Glofitamab

Basel, 30 January 2025 Group sales grew by 7%1 at constant exchange rates (CER; 3% in CHF), driven by strong demand for both medicines and diagnostics.Excluding COVID-19, Group sales increased by 9%. COVID-19 will not adversely impact our results from 2025 onwards.The fourth quarter was the third consecutive quarter of 9% sales growth, highlighting the very positive momentum.Pharmaceuticals Division sales rose by 8% (excluding COVID-19 medicine: 9%) on growing demand for newer medicines; top growth drivers were Vabysmo (severe eye diseases), Phesgo (breast cancer), Ocrevus (multiple sclerosis) and Hemlibra (haemophilia A).Diagnostics Division sales increased by 4%, reflecting the base effect of the sales of COVID-19 tests in the prior-year period; strong momentum in the Diagnostics Division’s base business continued with an increase of 8% due to higher demand for immunodiagnostic, pathology and molecular solutions.Core operating profit grew by 14% (8% in CHF), driven by higher sales, improved gross margin and effective cost management; core earnings per share rose by 7% (1% in CHF).Core earnings per share excluding the impact of the resolution of tax disputes in 2023 rose by 12%, exceeding the guidance for 2024.IFRS net income decreased by 19% (26% in CHF), mainly due to impairment charges to goodwill related to Flatiron Health and Spark Therapeutics.Operating free cash flow increased by 34% (CER) to CHF 20.1 billion.Highlights: Launch of cobas Mass Spec, a transformative innovation in mass spectrometryEU approval for Vabysmo prefilled syringeUS acceptance of supplemental Biologics License Application for Columvi combinationPositive data on blood cancer medicines Columvi, Lunsumio and Polivy, eye medicine Vabysmo, Duchenne muscular dystrophy medicine Elevidys and breast cancer therapy ItovebiAcquisition of Poseida Therapeutics for a range of potentially first- and best-in-class cell therapies across oncology, immunology and neurologyCE mark for new and updated molecular cobas 6800/8800 systems for enhanced laboratory efficiency and testing capabilities Board proposes dividend increase to CHF 9.70. If approved by shareholders, this would be the 38th consecutive dividend increase. Outlook for 2025 Roche (SIX: RO, ROG; OTCQX: RHHBY) expects an increase in Group sales in the mid single digit range (CER). Core earnings per share are targeted to develop in the high single digit range (CER). Roche expects to further increase its dividend in Swiss francs. Key figures CHF millions % change January–December 2024 2023 At CER1 In CHF Group sales 60,495 58,716 7 3 Pharmaceuticals Division 46,171 44,265 8 4 Diagnostics Division 14,324 14,451 4 -1 Core operating profit 20,823 19,240 14 8 Core EPS – diluted (CHF) 18.80 18.57 7 1 IFRS net income 9,187 12,358 -19 -26 Roche CEO Thomas Schinecker: “2024 was a strong year for Roche. In the fourth quarter, we continued our very positive momentum for the third consecutive quarter with Group sales growth of 9% (CER). Core earnings per share exceeded the guidance raised at half year. We are proud to have made a positive impact on patients’ lives in 2024 with the launch of two new medicines – Itovebi for a hard-to-treat breast cancer and PiaSky for a serious blood disorder – as well as our new solution for continuous blood glucose monitoring and our innovative system for fully automated mass spectrometry. Last year, we substantially strengthened our pipeline through the acceleration of internal key programmes and new partnerships and acquisitions such as Poseida Therapeutics for cell therapy in oncology and autoimmune diseases. Roche is well positioned for future growth.” Group resultsIn 2024, Roche achieved sales growth of 7% (3% in CHF) to CHF 60.5 billion. Core earnings per share rose by 12%, excluding the base effect of the resolution of tax disputes in 2023. Including this impact, core earnings per share increased by 7%. The appreciation of the Swiss franc against most currencies had a significant impact on the results reported in Swiss francs compared to constant exchange rates. Strong demand for both pharmaceutical products and diagnostic solutions more than made up for the expected decline of CHF 1.1 billion in COVID-19-related sales and an impact of CHF 1.0 billion from the loss of exclusivity on Avastin (various types of cancer), Herceptin (breast and gastric cancer), MabThera/Rituxan (blood cancer, rheumatoid arthritis), Esbriet (lung disease), Lucentis (severe eye diseases) and Actemra/RoActemra (rheumatoid arthritis, COVID-19). Core operating profit rose by 14% (8% in CHF) to CHF 20.8 billion, driven by higher sales, improved gross margin and effective cost management. IFRS net income decreased by 19% (26% in CHF) to CHF 9.2 billion, mainly due to impairment charges to goodwill of CHF 3.2 billion related to Flatiron Health and Spark Therapeutics. Sales in the Pharmaceuticals Division increased by 8% to CHF 46.2 billion, with newer medicines for severe diseases continuing their strong growth. The top four growth drivers – Vabysmo, Phesgo, Ocrevus and Hemlibra – achieved total sales of CHF 16.9 billion. This represents a plus of CHF 3.3 billion at CER compared to 2023. Vabysmo, launched in early 2022, continued to be a major growth driver, generating sales of CHF 3.9 billion on growing demand in all regions. Sales of Avastin, Herceptin, MabThera/Rituxan, Esbriet, Lucentis and Actemra/RoActemra decreased by a combined CHF 1.0 billion (CER) due to the impact of loss of exclusivity. Sales of the COVID-19 medicine Ronapreve were minimal compared to sales in Japan of CHF 0.5 billion in 2023. In the United States, sales rose by 9%. Vabysmo, Ocrevus, Xolair (allergies) and Polivy were the main growth drivers. This growth more than compensated for the decline in sales of Lucentis (severe eye diseases) and lower sales of medicines with expired patents. Sales in Europe grew 8% as sales growth due to the continued rollout of Vabysmo and the uptake of Phesgo, Ocrevus, Hemlibra and Evrysdi (spinal muscular atrophy) more than compensated for the decline in sales of medicines with expired patents, the impact of biosimilar competition on Actemra/RoActemra sales and lower sales of Perjeta (breast cancer) due to ongoing conversion of patients to Phesgo. In Japan, sales decreased by 16%, reflecting the base effect of Ronapreve sales in the first half of 2023 that did not reoccur in 2024. Excluding Ronapreve, sales in Japan fell by 2% as price cuts and biosimilar and generic erosion more than offset the growth in sales of Phesgo, Vabysmo and Hemlibra. Sales in the International region grew by 17%, led by China, Canada and Brazil. In China, sales rose by 6%, driven by continued sales growth of Perjeta, Alecensa (early-stage lung cancer) and Avastin as well as higher sales of Xofluza (influenza) and the rollout of Polivy. The Diagnostics Division’s base business sales increased by 8%, led by the increased demand for immunodiagnostic products and by higher sales of clinical chemistry tests, advanced staining solutions and companion diagnostics. Overall, the Diagnostics Division reported sales growth of 4% to CHF 14.3 billion, reflecting the anticipated drop in demand for COVID-19-related products (sales of CHF 0.2 billion in 2024 compared to CHF 0.8 billion in 2023). Sales in the Europe, Middle East and Africa (EMEA) region increased by 5%, driven by higher sales of immunodiagnostic products, clinical chemistry tests and advanced staining solutions. In North America, there was growth in the underlying base business across customer areas. Sales in Asia-Pacific decreased by 5% as higher sales of immunodiagnostic products were offset by the expected drop in demand for COVID-19-related tests. Pharmaceuticals Division: pipelineWith 71 new molecular entities (NMEs) and a total of 122 projects, Roche has a promising pipeline with a wide variety of therapeutic approaches. Pharmaceuticals research and development (R&D) expenditure grew by 1% to CHF 11.1 billion (Group R&D: 1% to CHF 13.0 billion). Oncology remained the primary area for R&D, with substantial investments also in the areas of immunology and cardiovascular, renal and metabolism. Pharmaceuticals: key developments Compound Milestone Regulatory VabysmoSevere eye diseases Vabysmo prefilled syringe (PFS) is now approved in the EU for three retinal conditions that can cause blindness Vabysmo PFS is the first and only prefilled syringe containing a bispecific antibody, offering a convenient alternative to currently available Vabysmo vials.Vabysmo has demonstrated rapid and robust vision and anatomical improvements in neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME) and retinal vein occlusion (RVO).The ready-to-use Vabysmo PFS is co-packaged with the only CE-marked needle specifically designed for intravitreal injection. More information: Media Release, 13 December 2024 ColumviBlood cancer FDA accepts supplemental Biologics License Application for Columvi combination for people with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) The application is based on data from the phase III STARGLO study where Columvi plus chemotherapy showed a statistically significant and clinically meaningful improvement in overall survival.This regimen could provide an off-the-shelf, fixed-duration treatment option for patients to start soon after diagnosis, which is important for those who are at high risk of disease progression.Improving survival outcomes is needed for people with an aggressive disease like relapsed or refractory DLBCL, especially those who are not eligible for transplant. More information: Media Release, 5 December 2024 Phase III, pivotal and other key read-outs ItovebiBreast cancer Itovebi demonstrated statistically significant and clinically meaningful overall survival benefit in a certain type of HR-positive advanced breast cancer Updated results for overall survival (OS) – a key secondary endpoint – reinforce the significant benefit of the regimen based on Itovebi (inavolisib) for patients with advanced PIK3CA-mutated, HR-positive, HER2-negative breast cancer in the first-line setting.Primary analysis showed the regimen based on Itovebi reached statistical significance, more than doubling progression-free survival in this patient population.Full OS results from the phase III INAVO120 study will be presented at an upcoming medical meeting. More information: Media Release, 28 January 2025 ElevidysDuchenne muscular dystrophy Roche announces new results from EMBARK, demonstrating significant sustained benefits of Elevidys in ambulatory individuals with Duchenne muscular dystrophy (DMD) Across three key functional outcomes, North Star Ambulatory Assessment (NSAA), Time to Rise (TTR) and 10-metre walk/run (10MWR), results were statistically significant and clinically meaningful two years after treatment with Elevidys, compared to a pre-specified propensity-weighted untreated external control group.Functional differences between individuals treated with Elevidys and those in the external control group increased between one year and two years after treatment.No new safety signals were observed, further reinforcing the consistent and manageable safety profile observed with Elevidys to date. More information: Media Release, 27 January 2025 PrasinezumabParkinson’s disease Phase IIb study of prasinezumab misses primary endpoint, but suggests possible benefit in early-stage Parkinson’s disease PADOVA study showed numerical delay in motor progression and positive trends on multiple secondary and exploratory endpoints.Prasinezumab continues to be well tolerated and no new safety signals were observed.Roche is further evaluating the data and will work together with health authorities to determine next steps. More information: Media Release, 19 December 2024 Columvi/LunsumioBlood cancer New and updated data for fixed-duration Columvi and Lunsumio presented at annual meeting of American Society of Hematology (ASH) 2024 reinforce their potential to improve outcomes for people with lymphoma Long-term data confirm fixed-duration Columvi and Lunsumio achieve durable remissions beyond the end of treatment, with real-world data suggesting reduced treatment-related travel burden due to less frequent dosing.First presentation of Lunsumio given subcutaneously showed non-inferiority to intravenous treatment with a consistent safety profile, potentially providing an additional outpatient option with a shorter administration time.Positive results for Roche’s two bispecifics antibodies validate the company’s efforts to provide multiple treatment options that suit the diverse needs of lymphoma patients and healthcare providers. More information: Media Release, 10 December 2024 PolivyBlood cancer Five-year results confirm Polivy combination therapy as new standard of care for previously untreated aggressive lymphoma Exploratory long-term follow-up analysis of the phase III POLARIX study indicated a positive trend in overall survival in favour of Polivy in combination with R-CHP for the first-line treatment of people with DLBCL.Patients treated with Polivy in combination with R-CHP required fewer subsequent treatments, which potentially reduces the burden on patients and healthcare systems.These encouraging five-year results continue to highlight the potential of this Polivy combination to improve outcomes in the first-line treatment of people with DLBCL, an area that had little advancement in nearly two decades. More information: Media Release, 8 December 2024 TiragolumabLung cancer Roche reports update on phase III SKYSCRAPER-01 study results SKYSCRAPER-01 is a global phase III, randomised, double-blind study evaluating tiragolumab plus Tecentriq compared to Tecentriq alone in 534 patients with PD-L1-high previously untreated, locally advanced unresectable or metastatic non-small cell lung cancer (NSCLC). The study did not reach the primary endpoint of overall survival at the final analysis. More information: Media Release, 26 November 2024 VabysmoSevere eye diseases Vabysmo improves vision in under-represented populations with DME in a first-of-its-kind study The ELEVATUM study showed clinically meaningful improvement in vision and reduction in retinal fluid in African American, Black, Hispanic and Latino people with DME treated with Vabysmo. Efficacy and safety from this phase IV study were consistent with data from the Vabysmo phase III DME studies.These racial and ethnic groups are disproportionately affected by diabetes and are at higher risk of developing DME, a leading cause of vision loss. More information: Media Release, 18 October 2024 Other Poseida Therapeutics tender offer Roche purchases shares in tender offer for Poseida Therapeutics Roche’s wholly owned subsidiary Blue Giant Acquisition Corp. accepted for payment all shares validly tendered and not validly withdrawn pursuant to its tender offer for all outstanding shares of common stock of Poseida Therapeutics at a price of USD 9.00 per share in cash, plus a non-tradeable contingent value right (CVR), to receive certain contingent payments of up to an aggregate of USD 4.00 per share in cash. The tender offer expired at one minute following 11:59 p.m., New York City time, on 7 January 2025, and was not extended. More information: Media Release, 8 January 2025 Poseida Therapeutics tender offer Roche commences tender offer for all shares of Poseida Therapeutics for USD 9.00 per share in cash, plus a non-tradeable contingent value right for up to USD 4.00 per share in cash The tender offer is being made pursuant to the previously announced merger agreement dated 25 November 2024.Following the successful completion of the tender offer, any shares not acquired in the tender offer will be acquired in a second-step merger at the same price of USD 9.00 per share, plus the contingent value right. The transaction is expected to close in the first quarter of 2025. More information: Media Release, 9 December 2024 Poseida Therapeutics acquisition Roche enters into a definitive agreement to acquire Poseida Therapeutics, including cell therapy candidates and related platform technologies The acquisition supports Roche’s pharmaceuticals strategy and allows for a range of potentially first- and best-in-class therapies across oncology, immunology and neurology, uniquely positioning Roche in the new field of donor-derived off-the-shelf cell therapies.Roche will acquire Poseida Therapeutics for USD 9.00 per share in cash at closing, which represents a total equity value of approximately USD 1.0 billion. Stockholders will also receive a non-tradeable contingent value right for up to an aggregate of USD 4.00 per share in cash, representing a total deal value of up to approximately USD 1.5 billion. More information: Media Release, 26 November 2024 ItovebiBreast cancer NEJM publishes landmark phase III results for Itovebi, showing more than doubling of progression-free survival in a certain type of HR-positive advanced breast cancer The regimen based on Itovebi (inavolisib) demonstrated a statistically significant and clinically meaningful benefit, reducing the risk of disease worsening or death by 57% compared with palbociclib and fulvestrant alone in the INAVO120 study.The FDA recently approved the regimen based on Itovebi as a first-line treatment for people with HR-positive, HER2-negative breast cancer with a PIK3CA mutation, one of the most common gene mutations in HR-positive disease. More information: Media Release, 31 October 2024 Pharmaceuticals sales Sales CHF millions As % of sales % change January–December 2024 2023 2024 2023 At CER In CHF Pharmaceuticals Division 46,171 44,265 100.0 100.0 8 4 United States 24,774 23,259 53.7 52.5 9 7 Europe 8,832 8,306 19.1 18.8 8 6 Japan 2,874 3,745 6.2 8.5 -16 -23 International* 9,691 8,955 21.0 20.2 17 8 *Asia-Pacific, CEETRIS (Central Eastern Europe, Türkiye, Russia and Indian subcontinent), Latin America, Middle East, Africa, Canada, others Top 20 best-selling pharmaceuticals Total United States Europe Japan International CHF m % CHF m % CHF m % CHF m % CHF m % OcrevusMultiple sclerosis 6,744 9 4,819 5 1,306 14 - - 619 29 HemlibraHaemophilia A 4,503 12 2,654 9 926 11 367 8 556 41 VabysmoEye diseases (nAMD, DME, RVO) 3,864 68 2,940 57 622 128 125 40 177 168 TecentriqCancer immunotherapy 3,640 0 1,763 -7 863 4 380 0 634 23 Perjeta3Breast cancer 3,616 1 1,345 3 646 -15 116 -40 1,509 15 Actemra/RoActemra3RA, COVID-19 2,645 5 1,331 11 658 -14 309 9 347 19 Xolair3Asthma 2,470 16 2,470 16 - - - - - - Kadcyla3Breast cancer 1,998 7 765 3 564 -1 98 5 571 23 PhesgoBreast cancer 1,740 62 570 38 738 40 136 ** 296 111 EvrysdiSpinal muscular atrophy 1,631 18 588 19 572 14 93 10 378 25 AlecensaLung cancer 1,548 7 525 15 284 -1 198 3 541 7 Herceptin3Breast and gastric cancer 1,381 -11 265 -18 303 -13 14 -50 799 -6 MabThera/Rituxan3Blood cancer, RA 1,379 -13 842 -13 150 -15 17 -25 370 -10 Avastin3Various cancer types 1,233 -17 383 -19 85 -11 197 -32 568 -10 Activase/TNKase3Cardiac diseases 1,202 5 1,140 5 - - - - 62 5 PolivyBlood cancer 1,121 39 568 70 192 13 198 -4 163 76 Gazyva/Gazyvaro3Blood cancer 910 16 463 20 245 9 29 -15 173 23 Pulmozyme3Cystic fibrosis 455 4 303 2 73 -3 1 21 78 22 CellCept3Immunosuppressant 399 7 23 -22 124 2 40 -3 212 17 Mircera3Anaemia related to kidney disease 397 -3 - - 42 -3 38 -23 317 1 ** Over 500%DME: diabetic macular edema / nAMD: neovascular or ‘wet’ age-related macular degeneration / RVO: retinal vein occlusion / RA: rheumatoid arthritis Diagnostics: key developments Product Milestone cobas liat STI multiplex assay panelsSexually transmitted infections Roche receives FDA clearance with CLIA waiver for cobas liat molecular tests to diagnose sexually transmitted infections at the point of care More than 1 million curable sexually transmitted infections (STIs) are acquired every day worldwide in people 15–49 years old, most of which are asymptomatic.FDA CLIA-waived tests broaden access to accurate, easy-to-use diagnostics for all patients in decentralised settings like urgent care centres, retail clinics and community health venues.The tests use highly sensitive gold-standard PCR technology, providing results in 20 minutes to allow healthcare providers to confidently diagnose and determine appropriate treatment in the same visit. More information: Media Release, 22 January 2025 cobas Mass Spec Roche transforms mass spectrometry diagnostics with launch of cobas Mass Spec solution Roche launched its cobas Mass Spec solution, bringing mass spectrometry to the routine clinical lab.Clinical mass spectrometry testing offers unparalleled sensitivity and specificity, providing clinicians with additional diagnostic insights.cobas Mass Spec solution will offer a fully automated, integrated and standardised workflow with IVDR-compliant assays. More information: Media Release, 18 December 2024 cobas 6800/8800 systems 2.0Various tests Roche receives CE mark for new molecular cobas 6800/8800 systems upgrade, enhancing laboratory efficiency and testing capabilities The new cobas 6800/8800 systems 2.0 upgrade enhances throughput and run flexibility, enables sample prioritisation and is available for existing systems in healthcare settings around the world.Laboratories can now perform a wider range of tests on a single solution, thereby simplifying laboratory logistics and helping to optimise the use of resources. More information: Media Release, 13 December 2024 Elecsys Amyloid Plasma PanelAlzheimer’s disease Roche presents new data at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, demonstrating its growing momentum in diagnostics for Alzheimer’s disease New data highlight the potential of the Roche Elecsys Amyloid Plasma Panel and Elecsys pTau181 for ruling out Alzheimer’s disease-related amyloid pathology with very good accuracy.In the largest worldwide clinical trial of its kind, the blood-based test showed very good accuracy in ruling out Alzheimer’s pathology in those being investigated for the disease, potentially avoiding the need for further invasive and unnecessary tests.Results further demonstrate Roche’s commitment to bringing diagnostic clarity for Alzheimer’s disease to people at an early stage of cognitive decline. More information: Media Release, 31 October 2024 Diagnostics sales Sales CHF millions As % of sales % change January–December 2024 2023 2024 2023 At CER In CHF Diagnostics Division 14,324 14,451 100.0 100.0 4 -1 Customer Areas4 Core Lab 8,004 7,750 55.9 53.6 8 3 Molecular Lab5 2,590 2,567 18.1 17.8 4 1 Near Patient Care6 2,167 2,746 15.1 19.0 -17 -21 Pathology Lab 1,563 1,388 10.9 9.6 17 13 Regions Europe, Middle East, Africa 4,822 4,768 33.7 33.0 5 1 North America 4,335 4,173 30.3 28.9 6 4 Asia–Pacific 4,099 4,496 28.6 31.1 -5 -9 Latin America 1,068 1,014 7.4 7.0 22 5 More information on Roche performance in 2024: 2024 Finance Report2024 Annual Report2024 presentationAppendix with tables About Roche Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice. For over 125 years, sustainability has been an integral part of Roche’s business. As a science-driven company, our greatest contribution to society is developing innovative medicines and diagnostics that help people live healthier lives. Roche is committed to the Science Based Targets initiative and the Sustainable Markets Initiative to achieve net zero by 2045. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com. All trademarks used or mentioned in this release are protected by law.References[1] Unless otherwise stated, all growth rates and comparisons to the previous year in this document are at constant exchange rates (CER: average rates 2023) and all total figures quoted are reported in CHF.[2] Pharmaceuticals Division base business: excluding COVID-19 medicine Ronapreve. Diagnostics Division base business: excluding COVID-19-related products.[3] Products launched before 2015.[4] Core Lab: diagnostics solutions in the areas of immunoassays, clinical chemistry and CustomBiotech.Molecular Lab: diagnostics solutions for pathogen detection and monitoring, donor screening, sexual health and genomics, genomic tumour profiling.Near Patient Care: diagnostics solutions in emergency rooms, medical practices and directly with patients, including integrated personalised diabetes management.Pathology Lab: diagnostics solutions for tissue biopsies and companion diagnostics.[5] Sales in the Molecular Lab customer area include sales from the Foundation Medicine business, which moved under the responsibility of the Diagnostics Division from the Pharmaceuticals Division effective 1 January 2024. The comparative information for 2023 has been restated accordingly.[6] Sales in the new Near Patient Care customer area include sales from Diabetes Care and the Point of Care business, both previously shown as separate customer areas. The comparative information for 2023 has been restated accordingly. Cautionary statement regarding forward-looking statementsThis document contains certain forward-looking statements. These forward-looking statements may be identified by words such as ‘believes’, ‘expects’, ‘anticipates’, ‘projects’, ‘intends’, ‘should’, ‘seeks’, ‘estimates’, ‘future’ or similar expressions or by discussion of, among other things, strategy, goals, plans or intentions. Various factors may cause actual results to differ materially in the future from those reflected in forward-looking statements contained in this document, such as: (1) pricing and product initiatives of competitors; (2) legislative and regulatory developments and economic conditions; (3) delay or inability in obtaining regulatory approvals or bringing products to market; (4) fluctuations in currency exchange rates and general financial market conditions; (5) uncertainties in the discovery, development or marketing of new products or new uses of existing products, including without limitation negative results of clinical trials or research projects, unexpected side effects of pipeline or marketed products; (6) increased government pricing pressures; (7) interruptions in production; (8) loss of or inability to obtain adequate protection for intellectual property rights; (9) litigation; (10) loss of key executives or other employees; and (11) adverse publicity and news coverage. The statement regarding earnings per share growth is not a profit forecast and should not be interpreted to mean that Roche’s earnings or earnings per share for this or any subsequent period will necessarily match or exceed the historical published earnings or earnings per share of Roche. Roche Global Media RelationsPhone: +41 61 688 8888 / e-mail: media.relations@roche.com Hans Trees, PhDPhone: +41 79 407 72 58 Sileia UrechPhone: +41 79 935 81 48 Nathalie AltermattPhone: +41 79 771 05 25 Lorena CorfasPhone: +41 79 568 24 95 Simon GoldsboroughPhone: +44 797 32 72 915 Karsten KleinePhone: +41 79 461 86 83 Nina MählitzPhone: +41 79 327 54 74 Kirti PandeyPhone: +49 172 636 72 62 Yvette PetillonPhone: +41 79 961 92 50 Dr Rebekka SchnellPhone: +41 79 205 27 03 Roche Investor Relations Dr Bruno EschliPhone: +41 61 687 52 84e-mail: bruno.eschli@roche.com Dr Sabine BorngräberPhone: +41 61 688 80 27e-mail: sabine.borngraeber@roche.com Dr Birgit MasjostPhone: +41 61 688 48 14e-mail: birgit.masjost@roche.com Investor Relations North America Loren KalmPhone: +1 650 225 32 17e-mail: kalm.loren@gene.com Attachments 30012025_MR_FY Roche 2024_EN Communications appendix tables_FY 2024 Sales + Results

点击蓝字 关注我们 编者按 BTK抑制剂作为治疗B细胞恶性肿瘤的重要药物，在临床应用中已展现出显著的疗效。然而，随着其广泛使用，部分患者逐渐出现耐药情况，这对治疗效果构成了严峻挑战。 2025年1月17～19日，“中国临床肿瘤学会(CSCO)白血病、淋巴瘤及骨髓瘤专家委员会工作会议暨2025年CSCO血液肿瘤学术大会”在美丽海口盛大召开。会上，北京大学肿瘤医院淋巴瘤科林宁晶教授带来了题为“BTK抑制剂耐药治疗策略”的精彩报告，为解决这一难题带来极具价值的参考和启示。《肿瘤瞭望-血液时讯》特整理课件内容，以飨读者。 cBTKi概况 布鲁顿酪氨酸激酶（BTK）是非受体型酪氨酸激酶TEC家族中的一员，在B细胞受体（BCR）的下游发挥作用，参与B细胞的增殖、成熟、分化和凋亡的全过程。作为BCR信号传导中的关键一环，BTK早已成为治疗B细胞恶性肿瘤的实力靶点。 BTK蛋白包含659个氨基酸，具有5个不同的蛋白相互作用域。其中SH3结构域的Y223和激酶结构域的Y551是两个关键的酪氨酸磷酸化位点。在BCR信号传导过程中，SYK对Y551位点的磷酸化增强了BTK的催化活性，并启动随后的Y223自磷酸化。 共价BTK抑制剂（cBTKi）作用机制相似，通过和BTK激酶结构域的C481位点共价结合，抑制ATP结合口袋，从而抑制PLCG2等主要下游信号通路的激活，阻止恶性B细胞增殖并促进细胞凋亡[1]。目前上市的cBTKi有伊布替尼（2013年）、阿可替尼（2017年）、泽布替尼（2019年）、奥布替尼（2020年）。 根据各自的临床研究，四种cBTKi治疗复发难治套细胞淋巴瘤（MCL）的疗效分别为：伊布替尼中位无进展生存期（mPFS）13个月、中位缓解持续时间（mDOR）17.5个月[2-3]；阿可替尼mPFS 22个月、mDOR 28.6个月[4-6]；泽布替尼mPFS 33个月、mDOR未达到[7-8]；奥布替尼22个月、22.9个月[9]（非头对头研究，数据无法直接对比）。cBTKi治疗常见的不良反应有出血、腹泻、感染、血小板（PLT）减低、中性粒细胞（NEU）减低等。 cBTKi耐药后的生存 cBTKi的耐药机制包括BTK突变和PLCG2突变。（1）BTK结合位点突变：主要突变类型为BTK上的C481位半胱氨酸突变为丝氨酸（C481S），破坏抑制剂和BTK的共价结合导致耐药。除C481S外，还可能产生C481Y/F/R/G、L528W等突变类型[10]。（2）BTK下游底物PLCG2（PLCγ2）突变：PLCG2 是BTK的酶促底物，其突变可使PLCG2绕过BTK被旁路激活，导致耐药。主要突变类型为第665位精氨酸突变为色氨酸（R665W），还可发生L485F、S707Y突变，均可介导耐药[11]。 BTK抑制剂发生耐药后患者的生存较差，慢性淋巴细胞性白血病（CLL）患者预期总生存（OS）为18个月，Richter综合征患者为4个月，MCL患者为6～10个月[12-13]。临床前研究显示，cBTKi对C481S突变细胞活性极低[14]。 cBTKi治疗失败后选择有限，预后不佳。一项美国真实世界研究[15]显示，cBTKi治疗失败后，47.6%（352/739）MCL患者接受后续治疗，下一线治疗的mDOR为2.6个月，从cBTKi停药至下一线治疗停止或死亡的中位时间为3.9个月，自cBTKi停药后的mOS为10.3个月；而近40%的患者在cBTKi 停药后没有接受后续治疗，部分原因可能是缺乏可用于这些患者的治疗选择。SCHOLAR-2研究[16]同样显示，从首次BTKi治疗停药后的mOS：整体人群（N=240）为4.0个月、未接受Post-BTKi治疗（N=91）为0.4个月、接受Post-BTKi治疗（N=149）为11.4个月；在149例接受Post-cBTKi治疗的患者中，从首次开始Post-BTKi治疗后的mOS为9.7个月。 cBTKi耐药后的新药探索 01 非共价BTK抑制剂 不同于cBTKi和C481结合，非共价BTK抑制剂（如匹妥布替尼）通过可逆结合与BTK的ATP结合区域有广泛的相互作用，不依赖C481即可发挥BTK抑制作用。 BRUIN研究是一项多中心I/II期单臂研究，MCL队列探讨了匹妥布替尼治疗cBTKi经治MCL的疗效。结果显示，在主要疗效分析集（PAS）中总缓解率（ORR）57.8%、完全缓解率（CR）20%，mDOR 21.6个月、mPFS 7.4个月；在全组中mOS也可达到23.5个月[17-18]。基于此，2023年1月27日，FDA加速批准匹妥布替尼用于既往cBTKi经治的MCL患者。匹妥布替尼在中国的桥接研究同样显示，在PAS中ORR 71.4%、CR 14.3%，mPFS 9.43个月；在有效性分析组（EAS）中，mOS 15.5个月[19]。 洛布替尼作为新一代BTKi，具有双重作用机制，可以通过共价及非共价结合方式抑制野生型和突变型BTK活性。I期研究纳入33例MCL患者，其中19例（57.6%）既往用过BTKi，采用洛布替尼治疗，中位随访5.5个月，在可评价的31例患者中ORR 77.4%、CR 38.7%；在既往使用过BTKi的17例患者中ORR 70.6%、CR 35.3%。常见不良事件（AE）包括：PLT减低30.3%，NEU减低27.3%，贫血27.3%，新冠24.2%；≥3级AE发生率为27.3%，严重AE（SAE）发生率为9.1%[20]。 02 BTK降解剂 蛋白降解靶向嵌合体（Proteolysis-Targeting Chimera，PROTAC）是一种创新的药物技术，它利用细胞内的泛素-蛋白酶体系统来清除细胞中无用或有害的蛋白质。PROTAC通过一种小分子嵌合体，同时结合意向降解的目标蛋白（POI）和E3泛素连接酶，促使目标蛋白被标记（泛素化），随后被细胞内的蛋白酶体降解。 相比于激酶小分子抑制剂通过“结合”来限制某些蛋白的功能，PROTAC的优势在于其能通过诱导蛋白降解，而非简单抑制其功能，不太容易受到因结合亲和力降低或者绕道突破作用等带来的“突变”影响，因此有望克服传统小分子药物的耐药性问题。 目前BTK降解剂均处在早期研发阶段，在研的有NX-2127（降解BTK & IKZF1/3）、NX-5948（降解BTK）、BGB-16673（降解BTK）等等，它们在I期研究中已观察到初步疗效和良好的安全性。NX-2127-001研究显示，NX-2127治疗BTKi经治的CLL的ORR为40.7%[21]；NX-5948-301研究显示，NX-5948治疗19例B细胞非霍奇金淋巴瘤（B-NHL）的ORR为76.7%，52.6%患者为BTKi治疗后[22]；CaDAnCe-101研究显示，49例CLL患者中，92%为cBTKi经治，86%为Bcl-2抑制剂经治， 接受BGB-16673治疗的ORR为78%，200 mg组甚至达到了94%[23]。 03 CAR-T细胞治疗 ZUMA-2研究显示，Brexu-cel治疗BTKi经治的MCL ORR 91%，CR 68%；全组患者的mDOR 28.2个月，mPFS 25.8个月，mOS 46.6个月；安全性方面，细胞因子释放综合征（CRS）发生率为91%，神经系统事件（NE）发生率为63%[24-25]。2023 ASH大会公布了ZUMA-2研究4年随访结果和ZUMA-18研究的初步结果，合并分析2个研究，mOS达46.6个月，24个月OS率达62%[26]。 TRANSCEND NHL 001研究显示，Liso-cel治疗BTKi经治的MCL ORR 83.1%，CR 72.3%；全组患者的mDOR 15.7个月，mPFS 15.3个月，mOS 18.2个月；安全性方面，CRS发生率为61%，NE发生率为31%[27]。多中心单臂II期临床试验显示，Relma-cel治疗BTKi经治的MCL最佳ORR为78.57%，最佳CR率为66.67%；安全性方面，CRS发生率为55.36%，NE发生率为10.71%[28]。 04 双特异性抗体 一项I/II期研究显示，Mosunetuzumab治疗BTKi失败的MCL ORR 44%，CR 24%，mDOR 10.3个月，mPFS 3.7个月，mOS 7.3个月；安全性方面，CRS发生率为52%，3例患者发生免疫效应细胞相关神经毒性综合征（ICANS）[29]。另一项Ib/II期研究显示，Mosunetuzumab联合Pola（M-Pola）治疗BTKi经治的R/R MCL ORR 75%，CR 70%；mPFS 15.8个月，mDOR 13.3个月，mOS 17.9月；安全性方面，CRS发生率为50%，ICANS发生率为15%[30]。 截至2023年9月4日，NP30179 I/II期研究共纳入61例R/R MCL患者，其中60例接受Glofitamab治疗，中位治疗7.4个月，结果显示在BTKi经治（N=31）患者中，mDOR为12.6个月，mPFS为8.6个月[31-32]。基于该项研究的结果，一项III期随机开放对照研究——GLOBRYTE研究已于2023年10月启动，旨在比较Glofitamab vs. BR/R2治疗BTKi失败的MCL，80家中心参与，计划纳入182例患者，我们期待该研究的结果早日公布。 —  小 结  — cBTKi在复发难治非霍奇金淋巴瘤（NHL）患者中疗效显著，已获批多个适应证；针对cBTKi治疗失败或者不耐受患者，非共价BTKi、BTK降解剂、CAR-T细胞治疗、双特异性抗体等众多新药的出现，为MCL后线治疗带来更多的选择和新的希望。 参考文献：（上下滑动查看更多） [1]Gu D, et al. J Hematol Oncol. 2021 Mar 6;14(1):40. [2]N Engl J Med. 2013;369(6): 507-516 [3]Blood. 2015;126(6):739-74 [4]Lancet 2018,391(10121),659-667 [5]Blood 2020,136(Suppl 1),38–39 [6]Haematologica 2024,109(1),343-350 [7]CCR 2020,26(16),4216-4224 [8]Blood 2022,139 (21),3148–3158 [9]Blood Adv 2023,7(16),4349–4357 [10]Nakhoda S, et al. 2023 Jan;200(2):137-149. [11]Wu J, et al. J Hematol Oncol. 2016 Sep 2;9(1):80. [12]Stephens DM, et al. Blood. 2021 Sep 30;138(13):1099-1109. [13]Burkart M, et al. J Pers Med. 2022 Mar 1;12(3):376. [14]Gomez EB, Ebata K, Randeria HS, et al. Blood. 2023 Jul 6;142(1):62-72 [15]Lisa M Hess, et al. Adv Hematol. 2022 Dec 28:2022:8262787. [16]Georg Hess, et al. Br J Haematol. 2023 Aug;202(4):749-759. [17]JCO 2023,41(24),3988-3997 [18]Blood 2023,142(S1),981 [19]Blood 2023,142(S1),3636 [20]Blood 2023,142(S1),3033 [21]Blood 2023; 142(S1): 4463 [22]Blood 2024; 144 (S1): 884 [23]Blood 2024; 144(S1): 885 [24]NEJM 2020;382:1331-42 [25]JCO 2023;41(3): 555-567 [26]2023 ASH Oral 106 [27]J Clin Oncol. 2024;42(10):1146-1157 [28]Blood 2023; 142 (S1): 3024. [29]Blood 2024；144(S1)：1646 [30]Blood 2023,142(S1),734 [31]2024 ASCO 7008 [32]2024 EHA S231 林宁晶 北京大学肿瘤医院淋巴肿瘤内科 医学博士，主任医师 2006.12-2008.2于美国杜克大学肿瘤中心进行博士后研究 中国医药教育协会淋巴瘤分会 副主任委员 中国研究型医院学会细胞研究与治疗专委会副主任委员 专业为淋巴瘤诊治与转化研究 （来源：《肿瘤瞭望–血液时讯》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。