FDA Issues Complete Response Letter for the Patritumab Deruxtecan BLA Submission


A biologics license application (BLA) for patritumab deruxtecan receives complete response letter due to inspection findings at third-party manufacturer.

The biologics license application for patritumab deruxtecan (HER3-DXd; Merck) for the treatment of patients with previously treated locally or metastatic epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer (NSCLC) received a complete response letter (CRL) from the FDA due to inspection findings of a third-party manufacturing facility.1 The CRL did not identify any issue with the efficacy or safety data from the trial, and the companies indicate actions to address the FDA’s feedback to accelerate patient access to HER3-DXd.

egfr mutated non small cell lung cancer

The success of patritumab deruxteca demonstrated in the clinical trial has potential to address the unmet needs of these patients, providing new treatment options for those with resistances to existing therapies. Image Credit: © patsuda - stock.adobe.com

NSCLC accounts for approximately 80% to 90% of all lung cancer cases worldwide, and EGFR mutations occur in about 10% to 15% of patients in the United States. Mutations in the EGFR gene result in the overactivation of EGFR proteins, leading to the abnormal growth and survival of malignant cells. EGFR proteins can have various mutations, of which EGFR 19 deletion and L858R point mutation are the most common.2-4

Standard-of-care typically involves an initial treatment with 1 or 2 EGFR tyrosine kinase inhibitor (TKI) regimens, followed by platinum-based chemotherapy (PBC) upon disease progression. Unfortunately, salvage therapies after disease progression following TKI regimens and PBC have poor efficacy and outcomes, leaving patients with limited options after initial therapies have failed. However, studies have identified that human epidermal growth factor receptor 3 (HER3; receptor tyrosine-protein kinase erbB-3 [ERBB3]) expression, which is found in 85% to 100% of EGFR mutations, may be associated with EGFR TKI therapy resistance. HER3 is consistent with poorer treatment outcomes, such as shorter relapse-free survival and significantly reduced survival.4,5

HER3-DXd is an investigational HER3-directed antibody drug conjugate (ADC) consisting of human immunoglobulin G1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. By targeting and binding to HER3, HER3-DXd facilitates death of malignant cells and improves therapeutic outcomes for patients.4,5

The safety and efficacy of HER3-DXd was studied in HERTHENA-Lung01 (NCT04619004) in 225 patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with EGFR TKI therapy and PBC. The global, open-label, two-arm phase 2 trial randomized patients to receive either 5.6 milligrams per kilogram of HER3-DXd (n=225) or an uptitration regimen (n=50). The primary end point was objective response rate (ORR) with secondary end points including duration of response (DoR), progression free survival (PFS), disease control rate, and time to response, which were all assessed by blinded independent central review (BICR).4,5

The findings demonstrated an ORR by blind independent central review of 29.8%(95% CI, 23.9 to 36.2), as well as a median DoR of 6.4 months (95% CI: 4.9-7.8), a median PFS of 5.5 months, and median overall survival of 11.9 months. The study authors observed a manageable safety profile that was consistent with observations from prior phase 1 trials. Treatment-emergent adverse events (TEAEs) were observed in 64.9% of patients. The most frequent grade 3 or higher TEAEs (occurring in ≥5% of patients) included thrombocytopenia (21%), neutropenia (19%), anemia (14%), leukopenia (10%), fatigue (6%), hypokalemia (5%), and asthenia (5%).4,5

The HERTHENA-Lung01 results underscore the significance of HER3-DXd as a target for HER3 in EGFR-mutated NSCLC, a risk factor for resistance to EGFR TKI therapy. The FDA’s CRL, which indicated no concerns with the safety and efficacy data collected from the trial, is a small setback for the approval of this treatment for patients with EGFR-mutated NSCLC. The success of HER3-DXd demonstrated in the clinical trial has potential to address the unmet needs of these patients, providing new treatment options for those with resistances to existing therapies.


1. Patritumab deruxtecan bla submission receives complete response letter from fda due to inspection findings at third-party manufacturer. Merck. June 26, 2024. Accessed June 27, 2024. https://www.merck.com/news/patritumab-deruxtecan-bla-submission-receives-complete-response-letter-from-fda-due-to-inspection-findings-at-third-party-manufacturer/

2. A patient with newly diagnosed, advanced egfr-mutated non–small cell lung cancer. Cancer Network. January 15, 2020. Accessed June 27, 2024. https://www.cancernetwork.com/view/patient-newly-diagnosed-advanced-egfr-mutated-nonsmall-cell-lung-cancer

3. EGFR gene. National Cancer Institute. Accessed June 27, 2024. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/egfr-gene

4. What is EGFR-positive lung cancer? Medical News Today. September 6, 2023. Accessed June 27, 2024. https://www.medicalnewstoday.com/articles/egfr-mutation-lung-cancer

5. Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor–Mutated Non–Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. Journal of Clinical Oncology. September 10, 2023. Doi:10.1200/jco.23.01476

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