达到了无事件生存期（EFS）的主要终点。 KEYNOTE-689是一项随机、开放标签的III期临床研究（NCT03765918），旨在评估帕博利珠单抗单药作为新辅助治疗，术后继续联合标准放疗（±顺铂）作为辅助治疗和维持治疗，与未经新辅助治疗、单独的辅助放疗（±顺铂）作为辅助治疗方案相比，在可切除的III期或IVA期LA-HNSCC初治患者中的疗效和安全性。 在由独立的数据监查委员会（iDMC）进行的预先指定的第一次中期分析中，接受帕博利珠单抗围手术期治疗的患者的EFS有统计学意义和临床意义的改善。该研究还显示，与单独辅助放疗相比，帕博利珠单抗组患者的主要病理反应（mPR，关键次要终点）具有统计学意义改善。帕博利珠单抗的安全性与先前报道的研究中观察到的一致；未发现新的安全信号。 在接受帕博利珠单抗新辅助治疗和术后联合标准放疗（±顺铂）作为辅助和维持治疗的患者中，观察到总生存期（OS）的改善趋势，这是另一个关键的次要研究终点。在第一次中期分析时，CPS≥10的PD-L1患者的OS结果未达到统计学意义。由于统计检验的层级关系，未对CPS≥1的患者和意向治疗（ITT）人群进行正式检验。OS将在下一次期中分析中进行评估。 默沙东研发实验室高级副总裁兼全球临床开发肿瘤学负责人Marjorie Green博士表示：“KEYNOTE-689 是近二十年来首次针对可切除手术的局部晚期头颈部鳞状细胞癌患者取得阳性结果的试验，因此这些结果意义重大，这些具有统计学意义和临床意义的发现有望改变临床实践，并继续凸显Keytruda在某些早期疾病患者具有潜在的治疗作用。” 默沙东表示会将这些研究结果在即将举行的医学会议上公布，并提交给监管机构。 头颈癌是指在喉咙、喉、鼻子、鼻窦和口腔内或周围发生的肿瘤。大多数头颈部癌症是鳞状细胞癌，起源于构成头部和颈部结构薄表层的扁平鳞状细胞。局部晚期头颈部鳞状细胞癌（LA-HNSCC）是一种在原始位置之外生长但尚未扩散到身体远处部位的癌症。有几个因素会大大增加患头颈癌的风险，包括吸烟和饮酒以及人乳头瘤病毒（HPV）。据估计，2022 年全球头颈癌新诊断病例超过 891,500 例，死于该疾病的人数超过 458,100 人。据估计，2024年美国将新增58,450多例头颈癌确诊病例，并将有超过12,230人死于该病。 帕博利珠单抗目前在美国、欧洲、中国、日本和世界其他国家被批准作为单药和联合方案用于治疗适合的不可切除的转移或复发性HNSCC患者。 Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。 免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

KEYNOTE-689 is the first Phase 3 trial to demonstrate statistically significant and clinically meaningful improvement in EFS in the intent-to-treat population in the neoadjuvant and adjuvant setting for an anti-PD-1 therapy in earlier stages of head and neck squamous cell carcinoma RAHWAY, NJ, USA I October 08, 2024 I Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the Phase 3 KEYNOTE-689 trial evaluating KEYTRUDA ® (pembrolizumab), Merck’s anti-PD-1 therapy, as a perioperative treatment for patients newly diagnosed with stage III or IVA, resected, locally advanced head and neck squamous cell carcinoma (LA-HNSCC) met its primary endpoint of event-free survival (EFS). The study evaluated KEYTRUDA as neoadjuvant therapy, then continued after surgery in combination with standard-of-care radiotherapy (with or without cisplatin) as adjuvant therapy, followed by KEYTRUDA as maintenance therapy, compared to adjuvant radiotherapy (with or without cisplatin) alone. At a pre-specified first interim analysis conducted by an independent Data Monitoring Committee, there was a statistically significant and clinically meaningful improvement in EFS for patients receiving the KEYTRUDA perioperative treatment regimen. The study also showed a statistically significant improvement in major pathological response (mPR), a key secondary endpoint, for patients in the KEYTRUDA arm compared with adjuvant radiotherapy alone. The safety profile of KEYTRUDA was consistent with that observed in previously reported studies; no new safety signals were identified. “These results are substantial, as KEYNOTE-689 marks the first positive trial in two decades for patients with resected, locally advanced head and neck squamous cell carcinoma,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “These statistically significant and clinically meaningful findings have the potential to be practice-changing and continue to highlight the promising role of KEYTRUDA for certain patients with earlier stages of disease.” A trend toward improvement in overall survival (OS), another key secondary endpoint, was observed for KEYTRUDA as neoadjuvant treatment and KEYTRUDA in combination with standard-of-care radiotherapy (with or without cisplatin) as treatment after surgery and maintenance therapy with KEYTRUDA. The OS results did not reach statistical significance in patients whose tumors were PD-L1 Combined Positive Score (CPS) ≥10 at the time of this first interim analysis. Due to the statistical testing hierarchy, formal testing was not performed in the CPS ≥1 and intention-to-treat (ITT) populations. OS will be evaluated at the next interim analysis. Results will be presented at an upcoming medical meeting and will be submitted to regulatory authorities. KEYTRUDA is currently approved as monotherapy and in combination regimens for appropriate patients with metastatic or unresectable, recurrent HNSCC in the U.S., Europe, China, Japan and other countries around the world. For more information, please see the “Selected KEYTRUDA ® (pembrolizumab) Indications in the U.S.” section below. About KEYNOTE-689 KEYNOTE-689 is a randomized, active-controlled, open-label Phase 3 trial (ClinicalTrials.gov, NCT03765918 ) evaluating KEYTRUDA as neoadjuvant treatment then followed by KEYTRUDA in combination with standard-of-care radiotherapy (with or without cisplatin) as adjuvant treatment and then as a maintenance therapy in treatment-naïve patients with newly diagnosed, stage III or IVA resected locally advanced, head and neck squamous cell carcinoma. Efficacy outcomes are classified by PD-L1 CPS status. The primary endpoint is EFS, and secondary endpoints include OS, mPR, pathological complete response and safety. The study enrolled an estimated 704 patients who were randomized (1:1) to receive either: About head and neck cancer Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is cancer that has grown outside the original location, but has not yet spread to distant parts of the body. There are several factors that greatly increase the risk of developing head and neck cancer, including tobacco and alcohol use and human papillomavirus (HPV). It is estimated there were more than 891,500 new cases of head and neck cancer diagnosed and over 458,100 deaths from the disease in 2022 globally. In the U.S., it is estimated there will be more than 58,450 new cases of head and neck cancer diagnosed and more than 12,230 deaths from the disease in 2024. 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 studying KEYTRUDA in earlier disease states, with approximately 25 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. 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. 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: 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. 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: 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. 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. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 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. 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: 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. 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). 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 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. 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, 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. 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. 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 . SOURCE: Merck