Patritumab Deruxtecan Demonstrates Clinical Promise Among Patients With Advanced Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations

According to results from cohort 2 of the phase 1 U31402-A-U102 trial, patritumab deruxtecan (HER3-DXd), an investigational HER3-directed antibody-drug conjugate, demonstrated promising clinical efficacy and safety among previously treated patients with advanced non-small cell lung cancer with uncommon epidermal growth factor receptor (EGFR) mutations.

As previously reported, HER3-DXd “has shown durable antitumor activity in previously treated patients with EGFR-mutated advanced [NSCLC],” stated Conor Steuer, MD, Winship Cancer Institute of Emory University, Atlanta, Georgia, and coauthors. Here, “we extend these observations to patients with advanced NSCLC with other/no identified driver genomic alterations.”

In this open-label study, researchers enrolled 47 patients with advanced squamous or nonsquamous NSCLC with either an uncommon or no EGFR mutation who experienced disease progression on prior therapies. Patients received 5.6 mg/kg of intravenous HER3-DXd once every 3 weeks in 21-day cycles. The primary end point was the confirmed objective response rate (ORR). Key secondary end points included duration of response, progression-free survival (PFS), overall survival (OS), and safety. 

At analysis, the confirmed ORR was 27.7%. The confirmed ORR was 28.6% in patients with identified driver genomic alterations and 26.9% in patients without identified driver genomic alterations. The median duration of response was 8.1 months, the median PFS was 5.5 months, and the median OS was 15.2 months. Grade ≥3 treatment-emergent adverse events occurred in 51.1% of patients, 12.8% of which were serious. Treatment discontinuation due to treatment-emergent adverse events occurred in 12.8% of patients. No treatment-emergent deaths were reported. Grade 1/2 adjudicated treatment-related interstitial lung disease occurred in 10.6% of patients. 

“This observed efficacy, together with the tolerable safety profile, warrants further clinical evaluation,” concluded Dr Steuer et al. “Additional studies of HER3-DXd are planned in patients with NSCLC with and without common EGFR-activating mutations, both as monotherapy and in drug combinations.” 

“Patritumab deruxtecan demonstrated activity in a molecularly heterogeneous patient population that had received previous treatment,” added Journal of Clinical Oncology associate editor Thomas Stinchcombe, MD, Duke Cancer Center, Durham, North Carolina.

Source: 

Steuer CE, Hayashi H, Su WC, et al. Patritumab deruxtecan (HER3-DXd; MK-1022) in non–small cell lung cancer after platinum-based chemotherapy and immunotherapy. J Clin Oncol. Published online: June 24, 2025. doi: 10.1200/JCO-24-02744