Datopotamab deruxtecan granted breakthrough therapy designation in US for patients with previously treated advanced EGFR-mutated non-small cell lung cancer

Rhea-AI Summary

Datopotamab deruxtecan (Dato-DXd) has received Breakthrough Therapy Designation (BTD) from the FDA for treating adult patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) who have experienced disease progression after EGFR-TKI and platinum-based chemotherapy treatments.

The designation is based on data from the TROPION-Lung05 Phase II trial and supported by the TROPION-Lung01 Phase III trial. This marks the first BTD for datopotamab deruxtecan, a TROP2-directed DXd antibody drug conjugate jointly developed by AstraZeneca and Daiichi Sankyo. The companies have already submitted a Biologics License Application for accelerated approval in the US.

Positive

• Received FDA Breakthrough Therapy Designation, potentially accelerating regulatory review
• Submitted Biologics License Application for accelerated approval in the US
• Addresses significant unmet medical need in EGFR-mutated NSCLC market

Negative

• None.

Insights

Medical Research Analyst

This BTD marks a significant milestone for datopotamab deruxtecan in treating EGFR-mutated NSCLC patients who have progressed after standard therapies. The designation, supported by TROPION-Lung05 Phase II and TROPION-Lung01 Phase III trials, indicates promising clinical results that could substantially improve treatment outcomes. With 10-15% of NSCLC patients in the US/Europe and 30-40% in Asia harboring EGFR mutations, this represents a substantial market opportunity. The TROP2-directed ADC approach is particularly innovative as there are currently no approved TROP2-directed ADCs for lung cancer, potentially positioning AstraZeneca and Daiichi Sankyo as first-movers in this specific treatment space.

Market Research Analyst

The BTD and concurrent Biologics License Application submission significantly accelerate datopotamab deruxtecan's path to market in a lucrative indication. With nearly 2.5 million global lung cancer cases diagnosed in 2022 and NSCLC accounting for 80% of cases, this represents a substantial commercial opportunity. The collaboration between AstraZeneca and Daiichi Sankyo leverages both companies' strengths in oncology, potentially creating a powerful market position. This development could strengthen AstraZeneca's already robust oncology portfolio and provide a new revenue stream in the highly competitive lung cancer market.

First Breakthrough Therapy Designation for AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan

Based on TROPION-Lung05 Phase II trial and supported by data from TROPION-Lung01 Phase III trial

WILMINGTON, Del.--(BUSINESS WIRE)-- Datopotamab deruxtecan (Dato-DXd) has been granted Breakthrough Therapy Designation (BTD) in the US for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) with disease progression on or after treatment with an EGFR-tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy.

The US Food and Drug Administration (FDA) BTD is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat serious conditions and address significant unmet medical needs. The medicine needs to have shown encouraging preliminary clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines.

The FDA granted this BTD based on data from the TROPION-Lung05 Phase II trial with supporting data from the TROPION-Lung01 Phase III trial. Results from a pooled analysis of patients with previously treated EGFRm NSCLC in these studies were presented this month at the European Society of Medical Oncology (ESMO) Asia 2024 Congress. This is the first BTD for datopotamab deruxtecan.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “This Breakthrough Therapy Designation reinforces datopotamab deruxtecan as a promising potential therapy for patients with EGFR-mutated lung cancer who continue to face significant unmet needs following disease progression on or after initial treatments. We are proud to have long supported patients with EGFR-mutated lung cancer and look forward to the possibility of bringing another innovative treatment option to this community.”

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: “The Breakthrough Therapy Designation granted by the FDA underscores the significant unmet need for new treatments for patients with previously treated EGFR-mutated non-small cell lung cancer who have experienced disease progression. Datopotamab deruxtecan has the potential to play an important role in improving outcomes and we look forward to working closely with the FDA to bring this medicine to patients as quickly as possible.”

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by AstraZeneca and Daiichi Sankyo.

AstraZeneca and Daiichi Sankyo recently announced the submission of a new Biologics License Application for accelerated approval in the US for datopotamab deruxtecan for the treatment of adult patients with locally advanced or metastatic EGFRm NSCLC who have received prior systemic therapies, including an EGFR-directed therapy.

Notes

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 80% of cases.² 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.^3,4 The majority of EGFR mutations occur in tumors of nonsquamous histology.⁵

For patients with tumors that have an EGFR mutation, the established 1st-line treatment in the metastatic setting is an EGFR-TKI.⁶ While EGFR-TKIs have improved outcomes in the 1st-line setting, most patients eventually experience disease progression and receive subsequent therapies, such as chemotherapy.^7-10

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

TROPION-Lung05

TROPION-Lung05 is a global, multicenter, 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 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 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, 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.

TROPION-Lung01

TROPION-Lung01 is a global, randomized, multicenter, 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 PFS results and interim OS results from TROPION-Lung01 were presented at the ESMO 2023 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 and simultaneously published in the Journal of Clinical Oncology in September 2024.

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 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 commercialize fam-trastuzumab deruxtecan-nxki 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 fam-trastuzumab deruxtecan-nxki 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 osimertinib and gefitinib; durvalumab and tremelimumab; fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan in collaboration with Daiichi Sankyo; 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 catalyze 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.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 125 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca.

References

1. 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 December 2024.
2. 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 December 2024.
3. 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.
4. 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.
5. Prabhakar C. Translational Lung Cancer Research. 2015; 4(2), 110-118.
6. 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 December 2024.
7. Chen R, et al. Emerging therapeutic agents for advanced non-small cell lung cancer. J Hematol Oncol. 2020:13(1):58.
8. 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.
9. Morgillo F, et al. ESMO Open. 2016;1:e000060. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC5070275/. Accessed December 2024.
10. Han B, et al. Onco Targets Ther. 2018;11:2121-9. Available at: https://www.dovepress.com/efficacy-of-pemetrexed-based-regimens-in-advanced-non-small-cell-lung--peer-reviewed-fulltext-article-OTT. Accessed December 2024.
11. Mito R, et al. Clinical impact of TROP2 in non-small cell lung cancers and its correlation with abnormal p53 nuclear accumulation. Pathol Int. 2020;70(5):287-294.
12. 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.

US-96427 Last Updated 12/24

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FAQ

What is the new FDA designation for AstraZeneca's (AZN) datopotamab deruxtecan?

Datopotamab deruxtecan received Breakthrough Therapy Designation for treating advanced EGFR-mutated non-small cell lung cancer in patients who progressed after EGFR-TKI and platinum-based chemotherapy.

Which clinical trials supported AZN's breakthrough therapy designation for Dato-DXd?

The FDA designation was based on data from the TROPION-Lung05 Phase II trial with supporting data from the TROPION-Lung01 Phase III trial.

What is the target patient population for AZN's datopotamab deruxtecan?

The drug targets adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer who have progressed on or after EGFR-TKI and platinum-based chemotherapy.