REG - AstraZeneca PLC - Dato-DXd new BLA submitted, NSQ BLA withdrawn

AstraZenecaAnnouncement

12/11/2024 07:00

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RNS Number : 7933L  AstraZeneca PLC  12 November 2024

 

 

12 November 2024

 

Datopotamab deruxtecan new BLA submitted for accelerated approval in the US
for patients with previously treated advanced EGFR-mutated non-small cell lung
cancer

 

AstraZeneca and Daiichi Sankyo's new application is based on the
TROPION-Lung05 Phase II trial and supported by data from additional trials
including TROPION-Lung01

 

Previously submitted BLA based on TROPION-Lung01 Phase III trial for patients
with nonsquamous NSCLC has been voluntarily withdrawn

 

AstraZeneca and Daiichi Sankyo have submitted a new Biologics License
Application (BLA) for accelerated approval in the US for datopotamab
deruxtecan (Dato-DXd) for the treatment of adult patients with locally
advanced or metastatic epidermal growth factor receptor-mutated (EGFR)
non-small cell lung cancer (NSCLC) who have received prior systemic therapies,
including an EGFR-directed therapy.

 

The companies have voluntarily withdrawn the BLA in the US for datopotamab
deruxtecan for patients with advanced or metastatic nonsquamous NSCLC based on
the TROPION-Lung01 Phase III trial.

 

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 US Food and Drug Administration (FDA).

 

The new BLA is based on results from the TROPION-Lung05 Phase II trial and
supported by data from the TROPION-Lung01 Phase III and TROPION-PanTumor01
Phase I 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) Asia 2024 Congress (LBA7
(https://cslide.ctimeetingtech.com/asia2024/attendee/confcal/presentation/list?q=lung05)
).

 

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca,
said: "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. TROPION-Lung01 has also provided exciting exploratory data
supporting our biomarker development, which will be validated in ongoing and
planned Phase III lung cancer trials."

 

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: "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. The potential approval of datopotamab
deruxtecan could offer renewed hope for patients with this formidable
disease."

 

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
with Tagrisso (osimertinib) as treatment for patients with advanced or
metastatic EGFR-mutated nonsquamous NSCLC in the ongoing TROPION-Lung14
(https://clinicaltrials.gov/study/NCT06350097) and TROPION-Lung15
(https://clinicaltrials.gov/study/NCT06417814) Phase III trials. In addition,
ongoing Phase III trials in 1st-line advanced or metastatic nonsquamous NSCLC,
AVANZAR (https://clinicaltrials.gov/study/NCT05687266) and TROPION-Lung10
(https://clinicaltrials.gov/study/NCT06357533) , have the potential to
validate the QCS (quantitative continuous scoring) biomarker for TROP2
identified in an exploratory analysis of TROPION-Lung01
(https://www.astrazeneca.com/media-centre/press-releases/2024/novel-computational-pathology-based-trop2-biomarker-for-dato-dxd-was-predictive-of-clinical-outcomes-in-patients-with-nsclc-in-tropion-lung01-phase-iii-trial.html)
. An additional trial in patients with biomarker-positive tumours in the
2nd-line nonsquamous NSCLC setting is also planned.

 

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-cell lung cancer (SCLC) or NSCLC, the
latter accounting for about 80% of cases.(2)  Approximately 10-15% of
patients with NSCLC in the US and Europe, and 30-40% of patients in Asia have
an EGFR mutation.(3,4) The majority of EGFR mutations occur in tumours of
nonsquamous histology.(5)

 

For patients with tumours that have an EGFR mutation, the established 1st-line
treatment in the metastatic setting is an EGFR-tyrosine kinase inhibitor
(TKI).(6) While EGFR-TKIs have improved outcomes in the 1st-line setting, most
patients eventually experience disease progression and receive
chemotherapy.(7-10)

 

TROP2 is a protein broadly expressed in the majority of NSCLC tumours.(11)
There is currently no TROP2-directed ADC approved for the treatment of lung
cancer.(6,12)

 

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 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 tumours 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, 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
(https://clinicaltrials.gov/study/NCT04484142) .

 

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 (https://clinicaltrials.gov/study/NCT04656652) .

 

Primary PFS and interim OS results from TROPION-Lung01 were presented
(https://www.astrazeneca.com/media-centre/press-releases/2023/datopotamab-deruxtecan-improved-progression-free-survival-vs-chemotherapy-in-tropion-lung01-phase-iii-trial.html)
at the ESMO 2023 Congress. Final OS results were presented
(https://www.astrazeneca.com/media-centre/press-releases/2024/dato-dxd-showed-median-overall-survival-of-146-months-in-patients-with-advanced-nsclc-in-tropion-lung01-phase-iii-trial.html)
at IASLC 2024 World Conference on Lung Cancer hosted by the International
Association for the Study of Lung Cancer and simultaneously published
(https://ascopubs.org/doi/10.1200/JCO-24-01544) 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 (6 mg/kg). The dose expansion
part of TROPION-PanTumor01 is enrolling several different cohorts including
patients with NSCLC, triple-negative breast cancer (TNBC), HR-positive,
HER2-low or negative breast cancer, SCLC, 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 Asia and North
America. For more information visit ClinicalTrials.gov
(https://clinicaltrials.gov/study/NCT03401385) .

 

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 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 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-low or
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
(https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html#modal-historic-confirmation)
and datopotamab deruxtecan in July 2020
(https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-daiichi-sankyo-enter-collaboration-to-develop-and-commercialise-new-antibody-drug-conjugate.html#modal-historic-confirmation)
, 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
(trastuzumab deruxtecan) 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 (https://www.astrazeneca.com/) and follow the
Company on social media @AstraZeneca
(https://www.linkedin.com/company/astrazeneca/) .

 
Contacts

For details on how to contact the Investor Relations Team, please click here
(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
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.

 

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
(https://gco.iarc.who.int/media/globocan/factsheets/cancers/15-trachea-bronchus-and-lung-fact-sheet.pdf)
. Accessed November 2024.

2.     Cancer.net. Lung Cancer - Non-Small Cell: Statistics. Available at:
https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics#:~:text=NSCLC%20is%20the%20most%20common,be%20diagnosed%20with%20lung%20cancer
(https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics#:~:text=NSCLC%20is%20the%20most%20common,be%20diagnosed%20with%20lung%20cancer)
. Accessed November 2024.

3.     Szumera-Ciećkiewicz A, et al. EGFR Mutation Testing on Cytological
and Histological 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
(https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html)
. Accessed November 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://esmoopen.bmj.com/content/1/4/e000060
(https://esmoopen.bmj.com/content/1/4/e000060) . Accessed November 2024.

10.  Han B, et al. Onco Targets Ther. 2018;11:2121-9. Available
at: https://www.dovepress.com/oncotargets-and-therapy-journal
(https://www.dovepress.com/oncotargets-and-therapy-journal) . Accessed
November 2024.

11.  Mito R, et al. Clinical impact of TROP2 in non‐small 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.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

 

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