HER3

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

YL201/IMDELLTRA combination therapy could offer a novel, synergistic action against ES-SCLC. Credit: Sebastian Kaulitzki/ Shutterstock Amgen and MediLink Therapeutics have agreed to a research and supply collaboration to develop a combination therapy for extensive-stage small cell lung cancer (ES-SCLC). Suzhou, China-based biotech MediLink announced the agreement in a 7 October release. Amgen will orchestrate a global Phase I trial investigating a combined regimen of its DLL3-/CD3-targeting T cell engager Imdelltra (tarlatamab) with MediLink’s B7-H3-targeting antibody-drug conjugate (ADC) YL201 in ES-SCLC. For the Phase I study, MediLink will supply YL201, an ADC that has already shown promise as a monotherapy for ES-SCLC. The drug targets the immune checkpoint protein B7-H3, overexpressed on malignant and cancer-initiated cells, to deliver MediLink’s tumour microenvironment activable LINker-payload (TMALIN)-based ADC. Given the broad presence of B7-H3 expression in cancers, YL201 could have a wide application. At the European Society of Medical Oncology meeting (ESMO) 2024 , MediLink announced data from a Phase I/II trial investigating the drug in advanced solid tumours including SCLC. It is currently being investigated in four Phase I and II studies (NCT06394414, NCT05434234, NCT06057922, NCT06241846), with a Phase III trial planned (NCT06612151) in relapsed SCLC. Amgen’s Imdelltra has also demonstrated potential in this indication. Following an accelerated approval for treating ES-SCLC in May 2024 , Imdelltra generated $12m, as per its Q2 earnings report. Annual revenue is expected to expand as the drug gains approval in other markets, and reach $1bn by 2030, as estimated by GlobalData. The drug acts by binding both DLL3, a protein highly expressed in SCLC cells, and CD3, expressed in T cells, to promote lysis of cancer cells by the immune system. See Also: Merck unveils €290m biosafety testing facility in Maryland, US Boehringer and Circle Pharma link to develop new cancer treatment GlobalData is the parent company of Pharmaceutical Technology . ES-SCLC is a particularly aggressive carcinoma with a notably poor prognosis. It accounts for roughly two-thirds of SCLC cases, comprising around 15% of the 2.4 million new lung cancer cases worldwide each year. Current therapeutic options for SCLC include Merck & Co’s Keytruda (pembrolizumab), Bristol Myers Squibb ’s Opdivo (nivolumab), AstraZeneca ’s Imfinzi (durvalumab), and Roche’s Tecentriq (atezolizumab). MediLink is developing ADCs across several other cancer indications as well. In October 2 023 , it sold the developmental and commercialisation rights outside of China for its HER3-targeting ADC to BioNTech for $70m upfront in a deal including $1bn in milestone payments. In January 2024 , the company partnered with Roche to develop YL211 in solid tumours, a deal worth a further $1bn. Earlier this year it presented positive safety data on YL202/BNT326 for NSCLC and breast cancer at the American Society of Clinical Oncology (ASCO) meeting 2024 .

In the ADC renaissance of the last few years, Japan’s venerable pharma company Daiichi Sankyo has won many of the headlines. But if MediLink Therapeutics has its way, Chinese biotechs will cement the treatments’ dominance in oncology — and prove that China’s new generation of drugmakers can truly compete on the global stage. MediLink has raised $120 million in funding and counts BioNTech and Roche as partners. The Suzhou-based company is at the forefront of a dealmaking wave in which multinational pharma companies have increasingly looked to China as a source of early drug candidates. And MediLink’s licensing deals with multinational pharmas are a bright spot amid growing US-China tensions that have cast a chill over much of the local industry’s work with US companies. The biotech, founded in 2020, came on the scene just as “nearly every pharma was looking for ADCs” again after the drugs had fallen out of favor a decade prior, said Jiaqiang Cai, MediLink’s co-founder and chief scientific officer. That wasn’t always the case. Cai previously worked at Sichuan Kelun-Biotech, which began pursuing ADCs in 2013 after the FDA approval of Roche’s Kadcyla sparked an ADC me-too frenzy in China. While he believed Kelun had a me-better molecule, at 2019’s JP Morgan conference in San Francisco, everyone turned him down for meetings to talk about licensing deals. They saw no future in ADCs, and “nobody believed everything we did in China at that time,” he said. A few months later, Merck came calling after AstraZeneca’s up to $7 billion ADC deal with Daiichi Sankyo stunned the industry. Merck licensed Kelun’s TROP2 ADC and eventually inked two more deals for other programs, each with billions of dollars in potential milestones. By then, Cai had left to work for another domestic pharma company in Shanghai. But Tony Xue, his former ADC partner at Kelun, wondered if they could repeat the success with a new startup and a new platform. “Kelun’s technology is actually very good for TROP2. But for many other targets, [it’s] probably too unstable, and also [the] potency is too high,” Cai said. That fine balance of delivering enough chemotherapy to kill cancer without poisoning the rest of the body has long been the key challenge for ADCs. MediLink works with a version of the standard antibody-linker-payload combo that is stable in healthy tissue and doesn’t require internalization of the antibody — meaning its cancer-killing drugs can be unleashed outside the cell, removing some barriers to efficacy. The concept isn’t new. But the way MediLink turned it into reality is emblematic of the fast, iterative engineering that’s helped many Chinese startups get ahead in the drug discovery race. The tiny team led by Xue, Cai and COO Joey Xiao came up with six different ideas of how to structure the payload-linker complex, then hired a CRO to test them all in parallel. They got to work in December 2020. Three months later, in February 2021, they had a molecule that met their criteria. And in June of that year, optimization was complete. “During six months, they made 200 molecules for us. And only six chemists,” he said. Roche made MediLink the first partner for its Shanghai R&D group, and sees the startup “as a fast-growing China biotech with R&D expertise and proprietary ADC platform technology, including differentiated TOP1 inhibitor payload and linker,” a spokesperson for the Swiss drugmaker said. There can be downsides to speed: MediLink and BioNTech’s HER3 ADC was placed on a clinical hold by regulators earlier this year after patient deaths were deemed related to treatment. The serious toxicity arose as MediLink expanded the patient cohort in a short period of time. “We moved too fast,” Cai told Endpoints. But he said the companies also reacted swiftly to pause enrollment and notify regulators. They ended up adjusting the dose, and the hold was lifted in August . With money from the out-licensing deals, MediLink has been able to grow its team to almost 180 people, even though it hasn’t raised any new venture funding since closing a $70 million Series B in 2022. With many of MediLink’s assets already claimed by a partner (before BioNTech and Roche, it also struck deals with Zai Lab, Harbour BioMed and Henlius) the company’s leaders are hoping to keep some candidates in-house before considering more deals, which Cai said would likely happen at a later phase. “For anything you try to license out, you need to get the idea earlier than others, and then you have something other people don’t have,” he said. When asked about concerns that promising data from Chinese patients wouldn’t translate in trials outside the country, Cai noted that the much higher body weight for US patients could skew the pharmacokinetics, and different dose settings may be required in different countries. “I believe eventually it will work,” he said. Key investors: LYFE Capital, Qiming Venture Partners, Legend Capital, Loyal Valley Capital, Apricot Capital, C&D Emerging Capital, Highlight Capital Find the full list of 2024 Endpoints 11 winners here .