Cabozantinib (s)-Malate

Updated data for casdatifan in late-line kidney cancer demonstrated median progression-free survival (PFS) of 15.1 months and a confirmed overall response rate (cORR) of 45% for the 100mg once-daily (QD) cohort At least two additional data presentations for casdatifan are expected in 2026: updated data for casdatifan plus cabozantinib and initial data in early-line kidney cancer In addition to the ongoing Phase 3 PEAK-1 study, Arcus plans to initiate a Phase 3 study in the first-line (1L) metastatic setting evaluating casdatifan in a tyrosine kinase inhibitor (TKI)-free combination by the end of 2026 With $1.0 billion in cash, cash equivalents and marketable securities at year-end, Arcus is well positioned to advance casdatifan with cash runway until at least the second half of 2028 HAYWARD, Calif.--(BUSINESS WIRE)-- Arcus Biosciences, Inc. (NYSE:RCUS), a clinical-stage, global biopharmaceutical company focused on developing differentiated molecules and combination therapies for patients with cancer and inflammatory and autoimmune diseases, today reported financial results for the year and quarter ended December 31, 2025, and provided a pipeline update on its clinical-stage investigational molecules and discovery programs. “This week’s updated data at ASCO GU continue to validate casdatifan’s profile as the best-in-class HIF-2a inhibitor and new potential standard-of-care therapy for ccRCC,” said Terry Rosen, Ph.D., chief executive officer of Arcus. “We are focused on rapidly enrolling PEAK-1, our Phase 3 study evaluating casdatifan plus cabozantinib in IO-experienced patients, as well as determining the optimal TKI-free casdatifan-based regimen for a registrational trial in the 1L setting by the end of the year. Together, the IO-experienced and first line settings represent an over $5 billion peak sales opportunity for casdatifan. We remain extremely well-positioned to execute on our casdatifan program and our emerging inflammation portfolio, with cash runway until at least the second half of 2028.” Casdatifan (HIF-2a inhibitor) Recent Data Update: Earlier this week, Arcus shared updated ORR and PFS data from the cohorts of the Phase 1/1b ARC-20 study evaluating casdatifan monotherapy in late-line ccRCC. These data will be presented by Dr. Toni Choueiri of the Dana-Farber Cancer Institute at ASCO GU on February 28, 2026. In the 100mg QD cohort, with 17.9 months of median follow up, cORR increased to 45.2% with an mPFS of 15.1 months as of the data cut-off (DCO) date of January 30, 2026. In the pooled analysis (n=121), with 20.8 months of median follow up, cORR increased to 34.7% and mPFS was stable at 12.2 months as of the DCO. New biomarker data demonstrated a strong correlation between the magnitude and durability of erythropoietin suppression by casdatifan and clinical benefit, including rate of primary progression, cORR and PFS. The safety profile of casdatifan remained consistent with prior analyses. In the 100mg QD cohort, with 17.9 months of median follow up, cORR increased to 45.2% with an mPFS of 15.1 months as of the data cut-off (DCO) date of January 30, 2026. In the pooled analysis (n=121), with 20.8 months of median follow up, cORR increased to 34.7% and mPFS was stable at 12.2 months as of the DCO. New biomarker data demonstrated a strong correlation between the magnitude and durability of erythropoietin suppression by casdatifan and clinical benefit, including rate of primary progression, cORR and PFS. The safety profile of casdatifan remained consistent with prior analyses. Casdatifan Development Program: IO-experienced ccRCC: PEAK-1, a Phase 3 study evaluating casdatifan + cabozantinib versus cabozantinib in immunotherapy (IO)-experienced metastatic ccRCC, started enrollment in 3Q25 and is now enrolling globally. Similar Phase 3 trials in this setting have completed enrollment in 18 months or less, and Arcus’s goal is to achieve a similar timeline. 1L ccRCC: Arcus is focused on TKI-free regimens, which are enabled by the consistently low rate of primary progression observed with casdatifan across all cohorts and settings evaluated to date. Emerging data from the following cohorts are designed to determine the optimal 1L registrational strategy with the goal of initiating a Phase 3 study by the end of 2026: Casdatifan plus zimberelimab (Arcus’s anti-PD-1 antibody) and ipilimumab: Arcus is now enrolling a cohort evaluating this combination as part of ARC-20. Casdatifan plus zimberelimab: The cohort evaluating this combination in ARC-20 has completed enrollment. Arcus plans to present data from this cohort in the second half of 2026. Arcus expects this to be the backbone of its front-line strategy. Casdatifan plus volrustomig (AstraZeneca’s anti-PD-1/CTLA-4 bispecific antibody): This combination is being evaluated in the eVOLVE-RCC02 study (which is being operationalized by AstraZeneca). Additional combinations in ccRCC and tumor types: This year, Arcus plans to evaluate the potential of casdatifan in at least one additional combination in 1L ccRCC and in another tumor type. Casdatifan plus zimberelimab (Arcus’s anti-PD-1 antibody) and ipilimumab: Arcus is now enrolling a cohort evaluating this combination as part of ARC-20. Casdatifan plus zimberelimab: The cohort evaluating this combination in ARC-20 has completed enrollment. Arcus plans to present data from this cohort in the second half of 2026. Arcus expects this to be the backbone of its front-line strategy. Casdatifan plus volrustomig (AstraZeneca’s anti-PD-1/CTLA-4 bispecific antibody): This combination is being evaluated in the eVOLVE-RCC02 study (which is being operationalized by AstraZeneca). Planned Data Readouts: Arcus expects to have at least two data readouts for casdatifan in 2026: More mature ORR data and initial PFS data for approximately 45 patients treated in the ARC-20 cohort evaluating casdatifan plus cabozantinib in the IO-experienced setting will be presented at an investor event or at a medical conference. All patients will have had at least 12 months of follow-up. Initial data from the ARC-20 cohorts evaluating casdatifan in early-line settings, including the cohort evaluating casdatifan plus zimberelimab in 1L ccRCC. Quemliclustat (small-molecule CD73 inhibitor) Enrollment was completed for PRISM-1, a Phase 3 trial of quemliclustat combined with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in 1L metastatic pancreatic ductal adenocarcinoma, in September 2025. Results from this study are expected in the first half of 2027. Emerging I&I Portfolio Arcus expects to advance its first inflammation program, a potential best-in-class oral MRGPRX2 antagonist for atopic dermatitis and chronic spontaneous urticaria, into clinical development in 2026. The molecule was designed to have exquisite potency, enabling the ability to elicit maximal pharmacology at substantially lower exposure relative to the most advanced MRGPRX2 antagonist in clinical development, thereby avoiding potential exposure-limiting toxicities. Clinical development will begin with a first-in-human healthy volunteer study followed quickly by a proof-of-concept study, with potential for data within a year from entry into the clinic. Arcus also expects to advance an oral small-molecule TNF inhibitor, a potential treatment for rheumatoid arthritis, psoriasis and inflammatory bowel disease, into the clinic in late 2026 or early 2027. The molecules are being designed to selectively block TNFR1 signaling in order to achieve better safety and efficacy than approved anti-TNF antibodies. The molecule was designed to have exquisite potency, enabling the ability to elicit maximal pharmacology at substantially lower exposure relative to the most advanced MRGPRX2 antagonist in clinical development, thereby avoiding potential exposure-limiting toxicities. Clinical development will begin with a first-in-human healthy volunteer study followed quickly by a proof-of-concept study, with potential for data within a year from entry into the clinic. The molecules are being designed to selectively block TNFR1 signaling in order to achieve better safety and efficacy than approved anti-TNF antibodies. Domvanalimab (Fc-silent anti-TIGIT antibody) plus Zimberelimab (anti-PD-1 antibody) Status Update: Arcus and Gilead are in the process of rapidly winding down activities related to the Phase 3 STAR-221 and Phase 2 EDGE-Gastric studies. A futility analysis of STAR-121, a Phase 3 study evaluating domvanalimab plus zimberelimab and chemotherapy in 1L non-small cell lung cancer, will be conducted in the next couple of months to determine next steps for the program. Financial Results for Fourth Quarter and Full Year 2025: Cash, Cash Equivalents and Marketable Securities were $1.0 billion as of December 31, 2025, compared to $992 million as of December 31, 2024. The increase is primarily due to $429 million in net proceeds from issuances of our common stock, the additional $50 million drawdown under our term loan facility, and $37 million from Taiho for development milestones and option payments, partially offset by cash used in research and development activities. Arcus expects its cash and investments will be sufficient to provide funding until at least the second half of 2028. Revenues were $33 million for the fourth quarter 2025, compared to $36 million for the same period in 2024. Fourth quarter 2025 revenues included (i) $23 million related to programs under the Gilead collaboration, (ii) $7 million related to Taiho's exercise of its option to casdatifan, and (iii) $3 million related to Gilead’s ongoing rights to access Arcus’s research and development pipeline. GAAP revenue for the full year 2026 is expected to be between $45 to $55 million. Research and Development (R&D) Expenses were $121 million for the fourth quarter 2025, compared to $111 million for the same period in 2024. The net increase of $10 million was primarily attributable to higher late-stage development costs, driven by increased enrollment and clinical activities in our Phase 3 studies for casdatifan and quemliclustat, partially offset by lower early-stage development costs, as earlier study activities for domvanalimab and etrumadenant approached completion. For the fourth quarter 2025 and 2024, Arcus recognized gross reimbursements of $28 million and $41 million, respectively, for shared collaboration expenses, primarily from Gilead. Gross reimbursements were $127 million for the full year 2025, compared to $165 million for 2024. Our partnership reimbursements decreased compared to the prior year, primarily due to Gilead-led activities representing a larger share of total joint development costs and an increase in programs fully funded by us. R&D expenses are expected to decrease meaningfully for the full year 2026 relative to 2025; the magnitude of the decrease will be determined in part by the results of the futility analysis of STAR-121. Non-cash stock-based compensation expense was $8 million for each of the fourth quarter 2025 and 2024. General and Administrative (G&A) Expenses were $26 million for the fourth quarter 2025, compared to $28 million for the same period in 2024. Non-cash stock-based compensation expense was $7 million for the fourth quarter 2025, compared to $9 million for the same period in 2024. Net Loss was $106 million for the fourth quarter 2025, compared to $94 million for the same period in 2024. Conference Call Information: Arcus will host a conference call and webcast today, February 25, 2026, at 1:30 PM PT/4:30 PM ET to discuss its fourth-quarter and full-year 2025 financial results and pipeline updates. To access the call, please dial +1 (646) 844-6383 (local) or +1 (833) 470-1428 (toll-free), using Access Code: 190500. Participants may also register for the call online using the following link: https://events.q4inc.com/attendee/640976415. To access the live webcast and accompanying slide presentation, please visit the “Investors & Media” section of the Arcus Biosciences website at www.arcusbio.com. A replay of the webcast will be available following the live event. About Arcus Biosciences Arcus Biosciences is a clinical-stage, global biopharmaceutical company focused on developing differentiated molecules for the treatment of cancer and inflammatory and autoimmune diseases. In partnership with industry collaborators, patients and physicians around the world, Arcus is expediting the development of its late-stage portfolio of first- and/or best-in-class medicines against well-characterized biological targets and pathways and studying novel, biology-driven combinations that have the potential to help people with cancer live longer. Founded in 2015, the company has advanced multiple investigational medicines into registrational clinical trials including casdatifan, a HIF-2a inhibitor for clear cell renal cell carcinoma, and quemliclustat, a small-molecule CD73 inhibitor for pancreatic cancer. For more information about Arcus Biosciences’ clinical and preclinical programs, please visit www.arcusbio.com. Forward-Looking Statements This press release contains forward-looking statements. All statements regarding events or results to occur in the future contained herein are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, the timing of milestones, including future data presentations, initiation of new cohorts and clinical studies and completion of enrollment for ongoing studies; potential for casdatifan to become a standard-of-care therapy; and advantages of Arcus’s inflammation and immunology programs. All forward-looking statements involve known and unknown risks and uncertainties and other important factors that may cause Arcus’s actual results, performance or achievements to differ materially from those expressed or implied by the forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to, risks associated with: interim data not being guarantees of future data or replicated in other studies evaluating casdatifan, including the Phase 3 PEAK-1 study; the unexpected emergence of adverse events or other undesirable side effects with casdatifan; risks associated with manufacturing or supplying product for clinical trials evaluating casdatifan; adverse data from toxicology studies that affect Arcus’s ability to advance development candidates from its immunology and inflammation programs, uncertainties in timelines associated with the conduct of clinical studies and with respect to the regulatory approval process; changes in the competitive landscape for Arcus’s programs; and the inherent uncertainty associated with pharmaceutical product development and clinical trials. Risks and uncertainties facing Arcus are described more fully in the “Risk Factors” section of Arcus’s most recent periodic report filed with the U.S. Securities and Exchange Commission (SEC) and in other filings that Arcus makes with the SEC from time to time, which are available at www.sec.gov. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this press release. Arcus disclaims any obligation or undertaking to update, supplement or revise any forward-looking statements contained in this press release, except to the extent required by law. The Arcus name and logo are trademarks of Arcus Biosciences, Inc. All other trademarks belong to their respective owners. ARCUS BIOSCIENCES, INC. Consolidated Statements of Operations (unaudited) (In millions, except per share amounts) Three Months Ended December 31, Years Ended December 31, 2025 2024 2025 2024 Revenues: License and development service $ 29 $ 28 $ 221 $ 222 Other collaboration 4 8 26 36 Total revenues 33 36 247 258 Operating expenses: Research and development 121 111 523 448 General and administrative 26 28 110 120 Impairment of long-lived assets — — — 20 Total operating expenses 147 139 633 588 Loss from operations (114 ) (103 ) (386 ) (330 ) Non-operating income (expense): Interest and other income, net 10 12 41 52 Interest expense (2 ) (2 ) (8 ) (4 ) Total non-operating income, net 8 10 33 48 Loss before income taxes (106 ) (93 ) (353 ) (282 ) Income tax expense — (1 ) — (1 ) Net loss $ (106 ) $ (94 ) $ (353 ) $ (283 ) Net loss per share: Basic and diluted $ (0.89 ) $ (1.03 ) $ (3.29 ) $ (3.14 ) Shares used to compute net loss per share: Basic and diluted 118.5 91.7 107.4 90.1 Selected Consolidated Balance Sheet Data (unaudited) (In millions) December 31, 2025 December 31, 2024 Cash, cash equivalents and marketable securities $ 1,010 $ 992 Total assets 1,139 1,150 Total liabilities 508 665 Total stockholders’ equity 631 485 Derived from the audited financial statements included in the Company's Annual Report on Form 10-K filed with the Securities and Exchange Commission on February 25, 2026. Investor Inquiries: Pia Eaves VP of Investor Relations & Strategy (617) 459-2006 peaves@arcusbio.com Media Inquiries: Holli Kolkey VP of Corporate Affairs (650) 922-1269 hkolkey@arcusbio.com Maryam Bassiri AD, Corporate Communications (510) 406-8520 mbassiri@arcusbio.com

本文从抗肿瘤药物剂量选择的总体原则出发，按照药物研发的整个历程，分为三个议题进行讲解：一是首次上市的剂量探索和优化，二是扩展适应症过程中单药及联合用药的剂量选择，三是上市后的剂量优化。第一部分：总体原则一、优化给药策略——大势所趋 抗肿瘤药物的给药策略优化，是目前整个药物研发领域的大势所趋。 随着新靶点、新机制、新结构的创新型药物研发，如何制定合理的给药策略面临新的挑战。如果说以前很多抗肿瘤药物像“手榴弹”一样简单粗暴，那么随着现在ADC产品、RDC产品、双抗产品越来越多，给药剂量选择已经越来越精细化、人性化。 因此，给药策略是进入关键注册研究之前讨论的核心要点之一。 近期，CDE在多项指导原则中已经强调了剂量优化的必要性，包括2024年发布的《模型引导的创新药物剂量探索和优化技术指导原则》。同时，在国际创新联盟（IQ联盟）的一项调研工作中，有93%的申办方认为，现在剂量优化的相关指导原则对他们的临床开发策略会产生影响。因此，越来越多的申办方开始重视早期药物研发中的剂量选择研究。二、优化剂量的目标——双赢 剂量优化的目标是为了实现双赢： 从患者角度（以患者为中心的药物研发）： 使患者的获益/风险比达到最大化 充分暴露：提高/维持疗效并延缓耐药 减少不良反应：包括延迟毒性发生、降低毒性级别和频率，提高生活质量 可耐受：最小程度的剂量调整，使患者能够持续用药 从申办方角度： 最大化投资回报，最终使患者获益 尽量减少暴露于亚治疗剂量的患者人数 加速开发潜在的有效药物，提高成功概率 使可能失败的候选药物及时终止，避免资源浪费 在后面案例分享中，会结合具体案例讲解如何提高成功、如何减少失败。三、给药方案的要素 在讲解给药之前，需要先理解给药方案到底包含哪些要素。 给药方案是一个比较复杂的系统，不仅仅是“固定剂量”或“每周一次”这么简单，它包含多个可变要素： 剂量层面： 可以是基于固定剂量，也可以是基于体重、基于体表面积 可以是起始剂量，也可以是维持剂量 缓解后是否需要降低剂量 高剂量冲击 vs 低剂量长期 给药频率层面： 给药间隔有多种可变的变量 给药周期层面： 是持续用药，还是采用有限的周期数 什么时候可以停药 联合治疗层面： 两个药是一起用，还是哪个可以提前终止 给药途径层面： 静脉给药还是皮下给药，等等 所以，首先大家心中要有一个“big picture”——给药方案的要素是非常丰富的。四、剂量合理性评估的证据框架 面对这么多要素，申办方可能会想：这该怎么探索？ 2024年，CDE临床药理部门牵头，联合临床一部，制定了《模型引导的创新药物剂量探索和优化技术指导原则》，其中已经非常清楚地列出了剂量合理性评估的整个证据框架。来划一下重点： 剂量选择的基础证据： 拟定剂量/暴露量下具有临床意义的有效性、安全性证据 不同剂量/暴露量水平、多个用药周期的有效性、安全性和耐受性数据 关键性支持证据： 基于模型得到的充分的剂量/暴露-效应关系分析 这是剂量选择和评价药物治疗窗的关键支持证据 重要组成部分： 基于机制的靶组织/替代组织中靶点占有率 生物标志物的药动学-药效学关系 有力支撑： 稳健可靠的模型可有力支持剂量选择的合理性 在国际创新联盟（IQ）面向各大药企的调研报告中，对不同要素在早期研发剂量选择中的重要性进行了问卷调查，结果与CDE的指导原则是比较匹配的。整体来说，业界也是按照这样一个阶梯性的证据链框架，来制定创新药物的剂量选择策略。五、给药剂量探索及优化贯穿药物研发全周期 给药剂量的探索和优化，从哪里开始，到哪里结束？ 实际上，它是贯穿于药物研发全周期的。 它的起点不是在进入人体的时候，而是在临床前阶段就要开始。从开始评估质量指标和首次剂量范围的时候，就要基于临床前数据，包括可以预测人体有效剂量和毒性剂量的范围，同时还有初步的剂量效应关系以及生物标志物的探索。 它的终点也不仅仅是上市。上市后可能还有剂量优化要求，同时还有很多新适应症的探索。可以基于临床研究中发现的一些问题，不断去优化、去改进，为后续药物在上市后用得更好、更安全提供支持。 所以，对于业界的同仁来说，一定要理解：给药剂量探索一定是全研发周期的。第二部分：首次上市的剂量探索及优化一、剂量探索的新模式 剂量探索实际上已经进入了一个新的模式。 以前的时候，是3+3的剂量递增，达到最大耐受剂量（MTD）后，在不同的肿瘤中进行扩展，如果观察到比较好的疗效，就可以进入三期研究。 但是现在，越来越多的研究开始采用剂量优化的模式。 新模式的关键要素： 剂量探索阶段，建议评估两个及以上的剂量水平，保证足够的样本量、药代动力学/药效学采样以及治疗/随访时间。 考虑药物预期治疗窗以及模型构建的设计需要，设置合理的剂量探索范围与间隔，收集药代动力学、药效学、生物标志物、免疫原性（如适用）以及相关协变量、安全有效性数据等。 探索性临床试验无需证明拟选择给药方案相较于对照组的统计学优效或非劣效性，或不同剂量组间的统计学比较，更多的是进行趋势性比较。 现在的剂量探索中会设置不同剂量组，同时也看到很多产品在早期就选择了和标准治疗进行对照。 所以，现在已经步入了一个新的剂量探索模式。这种模式和以往的模式到底好在哪里？后面的案例中我们会具体讲解。二、首个适应症临床开发需考虑的因素 首个适应症临床开发的起点在临床前： 务必明确治疗窗——不同适应症的治疗窗可能会不一样 确定相关生物标志物——不是等到人体后再探索，而是在这个阶段就要考虑 剂量范围的设定——包括剂量递增设计 有些申办方会选择剂量回填，这是在人体上定义剂量窗的上限和下限。通过剂量回填可以提供更多的样本量，让数据分析更加稳健。 进一步验证非临床中提到的相关生物标志物是否在人体上能够得以重现 获得抗肿瘤活性证据——通常在剂量优化前要获得抗肿瘤活性的证据，这样才能有信心去进一步精细化优化 如果剂量递增中缺乏抗肿瘤活性，可考虑采用“无悔剂量”——有足够耐受性及最大限度提高靶点饱和度/通量调节，尽快启动扩展 剂量优化中的给药方案应具有使患者获益的可能性——最低剂量也要让患者高于非临床的起效剂量 尽可能提高剂量优化效率——基于药物特点（小分子、抗体、ADC、双抗）设计高效的临床研究，采用生物标志物和替代疗效终点，加速研发 非常重要的一点：应用临床药理相关工具 接下来会用三个案例，分别从有效性驱动、安全性驱动、药效指标驱动三个角度，讲解不同情况下的剂量优化。三、案例分享案例1：有效性驱动的剂量优化（某国产ADC产品） 这是一个国产的ADC产品。ADC是目前制药领域研发的热点。这个ADC靶向Nectin-4，搭载的是拓扑异构酶抑制剂类小分子（与已上市产品不同）。 在剂量爬坡过程中，采用了传统的加速滴定和波动设计。探索了最高8毫克，每三周给药一次。同时参考了同类产品的数据，也进行了第一天和第八天的分次给药（两阶段给药方式）。 在PK剂量扩展阶段，最终选择了两个剂量进行扩展：6毫克和8毫克。 在剂量递增过程中，8毫克剂量组报告了1例剂量限制性毒性（DLT），但同时也看到了一些安全性数据，所以没有继续往上爬。 那么，6毫克和8毫克如何进行剂量选择？ 从安全性数据看，8毫克剂量组的安全性比6毫克组有一定提升，但导致治疗中断的比例较高（约70%）。 再看两组的客观缓解率（ORR）和疾病控制率（DCR）： 6毫克组（N=31）：ORR 41.9%，DCR 90.3% 8毫克组（N=32）：ORR 50.0%，DCR 84.4% 分次给药组（N=11）：ORR 18.2%，DCR 54.5% 两组ORR差异并不明显，难以直接选择剂量。 再看缓解持续时间（DoR）： 6毫克组：7.6个月 8毫克组：5.5个月 也就是说，低剂量组反而可以拿到更好的缓解持续时间。 这个时候应该怎样选择？ 好在剂量扩展阶段入组了一定样本量，可以进行无进展生存期（PFS）分析。结果显示，两个组的中位PFS都是5.8个月，没有显著差异。 在这种情况下，ORR没有显著差异，PFS也没有显著差异，选择6毫克能够获得更好的安全性，患者能够持续用药，获得更好的持续缓解，显然是更好的剂量选择。 从这个案例可以看到： 当小分子毒性药物发生变化，包括连接子发生变化后，临床剂量探索的量效反应和以前的同类产品其实是不一样的 基于ORR有时很难选择合理剂量，但有PFS这类与时间相关的生存数据后，可以大大增强剂量选择的信心 最终，该产品选择了6毫克进行后续研发。案例2：安全性驱动的剂量优化（Elranatamab，BCMA-CD3双抗） 这是一个BCMA-CD3双特异性抗体，用于多发性骨髓瘤。我们知道，双抗这类产品通常有一个不良反应——细胞因子释放综合征（CRS）。 这个药物的剂量方案实际上比较复杂，包括两次分阶梯剂量、预激剂量、每周给药、之后降低剂量等。 关于CRS的剂量优化： 首先，研究比较了静脉注射和皮下注射两种给药途径。发现皮下给药可以降低CRS发生率，且能延迟CRS发生。 数据显示： 1000μg/kg剂量下，皮下给药≥2级CRS发生率为33.3% 而50μg/kg静脉给药≥2级CRS发生率为83.3% 而且皮下给药临床使用更加便利，所以选择了皮下制剂进行后续研发。 暴露-效应分析的应用： 研究发现，CRS主要发生在首次给药24小时内，且与首次给药后的Cmax显著相关。在600-1000μg/kg之间，CRS等级/发生率无显著差异。 通过模型分析，44毫克（600μg/kg）的预激剂量可以改善CRS后果，特别是CRS/住院的持续时间。 更多的暴露-效应分析显示，12/32毫克方案与44毫克方案相比，能更好地降低所有等级和2级以上CRS发生率。 所以我们可以看到，在一个非常复杂的分阶梯给药的CRS探索过程中，临床药理学的模型发挥了非常重要的作用。后续将按照模型推导，在临床中进一步验证，最终选定剂量。 这个案例非常好地反映了如何基于模型进行相关分析。案例3：药效指标驱动的剂量优化（Belzutifan，HIF2α抑制剂） Belzutifan是一个HIF2α抑制剂，用于治疗希佩尔-林道综合征（VHL综合征）。 从小分子靶向药物可以看到，当信号通路达到一定抑制程度后，更高的剂量并不会带来更多疗效，只会增加安全性风险。长期给药的低级别不良反应会影响生活质量，严重不良反应会影响患者接受其他有效治疗的机会。 在Belzutifan的早期临床数据中，随着暴露量增加，客观缓解率并没有提高，而三级以上贫血的发生率却随之增高。 在20-240毫克的剂量探索过程中，研究者确定了一个药效学指标——EPO水平。 为什么选择EPO？对于HIF2α抑制剂来说，这是一个靶点相关的不良反应。在早期研究中，HIF2α基因敲除的动物模型中就已经观测到贫血及EPO下降。所以在非临床阶段就已经进行了相关指标的检测和验证。 研究发现，在120毫克剂量下，EPO的抑制率已经达到了效应平台。基于这些数据，研究者没有进行平行的剂量比较，而是直接选择了120毫克进行后续临床研发——因为这个剂量下已经达到了很好的疗效，且安全性可接受。 这个案例说明：药效学指标的选择和验证，往往是从非临床阶段就开始的。有了前期的积累，才能在临床阶段快速选择指标进行验证，推进整个药物的临床开发。第三部分：扩展适应症——单药及联合用药一、单药扩展适应症的剂量考虑 单药扩展适应症包括两个方面：同一瘤种从末线到前线，以及不同瘤种之间的扩展。 同一瘤种从末线到前线： 患者疾病负荷及耐受情况不同 例如靶向PSMA的放射性治疗药物Pluvicto：末线治疗时给予4-6周期，根据耐受情况可增加2周期；前线治疗（转移患者）时仅给予4周期 不同疾病中靶点表达、患者情况是否需要调整： 例如MEK抑制剂用于黑色素瘤 vs 丛状神经纤维瘤，剂量可能不同 泛瘤种研发——给药剂量适用性是需要重点考虑的问题： 考虑不同肿瘤中相同剂量是否合适（例如ADC药物） PK差异：是否存在位置、肿瘤负荷及其他因素影响PK？PK差异是否会导致安全性及疗效的变化（例如肝癌患者肝功能受损的情况）？ 固定剂量给药的合理性（例如小分子药物） 某些特殊瘤种是否需要排除（因为PK的特殊性） 所以，当扩展适应症的时候，需要认真考虑：我的剂量要不要发生变化？ 案例：伯瑞替尼（MET抑制剂） 伯瑞替尼是国产的MET抑制剂。首次上市用于肺癌时，剂量为200毫克QD。新增适应症用于胶质母细胞瘤时，选择了300毫克QD。 前期进行了剂量探索，发现随着剂量增加，血浆浓度特别是脑脊液中的药物浓度也随之增加。对于中枢神经系统肿瘤来说，必须要透过血脑屏障。而且胶质母细胞瘤是进展很快的肿瘤，相对更高的剂量，以及患者可接受的耐受性可能会更高。 在一期剂量探索中，已经看到部分患者出现了初步的疗效数据（PR）。同时，通过脑脊液和血液的浓度测定，发现在300毫克剂量下能够达到非临床ED90以上。 在二三期研究中，采用随机对照临床试验设计，入组84例患者，主要终点是总生存期（OS），最终取得了很好的结果（HR=0.51）。该产品最终成功获批新增适应症。 所以，在某些扩展适应症的情况下，确实需要考虑剂量是否需要发生变化。二、联合用药的剂量考虑 联合用药是肿瘤领域关注的另一个热点。联合用药同样要考虑剂量，包括给药方案是否需要调整。因为这个时候，你不再是一个“快乐的单身汉”，已经有了“另外一半”，有些时候要考虑一下对方的感受。 联合用药的考虑要点： 剂量和单药可能相同，也可能不同 单药充分的数据为联合用药提供依据（不排除某些药物可能会直接联合） 给药周期、频率等因素匹配 有效性是否增效？ 不良反应是否叠加？ 如何保证疗效的情况下调整剂量？ 药物相互作用 重点讲一下药物相互作用： 案例1：尼拉帕利联合阿帕他胺/阿比特龙 尼拉帕利（PARP抑制剂）在申办方的管线中，正好有两个不同机制的药物都是标准治疗——阿帕他胺（ARi）和阿比特龙（CYP17Ei），用于前列腺癌。 在早期探索中，研究者惊讶地发现：当尼拉帕利联合阿帕他胺后，尼拉帕利的暴露量相比单药降低非常多；但联合阿比特龙时，暴露量没有明显变化。 也就是说，某些时候药物相互作用可能导致无法进行联合。申办方最终选择了阿比特龙联合组开展研究，最终拿到了PMS的成功结果。 这个案例说明：药物联合需要考虑药物相互作用的影响。但存在药物相互作用，并不代表无法联合。 案例2：他拉唑帕利联合恩扎卢胺 他拉唑帕利（PARP抑制剂）单药用于乳腺癌的剂量是1毫克QD。联合恩扎卢胺（ARi）用于前列腺癌时，在早期剂量递增探索中发现，联合后的暴露量相比单药显著升高。 升了以后还能不能连？申办方进行了临床药理学模拟和探索。通过预测发现，如果高于0.75毫克，可能会出现比单药更高的暴露量，可能导致不耐受。所以他们选择了0.5毫克剂量与恩扎卢胺联合。 最终这个III期研究在HRRm人群中取得了很好的结果（主要终点rPFS，HR=0.424）。 从这两个案例可以看到，充分的单药PK数据为后续联合研发提供了非常重要的支持。这就是为什么在联合研发时，通常要求有充分的单药PK数据。第四部分：上市后剂量优化一、概述 上市后剂量优化，我们目前已经陆续有一些沟通交流申请——发现产品获批后临床反应比较大，想降低剂量。 我们调研了相关文献，发现在FDA的很多产品中，上市后要求里面有一些剂量优化的案例。回顾分析显示，大部分药物是基于安全性的驱动要求开展上市后研究。 在13款完成上市后研究的药品中，仅有2个产品改变了说明书剂量。从这个数据可以看出，上市后的剂量优化需要提供充分的证据。二、案例分享 案例1：尼拉帕利 尼拉帕利在NOVA研究支持首次注册上市时，用于卵巢癌二线治疗，剂量为300毫克QD。 III期研究中发现，68.9%的患者需要下调剂量。基于这一发现，研究者进一步分析： 通过回顾性分析，比较gBRCA阳性患者三个剂量组的PFS，未见显著差异。但是发现剂量与体重、基线血小板计数有相关性，与不良反应发生特别相关。 基于此，研究者提出了基于体重和基线血小板的新的给药方案： 体重<77公斤或基线血小板<15万/μL的患者：200毫克 体重≥77公斤且基线血小板≥15万/μL的患者：300毫克 基于上述分析，在后续开展的一线卵巢癌PRIMA研究中，III期进行中变更了给药方案。 中国基于桥接研究RCT的PFS数据，二线及一线研究均采用了新的给药方案。 这个案例说明：当有了充分的证据后，才敢在III期研究中变更方案。即便基于同样的分析，在已批准的适应症中可能仍然采用原剂量，而在新增适应症中选择新方案。 案例2：Cabozantinib（多靶点TKI） Cabozantinib于2012年首次上市，用于甲状腺髓样癌，给药剂量为140毫克QD。 EXAM研究中发现较高比例的剂量调整——82%的患者剂量下调，46%的患者进行了第二次剂量调整。 暴露-效应关系分析显示： 暴露量-有效性曲线较为平坦 暴露量-安全性呈线性关系 上市后研究中，选择了60毫克和140毫克两个剂量组进行平行比较，入组了相对较大的样本量（各100多例）。 研究发现： 低剂量确实可以改善安全性 但两组的ORR比较类似 最终PFS分析显示HR=1.24——也就是说，降低了剂量可能会影响PFS 基于上述研究，最终没有改变药物给药剂量。 从这个案例可以看出：ORR并不能预测PFS的情况。降低剂量虽然改善了安全性，但可能影响生存获益。第五部分：总结与展望一、核心要点总结 抗肿瘤药物的剂量优化需要纳入创新药早期临床研发，包括整个药物全生命周期的管理过程中——这是行业目前的现状。 基于多学科的证据，包括非临床和临床药理的数据，以及良好的临床研究设计，能够高效推进药物的临床开发。 首次剂量上市的探索和优化，强调创新。在越来越多的新型产品情况下，剂量探索完全需要量身定制。要基于整体的证据链，不断降低剂量的不确定性。 需要特别强调的是：不是说所有的产品都要开展随机对照。当已经有了充分的数据（包括一些罕见病等情况），有些情况下没有必要一定要做随机。 扩展适应症时，最需要考虑的是剂量要不要发生变化，无论是单药还是联合用药。 上市后剂量调整，我们强调稳健。需要提供非常充分的有效性数据。特别是降低剂量可能带来疗效损失的情况下，对于晚期肿瘤患者来说，疗效仍是重中之重，需要提供非常充分的证据。 与其上市后进行剂量调整，更多的我们还是强调在早期进行充分的剂量探索。二、结语 虽然创新药的研发过程中，并不是所有的药品都需要进行精益求精的探索，但我们相信，在剂量探索方面，值得花费更多的精力。也希望中国创新药能够取得更亮眼的成绩！ 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