FDA Issues Complete Response Letter for Patritumab Deruxtecan BLA Due to Third-Party Manufacturer Inspection Findings

The U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the Biologics License Application (BLA) submitted by Daiichi Sankyo and Merck for the accelerated approval of their drug patritumab deruxtecan (HER3-DXd). This drug is aimed at treating adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who have already undergone two or more systemic therapies.

The CRL was prompted by issues identified during an inspection of a third-party manufacturing facility. Notably, the CRL did not cite any concerns regarding the efficacy or safety data of the drug.

Patritumab deruxtecan is a specially designed HER3-directed DXd antibody drug conjugate. It was discovered by Daiichi Sankyo and is being developed in collaboration with Merck. Dr. Ken Takeshita, Global Head of R&D at Daiichi Sankyo, expressed the company's commitment to working with the FDA and the third-party manufacturer to address the identified issues promptly. He emphasized the potential significance of this medicine for patients with previously treated EGFR-mutated non-small cell lung cancer.

Dr. Marjorie Green, Senior Vice President and Head of Oncology, Global Clinical Development at Merck Research Laboratories, highlighted the urgency of bringing patritumab deruxtecan to patients who have limited treatment options. She noted that patients with previously treated EGFR-mutated NSCLC often experience recurrence and require more effective treatments.

The BLA for patritumab deruxtecan is based on primary results from the HERTHENA-Lung01 pivotal phase 2 trial. This trial evaluated the drug in 225 patients with EGFR-mutated locally advanced or metastatic NSCLC who had progressed after EGFR TKI and platinum-based chemotherapy. The trial demonstrated an objective response rate (ORR) of 29.8%, with one complete response and 66 partial responses. The median duration of response (DoR) was found to be 6.4 months.

The safety profile of patritumab deruxtecan observed in the HERTHENA-Lung01 trial was consistent with previous phase 1 clinical trials. The treatment discontinuation rate due to treatment-emergent adverse events (TEAEs) was 7.1%, while Grade 3 or higher TEAEs occurred in 64.9% of patients. Common grade 3 or higher TEAEs included thrombocytopenia (21%), neutropenia (19%), anemia (14%), leukopenia (10%), fatigue (6%), hypokalemia (5%), and asthenia (5%). Twelve patients experienced treatment-related interstitial lung disease (ILD), with one instance being a grade 5 event.

The HERTHENA-Lung01 trial is a global, multicenter, open-label, two-arm phase 2 trial that assessed the safety and efficacy of patritumab deruxtecan in patients with EGFR-mutated NSCLC following disease progression with EGFR TKI and platinum-based chemotherapy. Patients were randomized to receive either 5.6 mg/kg or an uptitration regimen, the latter of which was discontinued after a risk-benefit analysis from the phase 1 trial.

The primary endpoint of HERTHENA-Lung01 was the ORR as assessed by blinded independent central review (BICR). Secondary endpoints included DoR, progression-free survival, disease control rate, and time to response, among others, assessed by both BICR and investigator assessment.

The trial enrolled patients from various regions, including Asia, Europe, North America, and Oceania, providing a comprehensive evaluation of the drug's potential across diverse populations.

Daiichi Sankyo and Merck continue to collaborate closely to address the FDA's feedback and bring patritumab deruxtecan to patients in need, reinforcing their commitment to advancing cancer treatment options.