Belzutifan

Five-year follow-up data from KEYNOTE-942 underscore the continued potential of intismeran autogene (mRNA-4157 or V940) in combination with KEYTRUDA ® (pembrolizumab) for patients with resected high-risk melanoma Results from the final analysis of KEYNOTE-522, evaluating KEYTRUDA in combination with chemotherapy, demonstrate continued survival benefit for patients with high-risk early-stage triple-negative breast cancer (TNBC) New data for sacituzumab tirumotecan (sac-TMT), an investigational TROP2‑directed antibody‑drug conjugate, add to ongoing research of novel treatment approaches for patients with non‑small cell lung cancer Data from ASCENT-04/KEYNOTE-D19, evaluating KEYTRUDA plus Trodelvy ® (sacituzumab govitecan-hziy) for patients with metastatic TNBC, will be featured in the official ASCO 2026 Press Program RAHWAY, N.J.--(BUSINESS WIRE)-- $MRK #MRK --Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced new research from more than 100 abstracts across over 25 types of cancer from the company’s comprehensive oncology portfolio and pipeline will be presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting (May 29-June 2). The data reinforce the long-term impact of KEYTRUDA ® (pembrolizumab), Merck’s anti-PD-1 therapy, and Merck’s rapidly advancing pipeline across multiple tumor types and stages of disease, highlighting the company’s leadership in oncology and commitment to advancing innovative oncology research. “During ASCO, we will present data that showcase the strong momentum in our oncology pipeline, including long-term data for intismeran autogene, our investigational individualized neoantigen therapy (INT),” said Dr. Marjorie Green, senior vice president and head of oncology global clinical development, Merck Research Laboratories. “We look forward to sharing new research for our oncology medicines and novel treatment approaches, such as our INT and antibody-drug conjugates, which may help address significant unmet medical needs for patients living with cancer.” Key data from Merck’s portfolio and pipeline to be presented: Five-year follow-up data from the Phase 2b KEYNOTE-942 trial evaluating intismeran autogene in combination with KEYTRUDA for patients with high-risk melanoma following complete resection (Abstract #9500, Oral abstract session: Melanoma/skin cancers). 1 Final analysis results from the Phase 3 KEYNOTE-522 trial evaluating KEYTRUDA in combination with chemotherapy as pre-operative treatment and then continuing as a single agent after surgery for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) (Abstract #507, Oral abstract session: Breast cancer – local/regional/adjuvant). Data from the Phase 3 OptiTROP-Lung05 trial conducted in China, led by Kelun-Biotech, evaluating sac-TMT plus KEYTRUDA in advanced non-small cell lung cancer (Abstract #8506, Oral abstract session: Lung cancer – non-small cell metastatic). 2 Progression-free survival data from the Phase 3 ASCENT-04/KEYNOTE-D19 study evaluating KEYTRUDA plus Trodelvy (sacituzumab govitecan-hziy) in previously untreated PD-L1-positive metastatic TNBC ​​(Abstract #LBA1000, Oral abstract session: Breast cancer – metastatic).​ 3 Merck investor event Merck will hold an Oncology Investor Event to coincide with the 2026 ASCO Annual Meeting on Monday, June 1, 2026, 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 . All participants may join the call by dialing (800) 369-2154 (U.S. and Canada Toll-Free) or (517) 308-9422 and using the access code 8711041. Details on abstracts listed above and additional key abstracts for Merck Breast cancer Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: Final analysis results from the Phase 3 KEYNOTE-522 study. P. Schmid. Abstract #507, Oral abstract session: Breast cancer – local/regional/adjuvant Progression-free survival after next line of treatment (PFS2) and subsequent therapies (subs tx) in the ASCENT-04 study of participants (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC) treated with sacituzumab govitecan (SG) plus pembrolizumab (pembro) vs chemotherapy (chemo) plus pembro. K. Kalinsky.​ 3 Abstract #LBA1000, Oral abstract session: Breast cancer – metastatic Gastrointestinal cancers KEYNOTE-811: 6-year median follow-up of pembrolizumab plus trastuzumab and chemotherapy for previously untreated advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma. A. Kawazoe. Abstract #4040, Poster session: Gastrointestinal cancer – gastroesophageal, pancreatic and hepatobiliary Genitourinary cancers Enfortumab vedotin plus pembrolizumab (EV+P) vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): 3.5-year follow-up and response analyses from the Phase 3 EV-302 study. T. Powles. 4 Abstract #4507, Oral abstract session: Genitourinary cancer – kidney and bladder Extended follow up (6-years) of the Phase 2 LITESPARK-004 study of belzutifan in participants with von Hippel-Lindau disease-associated neoplasms. R. Srinivasan. Abstract #4550, Poster session: Genitourinary cancer – kidney and bladder Health-related quality of life (HRQoL) with neoadjuvant and adjuvant (neoadj-adj) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin ineligible: Phase 3 KEYNOTE-905 study. P. O’Donnell. 4 Abstract #4510, Clinical science symposium: New approaches to curing bladder and kidney cancer Health-related quality of life (HRQoL) with pembrolizumab or observation for high-risk muscle-invasive urothelial carcinoma after surgery: Results from the AMBASSADOR randomized trial (Alliance A031501). R. Chen.​ 5 Abstract #4513, Oral abstract session: Genitourinary cancer – kidney and bladder Belzutifan in docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): Phase 1b/2 KEYNOTE-365 cohort J. J. Arranz.​ Abstract #5058, Poster session: Genitourinary cancer – prostate, testicular and penile Gynecologic cancers Updated overall survival analysis and examination of subsequent therapy in endometrial cancer (EC) patients (pts) treated with pembrolizumab plus carboplatin/paclitaxel (CP) as compared to CP plus placebo (PBO) in the NRG-GY018 trial. R. Eskander. 6 Abstract #5502, Oral abstract session: Gynecologic cancer Exposure-response (E-R) analyses of efficacy and safety with raludotatug deruxtecan (R-DXd), a CDH6-directed antibody-drug conjugate (ADC), to inform dose selection for Phase (Ph) 3 development in platinum-resistant ovarian cancer (PROC). F. Hurtado. 7 Abstract #5570, Poster session: Gynecologic cancer Lung cancer Sacituzumab tirumotecan (sac-TMT) plus pembrolizumab (P) versus pembrolizumab(P) as first-line treatment for PD-L1-positive advanced non-small cell lung cancer (NSCLC): Results from the randomized Phase 3 OptiTROP-Lung05 study. C. Zhou.​ 2 Abstract #8506, Oral abstract session: Lung cancer – non-small cell metastatic Melanoma Individualized neoantigen therapy intismeran autogene (intismeran) plus pembrolizumab (pembro) in resected melanoma: 5-year update of the KEYNOTE-942 study. M. Carlino.​ 1 Abstract #9500, Oral abstract session: Melanoma/skin cancers Biomarkers Development and evaluation of a novel digital pathology image analysis pipeline for prediction of clinical outcomes with the TROP2-directed antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) in triple-negative breast cancer (TNBC). S. Tolaney.​ Abstract #1026, Poster session: Breast cancer – metastatic 1 In collaboration with Moderna 2 Led by Kelun-Biotech, conducted in China 3 In collaboration with Gilead. Trodelvy is a registered trademark of Gilead Sciences, Inc., or its related companies. 4 In collaboration with Astellas/Pfizer 5 Sponsored by U.S. National Cancer Institute (NCI)/led by Alliance for Clinical Trials in Oncology 6 Sponsored by U.S. National Cancer Institute (NCI)/led by NRG Oncology 7 In collaboration with Daiichi Sankyo About intismeran autogene (mRNA-4157 or V940) Intismeran autogene is a novel investigational messenger RNA (mRNA)-based individualized neoantigen therapy (INT) consisting of a synthetic mRNA coding for up to 34 neoantigens that is designed and produced based on the unique mutational signature of the DNA sequence of the patient’s tumor. Upon administration into the body, the algorithmically derived and RNA-encoded neoantigen sequences are endogenously translated and undergo natural cellular antigen processing and presentation, a key step in adaptive immunity. Individualized neoantigen therapies are designed to train and activate an antitumor immune response by generating specific T-cell responses based on the unique mutational signature of a patient’s tumor. About sacituzumab tirumotecan (sac-TMT) Sac-TMT is an investigational TROP2-directed ADC with a belotecan-derived topoisomerase I inhibitor payload and a bifunctional linker designed with the potential to maximize payload delivery to tumor cells and minimize payload loss while circulating in the body. Sac-TMT is the only TROP2 ADC designed with a focus on both ends of the linker. TROP2 is overexpressed on tumor cells compared to healthy cells in many common cancers, and through the TroFuse clinical development program, Merck is evaluating sac-TMT in 17 ongoing global Phase 3 trials across multiple tumor types, the broadest range of disease and treatment settings compared to any TROP2-directed ADC to date. The TroFuse development program spans early‑to-late‑stage disease in more than nine disease areas and includes more than 15,000 patients worldwide. Numerous Phase 3 trials are exploring sac-TMT as monotherapy and in combination with immunotherapies, aiming to improve survival and quality of life for patients with advanced and earlier-stage cancers. About raludotatug deruxtecan (R-DXd) Raludotatug deruxtecan is an investigational, potential first-in-class CDH6 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, raludotatug deruxtecan is comprised of a humanized anti-CDH6 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. About KEYTRUDA ® (pembrolizumab) injection for intravenous use, 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 2,800 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-authorized 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-authorized 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. 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, in combination with enfortumab vedotin, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, is indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-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. 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-authorized 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 whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA-authorized 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 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-authorized test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative 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-authorized test. Ovarian Cancer KEYTRUDA, in combination with paclitaxel, with or without bevacizumab, is indicated for the treatment of adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test, and who have received one or two prior systemic treatment regimens. 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. Contacts Media Contacts: Julie Cunningham julie.cunningham@merck.com Justine Moore (347) 281-3754 Investor Contacts: Peter Dannenbaum (732) 594-1579 Steven Graziano (732) 594-1583 Read full story here

2026年美国癌症研究协会（AACR）年会上，“新药展望”专题会议重磅披露12款创新肿瘤治疗药物，涵盖小分子与大分子两大领域，其中4款靶向蛋白降解药物、1款大环药物的集中亮相，标志着抗癌药物研发正式迈入“复杂分子+创新机制”的新阶段。不同于传统化疗药物的“无差别杀伤”，此次首秀的新药均以精准靶向、低毒高效为核心，从靶向蛋白降解剂的技术突破，到双抗、ADC的结构革新，再到大环分子与高选择性小分子的赛道拓展，全方位展现了全球抗癌药物研发的前沿趋势。 降解剂不再“冷门”——从“不可成药”到“精准降解” 靶向蛋白降解剂（TPD）作为近年来生物医药领域的研发热点，历经数十年发展，已从最初的概念验证迈入临床爆发期，彻底摆脱“冷门技术”的标签，成为突破“不可成药”靶点的核心利器。其核心优势在于“降解而非抑制”的作用模式——通过招募细胞内泛素-蛋白酶体系统，特异性降解致病蛋白，而非单纯阻断蛋白活性，既能有效克服传统抑制剂易产生的耐药性，又能显著提升靶点选择性、降低脱靶毒性，为多种难治性肿瘤的治疗提供了新路径。 回顾TPD的发展历程，从2001年PROTAC（蛋白水解靶向嵌合体）概念首次提出，到2019年首款PROTAC药物进入临床试验，再到近年来分子胶降解剂的快速崛起，技术迭代不断突破。早期TPD面临生物利用度低、脱靶效应明显、给药剂量过高的困境，限制了其临床转化；而随着基于结构的药物设计、冷冻电镜技术的应用，以及降解机制的深入研究，新一代TPD药物在选择性、药代动力学特征上实现了质的提升，此次AACR首秀的4款降解剂，正是这一技术进步的集中体现。 NEO-811（Neomorph研发）作为一款口服、潜在“first-in-class”的CRBN介导分子胶降解剂，聚焦VHL缺失型透明细胞肾细胞癌这一难治性亚型，靶向HIF-1β/ARNT。该药物通过基于结构的药物设计开发，得到生化、细胞及冷冻电镜研究的充分支持，在临床前研究中展现出极高的靶点选择性，能够有效抑制HIF-2α蛋白调控的基因表达，包括编码细胞周期蛋白D和血管内皮生长因子（VEGF）的基因。值得关注的是，ARNT作为HIF-1α和HIF-2α的必需二聚化伙伴，NEO-811的降解策略有望同时克服HIF-2α抑制剂（如belzutifan和casdatifan）的耐药性，以及HIF-1α介导的耐药性，为VHL缺失型肾癌患者提供新的治疗选择。目前，NEO-811正在局部晚期或转移性不可切除透明细胞肾细胞癌患者中开展1/2期临床试验，初步数据值得期待。 TNG961（Tango Therapeutics研发）是另一款口服、潜在“first-in-class”的CRBN介导分子胶降解剂，靶向HBS1L，主要用于治疗FOCAD缺失型癌症——这类癌症属于染色体9p21缺失肿瘤中的一个亚群，临床治疗手段有限。体外研究显示，TNG961可诱导高度选择性、剂量依赖性的HBS1L降解，且相对于结构相近且常见的CRBN新底物GSPT1保持良好选择性，进而破坏PELO依赖性核糖体救援机制，实现对肿瘤细胞的精准杀伤。该化合物对FOCAD缺失细胞相较野生型细胞表现出约100倍的选择性，在FOCAD缺失型胰腺癌及非小细胞肺癌（NSCLC）异种移植模型中可有效诱导肿瘤退缩，目前正处于支持IND的临床前研究阶段，有望填补该类癌症的治疗空白。 TRI-611（Triana Biomedicines研发）则聚焦ALK阳性非小细胞肺癌，是一款可进入中枢神经系统（CNS）的CRBN介导ALK分子胶降解剂，核心优势在于克服酪氨酸激酶抑制剂（TKI）耐药。该药物可驱动ALK融合蛋白发生泛素化并被降解，尤其针对具有临床意义的TKI耐药变体，解决了传统TKI治疗中耐药性频发的痛点。在皮下及颅内ALK阳性非小细胞肺癌体内肿瘤模型中，TRI-611每日口服给药可有效诱导肿瘤退缩，同时展现出广泛的蛋白组选择性，能够避免降解NTRK1等密切相关激酶，在减少TKI常见脱靶毒性的同时，实现持续的中枢神经系统靶点覆盖——这一特点尤为重要，因为ALK阳性NSCLC患者常出现脑转移，而传统药物难以穿透血脑屏障。目前，TRI-611正在ALK阳性NSCLC患者中开展1/2期临床试验，为耐药患者带来新的希望。 AMX-883（Amphista Therapeutics研发）的突破在于打破了传统TPD对CRBN或VHL的依赖，是一款口服、可逆共价结合的DCAF16介导BRD9蛋白降解剂，主要用于治疗急性髓系白血病（AML）。该药物对BRD9具有强效且高度选择性的活性，相较其他溴结构域蛋白（包括BRD4）具有超过1000倍的选择性，有效避免了脱靶毒性。在AML临床前模型中，AMX-883可快速且持续诱导BRD9降解，进而带来髓系分化标志物的时间依赖性表达，降低体内骨髓及外周血中的白血病负荷；更值得关注的是，该药物在venetoclax耐药细胞中同样保持活性，可抑制MCL-1和BCL-2等耐药相关标志物表达，增加细胞死亡标志物表达，为venetoclax耐药的AML患者提供了新的治疗方向。Amphista计划于2026年下半年启动其在AML中的临床研究。 这4款降解剂的集中亮相，清晰展现了TPD技术的发展趋势：从依赖单一泛素化系统（CRBN/VHL）向多元化泛素化系统（DCAF16）拓展，从非选择性降解向高特异性降解升级，从实体瘤向血液肿瘤全面覆盖。TPD的崛起，不仅拓展了“可成药靶点”的边界——让原本难以通过传统抑制剂靶向的蛋白（如HIF-1β、HBS1L）成为治疗靶点，更通过“精准降解”的模式，实现了疗效与安全性的双重提升，推动抗癌治疗从“控制病情”向“精准治愈”迈进。从“单打独斗”到“组合进击”——双抗、ADC与T细胞接合器的协同革命 随着肿瘤免疫治疗与靶向治疗的深度融合，抗体类药物已从传统单克隆抗体的“单打独斗”，升级为双抗、ADC（抗体偶联药物）、T细胞衔接器等新型制剂的“组合进击”。此次AACR首秀的多款抗体类新药，通过双靶点结合、双载荷递送、组织选择性设计等创新策略，实现了“1+1>2”的治疗效果，既提升了肿瘤杀伤的精准度，又降低了治疗毒性，破解了传统抗体类药物的临床局限，推动抗体类药物进入协同治疗的新阶段。 新一代抗体类药物的核心突破，在于通过结构设计实现“精准靶向+高效杀伤”的协同，摆脱了传统药物“要么疗效不足、要么毒性过高”的困境：双抗通过同时结合肿瘤细胞表面两个靶点，提升肿瘤识别的特异性；ADC通过抗体将细胞毒性载荷精准递送至肿瘤细胞，减少对正常细胞的损伤；T细胞衔接器则通过连接肿瘤细胞与免疫细胞，激活机体自身免疫反应，实现对肿瘤细胞的特异性杀伤。此次首秀的4款关键药物，正是这一设计理念的典型代表。 AZD8359（阿斯利康研发）是一款靶向STEAP2的T细胞衔接器，聚焦前列腺癌治疗，其核心创新在于“CD8优先激活”的结构设计。STEAP2是一种高度特异性的前列腺相关表面抗原，在前列腺癌各阶段均呈高度表达，是前列腺癌靶向治疗的理想靶点。该药物采用阿斯利康的TITAN技术平台，通过“2+1”抗体结构设计，优先募集CD8阳性T细胞而非CD4阳性T细胞——CD8阳性T细胞是肿瘤杀伤的核心效应细胞，而CD4阳性T细胞的过度激活易引发细胞因子释放综合征，导致治疗毒性。临床前研究显示，AZD8359可产生强效的STEAP2依赖性杀伤作用，与传统T细胞衔接器相比，其在体外可将细胞因子释放降低约40%，在体内于相当疗效水平下可降低超过10倍，同时对CD8阳性T细胞的激活作用强于CD4阳性T细胞；在STEAP2阳性异种移植模型中，该药物可实现肿瘤完全消退，支持其于2026年启动临床试验，有望为前列腺癌患者提供更安全、更有效的免疫治疗方案。 EPI-326（EpiBiologics研发）是一款针对EGFR驱动型肿瘤的组织选择性双特异性抗体，通过EGFR × ITGB6双靶点结合，实现对肿瘤细胞的精准降解。该药物的核心机制的是通过结合整合素β6亚基（ITGB6），促进肿瘤中野生型及突变型EGFR的降解，借助溶酶体介导的蛋白降解机制发挥作用——这一设计突破了传统EGFR抑制剂仅针对特定突变类型的局限，有望将EGFR靶向治疗的适用范围拓展至特定突变类型之外，覆盖更多EGFR驱动型肿瘤患者。临床前研究显示，EPI-326具有强效且持久的抗肿瘤活性，同时展现出良好的安全性及药代动力学（PK）特征，支持其作为单药治疗及联合治疗方案的潜力；目前，该药物正在EGFR突变型非小细胞肺癌及头颈部鳞状细胞癌（HNSCC）患者中开展1期临床试验，初步数据有望打破EGFR治疗的人群限制。 CD30dpADC（阿斯利康研发）则开启了ADC“双载荷”的新时代，是一款针对经典霍奇金淋巴瘤的双载荷抗CD30抗体偶联药物。该药物的核心创新在于将两种不同作用机制的细胞毒性载荷（经过验证的微管抑制剂MMAE和一款专有Top1抑制剂），通过新型非天然氨基酸偶联平台递送至同一肿瘤细胞，实现“协同杀伤”，同时克服单一载荷的耐药性。临床前研究显示，该ADC在CD30阳性淋巴瘤模型中表现出强大的抗肿瘤活性，在霍奇金淋巴瘤模型中可显著抑制肿瘤生长，在低剂量下可使间变性大细胞淋巴瘤模型中的肿瘤完全消退；尤为重要的是，在MMAE耐药模型中，该药物仍保持疗效，提示其在克服ADC耐药性方面具有潜在优势，有望成为经典霍奇金淋巴瘤无化疗或低化疗负担的治疗新选择。目前，该项目的先导药物预计将在不久的将来首次披露，有望推动ADC领域从“单一载荷”向“双载荷协同”转型。 JNJ-89862175（强生研发）是一款靶向ENPP3的ADC，主要用于治疗晚期实体瘤，其核心价值在于拓展了ADC的靶点边界。ENPP3作为一种肿瘤相关抗原，此前未被广泛应用于ADC靶点开发，该药物的研发凸显了ENPP3作为肿瘤靶向递送靶点的潜力，标志着ADC开发正从传统成熟表面靶点（如HER2、CD20）向新型靶点拓展。该ADC采用具有环境依赖性通透性的auristatin F载荷，可有效限制旁观者效应，减少对正常细胞的损伤；同时使用分支连接子设计，使其具备均一的高药物抗体比（DAR），提升了药物的杀伤效率。目前，JNJ-89862175正在开展1期临床试验，为晚期实体瘤患者提供新的治疗方向。 这4款抗体类新药的研发逻辑，本质上是对“联合治疗与耐药机制”博弈的精准回应——传统单一靶点抗体易引发肿瘤耐药，而双靶点、双载荷、组织选择性的设计，可通过多机制协同杀伤肿瘤细胞，延缓耐药发生。从“单打独斗”到“组合进击”，抗体类药物的进化，不仅提升了临床疗效，更拓宽了治疗范围，为不同类型、不同阶段的肿瘤患者提供了个性化治疗选择，推动抗癌治疗进入“精准协同”的新时代。不止于“小”——大环分子与CDK2抑制剂开辟新赛道 长期以来，小分子药物以“结构简单、口服便捷、成本较低”为核心优势，但也面临靶点选择性不足、易产生耐药性等局限。此次AACR首秀的小分子药物，打破了传统小分子“简单化”的研发思路，呈现出“回归复杂度与功能性”的趋势，其中大环分子与高选择性CDK抑制剂成为两大核心方向，凭借独特的结构优势与作用机制，开辟了小分子抗癌药物的新赛道，为难治性肿瘤的治疗提供了新的技术路径。 大环分子作为小分子药物的重要分支，其核心优势在于“结构灵活、靶向精准”——大环结构可通过构象调整，与靶点形成更紧密的结合，同时减少与体内其他蛋白的非特异性结合，在提升靶点选择性的同时，兼顾口服生物利用度，解决了传统小分子“选择性与生物利用度难以平衡”的痛点。而高选择性CDK抑制剂则针对传统CDK抑制剂“广谱抑制、毒性较高”的局限，通过精准靶向特定CDK亚型（如CDK2），在提升疗效的同时，降低对正常细胞的损伤，尤其在HR+/HER2−乳腺癌、CCNE1扩增肿瘤等领域展现出巨大潜力。此次首秀的CID-078与ECI830，分别代表了这两大方向的最新进展。 CID-078（Circle Pharma研发）是一款可口服的大环化合物，主要用于治疗晚期实体瘤，其核心作用机制是同时结合细胞周期蛋白A和细胞周期蛋白B的RxL结构域，抑制其与多个细胞周期复合体组分的相互作用，进而导致细胞周期阻滞及肿瘤细胞凋亡。该药物的优势在于大环结构带来的高选择性与良好的口服生物利用度——临床前研究显示，CID-078单药治疗可在多个E2F高表达模型中诱导肿瘤退缩，包括小细胞肺癌和三阴性乳腺癌模型，这两类肿瘤均属于难治性实体瘤，临床治疗手段有限；同时，该药物表现出良好的体内安全性特征，预测其人体口服生物利用度约为20%，满足口服给药的临床需求，为晚期实体瘤患者提供了便捷、安全的治疗选择。目前，CID-078已进入1期临床试验，初步数据有望验证其临床价值。 ECI830（诺华研发）是一款高效、高选择性的口服CDK2抑制剂，聚焦HR+/HER2−乳腺癌及CCNE1扩增肿瘤的治疗，其核心突破在于“高选择性靶向CDK2”，并与CDK4/6抑制剂展现出显著的协同效应。传统CDK抑制剂多为广谱抑制剂，同时抑制CDK1、CDK2、CDK4/6等多个亚型，易引发骨髓抑制、胃肠道反应等毒性；而ECI830具有高度的CDK2选择性，可精准抑制CDK2活性，包括抑制pRB1，在针对HR+/HER2−乳腺癌及CCNE1扩增肿瘤的治疗中，展现出独特的优势。临床前研究显示，ECI830与CDK4/6抑制剂ribociclib联用时，其对细胞周期通路的抑制更深，较任一单药治疗表现出更强的肿瘤生长抑制作用；在异种移植模型及患者来源模型中，ECI830与ribociclib和/或内分泌治疗联用，展现出显著的抗肿瘤效果；同时，该药物在CCNE1扩增模型中也显示出单药活性，有望解决CCNE1扩增肿瘤对传统治疗耐药的问题。目前，ECI830正在晚期HR+/HER2−乳腺癌及其他晚期实体瘤患者中开展1/2期临床试验，评估其单药及联合治疗方案，有望为这类患者提供新的治疗策略。 大环分子与高选择性CDK抑制剂的崛起，反映了小分子药物研发的核心趋势：不再追求“结构简单”，而是通过结构优化与机制创新，实现“选择性、生物利用度、疗效”的三重提升。对于大环分子而言，如何进一步提升口服生物利用度、降低合成难度，是未来研发的关键；而对于高选择性CDK抑制剂，如何通过联合治疗策略，进一步延缓肿瘤耐药、扩大治疗人群，将成为临床研究的重点。这两大赛道的开辟，不仅丰富了小分子抗癌药物的研发方向，更填补了部分难治性肿瘤的治疗空白，与降解剂、抗体类药物形成互补，构建起“多机制、多靶点”的抗癌治疗体系。 最后 2026年AACR年会12款抗癌新药的首秀，不仅展现了全球抗癌药物研发的前沿水平，更勾勒出抗癌治疗的未来趋势——靶向蛋白降解剂打破“不可成药”壁垒，抗体类药物实现“协同杀伤”升级，小分子药物走向“复杂精准”，三大领域齐头并进，推动抗癌治疗从“控制病情”向“精准治愈”跨越。 信息来源：公开资料整理 立即扫码加入药事纵横交流群