Raludotatug deruxtecan

BASKING RIDGE, NJ & RAHWAY, NJ, USA I June 26, 2024 I The U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the Biologics License Application (BLA) seeking accelerated approval of Daiichi Sankyo (TSE: 4568) and Merck’s (known as MSD outside of the United States and Canada) (NYSE: MRK) patritumab deruxtecan (HER3-DXd) for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) previously treated with two or more systemic therapies. The CRL results from findings pertaining to an inspection of a third-party manufacturing facility. The CRL did not identify any issues with the efficacy or safety data submitted. Patritumab deruxtecan is a specifically engineered potential first-in-class HER3 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by Daiichi Sankyo and Merck. “We will work closely with the FDA and the third-party manufacturer to address the feedback as quickly as possible in order to bring the first HER3 directed medicine to patients with previously-treated EGFR-mutated non-small cell lung cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “We remain confident in the ability to develop this medicine to its full potential.” “Patients with previously treated EGFR-mutated non-small cell lung cancer often experience recurrence and have limited treatment options,” said Marjorie Green, MD, Senior Vice President and Head of Oncology, Global Clinical Development, Merck Research Laboratories. “We are committed to working with Daiichi Sankyo and the FDA to prioritize bringing patritumab deruxtecan to these patients in need.” The BLA is based on the primary results from the HERTHENA-Lung01 pivotal phase 2 trial that were presented at the IASLC 2023 World Conference on Lung Cancer (#WCLC23) and simultaneously published in the Journal of Clinical Oncology . In HERTHENA-Lung01, patritumab deruxtecan was studied in 225 patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR TKI and platinum-based chemotherapy, which demonstrated an objective response rate (ORR) of 29.8% (95% CI: 23.9-36.2), including one complete response and 66 partial responses. The median duration of response (DoR) was 6.4 months (95% CI: 4.9-7.8). The safety profile of patritumab deruxtecan observed in HERTHENA-Lung01 was consistent with previous phase 1 clinical trials in NSCLC with a treatment discontinuation rate of 7.1% due to treatment-emergent adverse events (TEAEs). Grade 3 or higher TEAEs occurred in 64.9% of patients. The most common (≥5%) grade 3 or higher TEAEs were thrombocytopenia (21%), neutropenia (19%), anemia (14%), leukopenia (10%), fatigue (6%), hypokalemia (5%) and asthenia (5%). Twelve patients (5.3%) had confirmed treatment-related interstitial lung disease (ILD) as determined by an independent adjudication committee. One grade 5 ILD event was observed. About HERTHENA-Lung01 HERTHENA-Lung01 is a global, multicenter, open-label, two-arm phase 2 trial evaluating the safety and efficacy of patritumab deruxtecan in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR TKI and platinum-based chemotherapy. Patients were randomized 1:1 to receive 5.6 mg/kg (n=225) or an uptitration regimen (n=50). The uptitration arm was discontinued as the dose of 5.6 mg/kg of patritumab deruxtecan was selected following a risk-benefit analysis conducted from the phase 1 trial assessing the doses in a similar patient population. The primary endpoint of HERTHENA-Lung01 was ORR as assessed by blinded independent central review (BICR). Secondary endpoints included DoR, progression-free survival, disease control rate, and time to response – all assessed by both BICR and investigator assessment – as well as investigator-assessed ORR, overall survival, safety and tolerability. HERTHENA-Lung01 enrolled patients in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov . About EGFR-Mutated Non-Small Cell Lung Cancer Approximately 226,000 lung cancer cases were diagnosed in the U.S. in 2022. 1 Lung cancer is the third most common cancer and the leading cause of cancer-related deaths in the U.S. 1 NSCLC accounts for approximately 81% of all lung cancers in the U.S., with 52% having distant spread at diagnosis. 2,3 EGFR mutations occur in approximately one in five patients with NSCLC in Western populations. 4 About HER3 HER3 is a member of the EGFR family of receptor tyrosine kinases. 5 It is estimated that about 83% of primary NSCLC tumors and 90% of advanced EGFR-mutated tumors express HER3 after prior EGFR TKI treatment. 6,7 HER3 is associated with poor treatment outcomes, including shorter relapse-free survival and significantly reduced survival. 8,9 There is currently no HER3 directed therapy approved for the treatment of any cancer. About Patritumab Deruxtecan Patritumab deruxtecan (HER3-DXd) is an investigational HER3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, patritumab deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Patritumab deruxtecan was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration in December 2021 for the treatment of patients with EGFR-mutated locally advanced or metastatic NSCLC with disease progression on or after treatment with a third-generation TKI and platinum-based therapies. Patritumab deruxtecan is currently being evaluated as both a monotherapy and in combination with other therapies in a global development program, which includes HERTHENA-Lung02 , a phase 3 trial evaluating the efficacy and safety of patritumab deruxtecan versus platinum-based chemotherapy in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression on or after treatment with a third-generation EGFR TKI; HERTHENA-Lung01 , a phase 2 trial in metastatic or locally advanced NSCLC with an activating EGFR mutation previously treated with at least one EGFR TKI and one platinum-based chemotherapy-containing regimen; HERTHENA-PanTumor01 , a phase 2 trial in locally advanced or metastatic solid tumors, including melanoma, gastric and head and neck cancer, among other types of cancer, previously treated with at least one prior systemic therapy; a phase 1 trial in combination with osimertinib in EGFR-mutated locally advanced or metastatic NSCLC; and a phase 1 trial in previously treated patients with advanced NSCLC. A phase 1/2 trial in HER3 expressing metastatic breast cancer also has been completed. About the Daiichi Sankyo and Merck Collaboration Daiichi Sankyo and Merck entered into a global collaboration in October 2023 to jointly develop and commercialize patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug deruxtecan (R-DXd), except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply. About the DXd ADC Portfolio of Daiichi Sankyo The DXd ADC portfolio of Daiichi Sankyo currently consists of six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, 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. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, 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. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan and DS-3939 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 needs. For more information, please visit www.daiichisankyo.com . Merck’s Focus on Cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www-merck-com.libproxy1.nus.edu.sg/research/oncology/ . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . References: 1 World Health Organization. International Agency for Research on Cancer. U.S. Cancer Fact Sheet. Accessed June 2024. 2 American Society of Clinical Oncology. Lung Cancer – Non-Small Cell: Statistics . Accessed June 2024. 3 SEER. Adenocarcinoma of the Lung and Bronchus Stage Distribution of SEER Incidence Cases . 2012-2021. Accessed June 2024. 4 Tan AC, et al. J Clin Oncol . 2022;40(6):611-625. 5 Mishra R, et al. Onco Rev . 2018; 12(355):45-62. 6 Scharpenseel H, et al. Scientific Reports . 2019; 9:7406. 7 Yonesaka K, et al. Clin Cancer Res . 2022; 15:28(2):390-403. 8 Gandullo-Sánchez L et al. J Exp Clin Cancer Res . 2022; 41:310. 9 Yu H.A., et al. Annals of Oncology . 2024; 35(5): P437-447. SOURCE: Daiichi Sankyo

Pictured: Front view of Merck Research Laboratories in California/iStock, hapabapa The FDA on Thursday rejected Merck and Daiichi Sankyo’s investigational antibody-drug conjugate patritumab deruxtecan, which the partners were proposing for the treatment of locally advanced or metastatic non-small cell lung cancer bearing certain genetic mutations. In a complete response letter (CRL), the regulator cited issues with a third-party manufacturing facility but did not identify efficacy or safety problems with the application, according to the companies. Ken Takeshita, global head of R&D at Daiichi Sankyo, in a statement said that the partners will “work closely with the FDA and the third-party manufacturer to address the feedback as quickly as possible.” Patritumab deruxtecan was the centerpiece of the October 2023 deal between Merck and Daiichi Sankyo, which saw the pharma pay over $4 billion upfront and pledge around $18 billion in subsequent payments. In return, Merck gained the right to jointly develop and commercialize patritumab deruxtecan worldwide, except in Japan, where Daiichi Sankyo retained exclusive rights. The deal also gave Merck access to two of Daiichi’s other antibody-drug conjugates (ADCs)—ifinatamab deruxtecan, a mid-stage candidate being assessed for extensive-stage small cell lung cancer, and raludotatug deruxtecan, which is being trialed in advanced ovarian cancer. Designed and developed using Daiichi Sankyo’s proprietary DXd ADC platform, patritumab deruxtecan is an investigational candidate that works by targeting the HER3 protein, which is highly expressed across a wide variety of malignancies such as breast and lung cancer. Once bound to its target, patritumab deruxtecan enters tumor cells and releases its toxic payload, an exatecan derivative topoisomerase I inhibitor, which triggers cell death. The FDA has previously granted the ADC its Breakthrough Therapy designation for locally advanced or metastatic non-small cell lung cancer (NSCLC) bearing EGFR mutations. Merck and Daiichi Sankyo supported their Biologics License Application with data from HERTHENA-Lung01 study, a pivotal Phase II study that enrolled 225 patients who experienced disease progression after treatment with an EGFR tyrosine kinase inhibitor and platinum-based chemotherapy. Results from HERTHENA-Lung01 showed an objective response rate of 29.8%, including one patient who achieved complete response and 66 patients who reached partial response. Nearly 65% of patients developed grade 3 or higher treatment-emergent adverse events, with 7.1% dropping out due to side effects. The study documented one fatal case of interstitial lung disease. The FDA accepted patritumab deruxtecan’s application in December 2023 and granted it Priority Review status. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.