- The letter did not identify any issues with the efficacy or
safety data submitted in the application
The U.S. Food and Drug Administration (FDA) has issued a
Complete Response Letter (CRL) for the Biologics License
Application (BLA) seeking accelerated approval of Daiichi Sankyo
(TSE: 4568) and Merck’s (known as MSD outside of the United States
and Canada) (NYSE: MRK) patritumab deruxtecan (HER3-DXd) for the
treatment of adult patients with locally advanced or metastatic
EGFR-mutated non-small cell lung cancer (NSCLC) previously treated
with two or more systemic therapies.
The CRL results from findings pertaining to an inspection of a
third-party manufacturing facility. The CRL did not identify any
issues with the efficacy or safety data submitted.
Patritumab deruxtecan is a specifically engineered potential
first-in-class HER3 directed DXd antibody drug conjugate (ADC)
discovered by Daiichi Sankyo and being jointly developed by Daiichi
Sankyo and Merck.
“We will work closely with the FDA and the third-party
manufacturer to address the feedback as quickly as possible in
order to bring the first HER3 directed medicine to patients with
previously-treated EGFR-mutated non-small cell lung cancer,” said
Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “We remain
confident in the ability to develop this medicine to its full
potential.”
“Patients with previously treated EGFR-mutated non-small cell
lung cancer often experience recurrence and have limited treatment
options,” said Marjorie Green, MD, Senior Vice President and Head
of Oncology, Global Clinical Development, Merck Research
Laboratories. “We are committed to working with Daiichi Sankyo and
the FDA to prioritize bringing patritumab deruxtecan to these
patients in need.”
The BLA is based on the primary results from the HERTHENA-Lung01
pivotal phase 2 trial that were presented at the IASLC 2023 World
Conference on Lung Cancer (#WCLC23) and simultaneously published in
the Journal of Clinical Oncology.
In HERTHENA-Lung01, patritumab deruxtecan was studied in 225
patients with EGFR-mutated locally advanced or metastatic NSCLC
following disease progression with an EGFR TKI and platinum-based
chemotherapy, which demonstrated an objective response rate (ORR)
of 29.8% (95% CI: 23.9-36.2), including one complete response and
66 partial responses. The median duration of response (DoR) was 6.4
months (95% CI: 4.9-7.8).
The safety profile of patritumab deruxtecan observed in
HERTHENA-Lung01 was consistent with previous phase 1 clinical
trials in NSCLC with a treatment discontinuation rate of 7.1% due
to treatment-emergent adverse events (TEAEs). Grade 3 or higher
TEAEs occurred in 64.9% of patients. The most common (≥5%) grade 3
or higher TEAEs were thrombocytopenia (21%), neutropenia (19%),
anemia (14%), leukopenia (10%), fatigue (6%), hypokalemia (5%) and
asthenia (5%). Twelve patients (5.3%) had confirmed
treatment-related interstitial lung disease (ILD) as determined by
an independent adjudication committee. One grade 5 ILD event was
observed.
About HERTHENA-Lung01 HERTHENA-Lung01 is a global,
multicenter, open-label, two-arm phase 2 trial evaluating the
safety and efficacy of patritumab deruxtecan in patients with
EGFR-mutated locally advanced or metastatic NSCLC following disease
progression with an EGFR TKI and platinum-based chemotherapy.
Patients were randomized 1:1 to receive 5.6 mg/kg (n=225) or an
uptitration regimen (n=50). The uptitration arm was discontinued as
the dose of 5.6 mg/kg of patritumab deruxtecan was selected
following a risk-benefit analysis conducted from the phase 1 trial
assessing the doses in a similar patient population.
The primary endpoint of HERTHENA-Lung01 was ORR as assessed by
blinded independent central review (BICR). Secondary endpoints
included DoR, progression-free survival, disease control rate, and
time to response – all assessed by both BICR and investigator
assessment – as well as investigator-assessed ORR, overall
survival, safety and tolerability.
HERTHENA-Lung01 enrolled patients in Asia, Europe, North America
and Oceania. For more information about the trial, visit
ClinicalTrials.gov.
About EGFR-Mutated Non-Small Cell Lung Cancer
Approximately 226,000 lung cancer cases were diagnosed in the U.S.
in 2022.1 Lung cancer is the third most common cancer and the
leading cause of cancer-related deaths in the U.S.1 NSCLC accounts
for approximately 81% of all lung cancers in the U.S., with 52%
having distant spread at diagnosis.2,3 EGFR mutations occur in
approximately one in five patients with NSCLC in Western
populations.4
About HER3 HER3 is a member of the EGFR family of
receptor tyrosine kinases.5 It is estimated that about 83% of
primary NSCLC tumors and 90% of advanced EGFR-mutated tumors
express HER3 after prior EGFR TKI treatment.6,7 HER3 is associated
with poor treatment outcomes, including shorter relapse-free
survival and significantly reduced survival.8,9 There is currently
no HER3 directed therapy approved for the treatment of any
cancer.
About Patritumab Deruxtecan Patritumab deruxtecan
(HER3-DXd) is an investigational HER3 directed ADC. Designed using
Daiichi Sankyo’s proprietary DXd ADC Technology, patritumab
deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal
antibody attached to a number of topoisomerase I inhibitor payloads
(an exatecan derivative, DXd) via tetrapeptide-based cleavable
linkers.
Patritumab deruxtecan was granted Breakthrough Therapy
Designation by the U.S. Food and Drug Administration in December
2021 for the treatment of patients with EGFR-mutated locally
advanced or metastatic NSCLC with disease progression on or after
treatment with a third-generation TKI and platinum-based
therapies.
Patritumab deruxtecan is currently being evaluated as both a
monotherapy and in combination with other therapies in a global
development program, which includes HERTHENA-Lung02, a phase 3
trial evaluating the efficacy and safety of patritumab deruxtecan
versus platinum-based chemotherapy in patients with EGFR-mutated
locally advanced or metastatic NSCLC following disease progression
on or after treatment with a third-generation EGFR TKI;
HERTHENA-Lung01, a phase 2 trial in metastatic or locally advanced
NSCLC with an activating EGFR mutation previously treated with at
least one EGFR TKI and one platinum-based chemotherapy-containing
regimen; HERTHENA-PanTumor01, a phase 2 trial in locally advanced
or metastatic solid tumors, including melanoma, gastric and head
and neck cancer, among other types of cancer, previously treated
with at least one prior systemic therapy; a phase 1 trial in
combination with osimertinib in EGFR-mutated locally advanced or
metastatic NSCLC; and a phase 1 trial in previously treated
patients with advanced NSCLC. A phase 1/2 trial in HER3 expressing
metastatic breast cancer also has been completed.
About the Daiichi Sankyo and Merck Collaboration Daiichi
Sankyo and Merck entered into a global collaboration in October
2023 to jointly develop and commercialize patritumab deruxtecan
(HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug
deruxtecan (R-DXd), except in Japan where Daiichi Sankyo will
maintain exclusive rights. Daiichi Sankyo will be solely
responsible for manufacturing and supply.
About the DXd ADC Portfolio of Daiichi Sankyo The DXd ADC
portfolio of Daiichi Sankyo currently consists of six ADCs in
clinical development across multiple types of cancer. ENHERTU, a
HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2
directed ADC, are being jointly developed and commercialized
globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3
directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC,
and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being
jointly developed and commercialized globally with Merck. DS-3939,
a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.
Designed using Daiichi Sankyo’s proprietary DXd ADC Technology
to target and deliver a cytotoxic payload inside cancer cells that
express a specific cell surface antigen, each ADC consists of a
monoclonal antibody attached to a number of topoisomerase I
inhibitor payloads (an exatecan derivative, DXd) via
tetrapeptide-based cleavable linkers.
Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab
deruxtecan, raludotatug deruxtecan and DS-3939 are investigational
medicines that have not been approved for any indication in any
country. Safety and efficacy have not been established.
About Daiichi Sankyo 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.
With more than 120 years of experience, Daiichi Sankyo leverages
its world-class science and technology to create new modalities and
innovative medicines for people with cancer, cardiovascular and
other diseases with high unmet medical needs. For more information,
please visit www.daiichisankyo.com.
Merck’s Focus on Cancer Every day, we follow the science
as we work to discover innovations that can help patients, no
matter what stage of cancer they have. As a leading oncology
company, we are pursuing research where scientific opportunity and
medical need converge, underpinned by our diverse pipeline of more
than 25 novel mechanisms. With one of the largest clinical
development programs across more than 30 tumor types, we strive to
advance breakthrough science that will shape the future of
oncology. By addressing barriers to clinical trial participation,
screening and treatment, we work with urgency to reduce disparities
and help ensure patients have access to high-quality cancer care.
Our unwavering commitment is what will bring us closer to our goal
of bringing life to more patients with cancer. For more
information, visit https://www.merck.com/research/oncology/.
About Merck At Merck, known as MSD outside of the United
States and Canada, we are unified around our purpose: We use the
power of leading-edge science to save and improve lives around the
world. For more than 130 years, we have brought hope to humanity
through the development of important medicines and vaccines. We
aspire to be the premier research-intensive biopharmaceutical
company in the world – and today, we are at the forefront of
research to deliver innovative health solutions that advance the
prevention and treatment of diseases in people and animals. We
foster a diverse and inclusive global workforce and operate
responsibly every day to enable a safe, sustainable and healthy
future for all people and communities. For more information, visit
www.merck.com and connect with us on X (formerly Twitter),
Facebook, Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc., Rahway,
N.J., USA This news release of Merck & Co., Inc., Rahway,
N.J., USA (the “company”) includes “forward-looking statements”
within the meaning of the safe harbor provisions of the U.S.
Private Securities Litigation Reform Act of 1995. These statements
are based upon the current beliefs and expectations of the
company’s management and are subject to significant risks and
uncertainties. There can be no guarantees with respect to pipeline
candidates that the candidates will receive the necessary
regulatory approvals or that they will prove to be commercially
successful. If underlying assumptions prove inaccurate or risks or
uncertainties materialize, actual results may differ materially
from those set forth in the forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and health care
legislation in the United States and internationally; global trends
toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; the company’s ability to accurately predict future market
conditions; manufacturing difficulties or delays; financial
instability of international economies and sovereign risk;
dependence on the effectiveness of the company’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s Annual
Report on Form 10-K for the year ended December 31, 2023 and the
company’s other filings with the Securities and Exchange Commission
(SEC) available at the SEC’s Internet site (www.sec.gov).
_______________________________ References: 1 World Health
Organization. International Agency for Research on Cancer. U.S.
Cancer Fact Sheet. Accessed June 2024. 2 American Society of
Clinical Oncology. Lung Cancer – Non-Small Cell: Statistics.
Accessed June 2024. 3 SEER. Adenocarcinoma of the Lung and Bronchus
Stage Distribution of SEER Incidence Cases. 2012-2021. Accessed
June 2024. 4 Tan AC, et al. J Clin Oncol. 2022;40(6):611-625. 5
Mishra R, et al. Onco Rev. 2018; 12(355):45-62. 6 Scharpenseel H,
et al. Scientific Reports. 2019; 9:7406. 7 Yonesaka K, et al. Clin
Cancer Res. 2022; 15:28(2):390-403. 8 Gandullo-Sánchez L et al. J
Exp Clin Cancer Res. 2022; 41:310. 9 Yu H.A., et al. Annals of
Oncology. 2024; 35(5): P437-447.
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Daiichi Sankyo Global/US
Media: Jennifer Brennan Daiichi Sankyo, Inc.
jennifer.brennan@daiichisankyo.com +1 908 900 3183 (mobile)
Japan Media: DS-PR@daiichisankyo.co.jp Investor
Relations Contact: DaiichiSankyoIR@daiichisankyo.co.jp
Merck Media: Julie
Cunningham +1 617 519 6264 julie.cunningham@merck.com Nikki
Lupinacci +1 718 644 0730 Nicole.lupinacci@merck.com
Investors: Peter Dannenbaum +1 732 594 1579
peter.dannenbaum@merck.com Damini Chokshi +1 732 594 1577
damini_chokshi@merck.com
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