Application based on TROPION-Lung05 trial
and supported by data from TROPION-Lung01 and
TROPION-PanTumor01 trials
Approval would mark the first for
AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan in
lung cancer
AstraZeneca and Daiichi Sankyo’s Biologics License Application
(BLA) for datopotamab deruxtecan (Dato-DXd) has been accepted and
granted Priority Review 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)
who have received prior systemic therapies, including an
EGFR-directed therapy.
The Food and Drug Administration (FDA) grants Priority Review to
applications for medicines that, if approved, would offer
significant improvements over available options by demonstrating
safety or efficacy improvements, preventing serious conditions or
enhancing patient compliance.1 The Prescription Drug User Fee Act
date, the FDA action date for its regulatory decision, is
anticipated during the third quarter of 2025. Datopotamab
deruxtecan was previously granted Breakthrough Therapy Designation
(BTD) by the FDA for this patient population.
The BLA and BTD are based on data from the TROPION-Lung05 Phase
II trial and supported by data from the TROPION-Lung01 Phase III
trial. In addition, the BLA is supported by data from the
TROPION-PanTumor01 Phase I trial. In a pooled analysis of patients
with previously treated advanced or metastatic EGFRm NSCLC in the
TROPION-Lung05 and TROPION-Lung01 trials presented at the European
Society for Medical Oncology (ESMO) Asia 2024 Congress, datopotamab
deruxtecan demonstrated a confirmed objective response rate (ORR)
of 42.7% (95% confidence interval [CI] 33.6-52.2) as assessed by
blinded independent central review (BICR) and a median duration of
response (DoR) of 7.0 months (95% CI 4.2-9.8). The safety profile
of datopotamab deruxtecan was consistent with previous reports from
the TROPION-Lung05 and TROPION-Lung01 trials, with no new safety
concerns identified.
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “Acquired resistance to front-line therapies
and, ultimately, disease progression are unfortunate realities for
most patients with advanced EGFR-mutated non-small cell lung
cancer. This Priority Review, and the previously granted
Breakthrough Therapy Designation, recognize the potential for
datopotamab deruxtecan to provide a much-needed option to patients
whose disease has become resistant to current treatments.”
Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said:
“Treating advanced EGFR-mutated non-small cell lung cancer presents
a significant challenge due to the limited efficacy of available
treatments once the disease has progressed following front-line
therapies, including the use of an EGFR-tyrosine kinase inhibitor.
If approved, datopotamab deruxtecan could become the first
TROP2-directed antibody drug conjugate for lung cancer, providing a
promising option for patients.”
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 are evaluating datopotamab
deruxtecan alone and in novel combinations as treatment for
patients with NSCLC in seven Phase III trials including the
TROPION-Lung14 and TROPION-Lung15 trials of datopotamab deruxtecan
alone and with osimertinib as treatment for patients with 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 tumors of nonsquamous
histology.6
For patients with tumors 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
tumors.12 There is currently no TROP2-directed ADC approved for the
treatment of lung cancer.7,13
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 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, 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 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.
About TROPION-PanTumor01
TROPION-PanTumor01 is a first-in-human, open-label, two-part,
multicenter Phase I 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 (6mg/kg). The dose
expansion part of TROPION-PanTumor01 enrolled 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 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 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.
Datopotamab deruxtecan clinical development program
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’s innovative medicines are sold in more than 125
countries and used by millions of patients worldwide. For more
information, please visit www.astrazeneca-us.com and follow us on
social media @AstraZeneca.
References
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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.
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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.
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Szumera-Ciećkiewicz A, et al. EGFR
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Cell Lung Cancer: a Polish, Single Institution Study and Systematic
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Ellison G, et al. EGFR Mutation Testing in
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American Cancer Society. Targeted Drug
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https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html.
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Chen R, et al. Emerging therapeutic agents
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Majeed U, et al. Targeted therapy in
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Morgillo F, et al. Mechanisms of
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Han B, et al. Efficacy of pemetrexed-based
regimens in advanced non–small cell lung cancer patients with
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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.
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Rodríguez-Abreau D, et al. Pemetrexed plus
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US-96963 Last Updated 1/25
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