FDA Grants Priority Review for AstraZeneca and Daiichi Sankyo’s Datopotamab Deruxtecan for EGFR-Mutated Lung Cancer

FDA Grants Priority Review for AstraZeneca and Daiichi Sankyo’s Datopotamab Deruxtecan for EGFR-Mutated Lung Cancer

(IN BRIEF) AstraZeneca and Daiichi Sankyo’s Biologics License Application (BLA) for datopotamab deruxtecan has been accepted by the U.S. FDA for treating advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) in patients who have previously received systemic therapies. The FDA granted the application Priority Review, with a decision expected by the third quarter of 2025. The application is supported by positive data from the TROPION-Lung05 and TROPION-Lung01 trials, showing promising response rates and manageable safety profiles. If approved, datopotamab deruxtecan could be the first TROP2-directed antibody-drug conjugate for lung cancer.

(PRESS RELEASE) CAMBRIDGE, 13-Jan-2024 — /EuropaWire/ — AstraZeneca and Daiichi Sankyo have announced that the U.S. Food and Drug Administration (FDA) has accepted their Biologics License Application (BLA) for datopotamab deruxtecan (Dato-DXd), marking a significant step toward potential approval for the treatment of adult patients with advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). This patient group includes those who have previously undergone systemic therapies, including an EGFR-directed therapy. The FDA has granted the application Priority Review status, indicating that datopotamab deruxtecan, if approved, could offer substantial benefits over existing treatments by improving safety or efficacy, preventing serious conditions, or enhancing patient compliance. The FDA is expected to make its regulatory decision by the third quarter of 2025.

The application is supported by data from several key clinical trials, including the TROPION-Lung05 Phase II trial, the TROPION-Lung01 Phase III trial, and the TROPION-PanTumor01 Phase I trial. A pooled analysis from the TROPION-Lung05 and TROPION-Lung01 trials, presented at the European Society for Medical Oncology (ESMO) Asia 2024 Congress, demonstrated a confirmed objective response rate (ORR) of 42.7% and a median duration of response (DoR) of 7.0 months, as assessed by blinded independent central review (BICR). Additionally, the safety profile of datopotamab deruxtecan in these trials remained consistent with previous reports, with no new safety concerns identified.

Susan Galbraith, Executive Vice President of Oncology R&D at AstraZeneca, emphasized the importance of this development: “For most patients with advanced EGFR-mutated NSCLC, acquired resistance to first-line therapies and disease progression are unavoidable. This Priority Review, along with Breakthrough Therapy Designation, recognizes the potential of datopotamab deruxtecan to provide a crucial treatment option for patients whose disease has become resistant to current therapies.”

Ken Takeshita, MD, Global Head of R&D at Daiichi Sankyo, also highlighted the challenge of treating advanced EGFR-mutated NSCLC: “After disease progression on front-line therapies, including EGFR-tyrosine kinase inhibitors, the available treatment options are limited. If approved, datopotamab deruxtecan could become the first TROP2-directed antibody-drug conjugate for lung cancer, offering a promising new alternative for patients.”

Datopotamab deruxtecan is a TROP2-targeted antibody-drug conjugate (ADC) developed by Daiichi Sankyo and jointly advanced by AstraZeneca and Daiichi Sankyo. The companies are also evaluating the drug in combination with other treatments in multiple Phase III trials, including the TROPION-Lung14 and TROPION-Lung15 trials, to explore its potential in treating advanced or metastatic EGFRm nonsquamous NSCLC.

Notes

Advanced non-small cell lung cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.2 Lung cancer is broadly split into small or non-small cell lung cancer, the latter accounting for about 80% of cases.3  Approximately 10 to 15% of patients with NSCLC in the US and Europe, and 30 to 40% of patients in Asia have an EGFR mutation.4,5 The majority of EGFR mutations occur in tumours of nonsquamous histology.6

For patients with tumours that have an EGFR mutation, the established 1st-line treatment in the metastatic setting is an EGFR-TKI.7 While EGFR-TKIs have improved outcomes in the 1st-line setting, most patients eventually experience disease progression and receive subsequent therapies, such as chemotherapy.8-11

TROP2 is a protein broadly expressed in the majority of NSCLC tumours.12 There is currently no TROP2-directed ADC approved for the treatment of lung cancer.7,13

TROPION-Lung05
TROPION-Lung05 is a global, multicentre, single-arm, open-label Phase II 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 at least one TKI (with or without other systemic therapies) and on or after one regimen of platinum-based chemotherapy. Patients receiving up to four prior lines of treatment with tumours with one or more genomic alterations including EGFR, ALK, ROS1, NTRK, BRAF, RET or MET were eligible for the trial.

The primary endpoint of TROPION-Lung05 is ORR as assessed by BICR. Secondary efficacy endpoints include 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 Asia, Europe and North America. For more information visit ClinicalTrials.gov.

Primary results from TROPION-Lung05 were published in the Journal of Clinical Oncology in January 2025.

TROPION-Lung01
TROPION-Lung01 is a global, randomised, multicentre, open-label Phase III 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 Asia, Europe, North America, Oceania and South America. For more information visit ClinicalTrials.gov.

Primary results from TROPION-Lung01, as presented at the ESMO 2023 Congress, showed datopotamab deruxtecan demonstrated a statistically significant improvement in PFS over docetaxel. OS results were presented at the IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer and simultaneously published in the Journal of Clinical Oncology in September 2024.

TROPION-PanTumor01
TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicentre Phase I trial evaluating the safety and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumours 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 (6mg/kg). The dose expansion part of TROPION-PanTumor01 enrolled several different cohorts including patients with NSCLC, triple-negative breast cancer (TNBC), hormone receptor (HR)-positive, HER2-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 are also being evaluated. TROPION-PanTumor01 enrolled approximately 900 patients in Asia and North America. For more information visit ClinicalTrials.gov.

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 programmes in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanised 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.

Datopotamab deruxtecan is approved in Japan under the brand name Datroway for the treatment of adult patients with unresectable or recurrent HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer after prior chemotherapy based on the results of the TROPION-Breast01 trial. Datopotamab deruxtecan is an investigational medicine in all countries outside of Japan.

Datopotamab deruxtecan clinical development programme
A comprehensive global clinical development programme is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, TNBC and HR-positive, HER2-negative breast cancer. The programme includes seven Phase III trials in lung cancer and five Phase III trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings.

Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu (trastuzumab deruxtecan) in March 2019 and datopotamab deruxtecan 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.

AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and Imjudo (tremelimumab); Enhertu and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca.

References

1. FDA. Priority Review. Available at: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review. Accessed January 2025.

2. World Health Organization. Global Cancer Observatory: Lung. Available at: https://gco.iarc.who.int/media/globocan/factsheets/cancers/15-trachea-bronchus-and-lung-fact-sheet.pdf. Accessed January 2025.

3. American Cancer Society. Key Statistics for Lung Cancer. Available at: https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html#:~:text=NSCLC%20is%20the%20most%20common,be%20diagnosed%20with%20lung%20cancer.  Accessed January 2025.

4. Szumera-Ciećkiewicz A, et al. EGFR Mutation Testing on Cytological and Historical Samples in Non-Small Cell Lung Cancer: a Polish, Single Institution Study and Systematic Review of European Incidence. Int J Clin Exp Pathol. 2013;6(12): 2800-2812.

5. Ellison G, et al. EGFR Mutation Testing in Lung Cancer: a Review of Available Methods and Their Use for Analysis of Tumour Tissue and Cytology Samples. J Clin Pathol. 2013;66(2):79-89.

6. Prabhakar C. Translational Lung Cancer Research. 2015; 4(2), 110-118.

7. American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer. Available at: https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html. Accessed January 2025.

8. Chen R, et al. Emerging therapeutic agents for advanced non-small cell lung cancer. J Hematol Oncol. 2020:13(1):58.

9. Majeed U, et al. Targeted therapy in advanced non-small cell lung cancer: current advances and future trends. J Hematol Oncol. 2021;14(1):108.

10. Morgillo F, et al. Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open. 2016;1:e000060. Accessed January 2025.

11. Han B, et al. Efficacy of pemetrexed-based regimens in advanced non–small cell lung cancer patients with activating epidermal growth factor receptor mutations after tyrosine kinase inhibitor failure: a systematic review. Onco Targets Ther. 2018;11:2121-9. Accessed January 2025.

12. Mito R, et al. Clinical impact of TROP2 in non-small cell lung cancers and its correlationn with abnormal p53 nuclear accumulation. Pathol Int. 2020;70(5):287-294.

13. Rodríguez-Abreau D, et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Onc. 2021 Jul;32(7): 881-895

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