A Phase III, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Patients With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer

The purpose of this study is to evaluate the efficacy and safety of divarasib and pembrolizumab compared with pembrolizumab and pemetrexed and carboplatin or cisplatin, for the first-line treatment of adult participants with KRAS G12C-mutated, advanced or metastatic non squamous non-small cell lung cancer (NSCLC).

开始日期2025-05-01

申办/合作机构

Chugai Pharmaceutical Co., Ltd.

NCT06835465

/ Active, not recruiting临床1期

A Phase 1, Open-Label, Single-Dose, Two-Period, Fixed Sequence, Crossover Study to Determine the Effect of Rifampin on the Pharmacokinetics of Divarasib in Healthy Subjects

This is a phase 1, open-label, two-period, fixed sequence drug-drug interaction study to evaluate the impact of multiple doses of rifampin on the pharmacokinetics (PK) and safety of divarasib in healthy participants.

开始日期2025-02-21

申办/合作机构

Genentech, Inc.

NCT06734208

/ Recruiting临床1期

A Phase 1, Open-Label, Single-Dose, Parallel-Cohort Study to Evaluate the Pharmacokinetics of Divarasib in Subjects With Impaired Hepatic Function

This is a phase 1, open-label, single-dose, parallel-cohort study to determine the pharmacokinetics (PK) of divarasib in healthy participants and participants with varying degrees of hepatic impairment, as defined by Child-Pugh classification.

开始日期2025-01-31

申办/合作机构

Genentech, Inc.

100 项与 Divarasib 相关的临床结果

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100 项与 Divarasib 相关的转化医学

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100 项与 Divarasib 相关的专利（医药）

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项与 Divarasib 相关的文献（医药）

2025-02-01·DRUG METABOLISM AND DISPOSITION

In vitro metabolism of targeted covalent inhibitors and their thiol conjugates by gut microbiome from rats, mice, and humans

Article

作者: Torres, Elizabeth ; Zhang, Donglu ; Auster, Alexis ; Cai, Jingwei ; Khojasteh, S Cyrus ; Wang, Shuai ; Gu, Ting-Jia

Targeted covalent inhibitor (TCI) represents a noncanonical class of small molecules that function via "inactivating" the target protein through the formation of drug-protein adducts. The electrophilic groups (warheads) embedded in the TCIs are essential for their activity while also being recognized as sites susceptible to metabolism by various enzymes and endogenous nucleophiles. Given the growing knowledge of gut microbiome-mediated drug metabolism and its impact on drug absorption, distribution, metabolism, and excretion, the fate of the reactive warhead-containing TCIs in the gut warrants further understanding. In this study, we selected unsubstituted terminal acrylamides (ibrutinib, sotorasib, and divarasib), β-substituted acrylamides (afatinib, neratinib, and dacomitinib), an α-substituted acrylamide (adagrasib), an alkynamide (acalabrutinib), and a salicylaldehyde (voxelotor) to investigate. An anaerobic in vitro approach was utilized using both fecal slurry and feces-outgrown bacteria from rats, mice, and humans. The results showed that double bond reduction was the major metabolism captured for terminal acrylamides, but the activity decreases significantly when α or β substitutions are present; acalabrutinib was stable; and voxelotor was efficiently reduced to a benzyl alcohol metabolite. Synthesized TCI-GSH adducts can be efficiently hydrolyzed sequentially to cysteine adducts, which are rather stable from further microbiome modifications. There were no apparent species differences between rats, mice, and humans qualitatively, while the reductase activity observed was generally higher in the human gut microbiome. This study provides insights into both enzymatic and nonenzymatic reactions of TCIs and their thiol conjugates in the gut environment, which can be translated to the understanding of their absorption, distribution, metabolism, and excretion behavior during drug development. SIGNIFICANCE STATEMENT: Understanding the gut microbiome metabolism of targeted covalent inhibitors and their thiol conjugates will help interpret absorption, distribution, metabolism, and excretion studies for new targeted covalent inhibitors in delineating that from human metabolism, predicting clearance pathways, and assessing the impact on absorption/reabsorption. The species difference information can inform proper preclinical species for better human translation in overall drug behavior. The experimental conditions developed from this work can also be adapted to study gut microbiome metabolism in general across different species.

2025-02-01·ANNALS OF ONCOLOGY

Genomic landscape of clinically acquired resistance alterations in patients treated with KRASG12C inhibitors

Article

作者: Kim, J E ; Fece de la Cruz, F ; Kushner, E W ; Corcoran, R B ; Gainor, J F ; Parikh, A R ; Morales-Giron, A A ; Ehnstrom, S ; Klempner, S J ; Nakamura, H ; Pappas, L ; Norden, B L ; Lin, J J ; Heist, R S ; Matsubara, H ; Riedl, J M ; Kopetz, S ; Parseghian, C ; Ellis, H ; Vakaris, A ; Caughey, B ; Patel, P S ; Hata, A N ; Barnes, H

BACKGROUND:

Mutant-selective inhibitors of KRAS^G12C (KRAS^G12Ci) have demonstrated efficacy in KRAS^G12C cancers. However, resistance invariably develops, resulting in short-lived responses. We aimed to define the genomic landscape of acquired resistance to KRAS^G12Ci and to elucidate whether novel classes of KRAS inhibitors can overcome these resistance mechanisms.

METHODS:

To assess clinical frequencies of acquired resistance alterations, we evaluated genomic sequencing data from postprogression cell-free DNA samples in patients treated with KRAS^G12Ci at two United States cancer centers, alongside data from six previously published studies. Cell viability assays using engineered cell models were employed to functionally validate candidate resistance drivers and to evaluate novel classes of KRAS inhibitors.

RESULTS:

A total of 143 patients were analyzed. Most patients had non-small-cell lung cancer (NSCLC, n = 68) or colorectal cancer (CRC, n = 58) and were treated with single-agent KRAS^G12Ci (n = 109) or combined with anti-EGFR antibodies (n = 30). RAS/MAPK alterations emerged in 46% of patients (n = 66), with 39% developing one or more new KRAS alterations (n = 56) and 23% (n = 33) showing multiple concurrent alterations. The genomic landscape of acquired alterations included KRAS-activating mutations (25% of patients), KRAS amplifications (22%), RAF/MAPK mutations/fusions (21%), KRAS switch-II pocket mutations (14%), and NRAS/HRAS mutations (8%). Notably, the proportion of patients with one or more acquired RAS/MAPK alteration was significantly higher in CRC compared with NSCLC (69% versus 26%, P < 0.001). Functional studies confirmed most alterations as resistance drivers. Sotorasib, adagrasib, and divarasib demonstrated distinct activity against KRAS switch-II pocket mutations, yet all were responsive to the RAS(ON) G12C-selective tri-complex inhibitor RM-018. The KRAS-selective inhibitor Pan KRAS-IN-1 effectively targeted KRAS-activating mutations, and the RAS(ON) multiselective tri-complex inhibitor RMC-7797 demonstrated high potency across all RAS alterations.

CONCLUSIONS:

Acquired RAS/MAPK alterations are recurrent drivers of resistance to KRAS^G12Ci detected in CRC and, less frequently, in NSCLC. Preclinical data suggest that novel (K)RAS inhibitors may overcome many of these resistance alterations.

2024-11-25·Future Oncology

An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer

Review

作者: Ceylan, Furkan ; Nahit Sendur, Mehmet Ali ; Unal, Ahmet Arda ; Tenekeci, Ates Kutay

The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5 June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.

项与 Divarasib 相关的新闻（医药）

2025-03-30

·ioncology

ELCC重磅进展丨靶向KRAS G12C治疗NSCLC：一线联合疗法的获益-风险平衡仍具挑战性

点上方蓝字“ioncology”关注我们，然后点右上角“…”菜单，选择“设为星标”ELCC 2025 微专辑扫描二维码可查看更多内容2025年欧洲肺癌大会（ELCC）（3月26-29日，巴黎）公布的研究为携带KRAS G12C突变的非小细胞肺癌（NSCLC）患者治疗提供了新见解。该突变约占晚期非鳞状NSCLC病例的10%-13%（Lung Cancer. 2023;184:107293）。研究评估了adagrasib和氟泽雷塞在内的潜力药物的疗效与安全性。 II期KRYSTAL-7试验更新数据根据II期KRYSTAL-7试验更新数据，adagrasib联合帕博利珠单抗在54例PD-L1≥50%的晚期/转移性KRAS G12C突变NSCLC患者一线治疗中继续显示出鼓舞人心的疗效（摘要号5MO）。客观缓解率（ORR）为59%，中位缓解持续时间（DOR）达26.3个月。中位随访超过22个月时，中位无进展生存期（PFS）为27.7个月，18个月总生存（OS）率为62%。图1：KRYSTAL-7试验中adagrasib联合帕博利珠单抗在晚期/转移性KRAS G12C突变NSCLC中的生存获益（摘要号5MO）"与标准治疗帕博利珠单抗单药（基于KEYNOTE-024试验，其中位PFS约为10个月）相比，adagrasib的加入显著延长了PFS（N Engl J Med. 2016;375:1823–1833）"，荷兰癌症研究所的Adrianus Johannes De Langen博士表示。但他同时指出该联合方案存在较高毒性发生率：在KRYSTAL-7试验所有149例患者（无论PD-L1表达水平）中，68%的患者报告≥3级治疗相关不良事件（TRAEs）。3例患者出现5级TRAEs：肺炎（2例）和间质性肺病（1例）。7%的患者仅停用adagrasib，17%仅停用帕博利珠单抗，7%同时停用两种药物。De Langen评论道："adagrasib联合帕博利珠单抗的≥3级TRAEs发生率（68%）显著高于KEYNOTE-024试验中帕博利珠单抗单药的27%。这种高毒性可能意味着该方案仅适用于体能状态最佳的患者。"目前该方案正在进入III期试验阶段，将在KRAS G12C突变且PD-L1≥50%的NSCLC患者中比较adagrasib+帕博利珠单抗与帕博利珠单抗单药的疗效（NCT04613596）。 II期KROCUS试验的更新数据 2025 ELCC会议上还公布了II期KROCUS试验的更新数据，该研究在47例初治晚期KRAS G12C突变NSCLC患者中评估氟泽雷塞联合西妥昔单抗的疗效（摘要LBA1）。ORR达80%，58%患者肿瘤缩小≥50%。中位PFS为12.5个月，中位随访12.8个月时中位DOR尚未达到。不同PD-L1表达水平患者的缓解率一致。安全性方面，14.9%患者报告3级TRAEs（最常见皮疹和乏力各2%），无4/5级TRAEs。6.4%患者因TRAEs停药。研究者指出，计划在PD-L1<50%的初治KRAS G12C突变NSCLC患者中开展氟泽雷塞+西妥昔单抗对比帕博利珠单抗+化疗的III期试验。图2：KROCUS试验中氟泽雷塞联合西妥昔单抗在初治晚期KRAS G12C突变NSCLC患者中缓解持续时间和无进展生存（摘要LBA1）De Langen指出："虽然不同PD-L1水平的短期ORR和安全性数据良好，但这是首次公布氟泽雷塞联合西妥昔单抗的PFS数据。与adagrasib联合帕博利珠单抗方案相比，其持续缓解时间似乎有限。"他认为在氟泽雷塞+西妥昔单抗基础上加入免疫治疗可能有助于改善长期疗效。 De Langen总结强调："KRAS G12C突变NSCLC治疗是当前研究极为密集的领域，患者的治疗格局有望在近期快速演进。"目前有多项一线III期联合治疗方案试验正在进行，包括使用新型KRAS G12C抑制剂如olomorasib（NCT06119581）、divarasib（NCT06793215）和MK-1084（NCT06345729）的研究。 RAS（ON）抑制剂daraxonrasib ELCC 2025还报告了口服RAS（ON）多选择性三重复合抑制剂daraxonrasib（RMC-6236）的数据：daraxonrasib在经治局部晚期或转移性RAS突变NSCLC患者中获得阳性数据（摘要号6MO）。这项I/Ib期多中心开放标签研究显示，ORR为38%，中位DOR达15.5个月，中位PFS为9.8个月，中位OS为17.7个月。41%患者需调整剂量，4%停药，7%患者出现3级皮疹（唯一发生率≥5%的3级TRAE），无4/5级TRAEs。图3：daraxonrasib在经治局部晚期或转移性RAS突变NSCLC患者中的疗效（摘要6MO）参考文献：1. Garassino MC, et al. First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC) and PD-L1 ≥50% from the phase II portion of KRYSTAL-7. European Lung Cancer Congress 2025, Abstract 5MO2. Majem Tarruella M, et al. First-line (1L) fulzerasib + cetuximab in KRAS G12Cm advanced NSCLC: updated efficacy and safety from KROCUS study. European Lung Cancer Congress 2025, Abstract LBA13. Punekar S, et al. Safety and clinical activity of daraxonrasib (RMC-6236) in RAS mutant non-small cell lung cancer (NSCLC). European Lung Cancer Congress 2025, Abstract 6MO《肿瘤瞭望》在ELCC现场报道（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

临床3期临床2期临床结果

2025-03-06

·PRNewswire

TEPMETKO Continues to Strengthens its Position as a Leading METex14 Skipping NSCLC Therapy | DelveInsight

With increasing biomarker-driven cancer treatments, TEPMETKO benefits from growing adoption in precision oncology. Competition from other MET inhibitors like TABRECTA (capmatinib) exists, but TEPMETKO's once-daily dosing and efficacy profile offer differentiation. LAS VEGAS, March 6, 2025 /PRNewswire/ -- DelveInsight's " TEPMETKO Market Size, Forecast, and Market Insight Report" highlights the details around TEPMETKO, a kinase inhibitor indicated for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations. The report provides product descriptions, patent details, and competitor products (marketed and emerging therapies) of TEPMETKO. The report also highlights the historical and forecasted sales from 2020 to 2034 segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. EMD Serono's TEPMETKO (tepotinib) Overview TEPMETKO is a kinase inhibitor prescribed for adult patients with metastatic non-small cell lung cancer (NSCLC) carrying MET exon 14 skipping alterations. The active component is Tepotinib (as hydrochloride monohydrate), administered orally. Patients should be cautioned about the heightened risk of severe or fatal interstitial lung disease/pneumonitis, liver toxicity, and potential embryo-fetal toxicity, necessitating effective contraception during and shortly after treatment. Tepotinib specifically targets MET, including variants with exon 14 skipping mutations. It blocks HGF-dependent and independent MET phosphorylation, disrupting MET-driven signaling pathways. Additionally, at clinically relevant concentrations, Tepotinib inhibits melatonin 2 and imidazoline 1 receptors. In vitro studies show that it suppresses tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent cancer cells. In mouse models with MET-driven tumors, including those with MET exon 14 skipping alterations, Tepotinib reduced tumor growth, sustained MET phosphorylation inhibition, and, in one case, decreased metastasis formation. The recommended dose of TEPMETKO is 450 mg taken orally once daily until disease progression or intolerable toxicity occurs. Patients should take it at the same time each day, swallowing tablets whole without chewing, crushing, or splitting them. If a dose is missed and less than eight hours remain until the next scheduled dose, patients should skip it. In cases of vomiting after taking TEPMETKO, the next dose should be taken at the usual time. Learn more about TEPMETKO projected market size for NSCLC @ TEPMETKO Market Potential Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 81% of all diagnosed cases. Early detection greatly improves outcomes, but diagnosing NSCLC and other lung cancers is challenging because their symptoms are often mistaken for common illnesses or the long-term effects of smoking. Consequently, 80% of NSCLC cases are already at advanced stages by the time they are identified, making treatment more difficult. Around 80% of EGFR mutations in NSCLC involve either exon 19 deletions or the exon 21 L858R substitution, both of which are classified as sensitizing mutations. Until the last decade, chemotherapy was the primary treatment for advanced and metastatic lung cancer. However, this changed in 2015 with the approval of the first immune checkpoint inhibitor (ICI), KEYTRUDA (pembrolizumab), as a second-line therapy for advanced cases. This was followed by TECENTRIQ (atezolizumab) in 2016. Both therapies were later approved for first-line treatment, broadening their use to a larger patient population. In 2020, the combination of OPDIVO (nivolumab) and ipilimumab also received approval as a first-line treatment for metastatic NSCLC. According to DelveInsight, the NSCLC market size across the 7MM is projected to grow from USD 30 billion in 2024, with a substantial CAGR through 2034. This growth is largely driven by the introduction of emerging therapies during the forecast period (2025–2034). Discover more about the NSCLC market in detail @ Non-small Cell Lung Cancer Market Report Emerging Competitors of TEPMETKO The NSCLC pipeline is very robust with the promising therapies such as Telisotuzumab vedotin (AbbVie), Patritumab deruxtecan (Daiichi Sankyo/AstraZeneca), Datopotamab deruxtecan (Daiichi Sankyo/AstraZeneca), Eftilagimod alpha (Immutep), BNT311/GEN1046 (acasunlimab) (Genmab), V940 (mRNA-4157) + Pembrolizumab (Moderna Therapeutics/Merck), Plinabulin + Docetaxel (BeyondSpring), Olomorasib (LY3537982) (Eli Lilly and Company), Zipalertinib (Cullinan Oncology/Taiho Pharma), Ceralasertib (AZD6738) (AstraZeneca), TEDOPI (EP-2101; IDM 2101; OSE-2101) (OSE Immuno-therapeutics), Sigvotatug vedotin (PF08046047) (Pfizer), ANKTIVA (N-803) (ImmunityBio), Aumolertinib/Almonertinib/HS-10206 (Jiangsu Hansoh Pharmaceutical), Niraparib (GSK), Savolitinib (AstraZeneca/Hutchison MediPharma), TRODELVY (Gilead Sciences), Pyrotinib (Jiangsu HengRui Medicine), Ociperlimab (BGB-A1217) (BieGene), Volrustomig (AstraZeneca), Gotistobart (BNT316/ONC-392) (OncoC4/BioNTech), Ivonescimab (AK112/SMT112) (Akeso Biopharma/Summit Therapeutics), ZYNYZ (retifanlimab/INCMGA00012) (Incyte/Macrogenics), Divarasib (GDC-6036) (Roche/Genentech), Tiragolumab (RG6058) (Roche), Sacituzumab Tirumotecan (Merck and Kelun-Biotech), JEMPERLI (dostarlimab/TSR-042) (GSK and AnaptysBio), Zongertinib (BI-1810631) (Boehringer Ingelheim), BAY 2927088 (Bayer), Serplulimab (HLX10) (Shanghai Henlius Biotech), Rilvegostomig (AZD2936) (AstraZeneca), MK-1084 (Merck, Taiho Pharmaceutical, and Astex), Domvanalimab (Arcus Biosciences and Gilead Sciences), OPDUALAG (nivolumab and relatlimab) (Bristol-Myers Squibb), Belrestotug + JEMPERLI (iTeos Therapeutics and GSK), Firmonertinib (ArriVent BioPharma), Sunvozertinib (DZD9008) (Dizal Pharmaceutical), Cobolimab (GSK), Livmoniplimab (AbbVie), Fianlimab (REGN3767) (Regeneron Pharmaceuticals), BNT327/PM8002 (Biotheus/BioNTech), HS-20117 (Hansoh BioMedical), IO102-IO103 + Pembrolizumab (IO Biotech), Naptumomab estafenatox (NeoTX Therapeutics/Active Biotech), FF-10832 (FUJIFILM Corporation), BNT116 (BioNTechSE/Regeneron Pharmaceuticals), CAN-2409 (Candel Therapeutics), Mecbotamab Vedotin (BA3011/CAB-AXL-ADC) (BioAtla), Bemcentinib (BGB 324/BGB-3234/R-428) (BerGenBio/Rigel Pharmaceuticals), DOVBLERON (taletrectinib/AB-106/IBI-344) (Nuvation Bio/Innovent Biologics/Daiichi Sankyo/Nippon Kayaku), Lifileucel (Iovance Biotherapeutics), IBI363 (Innovent Biologics), Sotevtamab (AB-16B5) (Alethia Biotherapeutics), Avutometinib (VS6766) (Verastem Oncology), Vebreltinib (APL-101) (Apollomics), LP-300 (Lantern Pharma), JNJ-90301900 (Johnson & Johnson Innovative Medicine), AMG 193 (Amgen), Luveltamab tazevibulin (Sutro Biopharma), PRT3789 (Prelude Therapeutics), Disitamab vedotin (Seagen), PADCEV (enfortumab vedotin) (Astellas Pharma), RP1 (Replimune), TIVDAK (tisotumab vedotin) (Seagen), Zanidatamab (Jazz Pharmaceuticals), Utidelone injectable (UTD1) (Beijing Biostar Pharmaceuticals), REGN5093-M114 (Regeneron Pharmaceuticals), SLC-391 (SignalChem Lifesciences), fulzerasib (GenFleet), Davutamig (REGN5093) (Regeneron Pharmaceuticals), TAS3351 (Taiho Oncology), H002 (RedCloud Bio), JIN-A02 (J INTS BIO), FWD1509 (Forward Pharma), Sabestomig (AZD7789) (AstraZeneca), Sasanlimab (Pfizer), Selvigaltin (GB1211) (Galecto Biotech), Vepafestinib Helsinn (Healthcare/Taiho Pharmaceutical), EP0031 (A400/ KL590586) (Ellipses Pharma/Kelun-Biotech), Pamvatamig (MCLA-129) (Merus), Zidesamtinib (NVL-520) (Nuvalent), NVL-655 (Nuvalent), RMC-4630 (Revolution Medicines), REQORSA (quaratusugene ozeplasmid) (Genprex), PDC*lung01 (PDC*line Pharma), Evalstotug (BA3071) (BioAtla and BeiGene), PT-112 (Promontory Therapeutics), MRT-2359 (Monte Rosa Therapeutics), GAIA-102 (GAIA BioMedicine), Rigosertib (Traws Pharma), HMBD-001 (Hummingbird Bioscience), PLB1004 (Avistone Biotechnology), ANS03 (Avistone Biotechnology), MYTX-011 (Mythic Therapeutics), A166 (Sichuan Kelun-Biotech Bio-pharmaceutical), Atamparib (BN-2397) (Ribon Therapeutics), DELTACEL (KB-GDT-01) (Kiromic BioPharma), Carotuximab (ENV-105) (Kairos Pharma), YL202 (MediLink Therapeutics), and others. To know more about the number of competing drugs in development, visit @ TEPMETKO Market Positioning Compared to Other Drugs Key Milestones of TEPMETKO In February 2024, the FDA granted traditional approval to TEPMETKO for adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations. In February 2022, the EC approved TEPMETKO as monotherapy for the treatment of adult patients with advanced NSCLC harboring alterations leading to METex14 skipping who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy. In February 2021, Merck announced that the US FDA has approved TEPMETKO following priority review for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations. This indication was approved under accelerated approval based on ORR and DOR. In October 2020, TEPMETKO received ODD for treating NSCLC with MET genomic tumor aberrations In March 2020, EMD Serono (the biopharmaceutical business of Merck KGaA), announced that the MHLW approved TEPMETKO for the treatment of patients with unresectable, advanced, or recurrent NSCLC with METex14 skipping alterations. In September 2019, the US FDA granted BTD for tepotinib in patients with metastatic NSCLC harboring METex14 skipping alterations who progressed following platinum-based cancer therapy Discover how TEPMETKO is shaping the NSCLC treatment landscape @ TEPMETKO NSCLC TEPMETKO Market Dynamics TEPMETKO competes in a growing but highly specialized market where MET-targeted therapies are gaining traction due to their efficacy in addressing MET-altered tumors. The market for MET inhibitors is expanding as precision oncology advances and molecular diagnostics become more widely available, enabling better identification of patients who would benefit from targeted treatments like TEPMETKO. A key factor shaping TEPMETKO's market dynamics is competition. It directly competes with Novartis' TABRECTA (capmatinib), another MET inhibitor approved for the same indication. While TEPMETKO offers the advantage of once-daily dosing compared to TABRECTA's twice-daily regimen, both drugs have similar efficacy profiles, making physician and patient preference an important differentiator. Additionally, broader competition from next-generation MET inhibitors and combination therapies in clinical trials could impact TEPMETKO's long-term market position. Regulatory approvals and market access play a crucial role in TEPMETKO's adoption. The drug has been approved in multiple regions, including the U.S., Europe, and Japan, but reimbursement and pricing strategies vary by market. Payer policies, along with the cost-benefit analysis of MET inhibitors compared to other targeted therapies, influence prescription trends. Furthermore, real-world evidence and post-marketing studies will be critical in demonstrating TEPMETKO's sustained effectiveness and safety, which could support expanded indications and increased market penetration. Looking ahead, the MET inhibitor market is expected to grow with advances in biomarker-driven therapy, further refining patient selection. TEPMETKO's success will depend on continued clinical development, potential label expansions, and strategic partnerships to strengthen its competitive edge. As new entrants emerge, Merck KGaA's ability to differentiate TEPMETKO through combination strategies or enhanced formulations may determine its long-term sustainability in this evolving landscape. Dive deeper to get more insight into TEPMETKO's strengths & weaknesses relative to competitors @ TEPMETKO Market Drug Report Table of Contents Related Reports Non-small Cell Lung Cancer Market Non-small Cell Lung Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key NSCLC companies including Daiichi Sankyo, AstraZeneca, Gilead Sciences, BieGene, AbbVie, Roche, Merck, Novartis, Pfizer, Takeda Pharmaceuticals, Eli Lilly, BerGenBio, GlaxoSmithKline, Duality biologics, among others. Non-small Cell Lung Cancer Pipeline Non-small Cell Lung Cancer Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key non-small cell lung cancer companies, including BridgeBio Pharma, Daiichi Sankyo, EMD Serono, Merck, BridgeBio Pharma, Abbvie, Pfizer, Eli Lilly and Company BioNTech SE, Shenzhen TargetRx, Taiho Pharmaceutical, Chong Kun Dang, Bristol Myers Squibb, Innovent Biologics, Xuanzhu Biopharmaceutical, Bayer, GeneScience Pharmaceuticals, InventisBio, Apollomics, Imugene, Ono Pharmaceutical, Pierre Fabre, Jiangsu Hengrui Medicine Co., Bristol-Myers Squibb, Surface Oncology, Inhibrx, Sinocelltech, Mirati Therapeutics, REVOLUTION Medicines, Yong Shun Technology Development, Iovance Biotherapeutics, Galecto Biotech, among others. C-MET Metastatic Non-small Cell Lung Cancer Market C-MET Metastatic Non-small Cell Lung Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key C-MET mNSCLC companies, including Novartis, Merck, EMD Serono, AbbVie, Regeneron Pharmaceuticals, Mythic Therapeutics, Apollomics, Johnson & Johnson Innovation, Haihe Biopharma, among others. C-MET Non-small Cell Lung Cancer Pipeline C-MET Non-small Cell Lung Cancer Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key C-MET non-small cell lung cancer companies, including AbbVie, Janssen Research & Development, Beijing Pearl Biotechnology Limited Liability Company, Novartis, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

上市批准免疫疗法优先审批

2025-02-04

·药时代

罗氏砍掉十条管线？彻底放弃TIGIT？

正文共： 4763字 19图预计阅读时间： 10分钟大药企的管线及其调整是备受关注的焦点，药时代持续跟踪报道，其中包括罗氏的管线。罗氏在研产品众多，其中关注度非常高的一款产品就是TIGIT单抗RG6058（tiragolumab）。它是全球范围内推进最快的TIGIT抑制剂，被“全村”寄予了厚望。可惜进展和预期有很大的距离，也正因为如此，这款“开路先锋”得到格外大的关注。近日，两篇文章吸引了我们的注意力。一篇的题目是“罗氏：砍掉十条管线”，发布于2025年2月2日，阅读量已经1.4万。第二篇的题目是“罗氏：彻底放弃TIGIT”，发布于1月31日，目前阅读量接近6000。这两篇文章的题目让我们心里立即咯噔了一下，因为就在2024年12月11日，我们报道了罗氏2024年第三季度停止了4项乙肝在研产品，分别为RG6449、RG7854、RG6346及RG6084。这些项目分别处于I期/II期临床阶段，并在早前有部分临床试验数据公布。据罗氏官网披露信息显示，这四个产品很可能是罗氏已披露的乙肝管线的全部。【相关报道】罗氏停止多项乙肝新药管线！我们的反应就是：“怎么？罗氏又砍产品了？TIGIT彻底完了？” 情况真的是这样的吗？我们立即查看了长达76页的罗氏2024年全年财报PPT，希望从中找到答案。在第69页，罗氏披露了在2024年第四季度公司再次调整其管线，有增有减。临床1期增加了5个NME产品，分别为：RGXXXX*（P-MUC1C-ALLO1，实体瘤）、RG6810（DLL3 ADC，小细胞肺癌）、RG6620（KRAS G12D抑制剂，实体瘤）、RG6561（新分子实体，实体瘤）、CHU BRY10（慢性病）。 2024年11月26日，罗氏公司官宣15亿美元收购Poseida Therapeutics，该收购已经于2025年1月8日正式完成。此次收购将为罗氏带来Poseida的创新管线，P-MUC1C-ALLO1便是其中的一款产品。作为一种全同种异体CAR-T细胞疗法，P-MUC1C-ALLO1专门针对MUC1-C表位，这种表位在多种上皮来源的实体肿瘤中广泛表达。P-MUC1C-ALLO1在临床前研究中显示出对MUC1-C阳性肿瘤细胞的强大细胞毒性，同时对正常MUC1-C阳性的人类原代细胞的杀伤作用最小。靶向DLL3的ADC产品RG6810则是从中国信达生物引进的。 CHU BRY10是一款基于罗氏旗下中外制药公司开发的循环抗体®技术开发的抗体药物。管线瘦身方面，罗氏终止了一些产品的临床开发，原因包括：（1）未达公司内部研发标准：10个NME因未满足内部研发标准而被淘汰；（2）公司战略聚焦调整：部分管线因资源重新分配至高潜力项目（如CAR-T、ADC）而退出。 5个新分子实体（NMEs）被停止临床1期开发，它们是：（1）RG7827（FAP/4-1BB双抗，针对实体瘤）、（2）RG6194（Runimotamab，HER2/CD3双抗，针对乳腺癌）、（3）RG6323（efbalropendekin alfa，IL15/IL15Ra-Fc双特异性融合蛋白，针对血液瘤和实体瘤）、（4）GPC3/CD3双抗（来自中外制药，针对实体瘤，尤其是肝细胞癌）、（5）SPYK04（口服小分子药物，由中外制药研发，针对实体瘤）。这基本上意味着这5个NME的命运就此结束，除非后期有机会被“复活”。此外，备受关注的TIGIT单抗RG6058（tiragolumab）针对不同适应症的5个临床试验被终止，其中包括1个一期、2个二期、2个三期。所以，严格地讲，“罗氏砍掉十条管线”好像不是很准确。那么，罗氏彻底放弃TIGIT了吗？经历了2024年Q4调整后的罗氏管线如下：可以很清晰地看到，RG6058的三个三期临床试验还在其中，分别为：（1）联合Tecentriq用于治疗局部晚期食管癌；（2）联合Tecentriq用于一线治疗不可切除的III期非小细胞肺癌；（3）联合Tecentriq和Avastin用于一线治疗肝细胞癌。相应地，罗氏NDA/BLA递交计划这一页中依旧包括RG6058，其中，联合Tecentriq用于一线治疗不可切除的III期非小细胞肺癌的BLA计划2025年递交，另外两个都是2026年递交。基于以上信息和分析，我们认为罗氏还没有彻底放弃TIGIT。我们将继续密切关注还在管线中的三个三期临床试验，及时报道。专利悬崖则是备受关注的第二个焦点。2024年，罗氏受到专利到期（LOE）的影响，因Avastin、Herceptin等重磅药物专利到期损失10亿瑞士法郎，2025年预计进一步影响12亿瑞士法郎。罗氏通过精简管线集中资源于肿瘤（如Divarasib）、神经（如Trontinemab）及代谢（CT-388）等领域，与此同时，通过licensing引进有价值有协同潜力的创新药产品，进行“腾笼换鸟”、升级迭代，期间蕴藏着很多BD机会。中国企业可关注其开放合作机会（如ADC、双抗），争取达成更多的合作，实现更多的出海。时间、水平有限，今天的分析就到这里。欢迎批评指正！也欢迎感兴趣的朋友们继续阅读下面更多的财报分析内容。如果您希望保存一份76页PPT自己认真学习，请在本文的评论区留下您的工作邮箱地址，我们上班后统一密送。谢谢！~ 一、核心财务表现：超预期增长，现金流强劲收入与利润集团销售额：2024年实现销售额605亿瑞士法郎（+7%，恒定汇率CER），超出中单位数增长指引，基础业务（排除新冠产品及专利到期影响）增长达9%。分部表现：制药业务销售额462亿瑞郎（+8% CER），诊断业务143亿瑞郎（+4% CER；排除新冠产品后+8%）。盈利能力：核心营业利润（Core OP）增长14%，利润率提升2.1个百分点至34.4%；核心每股收益（Core EPS）增长12%（排除税务争议后）。现金流：运营自由现金流（OFCF）同比增长34%至212亿瑞郎，体现强劲的运营效率。关键驱动与挑战新冠产品收入下滑：新冠相关诊断及治疗药物销售额减少11亿瑞郎，符合预期。专利到期（LOE）影响：因Avastin、Herceptin等重磅药物专利到期损失10亿瑞郎，2025年预计进一步影响12亿瑞郎。汇率波动：美元/欧元兑瑞郎贬值拖累销售额增长约4个百分点，但2025年预计汇率影响趋缓。二、制药业务：创新产品驱动增长，管线布局前瞻核心产品表现肿瘤/血液病领域：Polivy（DLBCL）销售额增长39%，患者份额达29%；Hemlibra（血友病）患者份额42%，增长稳健。神经科学：Ocrevus（多发性硬化症）销售额67亿瑞郎（+9%），新剂型（皮下注射）快速渗透市场；Evrysdi（脊髓性肌萎缩症）增长18%。免疫与眼科：Xolair（过敏）因食物过敏适应症获批推动增长16%；Vabysmo（眼底病）销售额增长68%，预充注射器在美转化率超85%。新兴产品与管线亮点肿瘤：Giredestrant（ER+/HER2-乳腺癌）、Divarasib（KRAS突变实体瘤）III期数据读出。神经退行性疾病：Trontinemab（阿尔茨海默病）与Prasinezumab（帕金森病）临床进展。代谢与免疫：CT-388（GLP-1/GIP双激动剂）肥胖适应症进入II期，抗TL1A单抗拓展至克罗恩病与纤维化疾病。 2024年上市产品：Itovebi（PI3Kα突变乳腺癌）与PlaSky（阵发性睡眠性血红蛋白尿症）表现初显，后者获美欧批准。 2025年关键里程碑：战略合作与技术突破 CAR-T疗法：与Poseida合作开发通用型CAR-T，覆盖肿瘤、自身免疫及神经系统疾病，首款产品P-BCMA-ALLO1获FDA孤儿药认定。 ADC布局：通过信达生物合作引入DLL3 ADC（小细胞肺癌），强化实体瘤管线。三、诊断业务：基础业务韧性凸显，数字化与近患者护理发力区域与细分市场核心实验室（Core Lab）：免疫诊断（+9%）与临床化学（+8%）推动增长，占诊断收入的56%。分子诊断：血筛业务增长17%，新冠检测收入下滑但基础病毒检测增长10%。新兴市场：拉美增长22%，亚太受新冠检测退潮拖累（-5%）。创新产品与平台近患者护理（PoC）：Accu-Chek® SmartGuide CGM（连续血糖监测）获CE认证，cobas® Liat系统扩展呼吸道与性传播感染检测菜单。数字化病理：DP600扫描仪获美FDA初步诊断许可，推动病理实验室收入增长17%。质谱技术：cobas® i601系统上市，瞄准30亿瑞郎的LDT市场，目标2030年收入突破10亿瑞郎。四、战略与风险：聚焦长期增长，挑战犹存核心战略方向研发聚焦：2025年计划12项III期临床数据读出，4款新分子实体（NME）提交上市申请，包括抗纤维化药物astegolimab（COPD）及眼科药物vamikibart（糖尿病黄斑水肿）。数字化转型：navify®数字病理与分析平台升级，提升实验室效率；AI算法（如胸痛分诊、肾病风险评估）加速落地。可持续发展：推进绿色制造与供应链减碳，目标2030年实现运营碳中和。潜在风险与挑战专利悬崖：2025年LOE影响扩大，需依赖新产品填补收入缺口。竞争加剧：肿瘤领域面临PD-(L)1抑制剂生物类似药冲击，眼科市场需应对Vabysmo与Eylea的份额争夺。政策压力：全球药价管控趋严，美国《通胀削减法案》或影响高价药市场准入。五、中国视角：合作深化，市场潜力待释放本地化进展产品引入：Valpysmo（眼底病）、Lunsumio（淋巴瘤）等新药在华申报提速，2025年计划提交Elevidys（杜氏肌营养不良）上市申请。研发合作：与再鼎医药、信达生物等本土企业合作开发ADC与双抗，加速管线本土化。投资启示关注创新药企：罗氏在肿瘤、神经科学领域的开放合作模式（如CAR-T、ADC）为国内Biotech提供商业化契机。警惕政策风险：带量采购与医保谈判压力下，需评估罗氏高价创新药在中国市场的支付能力与准入策略。六、总结与展望罗氏2024年交出了一份“稳健增长与创新突破并存”的答卷，核心业务增长抵消了新冠退潮与专利到期的影响，现金流与股息连续38年增长彰显财务韧性。2025年，随着Giredestrant、Divarasib等重磅管线数据读出，以及数字化与近患者护理的深化，罗氏有望进一步巩固全球药企龙头地位。对中国市场而言，加速创新药引入、深化本土合作将是其增长关键，但需警惕政策与竞争的双重挑战。参考资料：罗氏2024年财报罗氏官网药时代已发表文章其它公开资料封面图来源：网络推荐阅读 DeepSeek预测：2035-2040年间，首位华人跨国药企CEO有望诞生 2025-02-03 2018-2024 | 全球知名VC公司如何看待生物制药江湖的这些年？ 2025-02-03 用火热的DeepSeek帮助设计1期临床试验方案。您对结果满意吗？ 2025-02-02 FDA会大规模裁员吗？快来看看投票结果！ 2025-02-02 版权声明/免责声明本文为原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 点击这里，查看更多商机!~

细胞疗法免疫疗法抗体药物偶联物财报并购

100 项与 Divarasib 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
KRAS G12C突变非鳞状非小细胞肺癌	临床3期	-	-	2025-05-01
晚期非小细胞肺癌	临床3期	中国	罗氏（中国）投资有限公司	2022-11-07
晚期非小细胞肺癌	临床3期	中国	F. Hoffmann-La Roche Ltd.	2022-11-07
晚期非小细胞肺癌	临床3期	澳大利亚	罗氏（中国）投资有限公司	2022-11-07
晚期非小细胞肺癌	临床3期	澳大利亚	F. Hoffmann-La Roche Ltd.	2022-11-07
KRAS G12C突变非小细胞肺癌	临床3期	中国	罗氏（中国）投资有限公司	2022-11-07
KRAS G12C突变非小细胞肺癌	临床3期	中国	F. Hoffmann-La Roche Ltd.	2022-11-07
KRAS G12C突变非小细胞肺癌	临床3期	澳大利亚	罗氏（中国）投资有限公司	2022-11-07
KRAS G12C突变非小细胞肺癌	临床3期	澳大利亚	F. Hoffmann-La Roche Ltd.	2022-11-07
转移性非小细胞肺癌	临床3期	中国	罗氏（中国）投资有限公司	2022-11-07

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04449874 (WCLC2024) 人工标引	临床1期	KRAS G12C突变阳性肿瘤 KRAS G12C	104	Divarasib 50-400 mg	餘鹹構夢範憲鏇範襯獵(膚築膚夢網顧糧膚繭簾) = 憲壓醖糧鏇窪顧壓壓襯構糧淵膚積範獵網齋醖 (蓋製衊顧繭繭餘範製憲 ) 更多	积极	2024-09-09
NCT04449874 (WCLC2024) 人工标引	临床1期	KRAS G12C突变阳性肿瘤 KRAS G12C	104	Divarasib+atezolizumab	餘鹹構夢範憲鏇範襯獵(膚築膚夢網顧糧膚繭簾) = 餘艱製願膚鹹顧範廠壓構糧淵膚積範獵網齋醖 (蓋製衊顧繭繭餘範製憲 ) 更多	积极	2024-09-09
WCLC2024	临床3期	转移性非小细胞肺癌 KRAS G12C+	-	Divarasib	艱範艱鑰簾鬱遞鑰淵構(網築襯顧繭醖製鹹鬱襯) = 憲糧築製艱顧鹽糧糧淵簾齋窪鹹膚築餘製艱選 (網製糧襯衊選製積鏇繭, 39.6 ~ 72.2) 更多	-	2024-09-09
NCT04449874 (Literature) 人工标引	临床1期	KRAS G12C突变的实体瘤 KRAS G12C Mutation	137	GDC-6036	-	积极	2023-08-24
NCT04449874 (Literature) 人工标引	临床1期	KRAS G12C突变的实体瘤 KRAS G12C Mutation	137	GDC-6036 (NSCLC)	構蓋製蓋顧鬱選衊構衊(膚淵鹹鏇選窪鑰範壓壓) = 簾齋簾遞夢顧積膚憲膚觸糧遞廠齋鹹鬱願夢範 (淵製獵網積憲廠壓範鏇, 39.9 ~ 66.7) 更多	积极	2023-08-24
NCT04449874 (GO42144, NEWS) 人工标引	临床1期	非小细胞肺癌 \| 结直肠癌 \| KRAS G12C突变阳性肿瘤 KRAS G12C Positive	137	Divarasib	願夢窪選憲餘鏇餘衊顧(窪選廠積醖壓齋繭淵築) = 齋壓齋網糧簾襯鑰鹹簾夢鹹廠蓋鏇衊淵顧製窪 (夢鏇鬱窪襯衊簾餘構廠 ) 更多	积极	2023-08-24
NCT04449874 (GO42144, NEWS) 人工标引	临床1期	非小细胞肺癌 \| 结直肠癌 \| KRAS G12C突变阳性肿瘤 KRAS G12C Positive	137	Divarasib (non-small-cell lung cancer)	鬱顧醖鹽鑰觸鬱積網選(鏇餘廠襯顧選鑰簾鏇繭) = 鹹構膚鏇願蓋築醖醖夢鹹艱範遞餘簾艱繭齋顧 (糧壓鑰範憲網鑰衊艱壓 ) 更多	积极	2023-08-24
NCT04449874 (Pubmed)	临床1期	转移性实体瘤 \| 晚期恶性实体瘤 \| 非小细胞肺癌 ... 更多	137	Divarasib	築構窪鹽鬱艱鹽願夢壓(壓襯廠範鏇壓簾窪鹽製) = 鏇簾觸壓蓋窪淵壓憲範繭積夢遞淵願繭夢窪壓 (繭憲膚簾糧網簾廠憲鹽, 39.9 ~ 66.7)	-	2023-08-24
NCT04449874 (AACR2023) 人工标引	临床1期	结直肠癌 KRAS G12C Mutation	29	GDC-6036+cetuximab	願網襯夢選繭繭簾鹽齋(鏇鑰構繭窪壓繭衊繭鹽) = 構襯繭觸壓壓艱遞廠蓋廠艱積膚衊廠糧觸製淵 (齋築憲繭淵鹹獵範艱鏇 ) 更多	积极	2023-04-14
NCT04449874 (ESMO2022)	临床1期	KRAS G12C突变的实体瘤	14	GDC-6036	簾構網鬱鹹遞獵製範範(餘鹽憲衊壓遞製夢範繭) = 鏇憲窪鑰廠鹽蓋醖鹽蓋構範艱鑰簾遞繭顧襯構 (鹽夢鹽醖餘願膚淵衊鹽 ) 更多	-	2022-09-12
NCT04449874 (ESMO2022) 人工标引	临床1期	KRAS G12C突变结直肠癌 KRAS G12C mutation	43	GDC-6036	窪襯齋鬱網壓淵夢齋鹽(醖鏇廠鏇壓遞膚願膚廠) = The most frequent GDC-6036-related AEs (≥ 10% pts) were nausea, diarrhea, vomiting, dyspepsia, fatigue, and decreased appetite 醖蓋醖鹽餘鏇獵鹽齋積 (選蓋糧鹽繭醖遞齋廠膚 ) 更多	积极	2022-09-10