HER2 antagonists(Receptor tyrosine-protein kinase erbB-2 antagonists), TOP1 inhibitors(DNA topoisomerase I inhibitors), ADCC(Antibody-dependent cell-mediated cytotoxicity (ADCC) effects)

Therapeutic Areas

NeoplasmsDigestive System DisordersRespiratory Diseases+ [5]

Active Indication

Metastatic human epidermal growth factor 2 positive carcinoma of breastStomach CancerHER2 Positive Solid Tumors+ [76]

Inactive Indication

HER2 Positive Transitional Cell CarcinomaHER2-expressing Gastroesophageal Junction AdenocarcinomaMeningeal Carcinomatosis+ [1]

Originator Organization

Daiichi Sankyo Co., Ltd.

Active Organization

Daiichi Sankyo Co., Ltd.

AstraZeneca PLC

Daiichi Sankyo, Inc.

+ [10]

Inactive Organization-

License Organization

Merck & Co., Inc.

AstraZeneca PLC

Daiichi Sankyo Co., Ltd.

+ [2]

Drug Highest PhaseApproved

First Approval Date

United States (20 Dec 2019),

HER2 Positive Breast Cancer

RegulationPriority Review (United States), Breakthrough Therapy (United States), Fast Track (United States), Accelerated Approval (United States), Orphan Drug (United States), Priority Review (China), Breakthrough Therapy (China), Orphan Drug (Japan), Orphan Drug (Australia), Priority Review (Australia), SAKIGAKE (Japan), Conditional marketing approval (China)

Structure/Sequence

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Sequence Code 18481L

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Sequence Code 44772H

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212

Clinical Trials associated with Fam-trastuzumab deruxtecan-NXKI

NCT07619521

/ RecruitingPhase 1/2IIT

Phase I/II Study of the MEK Inhibitor Selumetinib Plus DS-8201a (Trastuzumab Deruxtecan) in KRAS-Mutant, HER2-Expressing Pancreatic Ductal Adenocarcinoma

This phase I/II trial tests the safety, side effects, best dose and how well giving selumetinib with trastuzumab deruxtecan (DS-8201a) works for the treatment of pancreatic ductal adenocarcinoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced), that cannot be removed by surgery (unresectable) or that has spread from where it first started (primary site) to other places in the body (metastatic). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. DS-8201a is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Giving selumetinib with DS-8201a may be safe, tolerable and/or effective in treating patients with advanced, unresectable or metastatic pancreatic ductal adenocarcinoma.

Start Date01 Jun 2027

Sponsor / Collaborator

National Cancer Institute

NCT07578116

/ Not yet recruitingPhase 3IIT

Randomized Phase III Trial of Multimodality Therapy Versus Standard of Care Systemic Therapy in HER2 Positive (HER2+) De Novo (AJCC Stage IV) Oligometastatic Breast Cancer With Response to Initial Chemotherapy

This phase III trial evaluates the effect of adding locoregional therapy (surgery and radiation) and metastasis-directed stereotactic body radiation therapy (SBRT) to standard systemic therapy following standard HER2-targeted systemic therapy, compared to standard systemic therapy alone, in treating patients with HER2-positive stage IV breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic) or to a limited number of sites (oligometastatic). The usual approach for patients with (oligo)metastatic HER2-positive breast cancer is systemic drug treatment, which means medicines that travel through the whole body to treat both the breast and any areas where the cancer has spread. There are a number of approved HER2-targeted systemic therapy regimens available to patients. These typically include immunotherapy and/or chemotherapy. Immunotherapy drugs may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Unlike systemic therapy, locoregional therapies like surgery and radiation are focused treatments at the site of disease, delivered with the intent of sparing healthy tissues. Breast surgeries such as breast conserving therapy or total mastectomy are procedures in which the cancerous breast tissue (and healthy breast tissue in the case of total mastectomy) are surgically removed from the body. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Adding locoregional therapy, as well as metastasis-directed SBRT, to standard systemic therapy may help patients with (oligo)metastatic, HER2-positive stage IV breast cancer live longer overall or before their cancer progresses, and may help more patients achieve no evidence of disease, when compared to standard systemic therapy alone.

Start Date09 Mar 2027

Sponsor / Collaborator

SWOG

[+1]

NCT07785856

/ Not yet recruitingPhase 1/2IIT

A Phase Ib/II Study of Trastuzumab Deruxtecan (T-DXd) in Combination With a RAGE Inhibitor in Patients With T-DXd-Resistant HER2-Positive or HER2-Low Metastatic Breast Cancer

This phase Ib/II trial aims to evaluate the safety and preliminary efficacy of combining Trastuzumab Deruxtecan (T-DXd) with Azeliragon, a receptor for advanced glycation end products (RAGE) inhibitor in patients with T-DXd-resistant HER2-positive or HER2-low metastatic breast cancer at Houston Methodist Neal Cancer Center (HMNCC). Adults, 18 years of age or older, with histologically confirmed HER2-positive or HER2-low metastatic breast cancer with prior progression on T-DXd will be eligible to participate in the study.

Start Date01 Dec 2026

Sponsor / Collaborator

The Methodist Hospital Research Institute

100 Clinical Results associated with Fam-trastuzumab deruxtecan-NXKI

100 Translational Medicine associated with Fam-trastuzumab deruxtecan-NXKI

100 Patents (Medical) associated with Fam-trastuzumab deruxtecan-NXKI

1,188

Literatures (Medical) associated with Fam-trastuzumab deruxtecan-NXKI

01 Nov 2026·CANCER LETTERS

Preclinical evaluation of trastuzumab deruxtecan in a new HER2+ leptomeningeal colonization model

Article

Author: Edmondson, Elijah F ; Difilippantonio, Simone ; Zhang, Wei ; Khan, Imran ; Zimmer, Alexandra S ; Silvestri, Vanesa ; Steeg, Patricia S ; Lipkowitz, Stanley ; Wei, Debbie ; Kumar, Dinesh ; Robinson, Christina

Leptomeningeal metastases are devastating complications of advanced HER2+ breast cancer, with limited therapeutic options. We developed a xenograft model of human HER2+ breast cancer cell line JIMT1-BR3-LM4 leptomeningeal colonization by four iterative cycles of intrathecal injection. The model reliably produced leptomeningeal lesions in brain and spinal cord and tumor cells in the CSF, as confirmed by endpoints of BLI, MRI, pathologic analysis and immunofluorescent staining. Upon RNA-seq, the LM model exhibited significant transcriptional changes as compared to the starting brain-tropic line. In a preclinical experiment, two doses of trastuzumab deruxtecan (T-DXd) were compared to human IgG, trastuzumab (T), nab-paclitaxel (nab-P) and T + nab-P for leptomeningeal metastasis. T-DXd demonstrated efficacy in terms of BLI imaging of the brain (P < 0.0001) and spine (P = 0.008), leptomeningeal lesion number and size in the brain (P = 0.06); efficacy was dose-dependent. T-DXd 10 mg/kg reduced leptomeningeal tumor Ki67 positivity (P = 0.0008) and increased apoptosis (P < 0.0001). In the brain, a comparison of leptomeningeal and parenchymal lesion number showed a reduction by T-DXd of 53% and 72%, respectively, compared to human IgG, with comparable effects on tumor proliferation and apoptosis. T-DXd also extended median survival to 38 days compared with 20 -24 days in control IgG or T + nab-P, with some mice surviving beyond 60 days (P = 0.003). These findings support ongoing clinical translation of T-DXd for HER2+ leptomeningeal metastasis and highlight the value of this model for future therapeutic development.

01 Oct 2026·BIOORGANIC & MEDICINAL CHEMISTRY

Recent advances in Camptothecin-derived antibody-drug conjugates

Review

Author: Wang, Ye ; Yu, Dingyan ; Chen, Hongli ; Yu, Xianqiang ; Jiang, Biao

Antibody-drug conjugates (ADCs) represent a major advance in precision cancer therapy by combining the high target specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule payloads through chemical linkers. Among the payload classes topoisomerase I (Topo I) inhibitors, camptothecin and its derivatives have emerged as highly promising warheads owing to their distinct mechanism of action and strong antitumor activity. The clinical success of Enhertu and Trodelvy, which employ the camptothecin-derived payloads DXd and SN-38, respectively, has validated the therapeutic potential of camptothecin-based ADCs and accelerated the development of next-generation candidates. This review summarizes recent progress in camptothecin-based ADCs since 2021, with a focus on strategies for payload modification of camptothecin derivatives, and linker optimization. In addition, current limitations of camptothecin-based ADCs, including resistance and insufficient efficacy, are discussed together with emerging solutions such as combination strategies and dual-payload ADCs. This review is expected to provide a useful framework for the rational design and further development of camptothecin-based ADCs.

01 Oct 2026·JOURNAL OF HEPATOLOGY

Systemic therapy of biliary tract cancer: The road to personalised strategies

Review

Author: Harding, James J ; Lamarca, Angela ; Oh, Do Youn

Biliary tract cancers (BTC), including cholangiocarcinoma, gallbladder cancer, and ampullary cancer, remain poor-prognosis tumours. Chemo-immunotherapy is now established as the first-line standard of care. In parallel, precision medicine is now well established in the form of targeted therapies. These have transformed outcomes for defined subgroups, particularly intrahepatic cholangiocarcinoma with FGFR2 fusions/rearrangements, where pemigatinib and futibatinib provide meaningful response rates and durable disease control. On top of this, next-generation FGFR inhibitors aim to address secondary resistance. IDH1-mutant cholangiocarcinoma benefits from ivosidenib, with multiple combination strategies currently under investigation. HER2-directed therapies, including zanidatamab and trastuzumab deruxtecan, have shown promising efficacy in HER2-amplified or strongly overexpressing BTC, with ongoing clinical trials in the first-line setting. Tumour-agnostic targets (BRAF V600E, MSI-H/dMMR, RET/NTRK/NRG1 fusions) and other emerging therapies are further broadening therapeutic opportunities. However, key barriers to implementation include heterogeneous biomarker testing, limited tissue availability, the need for DNA/RNA hybrid-capture sequencing, and evolving resistance biology, underscoring the importance of optimised diagnostics and innovative trial designs to realise personalised care in BTC. This review provides detailed insights on these therapies, and most importantly a view to what the future may hold.

1,223

News (Medical) associated with Fam-trastuzumab deruxtecan-NXKI

28 Sep 2026

·www.biospace.com

Ifinatamab Deruxtecan Biologics License Application for Certain Patients with Previously Treated Extensive-Stage Small Cell Lung Cancer Voluntarily Withdrawn

TOKYO--(BUSINESS WIRE)--The Biologics License Application (BLA) seeking accelerated approval in the U.S. for Daiichi Sankyo (TSE: 4568) and Merck’s (NYSE: MRK), known as MSD outside of the United States and Canada, ifinatamab deruxtecan (I-DXd) for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy has been voluntarily withdrawn. The decision to withdraw the BLA is based on discussions with the U.S. Food and Drug Administration (FDA) that data supporting the application, including from the IDeate-Lung01 phase 2 trial, do not satisfy requirements needed to support an accelerated approval for the proposed indication. The accelerated approval pathway in the U.S. allows for earlier approval of medicines based on surrogate endpoints to treat serious conditions where there is an unmet medical need. Patient enrollment continues in the IDeate-Lung02 phase 3 trial evaluating the efficacy and safety of ifinatamab deruxtecan versus treatment of physician’s choice of chemotherapy (amrubicin, lurbinectedin or topotecan) in patients with relapsed ES-SCLC following disease progression with only one prior line of platinum-based chemotherapy. Ifinatamab deruxtecan is a specifically engineered, potential first-in-class B7-H3 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by Daiichi Sankyo and Merck. “Extensive-stage small cell lung cancer is a challenging disease to treat, leaving patients in need of new options,” said Abderrahmane Laadem, MD, Head, Therapeutic Area Oncology Development, Daiichi Sankyo. “Enrollment into the IDeate-Lung02 phase 3 trial is near completion and we look forward to assessing the potential for a future filing of ifinatamab deruxtecan with the FDA and other global regulatory authorities based on those results.” “While we are disappointed that the current dataset are not supportive of an approval at this time, we are continuing to evaluate the role of ifinatamab deruxtecan in patients with extensive-stage small cell lung cancer and other types of difficult-to-treat cancer,” said Marjorie Green, MD, Senior Vice President, Head of Oncology Global Clinical Development, Merck Research Laboratories. “We would like to thank the patients, their families and investigators who have participated or continue to participate in these studies.” In addition to the IDeate-Lung02 phase 3 trial, there are two additional phase 3 trials underway with ifinatamab deruxtecan in advanced/metastatic disease, including IDeate-Prostate01 for castration-resistant prostate cancer (CRPC) and IDeate-Esophageal01 for esophageal squamous cell carcinoma (ESCC). About IDeate-Lung01 IDeate-Lung01 is a global, multicenter, randomized, open-label, two-part phase 2 trial evaluating the safety and efficacy of ifinatamab deruxtecan in patients with ES-SCLC who were previously treated with at least one prior line of platinum-based chemotherapy and a maximum of three prior lines of therapy. Patients with asymptomatic brain metastases (untreated or previously treated) were eligible to participate. Patients with a history of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids or current ILD/pneumonitis at screening, clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, were not eligible. In the first part of the trial (dose optimization), patients were randomized 1:1 to receive ifinatamab deruxtecan (8 or 12 mg/kg) given intravenously once every three weeks. In the second part of the trial (dose expansion), patients received ifinatamab deruxtecan (12 mg/kg) intravenously at the same dosing interval. The primary endpoint is objective response rate (ORR) as assessed by blinded independent central review (BICR) per RECIST v1.1. Secondary endpoints include duration of response, progression-free survival, disease control rate, time to response, overall survival, pharmacokinetics and safety. Intracranial ORR was assessed by BICR as an exploratory analysis. IDeate-Lung01 enrolled 187 patients in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov . About Small Cell Lung Cancer Approximately 250,000 patients are diagnosed with small cell lung cancer (SCLC) each year globally. 1 There were approximately 27,000 new cases of SCLC in the U.S. in 2025, accounting for about 12% of all lung cancer cases. 2,3 SCLC is aggressive and progresses rapidly to the distant metastatic stage, which has a low five-year survival rate. 4,5 While conventional standard of care treatments for patients with advanced SCLC may help improve outcomes, there is a need for additional subsequent treatment approaches. 6,7,8,9 About B7-H3 B7-H3 is a transmembrane protein that belongs to the B7 family of proteins, which bind to the CD28 family of receptors that includes PD-1. 10,11 B7-H3 is overexpressed in a wide range of cancer types, including SCLC, CRPC and ESCC, and its overexpression has been shown to correlate with poor prognosis, making B7-H3 a promising therapeutic target. 12,13,14,15 About Ifinatamab Deruxtecan Ifinatamab deruxtecan is an investigational potential first-in-class B7-H3 directed ADC. Designed using the proprietary DXd ADC Technology of Daiichi Sankyo, ifinatamab deruxtecan is comprised of a humanized anti-B7-H3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Ifinatamab deruxtecan has been granted Orphan Drug Designation (ODD) by the U.S. FDA, European Commission, Japan Ministry of Health, Labour and Welfare, South Korea Ministry of Food and Drug Safety and Taiwan Food and Drug Administration for the treatment of SCLC. Ifinatamab deruxtecan also was granted ODD for the treatment of esophageal cancer by the FDA. About the Ifinatamab Deruxtecan Clinical Development Program A comprehensive global clinical development program is underway evaluating the efficacy and safety of ifinatamab deruxtecan monotherapy and in combination with other cancer medicines across multiple cancers. The program is currently comprised of three phase 3 trials in advanced/metastatic disease, including SCLC ( IDeate-Lung02 ), CRPC ( IDeate-Prostate01 ) and ESCC ( IDeate-Esophageal01 ). About the Daiichi Sankyo and Merck Collaboration Daiichi Sankyo and Merck, known as MSD outside of the United States and Canada, entered into a global collaboration in October 2023 to jointly develop and commercialize ifinatamab deruxtecan (I-DXd), raludotatug deruxtecan (R-DXd) and patritumab deruxtecan (HER3-DXd), except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply. In August 2024 , the global co-development and co-commercialization agreement was expanded to include gocatamig (MK-6070/DS3280), which the companies will jointly develop and commercialize worldwide, except in Japan where MSD will maintain exclusive rights. MSD will be solely responsible for manufacturing and supply for gocatamig. About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of nine ADCs in clinical development crafted from ADC technology discovered in-house by Daiichi Sankyo. The DXd ADC Technology platform of Daiichi Sankyo consists of seven ADCs in clinical development where each ADC is comprised of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADCs include Enhertu ® and Datroway ® , which are being jointly developed and commercialized globally with AstraZeneca, and ifinatamab deruxtecan (I-DXd), raludotatug deruxtecan (R-DXd) and patritumab deruxtecan (HER3-DXd), which are being jointly developed and commercialized globally with Merck. DS-3939 and DS3790 are being developed by Daiichi Sankyo. Additional ADCs being developed by Daiichi Sankyo include DS3610, which consists of an antibody attached to a novel payload that acts as an agonist of STING, and DS1025, which consists of a CD25 directed antibody attached to an immuno-oncology optimized cytotoxic payload. Ifinatamab deruxtecan, raludotatug deruxtecan, patritumab deruxtecan, DS-3939, DS3610, DS3790 and DS1025 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo (TSE: 4568) is a global healthcare company committed to becoming a trusted healthcare innovator, transforming the lives of people through its strength in science and technology. The company discovers and develops new standards of care to address diverse medical needs to fulfill its purpose of contributing to the enrichment of quality of life around the world. With a strategic focus on oncology, Daiichi Sankyo is advancing an industry-leading antibody drug conjugate portfolio along with identifying new breakthrough generating technologies to deliver practice-changing medicines to patients, healthcare professionals and society. For more information, please visit . REFERENCES: Wang Q, et al. Journal of Thoracic Oncology . 2023 Jan;18(1):31-46. National Cancer Institute. SEER Explorer. Cancer Stat Facts: Lung and Bronchus Cancer . Accessed September 2026. U.S. Centers for Disease Control and Prevention. United States Cancer Statistics. Types of Lung Cancer | U.S. Cancer Statistics | CDC . Accessed September 2026. Rudin CM, et al . Nat Rev Dis Primers . 2021;7(1):3. National Cancer Institute. SEER Explorer. Small cell carcinoma of the Lung and Bronchus: 5-year Relative Survival . Accessed September 2026. American Cancer Society. Treatment Choices for Small Cell Lung Cancer, by Stage . Accessed September 2026. Liu SV, et al. J Clin Oncol . 2021;39(6):619-30. Paz-Ares L, et al. ESMO Open . 2022;7(2):100408. von Pawel J, et al. J Clin Oncol . 2014; 32:4012-4019. Zhao B, et al. J Hematol Oncol . 2022;15(1):153. Janakiram M, et al. Immunol Rev . 2017;276(1):26-39. Qiu M-j, et al. Front. Oncol . 2021;11:600238. Picarda E, et al. Clin Cancer Res . 2016;22(14):3425-3431. Bendell JC, et al. J Clin Oncol . 2020;39(15 suppl 1). Abstract TPS3646. Kontos F, et al. Clin Cancer Res . 2021;27(5):1227-1235. Contacts MEDIA CONTACTS: Global: Jennifer Brennan jennifer.brennan@daiichisankyo.com +1 908 900 3183 (mobile) Japan: DS-PR_jp@daiichisankyo.com INVESTOR RELATIONS CONTACT: DaiichiSankyoIR_jp@daiichisankyo.com

Phase 2Clinical ResultPhase 3Orphan DrugLicense out/in

28 Sep 2026

·www.biospace.com

Callio Therapeutics Appoints Chris Hassig, PhD, as Chief Scientific Officer

Industry veteran brings more than two decades of oncology drug discovery leadership to advance Callio's dual-payload ADC pipeline SAN DIEGO and SEATTLE and SINGAPORE, Sept. 28, 2026 (GLOBE NEWSWIRE) -- Callio Therapeutics (“Callio” or “the Company”), a global, clinical-stage biotechnology company advancing dual-payload antibody-drug conjugates (ADCs) as the next frontier of rationally designed targeted cancer therapy, today announced the appointment of Chris Hassig, PhD, as Chief Scientific Officer (CSO). Hassig will lead Callio's research and discovery organization, overseeing the advancement of the Company's dual-payload ADC platform and pipeline. Hassig joins Callio from Boundless Bio, where he served as CSO, building the company's drug discovery organization from its inception through advancement of three internally discovered first-in-class molecules into clinical development. Prior to Boundless Bio, he was CSO of Sierra Oncology (acquired by GSK) and Vice President of Drug Discovery at Sanford Burnham Prebys Medical Discovery Institute. He previously held drug discovery and research roles at Kalypsys, Inc. and the Scripps Research Institute. "Chris is a highly accomplished oncology drug discovery leader, and I had the privilege of seeing that firsthand," said Zachary Hornby, Chief Executive Officer of Callio Therapeutics. "Over seven years together at Boundless Bio, Chris helped build a discovery engine that took novel biology from concept to clinic. Callio's dual-payload ADC platform is at a similar inflection point, and Chris's experience translating cutting-edge science into differentiated therapeutics makes him the right leader to help us realize our technology’s full potential for patients with cancer." "Callio is pursuing one of the most compelling unmet needs in oncology drug development today by designing ADCs to overcome resistance mechanisms that limit current therapies," said Hassig. "The team has already advanced CLIO-8221 into the clinic and built an ADC platform that systematically tests rationally designed dual-payload combinations for ADCs, optimized for specific tumor targets. I look forward to working with the innovative and talented Callio team to help build and advance a pipeline that can change outcomes for patients who currently have limited options." Hassig earned a BA in Chemistry and Biochemistry from the University of California, San Diego, and a PhD in Molecular and Cellular Biology from Harvard University. He completed a postdoctoral fellowship at the University of California, Berkeley. About Callio Therapeutics Callio Therapeutics is a clinical-stage biotechnology company that is developing dual-payload antibody-drug conjugates (ADCs) as the next frontier of targeted cancer therapy to address high incidence tumors where better therapies are needed. Its proprietary platform pairs modular, adaptable linker technology with rationally selected synergistic payload combinations designed to block key resistance mechanisms that enable cancer’s escape. The Company’s lead clinical program, CLIO-8221, is a HER2-targeted dual-payload ADC with potential to prevent and overcome treatment resistance that limits efficacy of current ADCs. Located in San Diego, Seattle, and Singapore, backed by top life science investors, and led by an experienced team with a track record of ADC development and oncology drug approvals, Callio Therapeutics is built to deliver the next generation of dual-payload ADCs and better outcomes for people living with cancer. For more information, visit and follow Callio Therapeutics on LinkedIn . About CLIO-8221 HER2 is a clinically validated target for antibody-drug conjugates (ADCs), with multiple approved therapies demonstrating clinical benefit across tumor types. However, most patients eventually progress on treatment despite their tumors retaining HER2 expression. Mechanistic resistance to cytotoxic payloads has emerged as a key driver of treatment failure. CLIO-8221 is a novel, first-in-class, dual-payload ADC targeting HER2, designed to overcome emergent resistance. CLIO-8221 delivers two mechanistically complementary payloads, a topoisomerase 1 (Topo1) inhibitor and an ATR inhibitor, directly to HER2-expressing tumors. While Topo1 inhibitors have shown strong clinical activity, activation of the DNA damage response following Topo1 inhibitor-induced replication stress represents a potential major driver of resistance. By simultaneously inhibiting Topo1 and blocking the DNA damage response through ATR inhibition, CLIO-8221 is engineered to overcome payload insensitivity and further sensitize tumors to Topo1 inhibition. Developed using proprietary linker and ADC platform technologies, CLIO-8221 aims to maximize anti-tumor activity while reducing systemic toxicity, offering the potential for deeper and more durable responses in patients with HER2-expressing tumors. CLIO-8221 is currently being evaluated in an ongoing Phase 1/2, first-in-human, dose-escalation and expansion study in adult patients with metastatic or unresectable HER2-expressing solid tumors, including those who previously received trastuzumab deruxtecan (T-DXd). The first patient was dosed in March 2026, and enrollment is ongoing in Australia and the US, with plans to open the study in China ( NCT07300943 ). Contacts Media: Jeremy Sauer media@calliotx.com Ally Stubin – ICR Healthcare ally.stubin@ICRHealthcare.com (646) 667-1861 Investors: ir@calliotx.com Stephanie Carrington – ICR Healthcare stephanie.carrington@ICRHealthcare.com (646) 277-1282

Executive ChangeADC

25 Sep 2026

·www.biospace.com

Avacta Group plc: The FOCUS-01 Clinical Trial Design and Preclinical Data Further Demonstrate the Potential of AVA6103 at AACR Conference on Pancreatic Cancer

LONDON and PHILADELPHIA, Sept. 25, 2026 (GLOBE NEWSWIRE) -- Avacta Therapeutics (AIM: AVCT, the "Company", "Avacta"), a life sciences company developing innovative, targeted oncology drugs, today announces the presentation of the FOCUS-01 trial design and preclinical data highlighting the potential of AVA6103 (FAP-Exd) in pancreatic ductal adenocarcinoma (PDAC). FOCUS-01 is the Phase 1 trial of AVA6103, the Company's first Next-Generation pre|CISION ® peptide-drug conjugate (PDC) and is being presented at the American Association for Cancer Research ("AACR") Conference on Pancreatic Cancer in San Diego, California, held between 25-28 September 2026. The presentation highlights the design of the FOCUS-01 Phase 1 study of AVA6103 and updated preclinical data supporting the assessment of AVA6103 in patients with PDAC. AVA6103 is designed to significantly increase the therapeutic window of the highly potent payload, exatecan, and the trial implements a dose-dense arm, dosing every two weeks (Q2W), to enhance the delivery of payload to the tumor over traditional dosing of ADCs at every three weeks (Q3W). Preclinical studies using the dose-dense regimen in patient-derived xenograft (PDX) mouse models of PDAC demonstrate that AVA6103 achieved tumor-targeted delivery of exatecan with highly durable complete and partial responses in multiple models observed for weeks following cessation of dosing. Additionally, researchers observed high FAP expression in PDAC with close proximity of FAP-expressing cancer-associated fibroblasts (CAFs) to both blood vessels and tumor cells, shown via multiplex immunofluorescence (mIF). These findings support the mechanism of action of the Next Gen pre|CISION medicines: efficient PDC delivery to the tumor, cleavage and release of payload with tumor cell uptake of released payload. Christina Coughlin, CEO of Avacta , commented: "The preclinical data presented at AACR underscore the significant potential of AVA6103 in addressing the challenges of pancreatic cancer, a disease with limited treatment options and poor prognosis. The robust preclinical efficacy, combined with the high FAP expression in PDAC, further strengthens our confidence in AVA6103 as a promising therapeutic candidate to improve treatment options for patients. "This adds to the momentum of AVA6103 and highlights the potential of our unique pre|CISION ® technology to bring hope to patients battling PDAC and other aggressive cancers. The first clinical data from the FOCUS-01 trial, providing clinical evidence consistent with tumor-specific delivery of exatecan by AVA6103, have further reinforced our confidence in this program and we are now moving towards an initial efficacy readout from the study in H1 2027." FOCUS-01: Trial in Progress The FOCUS-01 Phase 1a trial is a first in-human, multicenter dose escalation trial of AVA6103 and is enrolling patients with select tumor types predicted to be sensitive to the payload exatecan, including PDAC. Patients with PDAC are enrolled in the Q2W dosing arm, a dose-intense regimen designed to match standard of care in the indication. The ability to deliver dose intensity and flexible administration is unique to pre|CISION ® Next-Gen PDCs because: In contrast to antibodies, the pre|CISION ® peptide does not accumulate, enabling more frequent dosing when appropriate; and The pre|CISION ® Next-Gen mechanism retains and cleaves the conjugate inside the tumor, significantly limiting systemic exposure to the payload and enabling the interval between doses to be shortened, allowing delivery of higher dose intensity compared to ADCs. Preliminary safety and pharmacokinetic (PK) data from the first three dose levels of the FOCUS-01 trial, reported earlier this month , demonstrated proof of mechanism in patients treated in the first three cohorts in the trial. AVA6103 demonstrated a favorable safety pro was well tolerated through the first three dose levels up to a payload dose approximately 50% higher than the maximum tolerated dose (MTD) of conventional exatecan. The pharmacokinetic data of the PDC, released peptide and released exatecan patients were remarkably consistent with predictive PK modelling based on preclinical data, greatly increasing confidence that the safety profile, tumor selectivity and antitumor efficacy observed in the preclinical studies of AVA6103 will translate into the clinic. Enrollment is ongoing in both arms of the study with patients treated at dose level 4, which represents an absolute dose of payload that is more than double the MTD of conventional exatecan and approaches the equivalent topoisomerase I inhibitor payload dose of the approved dose of Enhertu ® in breast cancer. Details of the poster presentation Title: A Phase I Trial of FAP-Exd (AVA6103), a Fibroblast Activation Protein (FAP)-enabled pre|CISION® Peptide-drug Conjugate Delivering Sustained Tumor Microenvironment (TME) Release of Exatecan in Patients with FAP-positive Solid Tumors First Author : Alex Spira, MD Session: New Frontiers in Biology and Therapeutic Development Date: September 26, 2026 Enhertu ® (trastuzumab deruxtecan; T-DXd) is a protease cleavable-linker ADC, approved for both breast cancer and gastric cancer indications (an AstraZeneca/Daiichi Sankyo product). Enhertu ® is a registered trademark of Daiichi Sankyo Company, Limited and AstraZeneca. For further information from Avacta, please contact: Avacta Group plc Christina Coughlin, Chief Executive Officer via Cohesion Bureau Strand Hanson Limited (Nominated Adviser) James Harris / Chris Raggett / James Dance Zeus (Broker) James Hornigold / George Duxberry / Dominic King Cohesion Bureau Communications / Media / Investors Chris Maggos avacta@cohesionbureau.com About Avacta - Avacta Therapeutics is a clinical-stage life sciences company expanding the reach of highly potent cancer therapies through its proprietary pre|CISION® platform. pre|CISION® is a payload delivery system based on a tumor-specific protease (Fibroblast Activation Protein or FAP) that is designed to concentrate highly potent payloads in the tumor microenvironment while sparing normal tissues. Avacta's innovative pre|CISION® peptide drug conjugates (PDC) are a novel entry to the XDC drug class, leveraging the success of antibody drug conjugates with alternative methods of delivery beyond antibodies. Our pre|CISION® PDCs leverage this tumor-specific release mechanism in a small molecule format to provide unique benefits over traditional antibody drug conjugates (ADC), releasing active payload in the tumor and reducing systemic exposure and toxicity which enables dosing to be optimized to deliver the best outcomes for patients. The lead clinical program is AVA6103, a Next Generation FAP-enabled controlled release pre|CISION® version of exatecan that delivers the payload directly in the tumor with limited peripheral blood exposure and is currently in clinical development as a treatment for tumor types sensitive to exatecan including cervical cancer, HR+ breast cancer, small cell lung cancer, gastric cancer, colorectal cancer and pancreatic cancer. About AVA6103 (FAP-Exd) AVA6103 is the second clinical candidate and is the first asset in the pipeline based on the Next Generation innovative pre|CISION® controlled release mechanism that provides for prolonged release of payload directly in the tumor, minimizing systemic exposure. AVA6103 is being evaluated in the FOCUS-01 Phase 1 trial (F AP-Exd in O ncologic C ancers with U nmet needS). Preclinical data suggest this approach has optimized payload delivery with a high intratumoral concentration and prolonged exposure of released payload in the tumor, coupled with limited systemic exposure to the released payload. This information is provided by RNS, the news service of the London Stock Exchange. RNS is approved by the Financial Conduct Authority to act as a Primary Information Provider in the United Kingdom. Terms and conditions relating to the use and distribution of this information may apply. For further information, please contact rns@lseg.com or visit .

Phase 1Drug ApprovalAACRPDC

100 Deals associated with Fam-trastuzumab deruxtecan-NXKI

External Link

KEGG	Wiki	ATC	Drug Bank
D11529	Fam-trastuzumab deruxtecan-NXKI	L01XC	DB14962

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Metastatic human epidermal growth factor 2 positive carcinoma of breast	United States	Daiichi Sankyo, Inc.	15 May 2026
Stomach Cancer	India	AstraZeneca PLC	07 Oct 2025
HER2 Positive Solid Tumors	United Kingdom	Daiichi Sankyo UK Ltd.	09 Apr 2025
HR-positive/HER2-low Breast Carcinoma	United States	Daiichi Sankyo Co., Ltd.	28 Jan 2025
Hormone receptor positive HER2 positive breast cancer	South Korea	Daiichi Sankyo Co., Ltd.	19 Sep 2022
HER2 mutant non-small cell lung cancer	United States	Daiichi Sankyo, Inc.	11 Aug 2022
HER2 Positive Stomach Adenocarcinoma	Australia	AstraZeneca Pty Ltd.	08 Oct 2021
HER2-Low Breast Carcinoma	Australia	AstraZeneca Pty Ltd.	08 Oct 2021
Metastatic breast cancer	Canada	AstraZeneca Canada, Inc.	15 Apr 2021
HER2 positive Gastroesophageal Junction Adenocarcinoma	United States	Daiichi Sankyo, Inc.	15 Jan 2021
HER2-positive gastric cancer	Japan	Daiichi Sankyo Co., Ltd.	25 Sep 2020
HER2 Positive Breast Cancer	United States	Daiichi Sankyo, Inc.	20 Dec 2019

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-squamous non-small cell lung cancer	Phase 3	United States	Daiichi Sankyo Co., Ltd.	24 Oct 2025
Non-squamous non-small cell lung cancer	Phase 3	China	Daiichi Sankyo Co., Ltd.	24 Oct 2025
Non-squamous non-small cell lung cancer	Phase 3	Japan	Daiichi Sankyo Co., Ltd.	24 Oct 2025
Non-squamous non-small cell lung cancer	Phase 3	Argentina	Daiichi Sankyo Co., Ltd.	24 Oct 2025
Non-squamous non-small cell lung cancer	Phase 3	Belgium	Daiichi Sankyo Co., Ltd.	24 Oct 2025
Non-squamous non-small cell lung cancer	Phase 3	Brazil	Daiichi Sankyo Co., Ltd.	24 Oct 2025
Non-squamous non-small cell lung cancer	Phase 3	Chile	Daiichi Sankyo Co., Ltd.	24 Oct 2025
Non-squamous non-small cell lung cancer	Phase 3	France	Daiichi Sankyo Co., Ltd.	24 Oct 2025
Non-squamous non-small cell lung cancer	Phase 3	Germany	Daiichi Sankyo Co., Ltd.	24 Oct 2025
Non-squamous non-small cell lung cancer	Phase 3	Greece	Daiichi Sankyo Co., Ltd.	24 Oct 2025

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05048797 (DESTINY-Lung04, WCLC2026)	Phase 3	HER2 mutant non-small cell lung cancer First line HER2-mutant	454	Trastuzumab Deruxtecan (T-DXd) 5.4 mg/kg IV Q3W	srvftsylzl(trjtgufwpt) = xpuiqmzslw pwuqzhnnzj (vabwsgggmm, 63.6 - 75.9) View more	Positive	12 Sep 2026
NCT05048797 (DESTINY-Lung04, WCLC2026)	Phase 3		454	Pembrolizumab 200 mg IV Q3W plus platinum chemo (cisplatin 75 mg/m2 or carboplatin AUC 5 IV Q3W) and pemetrexed 500 mg/m2 IV Q3W	srvftsylzl(trjtgufwpt) = ldfcomgvoc pwuqzhnnzj (vabwsgggmm, 37.9 - 51.2) View more	Positive	12 Sep 2026
NCT04539938 (HER2CLIMB-04, Pubmed \| Clin Breast Cancer)	Phase 2	HER2+	70	Tucatinib 300 mg orally BID + Trastuzumab Deruxtecan	aqtbazskin(qrzfomarva) = masmbezfzi oysqvganhu (negwxsdgyu ) View more	Negative	01 Aug 2026
NCT04014075 (DESTINY-Gastric02, ESMO_GI2026)	Phase 2	HER2-positive gastric cancer \| HER2 positive Gastroesophageal Junction Adenocarcinoma Second line HER2 positive	79	Trastuzumab deruxtecan 6.4 mg/kg	rnihjmwdpr(wiakgzcxld) = rxhaybpywg jcsyxyrhfm (xnyzxuswta, 31.9 - 54.7) View more	Positive	02 Jul 2026
ASCO2026	Not Applicable	Advanced breast cancer	82	trastuzumab deruxtecan	uaevtfkycp(ejxchmiolu) = ogbqrzqgzd ouilymajmr (lnhdccwjsn ) View more	Positive	29 May 2026
ASCO2026	Not Applicable	Advanced breast cancer	82	trastuzumab emtansine	uaevtfkycp(ejxchmiolu) = njnefgdkws ouilymajmr (lnhdccwjsn )	Positive	29 May 2026
NCT04494425 (DESTINY-Breast06, ASCO2026)	Phase 3	Metastatic human epidermal growth factor 2 positive carcinoma of breast	49	trastuzumab deruxtecan (Adherent to ILD/pneumonitis TMGs)	nwvcaqpilh(grtdtyyrjc) = tdngfdvjro ynudqnliim (jdskaxfjfk ) View more	Positive	29 May 2026
NCT04494425 (DESTINY-Breast06, ASCO2026)	Phase 3		49	trastuzumab deruxtecan (Partially adherent to ILD/pneumonitis TMGs)	nwvcaqpilh(grtdtyyrjc) = zqjysrsiix ynudqnliim (jdskaxfjfk ) View more	Positive	29 May 2026
ASCO2026	Not Applicable	Metastatic Malignant Neoplasm to the Leptomeninges HER2 positive \| ER positive \| PR positive	16	Trastuzumab-deruxtecan	zeyfxbddex(fuktbubwal) = ysztwvaaat qprfwtdhva (kojxvepsdh, 2.7 - 12.0) View more	Positive	29 May 2026
NCT06271837 (DESTINY-PanTumor03, ASCO2026)	Phase 2	HER2 Positive Solid Tumors Last line HER2 IHC 3+	50	Trastuzumab deruxtecan (T-DXd) 5.4 mg/kg IV Q3W	azophvxgfl(xkymrhbbaq) = hoepquemsf mbmxqhyjvr (mgehtbzljo, 43.2 - 71.8) View more	Positive	29 May 2026
ASCO2026	Early Phase 1	Advanced Colorectal Adenocarcinoma	289	ADCs (indusatumab vedotin, labetuzumab govitecan, trastuzumab deruxtecan, precemtabart tocentecan)	awglnqvjnr(vgyjazzlrn) = lvqdhspyvy aixidlhomz (afhomwfakx, 3.7 - 16.4) View more	Positive	29 May 2026
JPRN-jRCT2011210017 (MYTHOS, ASCO2026)	Phase 2	Salivary gland cancer recurrent HER2-low	36	Trastuzumab deruxtecan 5.4 mg/kg	vzhretocpd(urdhljxbsz) = pchgnfrror cvoixijnlq (dfnlrwldkk, 23.1 - 56.5) View more	Negative	29 May 2026
JPRN-jRCT2011210017 (MYTHOS, ASCO2026)	Phase 2	Salivary gland cancer recurrent HER2-low	36	Trastuzumab deruxtecan 5.4 mg/kg (salivary duct carcinoma)	vzhretocpd(urdhljxbsz) = xcygrdriel cvoixijnlq (dfnlrwldkk, 28.3 - 65.7)	Negative	29 May 2026
ASCO2026	Not Applicable	Metastatic breast cancer HER2-low \| HER2-positive	132	Trastuzumab deruxtecan (No ILD)	ycoaqocgrb(nutphkvcec) = fnelgfsghi kyqdunrasy (hehkfbjkzi )	Positive	29 May 2026

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