Researchers want to learn if patritumab deruxtecan (MK-1022) can treat certain gastrointestinal (GI) cancers. The GI cancers being studied are advanced (the cancer has spread to other parts of the body). The goals of this study are to learn:
* About the safety and how well people tolerate of patritumab deruxtecan
* How many people have the cancer respond (get smaller or go away) to treatment

Start Date30 Oct 2024

Sponsor / Collaborator

Merck Sharp & Dohme LLC

[+1]

NCT05620914 / Not yet recruitingEarly Phase 1IIT

A Window of Opportunity Study of Patritumab Deruxtecan in Patients With Brain Metastases

The purpose of this study is to determine if the study drug, patritumab deruxtecan (HER3-DXd), can be measured in brain tumor tissue after recieving one dose of patritumab deruxtecan before surgery.

Start Date01 Oct 2024

Sponsor / Collaborator

Duke University

[+1]

NCT06383884 / Not yet recruitingPhase 2IIT

An Open Label, Phase 2 Basket Study of Patritumab Deruxtecan in Patients With Solid Tumor Harboring an NRG1 Fusion

The NRG1 gene is located on chromosome 8 (8p12 region) and encode NRG1. NRG1 gene is translated to generate six different proteins (I-VI) and at least 31 isoforms. NRG1 proteins are structurally related to EGF and contain an EGF-like motif that binds and activates ErbB3 and ErbB4. Upon ligand binding, these receptors form homodimers or heterodimers, which results in phosphorylation of the intrinsic kinase domain, and activation of the PI3K-AKT, MAPK, and other pathways.
The overall incidence of NRG1 fusions is very rare. In many tumor types, only limited numbers of NRG1 fusion variant have been identified. By percentage, there is no organ dominance of the presence of NRG1 fusions. In an analysis of 21, 858 tumor specimens that underwent anchored multiplex PCR for targeted RNA sequencing, the prevalence of NRG1 fusions was 0.2%. Of these, CD74 was the most common partner (29%), followed by ATP1B1 (10%), SDC4 (7%), and RBPMS (5%), and most CD74-NRG1 fusions have been reported in patients with lung IMA. NRG1 fusions result in aberrant expression of the epidermal growth factor (EGF)-like domain of neuregulin-1 (NRG1) on the cell surface binds primarily to ErbB3 and ErbB4, leading to heterodimerization or oligomerization with other ERBB family members. NRG1-mediated activation of ErbB3 promotes dimerization with EGFR, ErbB2, and ErbB4. These partners phosphorylate ErbB3, forming docking sites for SH2-domain proteins, leading to pathologic activation of multiple signal transduction pathways, including the phosphoinositide 3-kinase (PI3K) pathway. Subsequently, ErbB3 expression was noted at high levels, and the proteins were phosphorylated, in fusion-positive cases. Targeting ErbB3 signaling therefore represents a promising therapeutic approach for patients with NRG1 fusion-positive malignancies.

Start Date30 May 2024

Sponsor / Collaborator

Samsung Medical Center

100 Clinical Results associated with Patritumab Deruxtecan

100 Translational Medicine associated with Patritumab Deruxtecan

100 Patents (Medical) associated with Patritumab Deruxtecan

Literatures (Medical) associated with Patritumab Deruxtecan

31 Dec 2024·mAbs

Antibodies to watch in 2024

Article

Author: Crescioli, Silvia ; Kaplon, Hélène ; Wang, Lin ; Reichert, Janice M. ; Visweswaraiah, Jyothsna ; Chenoweth, Alicia

The 'Antibodies to Watch' article series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those recently granted a first approval in any country. In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi)). We briefly review 26 product candidates for which marketing applications are under consideration in at least one country or region, and 23 investigational antibody therapeutics that are forecast to enter regulatory review by the end of 2024 based on company disclosures. These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa). We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutic development efforts by the biopharmaceutical industry are robust and increasingly successful.

01 Oct 2024·BIOORGANIC CHEMISTRY

Novel antibody-drug conjugates based on DXd-ADC technology

Review

Author: Chen, Yuchen ; Ye, Qiang ; Hu, Xuefang ; Bai, Lan ; Shi, Jianyou ; Ren, Zhiwen ; Chen, Rong ; Hu, Yuan

In recent years, antibody-drug conjugate (ADC) technology, which uses monoclonal antibodies (mAbs) to specifically deliver effective cytotoxic payloads to tumor cells, has become a promising method of tumor targeted therapy. ADCs are a powerful class of biopharmaceuticals that link antibodies targeting specific antigens and small molecule drugs with potent cytotoxicity via a linker, thus enabling selective destruction of cancer cells while minimizing systemic toxicity. DXd is a topoisomerase I inhibitor that induces DNA damage leading to cell cycle arrest, making it an option for ADC payloads. The DXd-ADC technology, developed by Daiichi Sankyo, is a cutting-edge platform that produces a new generation of ADCs with improved therapeutic metrics and has shown significant therapeutic potential in various types of cancer. This review provides a comprehensive assessment of drugs developed with DXd-ADC technology, with a focus on mechanisms of action, pharmacokinetics studies, preclinical data, and clinical outcomes for DS-8201a, U3-1402, DS-1062a, DS-7300a, DS-6157a, and DS-6000a. By integrating existing data, we aim to provide valuable insights into the current therapeutic status and future prospects of these novel agents.

01 May 2024·Future oncology (London, England)

HERTHENA-Lung02: phase III study of patritumab deruxtecan in advanced EGFR -mutated NSCLC after a third-generation EGFR TKI

Article

Author: Fougeray, Ronan ; Novello, Silvia ; Wu, Yi-Long ; Sternberg, David W ; Jänne, Pasi A ; Mok, Tony ; Yu, Helena A ; Nishio, Makoto ; Steuer, Conor ; Meng, Jie ; Reck, Martin ; Fan, Pang-Dian ; Esker, Stephen

After disease progression on EGFR tyrosine kinase inhibitor (TKI) therapy, patients with EGFR-mutated NSCLC who are then treated with platinum-based chemotherapy (PBC) obtain only limited clinical benefit with transient responses. Therapies with greater efficacy and tolerable safety profiles are needed in this setting. The receptor tyrosine kinase HER3 is widely expressed in NSCLC, and increased expression is associated with poor treatment outcomes. In the U31402-A-U102 phase I trial, HER3-DXd showed promising antitumor activity with manageable safety in heavily pre-treated patients with EGFR-mutated NSCLC across a range of tumor HER3 expression levels and EGFR TKI resistance mechanisms. HERTHENA-Lung02 is the first phase III trial to evaluate the safety and efficacy of HER3-DXd versus PBC in patients with progression on a third-generation EGFR TKI. Clinical Trial Registration: NCT05338970 ( clinicaltrials.gov ); 2021-005879-40 (EudraCT Number).

156

News (Medical) associated with Patritumab Deruxtecan

31 Oct 2024

·pipelinereview.com

Three Phase 3 Trials of Datopotamab Deruxtecan-Based Combinations Initiated in Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer

TOKYO, Japan & BASKING RIDGE, NJ, USA I October 30, 2024 I The first patients have been dosed in three global, randomized phase 3 trials evaluating the efficacy and safety of datopotamab deruxtecan (Dato-DXd)-based combinations in patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN). TROPION-Lung10 is evaluating datopotamab deruxtecan plus rilvegostomig, AstraZeneca’s PD-1/TIGIT bispecific antibody, or rilvegostomig alone versus pembrolizumab in patients with previously untreated locally advanced or metastatic nonsquamous NSCLC with high PD-L1 expression (tumor cells [TC] ≥ 50%) and without actionable genomic alterations. TROPION-Lung14 is evaluating datopotamab deruxtecan plus osimertinib, AstraZeneca’s EGFR tyrosine kinase inhibitor (TKI), versus osimertinib alone in patients with previously untreated locally advanced or metastatic EGFR mutated nonsquamous NSCLC. TROPION-Lung15 is evaluating datopotamab deruxtecan with or without osimertinib versus platinum-based doublet chemotherapy in patients with locally advanced or metastatic nonsquamous EGFR mutated NSCLC whose disease progressed on prior treatment with osimertinib. “These three trials in either high PD-L1 expressing or EGFR mutated nonsquamous non-small cell lung cancer are critical to helping us understand the potential role of datopotamab deruxtecan in treating patients across different lines and types of lung cancer,” said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. “Our growing TROPION clinical program, which now consists of seven phase 3 trials demonstrates our commitment to understanding the full potential of datopotamab deruxtecan in lung cancer.” “Clinical research suggests that combining an antibody drug conjugate with a targeted treatment or a bispecific immunotherapy may drive stronger and more durable tumor responses in patients with a variety of cancers including lung cancer,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. “The initiation of these additional three phase 3 trials of datopotamab deruxtecan in combination with our agents, osimertinib and rilvegostomig illustrates our commitment to exploring potential synergies within our oncology pipeline as well as the full potential and combinability of this TROP2 directed antibody drug conjugate across multiple segments and settings of non-small cell lung cancer.” About TROPION-Lung10 TROPION-Lung10 is a global, multicenter, open-label, three-arm phase 3 trial where patients will be randomized in a 2:1:2 ratio to evaluate the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) in combination with rilvegostomig (750 mg) or rilvegostomig (750 mg) monotherapy versus pembrolizumab (200 mg) monotherapy in adult patients with previously untreated locally advanced or metastatic nonsquamous NSCLC with high PD-L1 expression (TC ≥ 50%) and without actionable genomic alterations. The dual primary endpoints of TROPION-Lung10 are progression-free survival (PFS) as assessed by blinded independent central review (BICR) and overall survival (OS) in patients with TROP2 positive tumors receiving datopotamab deruxtecan in combination with rilvegostomig versus the pembrolizumab arm. A pre-specified retrospective analysis from tumor biopsies collected pretreatment will be conducted following validation of a potential TROP2 biomarker determined by quantitative continuous scoring, a computational pathology approach. Key secondary endpoints for all arms of the trial include PFS as assessed by BICR and investigator and OS in the intention-to-treat (ITT) population, objective response rate (ORR) as assessed by BICR and duration of response (DoR) as assessed by BICR and investigator in both TROP2 biomarker positive and the ITT populations. The safety and tolerability of datopotamab deruxtecan in combination with rilvegostomig and rilvegostomig monotherapy as compared with pembrolizumab also will be assessed. TROPION-Lung10 will enroll approximately 675 patients in Asia, Europe, North America, Oceania and South America. For more information visit ClinicalTrials.gov . The TIGIT component of rilvegostomig is derived from the clinical-stage anti-TIGIT antibody, COM902, developed by Compugen Ltd. (Nasdaq/TASE: CGEN). About TROPION-Lung14 TROPION-Lung14 is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) in combination with osimertinib (80 mg) versus osimertinib (80 mg) monotherapy in adult patients with previously untreated locally advanced or metastatic nonsquamous NSCLC with an EGFR mutation (Exon 19 deletion and/or L858R). The randomized period of the trial is preceded by a single-arm safety run-in period which will enroll approximately 20 patients to evaluate the combination therapy. The primary endpoint of TROPION-Lung14 is PFS as assessed by BICR. Key secondary endpoints include central nervous system (CNS) PFS as assessed by CNS BICR, PFS as assessed by investigator, ORR as assessed by BICR and investigator, OS and safety. TROPION-Lung14 will enroll approximately 580 patients in Asia, Europe, North America, Oceania and South America. For more information visit ClinicalTrials.gov . About TROPION-Lung15 TROPION-Lung15 is a global, multicenter, open-label, three-arm phase 3 trial where patients will be randomized in a 1:1:1 ratio to evaluate the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) as monotherapy or in combination with osimertinib (80 mg) versus platinum-based doublet chemotherapy (pemetrexed in combination with carboplatin or cisplatin followed by pemetrexed maintenance) in adult patients with locally advanced or metastatic nonsquamous NSCLC with at least one EGFR mutation (G719X, Ex19del, S768I, L858R, and/or L861Q) and with disease progression following prior treatment with osimertinib. The dual primary PFS endpoints of TROPION-Lung15 are PFS as assessed by BICR for datopotamab deruxtecan monotherapy versus chemotherapy and datopotamab deruxtecan in combination with osimertinib versus chemotherapy. Key secondary endpoints include investigator-assessed CNS PFS as assessed by CNS BICR, ORR and DoR as assessed by BICR, OS and safety. TROPION-Lung15 will enroll approximately 630 patients in Asia, Europe, North America, Oceania and South America. For more information visit ClinicalTrials.gov . About Advanced Non-Small Cell Lung Cancer Nearly 2.5 million lung cancer cases were diagnosed globally in 2022. 1 NSCLC is the most common type of lung cancer, accounting for about 85% of cases. 2 Approximately 75% and 25% of NSCLC tumors are of nonsquamous or squamous histology, respectively, with EGFR mutations occurring in 14% to 38% of all NSCLC tumors worldwide. 3,4 A majority of EGFR mutations occur in tumors with nonsquamous histology. 5 For patients with tumors that do not express a known actionable genomic alteration (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET or MET), the current first-line standard of care in the metastatic setting is an immune checkpoint inhibitor and/or platinum-based chemotherapy based on PD-L1 expression. 6,7,8 For certain patients with tumors that have EGFR mutations, the established first-line treatment in the metastatic setting is an EGFR TKI. 9 While these treatment strategies have improved outcomes in the first-line metastatic setting, most patients eventually experience disease progression. 10,11,12 TROP2 is a protein broadly expressed in the majority of NSCLC tumors. 13 There is currently no TROP2 directed ADC approved for the treatment of lung cancer. 8,9 About Datopotamab Deruxtecan (Dato-DXd) Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, datopotamab deruxtecan is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple negative breast cancer and HR positive, HER2 negative breast cancer. The program includes seven phase 3 trials in lung cancer and five phase 3 trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings. About the Daiichi Sankyo and AstraZeneca Collaboration Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020 , except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan. About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 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 is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com . References 1 World Health Organization. Global Cancer Observatory: Lung . Accessed October 2024. 2 Economopoulou P, et al. Ann Transl Med . 2018; 6(8):138 3 National Cancer Institute. SEER Cancer Statistics Factsheets: Lung and Bronchus Cancer, CSR 1975-2017 . Accessed October 2024. 4 Pretelli G, et al. Int J Mol Sci . 2023; 24, 8878. 5 Prabhakar C. Translational Lung Cancer Research . 2015; 4(2), 110-118. 6 Mok TSK, et al. Lancet . 2019 May 4;393(10183):1819-1830. 7 Brahmer J.R. et al. KEYNOTE-024 5-year OS update . ESMO 2021 Virtual Congress. 2021 Sept 16 – 20; Abstract LBA51. 8 Rodríguez-Abreau D, et al. Ann Onc . 2021 Jul;32(7):881-895. 9 American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer . Accessed October 2024. 10 Chen R, et al. J Hematol Oncol . 2020:13(1):58. 11 Majeed U, et al. J Hematol Oncol . 2021;14(1):108. 12 Pircher A, et al. Anticancer Research . 2020;70(5):287-294. 13 Mito R, et al. Pathol Int . 2020;70(5):287-294. SOURCE: Daiichi Sankyo

Phase 3ImmunotherapyADCLicense out/in

24 Oct 2024

·medcitynews.com

Targeting the Blast Radius: Why Spatial AI Diagnostics Are Crucial for Maximizing the Impact of Antibody-Drug Conjugates - MedCity News

Antibody-drug conjugates (ADCs) are designed to deliver precise blows to cancer cells, much like a well-aimed strike. However, the real power of these therapies lies not only in their direct targeted impact but in the broader “blast radius” and “bystander killing” effect they generate within the tumor microenvironment. To fully understand and control this effect, we need to go beyond traditional diagnostic pathology methods. Spatial artificial intelligence (AI), which maps, analyzes, and interprets the complex cellular interactions in a patient’s tumor biopsy, and spatial biomarkers are crucial for guiding these powerful therapies and ensuring they achieve their intended results. The “blast radius” and “bystander killing” in ADCs presented by Sponsored Post The Promise of Value-Based Care and MedTech Innovation Monica Vajani, Executive Director for mHUB’s MedTech Accelerator, discusses how mHUB is helping innovators transition healthcare towards value-based care. By Monica Vajani - mHUB The “blast radius” refers to the zone of influence around the target cells where an ADC also affects nearby cells, not just the intended cancer cells. This effect can be beneficial by eliminating neighboring malignant cells, but it can also risk harming healthy tissue if not properly managed. “Bystander killing” occurs when a therapy like an ADC targets a specific protein in cancer cells but also affects adjacent cells that do not express the target protein. This secondary effect can contribute to the overall effectiveness of the treatment but requires careful consideration to avoid unintended damage. Spatial AI offers researchers and pathologists a powerful tool to analyze these complex interactions across hundreds and thousands of patient samples; it’s like how we went from using flat, physical maps to utilizing GPS on our mobile phones for getting directions–scaling a process easily that couldn’t be done manually before. Scientists are calling this new approach AI-powered spatial proximity scoring. The shortcomings of traditional pathology Sponsored Post The Future of Hospitals and Pharma Companies Will Depend on Strength of Healthcare Analytics Insights PurpleLab® stands out from others in this sector by providing its data analytics services to several different groups of users across healthcare and pharma companies. By pcallaghan Traditional pathology methods often classify cancer cells in binary terms, such as HER2 positive or negative. This oversimplification fails to capture the nuanced interactions within the tumor microenvironment that are critical to understanding how treatments like ADCs will perform. For instance, patients with HER2 “ultralow” expression might benefit from ADCs but are often overlooked by traditional methods. While the human eye can easily conduct binary scoring of cancer cells in traditional pathology, it struggles with the current need for continuous linear scoring (e.g., HER2 high, low, ultralow, and negative) or scoring cells within a specific blast radius. By relying on binary classifications, traditional pathology may overlook patients who could benefit from therapies if their tumor’s complexity were better understood. For example, patients with HER2 “ultralow” expression might not be considered for ADCs even though they could respond to treatment. AI can help scale both the detection of ultralow and low expressors and complex spatial proximity scoring. Spatial AI: Mapping the tumor microenvironment Spatial biomarkers are not just individual data points, but a map of interactions and patterns within the tumor. They reveal how different cell types are positioned relative to each other, how they interact, and how these interactions influence the tumor’s behavior and a patient’s response to treatment. This approach moves beyond static snapshots of individual proteins and provides a dynamic view of the tumor environment. Spatial AI combines advanced imaging techniques with machine learning to analyze tissue samples across multiple parameters, such as cells, proteins, location coordinates, and cellular interactions, to name a few. By mapping the spatial distribution of proteins, cells, and other critical factors, it uncovers patterns that the human eye cannot detect, such as subtle differences in protein expression or the optimal radius at which bystander killing leads to effective treatment outcomes. Innovative companies are drawing from geospatial analysis methodologies and applying those techniques to the biological realm. This approach, termed “biospatial,” uses AI to create detailed maps of the tumor microenvironment, allowing for a more accurate prediction of how therapies like ADCs will interact with both their intended targets and surrounding cells. Why spatial AI is essential for improving patient outcomes with ADCs ADCs are a powerful targeted and personalized treatment option for cancer patients. However, as the oncology field advances, the need for better companion diagnostics to predict treatment response is essential. Researchers are moving towards developing a deeper understanding of the comprehensive map of cell locations and interactions within each patient’s tissue sample and using AI algorithms to determine signature patterns that predict ADC response. By understanding the surrounding tumor biology and creating spatial biomarkers, clinicians can better determine which ADC therapies will lead to the best outcomes for specific patient subpopulations. For example, AstraZeneca and Daiichi Sankyo have shown how AI spatial scoring can help identify breast cancer patients who positively responded to HER2-directed ADC trastuzumab deruxtecan treatment even though traditional diagnostic methods scored them as a false HER2 negative. Per the guidelines, these patients would have been deemed ineligible for ADC treatment. Since these patients responded positively to therapy, possibly due to additional bystander effects, it demonstrates the potential of spatial AI to expand treatment options. Additionally, the partners developed a novel AI-powered biomarker to assess expression of the protein TROP2 and to conduct an exploratory analysis of their Phase III TROPION-Lung01 trial, evaluating TROP2-directed ADC datopotamab deruxtecan (Dato-DXd) in non-small cell lung cancer. In TROP2-QCS-positive patients, Dato-DXd lowered the risk of disease progression or death by 43%. This approach demonstrates possibilities for spatial AI to further derisk clinical trials and another pathway for pharma companies to improve patient selection. AstraZeneca is also deploying this novel AI-powered TROP2 biomarker for prospective enrollment in the AVANZAR trial, a combo study with Dato-DXd plus Imfinzi and chemotherapy, as first-line treatment of advanced NSCLC without actionable genomic alterations. Scientists are working closely with leading precision medicine and biopharmaceutical companies to leverage spatial AI and solve challenges in ADC development, such as improving patient selection and optimizing trial outcomes. As an example, groundbreaking technologies are currently being deployed to analyze failed trial samples using AI spatial proximity scoring. The goal is to determine whether spatial scoring could better predict treatment outcomes and accurately classify responders and non-responders. These types of studies could lead to new strategies informing patient selection for future trials where traditional methods failed to show efficacy. The future of cancer treatment As the field of oncology evolves, we need to shift away from traditional binary “yes-no” biomarkers to a more nuanced, spatial understanding of tumor biology. This approach will allow for more personalized treatment plans that are tailored to the unique characteristics of each patient’s tumor. Spatial AI is essential for fully realizing the potential of advanced cancer therapies, providing the detailed insights necessary to guide these treatments effectively. This ensures that each therapy hits its targets precisely while managing the broader impact on the tumor environment. Integrating spatial AI into clinical practice could become the standard for evaluating and administering complex therapies like ADCs. This integration would ensure that every aspect of the tumor’s biology is considered in treatment decisions, leading to better patient outcomes. We need to go beyond finding the right drug, and rather, amplify our understanding of how that drug interacts with the entire tumor. With spatial AI, we can bring a new level of precision to cancer therapy, offering patients safer, more effective and personalized treatments. Editor’s Note: The author has no financial relationship with any of the companies / products mentioned.

Phase 3Clinical ResultADC

18 Oct 2024

·www.biospace.com

Gilead Withdraws ADC Trodelvy in Bladder Cancer After Trial Failure

iStock, Sundry Photography The move is a blow to Gilead’s cancer portfolio. Trodelvy, an antibody-drug conjugate granted accelerated approval for bladder cancer in 2021, failed its confirmatory trial earlier this year. Gilead is withdrawing Trodelvy from the market in bladder cancer after a confirmatory study did not meet its primary endpoint. The antibody-drug conjugate (ADC), which will remain on the market in other indications, is a pillar of Gilead’s cancer portfolio. Trodelvy was approved for the indication under accelerated review in 2021, with a requirement that the company conduct a confirmatory trial to obtain a full approval. Results for that trial, called TROPiCS-04, were announced in June , showing that Trodelvy failed to improve overall survival in patients with metastatic bladder cancer. Gilead noted a higher number of deaths from adverse events in the Trodelvy arm than the group that received a treatment of the physician’s choice. The company said at the time that the data would be analyzed with next steps communicated at a later date. Gilead has now decided to take the drug off the market for the indication. Trodelvy’s traditional approvals in different types of advanced breast cancer are not affected by the withdrawal in bladder cancer. The accelerated approval in bladder cancer was granted on Phase II data from the single-arm TROPHY-U-01 study. Gilead conducted the TROPiCS-04 to confirm a clinical benefit. Gilead intends to report full results from that trial at an upcoming medical meeting. Trodelvy was the first Trop-2-directed ADC approved, according to Gilead. The company is testing it across a range of tumor types, including lung and gynecological cancers, but the outcomes, like the TROPiCS-04 study, have not been ideal so far. The therapy failed to improve overall survival in the Phase III EVOKE-1 trial of patients with previously treated metastatic non-small cell lung cancer (NSCLC) in January. Gilead later pointed to a subgroup of patients who didn’t respond to previous PD-1/L1 treatment who saw a benefit. Nevertheless, demand for Trodelvy helped drive Gilead’s oncology program to a 37% year-over-year improvement in product sales, with $2.9 billion recorded for full-year 2023, according to a year-end 2023 earnings report. Trodelvy booked $1.1 billion of that—a 56% increase year-over-year. The rest of the cancer earnings came from Gilead’s cell therapy portfolio. More recently, Gilead CEO Daniel O’Day reported that Trodelvy clocked a 23% increase year-over-year for the second quarter to $320 million. CFO Andrew Dickinson clarified on the second quarter earnings call that bladder cancer accounted for about 10% of Trodelvy’s sales. O’Day expressed confidence in the breast cancer indication while the lung and bladder cancer indications were under review. Gilead is awaiting results from a handful of Phase III trials that could support moving Trodelvy into earlier lines of treatment for breast cancer. The company faces fierce competition from AstraZeneca’s drug datopotamab deruxtecan, which is partnered with ADC powerhouse Daiichi Sankyo. Gilead will present third quarter earnings on November 6.

Accelerated ApprovalPhase 3Drug ApprovalADCFinancial Statement

100 Deals associated with Patritumab Deruxtecan

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
EGFR-mutated non-small Cell Lung Cancer	NDA/BLA	US	Daiichi Sankyo Co., Ltd.	22 Dec 2023
EGFR-mutated non-small Cell Lung Cancer	NDA/BLA	US	Merck & Co., Inc.	22 Dec 2023
Non-squamous non-small cell lung cancer	Phase 3	US	Daiichi Sankyo Co., Ltd.	08 Jul 2022
Non-squamous non-small cell lung cancer	Phase 3	CN	Daiichi Sankyo Co., Ltd.	08 Jul 2022
Non-squamous non-small cell lung cancer	Phase 3	JP	Daiichi Sankyo Co., Ltd.	08 Jul 2022
Non-squamous non-small cell lung cancer	Phase 3	AU	Daiichi Sankyo Co., Ltd.	08 Jul 2022
Non-squamous non-small cell lung cancer	Phase 3	AT	Daiichi Sankyo Co., Ltd.	08 Jul 2022
Non-squamous non-small cell lung cancer	Phase 3	BE	Daiichi Sankyo Co., Ltd.	08 Jul 2022
Non-squamous non-small cell lung cancer	Phase 3	CA	Daiichi Sankyo Co., Ltd.	08 Jul 2022
Non-squamous non-small cell lung cancer	Phase 3	FR	Daiichi Sankyo Co., Ltd.	08 Jul 2022

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04965766 (ICARUS-BREAST01, ESMO2024) Manual	Phase 2	Hormone receptor positive HER2 negative breast cancer Second line Hormone Receptor Positive \| HER2 Negative	99	Patritumab deruxtecan (HER3-DXd) 5.6 mg/kg IV	wizfxkkqky(cftsvaikqy) = kmwphldrus ujhrbtpyzx (zvabfwdhfb, 43.2 - 63.6) View more	Positive	13 Sep 2024
NCT04619004 (HERTHENA-Lung01, ESMO_ELCC2024) Manual	Phase 2	EGFR-mutated non-small Cell Lung Cancer EGFR Mutation	225	HER3-DXd 5.6 mg/kg IV Q3W	wrnootveuu(bhubtkaxve) = nxmylcelea dojmfizwqf (cugphltwta ) View more	Positive	22 Mar 2024
NCT04619004 (HERTHENA-Lung01, ESMO2023) Manual	Phase 2	EGFR-mutated non-small Cell Lung Cancer EGFR mutation	95	HER3-DXd 5.6 mg/kg	vvbaskejgw(bstwjlbazj) = xhyhzkcgud oepdrcbwzw (cvsxtgrheo ) View more	Positive	22 Oct 2023
NCT04619004 (HERTHENA-Lung01, ESMO2023) Manual	Phase 2	EGFR-mutated non-small Cell Lung Cancer EGFR mutation	95	HER3-DXd 5.6 mg/kg (Prior local CNS-directed radiotherapy <6 mo from start)	vvbaskejgw(bstwjlbazj) = trazncsqrg oepdrcbwzw (cvsxtgrheo ) View more	Positive	22 Oct 2023
NCT04619004 (HERTHENA-Lung01, WCLC2023) Manual	Phase 1/2	EGFR-mutated non-small Cell Lung Cancer EGFR Mutation	-	U3-1402 (Prior EGFR TKI (any) and PBC)	xdxygzcmhx(mpxxacaaix) = lfmgzsknzu bisgbfwnxa (pplrqmvyig ) View more	Positive	10 Sep 2023
NCT04619004 (HERTHENA-Lung01, WCLC2023) Manual	Phase 1/2	EGFR-mutated non-small Cell Lung Cancer EGFR Mutation	-	U3-1402 (Prior 3G EGFR TKI and PBC)	xdxygzcmhx(mpxxacaaix) = qdwuqzneah bisgbfwnxa (pplrqmvyig ) View more	Positive	10 Sep 2023
NCT04699630 (ASCO2023) Manual	Phase 2	Metastatic breast cancer	60	HER3-DXd	mfyoivynha(tzrybjqfpt) = bccldxaeiw pmdrrgdrzv (rhyzuvmbid, 23.1 - 48.1) View more	Positive	31 May 2023
NCT04965766 (ICARUS-BREAST01, ESMO_BC2023)	Phase 2	Advanced breast cancer First line HER3	100	HER3-DXd 5.6 mg/kg IV	vnbcnttnss(qevbommxho) = jwezxsxefu fjkwozbvbs (xtofstrjsx, 18.4 - 41.5)	Positive	12 May 2023
NCT04610528 (SOLTI TOT-HER3, ESMO_BC2023)	Phase 2	Triple Negative Breast Cancer ERBB3	-	HER3-DXd 5.6 mg/kg	cqkmynzvmu(oedvomuhnn) = dikwfrnqws fbncrbpxhc (ngmcacdiar )	Positive	12 May 2023
AACR2022	Not Applicable	Estrogen receptor positive breast cancer	-	HER3-DXd	czlrlcavsq(lgczxomxlc) = reprogrammed cell cycle progression from G2/M arrest to G1 arrest cponqqrcyw (dybohgwope )	-	15 Jun 2022
NCT03260491 (ASCO2022) Manual	Phase 1	Non-Small Cell Lung Cancer	47	Patritumab Deruxtecan 5.6 mg/ kg	qtgvleaung(ezkkjjxqqn) = dloorrnize doibbtfiqh (qcziuspdys, 16 - 43) View more	Positive	02 Jun 2022
JPRN-JapicCTI-163401 \| NCT02980341 (ASCO2022)	Phase 1/2	Metastatic breast cancer	182	Patritumab deruxtecan	mlcmrnegwl(jinzkyrqqa) = fprxqxkvkx mfawspqjgy (hbiehmamun ) View more	-	02 Jun 2022

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