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Summary of Incyte's 2025 Conference Call Company Overview - **Company**: Incyte Corporation (NasdaqGS: INCY) - **Event**: 2025 Conference Call held on October 19, 2025 - **Focus**: Update on two solid tumor programs: TGF receptor 2 by PD-1 bispecific and KRAS G12D inhibitor Key Points Industry and Company Focus - **Tumor Types**: - TGF receptor 2 by PD-1 bispecific targets microsatellite stable (MSS) colorectal cancer, which constitutes 80-90% of colorectal cancer patients [2][3] - KRAS G12D inhibitor focuses on pancreatic ductal adenocarcinoma (PDAC), specifically targeting the most common mutation in this patient population [4][48] Core Insights and Arguments - **TGF Receptor 2 by PD-1 Bispecific**: - MSS colorectal cancer has a significant unmet medical need as it does not respond to PD-1 inhibitors [2][3] - Previous trials showed a 0% response rate in three studies and only a 2% response in another for patients with MSS colorectal cancer [3] - The bispecific antibody INCA0890 is designed to target TGF receptor 2, which is a potent immunosuppressive factor in solid tumors [8][10] - The approach aims to selectively inhibit TGF signaling in tumor-infiltrating lymphocytes, avoiding systemic toxicity [24][25] - **KRAS G12D Inhibitor**: - No approved KRAS G12D inhibitors exist, presenting a unique opportunity for Incyte [4][48] - The G12D mutation is associated with a worse prognosis compared to wild-type patients [48] - The inhibitor shows potential for combination with standard chemotherapy regimens like gemcitabine/nab-paclitaxel and modified FOLFIRINOX [5][57] Clinical Data and Safety Profile - **TGF Bispecific**: - Phase 1 trial showed a favorable safety profile with only 4.6% of patients discontinuing due to treatment-related adverse events [36][39] - The majority of patients treated had advanced disease, with a median of 3 prior lines of therapy [36] - Efficacy data indicated responses in patients with liver metastases, which is unprecedented for immunotherapy in this context [42][46] - **KRAS G12D**: - Phase 1 trial demonstrated a 34% response rate and an 86% disease control rate among treated patients [54][66] - The safety profile was manageable, with no dose-limiting toxicities observed up to 1600 mg [51][52] - The drug showed deeper and quicker reductions in circulating tumor DNA (ctDNA) at higher doses, correlating with clinical responses [53] Market Opportunity and Future Plans - **MSS Colorectal Cancer**: - Represents a significant market with nearly 2 million diagnosed cases in the US, Western Europe, and Japan, and a dismal 16% five-year survival rate for stage 4 patients [62][63] - Incyte plans to initiate a Phase 3 trial in early 2026, focusing on first-line treatment in combination with standard chemotherapy [64][68] - **Pancreatic Ductal Adenocarcinoma**: - A rapidly progressive disease with a high mortality rate and limited treatment options [65] - Incyte aims to be the first targeted therapy for KRAS G12D patients, with plans to align with regulators for a registration program in 2026 [67][68] Additional Considerations - The TGF bispecific and KRAS G12D inhibitor programs are seen as strategic choices to address significant unmet medical needs in oncology [67][68] - The company is committed to a disciplined approach in capital allocation and program development based on emerging scientific data [74] This summary encapsulates the critical insights and future directions discussed during Incyte's 2025 conference call, highlighting the company's focus on innovative therapies for challenging cancer types.

Core Insights - The 2025 Nobel Prize in Physiology or Medicine was awarded to three scientists for groundbreaking discoveries in regulatory T cells, revealing how the immune system maintains self-balance through "peripheral immune tolerance," which is crucial for understanding autoimmune diseases and developing new cancer immunotherapy strategies [4][5] - Traditional animal models struggle to accurately simulate the human immune system due to species differences, leading to challenges in mechanism research, clinical translation, and model construction [4] - Humanized immune system mice provide a key technology to address these issues, allowing for effective preclinical evaluation of candidate drugs, significantly reducing subsequent development risks, and providing a reliable platform for assessing new cell therapies and bispecific antibodies [5] Course Overview - An online course titled "Applications of Humanized Immune System Mice in Tumor Immunity and Autoimmune Diseases" will be held on October 21, featuring Dr. Yu Jing, a senior scientist at Saiye Bio, focusing on scientific decision-making for obtaining valuable experimental data [5][7] - The course will cover the following topics: 1. Advances in tumor immunity: Translating Nobel-level discoveries into new treatment strategies and related research dynamics [7] 2. Model development history: Reviewing the evolution of models and the characteristics and applicable scenarios of PBMC, HSC, and other construction strategies [7] 3. Optimization strategies and application cases: Emphasizing research on tumor immunity and autoimmune diseases, drug efficacy, and safety evaluation [7] 4. Interactive session: The lecturer will answer common questions related to disease research [7] Research Applications - The huHSC-C-NKG-ProF model has been utilized in significant research, including: 1. CAR-T cell therapy for solid tumors, revealing how Foxp3 regulates CAR-T cell metabolism to enhance treatment efficacy [12] 2. Liver cancer immune evasion studies, identifying ETV5 as a potential biomarker for prognosis and a target for new treatment strategies [12] - Saiye Bio's humanized immune system mice, particularly the huHSC-C-NKG-ProF model, can reconstruct various human immune cells, providing a robust platform for research [13][14] Product Offerings - Saiye Bio offers several humanized immune system models, including: - huHSC-C-NKG-ProF: Full immune system reconstruction with a humanization rate of 40-60% after 8 weeks [16] - huHSC-C-NKG-ProM: Reconstructs lymphoid T and B cells with a similar humanization rate [16] - huHSC-C-NKG-ProN: Focuses on T, B, and NK cells with minimal myeloid development [16] - huHSC-C-NKG: Supports long-term presence of human cells with a lifespan exceeding one year [16] - huPBMC-C-NKG: Primarily reconstructs lymphoid T cells with a fast reconstruction speed [16]

Core Viewpoint - Junshi Biosciences has received FDA approval to conduct a Phase II/III study comparing JS207 (a PD-1/VEGF dual antibody) with Nivolumab for neoadjuvant treatment in patients with resectable, AGA-negative non-small cell lung cancer (NSCLC) [1][2] Group 1: Study Overview - The study is an open-label, two-arm, randomized, positive-controlled international multicenter Phase II/III trial aimed at comparing the efficacy and safety of JS207 and Nivolumab in patients with resectable, AGA-negative NSCLC [2] - This marks the first confirmatory study of a PD-1/VEGF dual-target drug in a surgical population, led by Professor Wu Yilong from Guangdong Provincial People's Hospital [2] Group 2: Clinical Context - Lung cancer is the most prevalent and deadly malignancy globally, with approximately 2.48 million new cases and 1.82 million deaths reported in 2022 [1] - NSCLC accounts for about 85% of all lung cancer cases, with 20-25% of patients being operable at diagnosis [1] - Despite radical surgical treatment, 30-55% of patients may experience recurrence and death post-surgery [1][4][5] Group 3: Product Information - JS207 is a recombinant humanized dual-specific antibody targeting PD-1 and VEGF, primarily used for treating advanced malignancies [10] - The drug has entered Phase II/III clinical research and is involved in multiple Phase II studies across various cancers, including NSCLC, colorectal cancer, triple-negative breast cancer, and liver cancer [10] - JS207 effectively blocks the binding of PD-1 to PD-L1 and PD-L2, and inhibits VEGF from binding to its receptors, enhancing anti-tumor activity by improving the tumor microenvironment [10][11] Group 4: Company Background - Junshi Biosciences, established in December 2012, focuses on the discovery, development, and commercialization of innovative therapies [12] - The company has developed a diverse pipeline of over 50 innovative drugs across five therapeutic areas, with five products already approved for market [12] - Junshi Biosciences aims to provide world-class, trustworthy innovative drugs to patients, with a global workforce of approximately 2,500 employees [12]

Core Viewpoint - 康方生物's innovative bispecific antibody drug, 依沃西, has shown promising results in a Phase III clinical trial for treating advanced squamous non-small cell lung cancer, which has garnered significant attention in the medical community [1] Group 1: Clinical Research Highlights - The Phase III clinical study (AK112-306/HARMONi-6) comparing 依沃西 combined with chemotherapy against替雷利珠单抗 combined with chemotherapy has been accepted by the prestigious medical journal, The Lancet [1] - The results will be presented at the 2025 European Society for Medical Oncology (ESMO) conference, specifically during the Late-Breaking Abstract session and the Presidential Symposium [1] - The lead researcher, Professor 陆舜 from Shanghai Chest Hospital, will deliver an oral presentation showcasing the outstanding results of the head-to-head trial [1] Group 2: Market Reaction - 康方生物's stock price increased by over 8%, currently trading at 130.5 HKD, with a trading volume of 749 million HKD [1]

Core Insights - Immune therapy has fundamentally changed the clinical approach to tumor treatment, particularly with PD-1/PD-L1 immune checkpoint inhibitors, which have received continuous FDA approvals for both monotherapy and combination therapy. However, the clinical benefits in advanced tumor patients remain limited due to low somatic mutation rates, few infiltrating lymphocytes, and low PD-L1 expression levels, indicating these tumors are "cold tumors" [2] - Various immune cytokines such as IL-2, IL-7, IL-12, and IL-15 have been identified to regulate T cell proliferation, survival, and function, with the potential to convert "cold tumors" into "hot tumors" and enhance anti-tumor responses when used in conjunction with immune checkpoint inhibitors. Nonetheless, their clinical application faces challenges including technical difficulties, safety concerns, and insufficient efficacy observed in advanced tumors [2] Group 1 - The recent study published in Cell Reports Medicine demonstrates the local delivery of IL-15 and anti-PD-L1 nanobody via in vitro transcribed circILNb, which activates robust anti-tumor immunity in "cold tumors" that are unresponsive to conventional immunotherapy [3][4] - The research team engineered a circCV-B3 vector to achieve scarless circular RNA (circRNA) engineering, allowing circILNb to co-encode IL-15 and anti-PD-L1 nanobody. This circILNb is purified through a biotin-avidin purification system and encapsulated in lipid nanoparticles (LNP) for intratumoral injection, leading to in situ protein expression and activation of existing CD8+ T cells and NK cells for local tumor control [6][8] Group 2 - The study highlights the potential of the circCV-B3 vector and BAPS as circRNA engineering methods, confirming that circILNb can serve as a non-protein therapeutic strategy for tumor immunotherapy [8]

Core Insights - The announcement of the Nobel Prize in Physiology or Medicine is expected to ignite a surge in the research and development of Treg cell therapy technologies and innovative drugs [1] Company Summary - Heptares Therapeutics-B (02142) saw its stock price increase by over 8% during trading, with a current price of 16.65 HKD and a trading volume of 62.23 million HKD [1] - The company is developing a next-generation antibody HBM4003 targeting the CTLA-4 pathway, which has shown excellent safety characteristics in clinical studies and has demonstrated clear efficacy signals in multiple tumor types, including colon cancer, liver cancer, and neuroendocrine tumors [1] - In the CCR8 target area, Heptares Therapeutics has developed the HBM1022 antibody, which is considered a highly promising candidate in its pipeline and may lead to breakthroughs in tumor immunotherapy [1]

Core Viewpoint - The report from China Merchants Securities Hong Kong initiates coverage on HeYue-B (02256) with a "Buy" rating, estimating a fair equity value of HKD 21 billion and a target price of HKD 32.5 for the next 12 months, highlighting the company's long-term growth potential and efficient small molecule development capabilities [1] Group 1: Product Development and Market Potential - HeYue's developed drug, Pimitinib, is expected to be launched in both China and the U.S., providing continuous sales revenue through profit-sharing [1] - The company is actively targeting two significant gene families, FGFR and KRAS, with FGFR4 as a late-stage clinical asset poised to become a new targeted small molecule in liver cancer [1] - The global sales peak for Pimitinib is projected to reach USD 1.5 billion, providing sustained cash flow for HeYue [1] Group 2: Clinical Advancements and Pipeline - HeYue has demonstrated the best efficacy globally for TGCT in the development of CSF-1R inhibitors, with superior safety and response rates compared to similar molecules [1] - The company has received over USD 150 million in cash from its collaboration with Merck, including milestone payments and sales revenue sharing, marking a significant achievement for a Chinese biotech firm in global commercialization [1] - HeYue has a robust pipeline with 22 candidate drugs, including 12 in clinical stages and 10 in preclinical stages, showcasing its leading recognition of frontier targets and clinical development capabilities [3] Group 3: Focus on FGFR and RAS Targets - The company has been deeply engaged in the FGFR target area for ten years, focusing on selective FGFR4 inhibitors and FGFR2/3 inhibitors, addressing unmet needs in liver and gastric cancers [2] - The selective FGFR4 inhibitor, Ipagotinib, is currently in critical Phase III clinical trials, potentially becoming the first approved selective inhibitor targeting FGFR4 globally [2] - HeYue is also developing early-stage molecules targeting G12D and pan-RAS, which will enhance its offerings in precision oncology [2]

Core Viewpoint - The report from China Merchants Securities Hong Kong initiates coverage on HeYue-B (02256) with a "Buy" rating, estimating a fair equity value of HKD 21 billion and a target price of HKD 32.5 for the next 12 months, highlighting the company's long-term growth potential and efficient small molecule development capabilities [1] Group 1: Product Development and Market Potential - HeYue's developed drug, Pimitinib, is positioned as the most effective CSF-1R small molecule globally and is set to launch in both China and the U.S., promising ongoing sales revenue for the company [1] - The company is actively targeting two significant families of important targets, FGFR and KRAS, with FGFR4 as a late-stage clinical asset expected to become a new targeted small molecule in the liver cancer field [1] - The global sales peak for Pimitinib is projected to reach USD 1.5 billion, providing a continuous cash flow for HeYue, with the drug being a key asset in Merck's pipeline [1] Group 2: Clinical Advancements and Pipeline - HeYue has demonstrated the best efficacy globally for TGCT in the development of CSF-1R inhibitors, with safety and response rates surpassing similar molecules [1] - The company has established a robust pipeline with 22 candidate drugs, including 12 in clinical stages and 10 in preclinical stages, showcasing its leading recognition of frontier targets and developing clinical capabilities [3] - The selective FGFR4 inhibitor, currently in pivotal Phase III trials, targets advanced liver cancer patients with FGF19 overexpression, marking a potential first in the global market if successful [2] Group 3: Strategic Focus on Targeted Therapies - The company has been focusing on the FGFR target for a decade, with a deep layout in selective FGFR4 inhibitors and FGFR2/3 inhibitors, addressing unmet needs in liver and gastric cancers [2] - The ongoing research on RAS targets, including early-stage molecules for G12D and pan-RAS, is expected to enhance the company's offerings in precision oncology [2] - The development of next-generation FGFR inhibitors and oral PD-L1 small molecules is anticipated to exceed market expectations through better data disclosure and potential business development transactions [3]

Summary of the Conference Call Industry Overview - The global PD-1/PD-L1 market is projected to reach $52.5 billion in 2024, with a year-on-year growth of 12.3% [2][4] - Merck's Keytruda holds a dominant market share of 56%, with sales of $29.48 billion, while BMS's Opdivo ranks second with a 19% market share and sales of $10.2 billion [4] - The top four products collectively account for over 90% of the market, indicating a high level of market concentration [2][4] Core Insights and Arguments - First-generation immuno-oncology (I/O) therapies have limited efficacy in solid tumors, benefiting only about 20% of patients, and are highly dependent on PD-L1 expression levels [2][7] - There is a pressing need for breakthrough treatment strategies to address primary and acquired resistance issues associated with first-generation therapies [8] - The second-generation I/O therapy market is expected to reach $200 billion, with innovative dual-target products like PD-VEGF and PD-IL2 emerging, particularly from Chinese companies such as Hengrui Medicine and BeiGene [2][9] Company-Specific Developments - Innovent Biologics' IBI363 is the world's first next-generation dual antibody, designed to provide breakthroughs in treating both hot and cold tumors, as well as resistant populations [2][9] - IBI363 extends the half-life of PD-1 monoclonal antibodies and employs alpha-bias IL-2 design to reduce peripheral toxicity while effectively stimulating CD8+ T cells [2][10] - Clinical data presented at the 2025 ASCO conference indicates that IBI363 shows broad therapeutic potential in various immune-resistant solid tumors, including melanoma, colorectal cancer, and non-small cell lung cancer [2][11] Mechanisms and Innovations - The mechanism of PD-1/PD-L1 inhibitors involves blocking the PD-1/PD-L1 signaling axis, which restores T cell function and enhances anti-tumor immune responses [5][6] - First-generation I/O therapies face limitations, particularly in cold tumors where CD8 T cells are restricted or absent, leading to low response rates [7] - The innovative alpha-bias design of IBI363 effectively stimulates activated CD8+ T cells, enhancing tumor-killing capabilities while minimizing side effects [10][12] Additional Important Points - The choice of alpha-bias design for IBI363 is based on the discovery that the IL-2 receptor alpha subunit is also highly expressed in activated CD8+ T cells, which can enhance tumor-killing efficiency [12] - The combination of PD-1 monoclonal antibodies with IBI363 is crucial for improving overall efficacy, as it targets key tumor-killing cells that express PD-1, CD25, and CD8 [13]