Patritumab deruxtecan represents a novel approach in cancer treatment, developed as a targeted therapy for specific types of malignancies. This investigational medicine delivers a potent anticancer agent directly to cancer cells, aiming to minimize harm to healthy tissues. It signifies an advancement in precision oncology, tailoring treatments to a patient’s unique tumor characteristics. This drug is currently being evaluated in a comprehensive global development program, both alone and in combination with other treatments for various cancers.
Understanding Patritumab Deruxtecan
Patritumab deruxtecan is classified as an Antibody-Drug Conjugate (ADC), a sophisticated therapeutic agent. Its design incorporates three distinct components. The first component is patritumab, a human monoclonal antibody engineered to recognize and bind to the HER3 protein.
The HER3 protein is a member of the epidermal growth factor receptor (EGFR) family, often found on the surface of various cancer cells. Elevated HER3 expression can promote uncontrolled cell growth and survival, making it a suitable target for cancer therapy. The second component is a cleavable linker, which acts as a bridge connecting the antibody to the therapeutic payload.
The third component is the cytotoxic payload, an exatecan derivative known as DXd, a topoisomerase I inhibitor. This intricate structure ensures the powerful chemotherapy agent is delivered precisely to cancer cells that express the HER3 protein, increasing its effectiveness while potentially reducing systemic side effects.
How Patritumab Deruxtecan Works
Patritumab deruxtecan works by selectively binding to HER3 proteins on cancer cell surfaces. Once bound, the antibody-drug conjugate is internalized into the cancer cell via endocytosis. Inside the cell, enzymes break down the cleavable linker, releasing the cytotoxic payload, deruxtecan.
The released deruxtecan, a topoisomerase I inhibitor, interferes with cancer cell DNA replication. Topoisomerase I unwinds DNA during replication; its inhibition leads to DNA strand breaks and damage. This DNA damage triggers programmed cell death (apoptosis), eliminating cancerous cells. A unique feature is its ability to diffuse out of the targeted cell and affect neighboring cancer cells with lower HER3 expression, known as the “bystander effect.” This enhances anticancer activity, allowing the drug to target a broader population of tumor cells within a heterogeneous tumor.
Conditions Treated
Patritumab deruxtecan is primarily investigated for non-small cell lung cancer (NSCLC), especially in patients with specific genetic mutations. It focuses on individuals with EGFR-activating mutations (e.g., exon 19 deletion or L858R) who progressed after prior treatments. This includes patients whose cancer advanced despite third-generation EGFR tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy.
HER3 overexpression is observed in about 83% of NSCLC tumors, often associated with increased metastasis and resistance to standard therapies. This makes HER3 a target for intervention in this patient population. The drug is also explored in other solid tumors, including breast cancer, where HER3 is highly expressed.
Clinical Trial Findings and Safety Profile
The HERTHENA-Lung01 Phase 2 trial investigated patritumab deruxtecan in metastatic or locally advanced NSCLC with an EGFR mutation. Patients in this study had previously received at least one EGFR TKI and platinum-based chemotherapy. The trial showed encouraging efficacy, with an objective response rate (ORR) of 29.8% and a median duration of response (DoR) of 6.9 months.
The HERTHENA-Lung02 Phase 3 trial evaluated patritumab deruxtecan against standard chemotherapy in EGFR-mutated NSCLC after TKI failure. This trial met its primary endpoint, demonstrating a statistically significant improvement in progression-free survival (PFS) for patients treated with patritumab deruxtecan compared to chemotherapy. PFS is the length of time a patient lives without disease progression, and ORR is the percentage of patients whose tumor shrinks or disappears.
Common side effects observed in clinical trials included gastrointestinal issues such as nausea, vomiting, and diarrhea, as well as myelosuppression, a reduction in blood cell production. Skin rash, and interstitial lung disease (ILD) or pneumonitis (lung inflammation), also occurred in some patients, mostly low grade (Grade 1 and 2). Close monitoring for these side effects, particularly respiratory symptoms, is important for patient safety.
Current Status
Patritumab deruxtecan has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for certain patients with metastatic EGFR-mutated non-small cell lung cancer. This designation expedites the development and review of drugs for serious conditions that have shown preliminary clinical evidence of substantial improvement over available therapies.
However, the Biologics License Application (BLA) for accelerated approval in the U.S. was voluntarily withdrawn in May 2025. This decision was influenced by the topline overall survival (OS) results from the confirmatory HERTHENA-Lung02 Phase 3 trial, where OS did not achieve statistical significance. Overall survival refers to how long patients live from the start of treatment.
Despite the withdrawal of the accelerated approval application, patritumab deruxtecan continues to be evaluated in a global clinical development program across various cancers. Ongoing confirmatory trials and further research are being conducted to assess its efficacy and safety profile and determine its place in the evolving treatment landscape for patients with specific types of advanced cancers.