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The first patient has been dosed in the TROPIONLung17 phase 3 trial evaluating Datroway (datopotamab deruxtecan) compared to docetaxel in patients with TROP2 NMR positive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) without actionable genomic alterations previously treated with immunotherapy and platinum-based chemotherapy.
Datroway is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca.
The current standard first-line treatment for advanced NSCLC without actionable genomic alterations is immunotherapy with or without platinum-based chemotherapy. However, most patients will eventually experience disease progression and traditional chemotherapy remains the current standard of care in the second-line and beyond settings. While TROP2 is a protein broadly expressed on the surface and inside of NSCLC cells, there is no established predictive biomarker that can identify patients who may benefit from a TROP2 directed antibody drug conjugate. TROPION-Lung17 is the first phase 3 clinical trial to prospectively enroll patients with tumors that test positively for TROP2 NMR, a biomarker measured using Quantitative Continuous Scoring (QCS), which is AstraZeneca’s computational pathology platform.
“We initiated TROPION-Lung17 to further evaluate Datroway in this patient population, building on results from retrospective analyses of several clinical trials, including TROPION-Lung01, which showed a correlation between TROP2 NMR positivity and outcomes for patients with lung cancer,” said Abderrahmane Laadem, MD, head, late-stage oncology clinical development, Daiichi Sankyo.
“TROPION-Lung17 is the first phase 3 trial to prospectively enroll patients using a TROP2 biomarker to determine whether Datroway can improve survival compared to current standard of care chemotherapy.”
“TROPION-Lung17 aspires to bring a precision medicine approach to patients with advanced lung cancer in the second-line setting, where traditional chemotherapy remains the standard of care,” said Leora Horn, MD, MSC, FRCPC, Senior vice president, late development oncology, AstraZeneca. “Research has shown Datroway has the potential to improve outcomes in this setting, and we are confident the TROP2 NMR biomarker and its investigational AI-powered companion diagnostic – previously granted a Breakthrough Device Designation in the US – can help us bring this medicine to the patients most likely to benefit.”
TROPION-Lung17 is the ninth phase 3 trial evaluating Datroway in NSCLC. Ongoing trials in advanced NSCLC include four phase 3 trials in the first-line metastatic setting evaluating Datroway in combination with immunotherapy in tumours without actionable genomic alterations (AVANZAR, TROPION-Lung07, TROPION-Lung08 and TROPION-Lung10) and one phase 3 trial of Datroway in combination with osimertinib, AstraZeneca’s EGFR tyrosine kinase inhibitor (TKI), (TROPION-Lung14) in EGFR-mutated NSCLC. Additional later-line phase 3 trials include evaluating Datroway with or without osimertinib (TROPION-Lung15) and Datroway alone (TROPION-Lung17).
TROPION-Lung17 is a global, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of Datroway (6 mg/kg) versus docetaxel in patients with TROP2 NMR positive locally advanced or metastatic nonsquamous NSCLC without actionable genomic alterations previously treated with PD-1/PDL1 inhibitor therapy and platinum-based chemotherapy. All patients will undergo prospective and central tumour testing for TROP2 NMR using the investigational VENTANA TROP2 (EPR20043) RxDx Device (comprised of the companion diagnostic assay and computational pathology algorithm) and those with TROP2 NMR positive tumours will be randomized in a 1:1 ratio to receive either Datroway or docetaxel.
The dual primary endpoints of TROPION-Lung17 are progression-free survival as assessed by blinded independent central review and overall survival. Key secondary endpoints include overall response rate, duration of response and safety.
TROPION-Lung17 will enroll approximately 400 patients across multiple sites in Asia, Europe and North America.
TROP2 is a protein broadly expressed in NSCLC tumours. TROP2 expression on the surface of tumour cells, as measurable with conventional pathology methods, has not been predictive of patient responses to TROP2 directed therapies. Normalized membrane ratio (NMR) refers to the QCS enabled measure of a tumour cell’s surface TROP2 expression, relative to its surface and cytoplasm TROP2 expression. NSCLC is considered TROP2 NMR positive if at least 75% of tumour cells have a greater proportion of TROP2 in the cytoplasm.
TROP2 NMR is being developed to identify patients with NSCLC most likely to benefit from treatment with Datroway.
Exploratory analyses of the TROPION-Lung01 phase 3, TROPION-Lung02 phase 2 and TROPIONPanTumor02 phase 2 trials have shown a correlation between TROP2 NMR positivity and improved clinical outcomes in patients with NSCLC treated with Datroway.
Daiichi Sankyo and AstraZeneca are collaborating with Roche Tissue Diagnostics to co-develop and commercialize the VENTANA TROP2 (EPR20043) RxDx Device as a novel AI-powered companion diagnostic for Datroway in lung cancer. The device was granted Breakthrough Device Designation by the US Food and Drug Administration. In addition to TROPION-Lung17, it is being used to analyze tissue samples in the TROPION-Lung10 and AVANZAR phase 3 trials.
Lung cancer is the most common cancer globally and is the leading cause of cancer-related death in both men and women.10 More than 2.48 million lung cancer cases were diagnosed in 2022, with 1.8 million deaths globally. NSCLC is the most common type of lung cancer, accounting for approximately 85% of cases.
For patients with advanced NSCLC without actionable genomic alterations, immunotherapy with or without platinum-based chemotherapy is the standard first-line treatment. While these medicines have improved outcomes in the first-line metastatic setting, most patients experience disease progression and traditional chemotherapy remains the standard of care in the second-line and beyond setting.
Datroway (datopotamab deruxtecan; datopotamab deruxtecan-dlnk in the US only) is a TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, Datroway is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programmes in AstraZeneca’s ADC scientific platform. Datroway 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.
Datroway (6 mg/kg) is approved in more than 40 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HR positive, HER2 negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease based on the results from the TROPION-Breast01 trial.
Datroway (6 mg/kg) is approved in Russia and the US for the treatment of adult patients with locally advanced or metastatic EGFR-mutated NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy based on the results from the TROPION-Lung05 and TROPION-Lung01 trials. Continued approval for this indication in the US may be contingent upon verification and description of clinical benefit in the confirmatory trial.
A comprehensive global clinical development programme is underway with more than 20 trials evaluating the efficacy and safety of Datroway across multiple cancers, including NSCLC, triple negative breast cancer and urothelial cancer. The program includes nine phase 3 trials in lung cancer, five phase 3 trials in breast cancer and one phase 3 trial in urothelial cancer evaluating Datroway as a monotherapy and in combination with other cancer treatments in various settings.
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize Enhertu in March 2019 and Datroway 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 Datroway.
The Daiichi Sankyo ADC portfolio consists of eight ADCs in clinical development crafted from ADC technology discovered in-house by Daiichi Sankyo.
The DXd ADC Technology platform of Daiichi Sankyo consists of six 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 & Co., Inc, Rahway, NJ, USA.
DS-3939 is being developed by Daiichi Sankyo.
Additional ADCs being developed by Daiichi Sankyo include DS-9606, which consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload and DS3610, which consists of an antibody attached to a novel immunomodulatory payload that acts as an agonist of STING.
Ifinatamab deruxtecan, raludotatug deruxtecan, patritumab deruxtecan, DS-3939, DS-9606 and DS3610 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.
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.
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