Patritumab Deruxtecan BLA Submission Receives Complete Response Letter from FDA Due to Inspection Findings at Third-Party Manufacturer


June 26, 2024 7:45 pm ET

The letter did not identify any issues with the efficacy or safety data submitted in the application

BASKING RIDGE, N.J. & RAHWAY, N.J., June 26, 2024 – 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 making patritumab deruxtecan available 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


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,


About EGFR-mutated non-small cell lung cancer

Approximately 226,000 lung cancer cases were diagnosed in the U.S. in 2022. Lung cancer is the third most common
cancer and the leading cause of cancer-related deaths in the U.S. NSCLC accounts for approximately 81% of all lung
cancers in the U.S., with 52% having distant spread at diagnosis. EGFR mutations occur in approximately 1 in 5
patients with NSCLC in Western populations.


About HER3

HER3 is a member of the EGFR family of receptor tyrosine kinases. It is estimated that about 83% of primary NSCLC
tumors and 90% of advanced EGFR-mutated tumors express HER3 after prior EGFR TKI treatment. HER3 is associated with
poor treatment outcomes, including shorter relapse-free survival and significantly reduced survival. 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


Patritumab deruxtecan was granted Breakthrough Therapy
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
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


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


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 and connect
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