Datopotamab Deruxtecan New BLA Submitted for Accelerated Approval in the U.S. for Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer
Daiichi Sankyo and AstraZeneca have submitted a new Biologics License Application (BLA) for accelerated approval of datopotamab deruxtecan to treat adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who have received prior therapies. The application is based on the TROPION-Lung05 phase 2 trial, supported by additional trial data. The companies have withdrawn their previous BLA for nonsquamous NSCLC following FDA feedback. New results from a pooled analysis of patients with previously treated EGFR-mutated NSCLC will be presented at ESMO Asia 2024. The companies are conducting additional phase 3 trials evaluating the treatment alone and in combination with osimertinib.
Daiichi Sankyo e AstraZeneca hanno presentato una nuova Domanda di Licenza Biologica (BLA) per l'approvazione accelerata di datopotamab deruxtecan per trattare pazienti adulti con cancro ai polmoni non a piccole cellule (NSCLC) localmente avanzato o metastatico con mutazioni dell'EGFR che hanno già ricevuto terapie precedenti. La richiesta si basa sullo studio di fase 2 TROPION-Lung05, supportato da ulteriori dati sperimentali. Le aziende hanno ritirato la loro precedente BLA per NSCLC non squamoso in seguito ai commenti della FDA. Nuovi risultati di un'analisi aggregata di pazienti con NSCLC mutato dell'EGFR e precedentemente trattato saranno presentati all'ESMO Asia 2024. Le aziende stanno conducendo ulteriori studi di fase 3 per valutare il trattamento da solo e in combinazione con osimertinib.
Daiichi Sankyo y AstraZeneca han presentado una nueva Solicitud de Licencia Biológica (BLA) para la aprobación acelerada de datopotamab deruxtecan para tratar a pacientes adultos con cáncer de pulmón no microcítico (NSCLC) localmente avanzado o metastásico que tienen mutaciones en EGFR y que han recibido terapias previas. La solicitud se basa en el ensayo de fase 2 TROPION-Lung05, respaldado por datos adicionales del ensayo. Las empresas han retirado su BLA anterior para el NSCLC no escamoso tras recibir comentarios de la FDA. Nuevos resultados de un análisis agrupado de pacientes con NSCLC mutado en EGFR previamente tratados se presentarán en ESMO Asia 2024. Las empresas están llevando a cabo ensayos clínicos adicionales de fase 3 evaluando el tratamiento solo y en combinación con osimertinib.
다이이치 산쿄와 아스트라제네카는 이전 치료를 받은 성인 환자의 국소 진행성 또는 전이성 EGFR 돌연변이 비소세포 폐암(NSCLC) 치료를 위한 다토포탐압 데룩스테칸의 가속 승인을 위한 새로운 생물학적 제품 허가 신청(BLA)을 제출했습니다. 이 신청은 추가 시험 데이터에 의해 지원되는 TROPION-Lung05 2상 시험에 기반하고 있습니다. 두 회사는 FDA 피드백에 따라 비편평 NSCLC에 대한 기존 BLA를 철회했습니다. 이전에 치료받은 EGFR 돌연변이 NSCLC 환자의 집단 분석에서 나온 새로운 결과는 ESMO 아시아 2024에서 발표될 예정입니다. 두 회사는 치료 단독 및 오시머티닙과의 병용 평가를 위한 추가 3상 시험을 진행하고 있습니다.
Daiichi Sankyo et AstraZeneca ont soumis une nouvelle Demande de Licence Biologique (BLA) pour l'approbation accélérée de datopotamab deruxtecan pour traiter des patients adultes atteints d'un cancer du poumon non à petites cellules (NSCLC) localement avancé ou métastatique et présentant des mutations de l'EGFR, qui ont déjà reçu des thérapies antérieures. La demande est basée sur l'essai de phase 2 TROPION-Lung05, soutenue par des données d'essai supplémentaires. Les entreprises ont retiré leur précédente BLA pour le NSCLC non squameux suite aux retours de la FDA. De nouveaux résultats d'une analyse groupée de patients atteints de NSCLC muté de l'EGFR et précédemment traités seront présentés à l'ESMO Asia 2024. Les entreprises mènent des essais supplémentaires de phase 3 évaluant le traitement seul et en combinaison avec l'osimertinib.
Daiichi Sankyo und AstraZeneca haben einen neuen Antrag auf biologische Lizenz (BLA) für die beschleunigte Genehmigung von datopotamab deruxtecan zur Behandlung von erwachsenen Patienten mit lokal fortgeschrittenem oder metastasiertem EGFR-mutiertem nicht kleinzelligem Lungenkrebs (NSCLC) eingereicht, die zuvor Therapien erhalten haben. Der Antrag basiert auf der Phase-2-Studie TROPION-Lung05, die durch zusätzliche Studiendaten unterstützt wird. Die Unternehmen haben ihren vorherigen BLA-Antrag für nicht-squamöses NSCLC nach dem Feedback der FDA zurückgezogen. Neue Ergebnisse einer gepoolten Analyse von Patienten mit zuvor behandelt EGFR-mutiertem NSCLC werden auf der ESMO Asia 2024 präsentiert. Die Unternehmen führen zusätzliche Phase-3-Studien durch, um die Behandlung allein und in Kombination mit Osimertinib zu bewerten.
- New BLA submission for accelerated approval targeting specific EGFR-mutated NSCLC patient population
- Multiple ongoing phase 3 trials expanding potential market opportunities
- Development of QCS biomarker for TROP2 could improve patient targeting
- Withdrawal of previously submitted BLA for nonsquamous NSCLC indicates regulatory setback
- Current submission based on phase 2 trial rather than more robust phase 3 data
Insights
The BLA submission for datopotamab deruxtecan in EGFR-mutated NSCLC represents a significant strategic pivot. The withdrawal of the broader nonsquamous NSCLC application in favor of a more targeted EGFR-mutated population suggests stronger efficacy data in this specific subset. This is particularly noteworthy as EGFR-mutated NSCLC patients often develop resistance to existing therapies, creating a substantial unmet medical need.
The submission package leverages data from multiple trials - TROPION-Lung05 (Phase 2), supported by TROPION-Lung01 (Phase 3) and TROPION-PanTumor01 (Phase 1). The upcoming presentation of pooled analysis at ESMO Asia 2024 could provide important efficacy insights. The parallel development of a TROP2 biomarker strategy through QCS scoring indicates a sophisticated approach to patient selection, potentially improving treatment outcomes.
This regulatory strategy refinement could accelerate datopotamab deruxtecan's path to market in a well-defined patient population. The EGFR-mutated NSCLC market represents a significant commercial opportunity, with high unmet need in treatment-resistant cases. The development of companion biomarker testing could create additional revenue streams and improve market positioning.
The ongoing phase 3 trials TROPION-Lung14 and TROPION-Lung15, testing combinations with osimertinib, suggest a comprehensive development strategy that could expand market presence. This positions AstraZeneca to potentially capture both monotherapy and combination therapy markets in EGFR-mutated NSCLC, strengthening their oncology portfolio.
- Daiichi Sankyo and AstraZeneca’s new application is based on the TROPION-Lung05 phase 2 trial and supported by data from additional trials including TROPION-Lung01
- Previously submitted BLA based on TROPION-Lung01 phase 3 trial for patients with nonsquamous NSCLC has been voluntarily withdrawn
The companies have voluntarily withdrawn the BLA in the
The decision to submit a new BLA for EGFR-mutated NSCLC and withdraw the previously submitted BLA for nonsquamous NSCLC was informed by feedback from the
The new BLA is based on results from the TROPION-Lung05 phase 2 trial and supported by data from the TROPION-Lung01 phase 3 and TROPION-PanTumor01 phase 1 trials. New results from a pooled analysis of patients with previously treated EGFR-mutated NSCLC in the TROPION-Lung05 and TROPION-Lung01 trials will be featured in a late-breaking presentation at the upcoming European Society for Medical Oncology (ESMO)
Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by Daiichi Sankyo and AstraZeneca.
“Treating EGFR-mutated non-small cell lung cancer is incredibly challenging following disease progression given that the complexity and variability of these mutations often lead to resistance,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “The potential approval of datopotamab deruxtecan could offer renewed hope for patients with this formidable disease.”
“TROPION-Lung01 was designed to test the potential to improve upon standard-of-care chemotherapy in a broad, previously treated, advanced lung cancer patient population. The results, together with data from TROPION-Lung05, showed an especially pronounced benefit for patients with an EGFR mutation which informed our discussions with the FDA and the decision to seek accelerated approval of datopotamab deruxtecan in this patient population,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “TROPION-Lung01 has also provided exciting exploratory data supporting our biomarker development, which will be validated in ongoing and planned phase 3 lung cancer trials.”
Daiichi Sankyo and AstraZeneca are evaluating datopotamab deruxtecan alone and with osimertinib, AstraZeneca’s EGFR tyrosine kinase inhibitor (TKI), as treatment for patients with advanced or metastatic EGFR-mutated nonsquamous NSCLC in the ongoing TROPION-Lung14 and TROPION-Lung15 phase 3 trials. In addition, ongoing phase 3 trials in first-line advanced or metastatic nonsquamous NSCLC, AVANZAR and TROPION-Lung10, have the potential to validate the QCS (quantitative continuous scoring) biomarker for TROP2 identified in an exploratory analysis of TROPION-Lung01. An additional trial in patients with biomarker-positive tumors in the second-line nonsquamous NSCLC setting is also planned.
About TROPION-Lung05
TROPION-Lung05 is a global, multicenter, single-arm, open-label phase 2 trial evaluating the efficacy and safety of datopotamab deruxtecan in patients with locally advanced or metastatic NSCLC with actionable genomic alterations who have progressed on or after one regimen of platinum-based chemotherapy and at least one TKI (with or without other systemic therapies). Patients receiving up to four prior lines of treatment with tumors with one or more genomic alterations including EGFR, ALK, ROS1, NTRK, BRAF, RET or MET were eligible for the trial.
The primary trial endpoint of TROPION-Lung05 is objective response rate (ORR) as assessed by blinded independent central review (BICR). Secondary efficacy endpoints include duration of response (DoR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), time to response (TTR), overall survival (OS) and safety.
TROPION-Lung05 enrolled 137 patients globally in
About TROPION-Lung01
TROPION-Lung01 is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan versus docetaxel in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. Patients with actionable genomic alterations were previously treated with an approved targeted therapy and platinum-based chemotherapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.
The dual primary endpoints of TROPION-Lung01 are PFS as assessed by BICR and OS. Key secondary endpoints include investigator-assessed PFS, ORR, DoR, TTR, and DCR as assessed by both BICR and investigator, and safety.
TROPION-Lung01 enrolled approximately 600 patients in
Primary PFS results and interim OS results from TROPION-Lung01 were presented at the 2023 ESMO (#ESMO23) Congress. Final OS results were presented at IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (#WCLC24) and simultaneously published in the Journal of Clinical Oncology in September 2024.
About TROPION-PanTumor01
TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicenter phase 1 trial evaluating the safety and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumors that have relapsed or are refractory to standard treatment or for which no standard treatment is available. The dose escalation portion of the trial enrolled patients with NSCLC to assess the safety and tolerability of datopotamab deruxtecan to determine the recommended dose for expansion (6 mg/kg). The dose expansion part of TROPION-PanTumor01 is enrolling several different cohorts including patients with NSCLC, triple negative breast cancer, HR positive, HER2 low or negative breast cancer, small cell lung cancer, urothelial, gastric, pancreatic, castration resistant prostate and esophageal cancer.
Safety endpoints include dose-limiting toxicities and serious adverse events. Efficacy endpoints include ORR, DoR, TTR, PFS and OS. Pharmacokinetic, biomarker and immunogenicity endpoints also are being evaluated.
TROPION-PanTumor01 enrolled approximately 900 patients in
About Advanced Non-Small Cell Lung Cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.1 Lung cancer is broadly split into small or non-small cell lung cancer, the latter accounting for about
For patients with tumors that have an EGFR mutation, the established first-line treatment in the metastatic setting is an EGFR-TKI.6 While EGFR TKIs have improved outcomes in the first-line setting, most patients eventually experience disease progression and receive chemotherapy.7,8,9,10
TROP2 is a protein broadly expressed in the majority of NSCLC tumors.11 There is currently no TROP2 directed ADC approved for the treatment of lung cancer.6,12
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 low or 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
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.
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Ellison G, et al. J Clin Pathol. 2013;66(2):79-89. |
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Prabhakar C. Translational Lung Cancer Research. 2015; 4(2), 110-118. |
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Chen R, et al. J Hematol Oncol. 2020:13(1):58. |
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Majeed U, et al. J Hematol Oncol. 2021;14(1):108. |
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FAQ
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