HERTHENA-Lung02 Evaluates Patritumab Deruxtecan in EGFR-Mutated NSCLC

Patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC) showed statistically significant improvement in progression-free survival (PFS) with patritumab deruxtecan (HER3-DXd) compared with platinum-based chemotherapy after EGFR tyrosine kinase inhibitor (TKI) therapy, according to the findings of the phase 3 HERTHENA-Lung02 study.

Furthermore, any treatment-emergent adverse events (TEAEs) among the study population were manageable.

The randomized, open-label study investigated HER3-DXd, an antibody-drug conjugate (ADC), in patients with advanced EGFR-mutated (Ex19del or L858R) NSCLC after disease progression during treatment with a third-generation EGFR TKI. Previous findings from the HERTHENA-Lung01 trial showed promising efficacy from HER3-DXd. HERTHENA-Lung02 was evaluated for PFS by blinded independent central review with a secondary end point of overall survival (OS).

During the 2025 American Society of Clinical Oncology Annual Meeting, Tony Mok, MD, of the State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, China, shared the findings of the study that included 586 patients. Most of the patients were women (61%) and Asian (60%) with a median age of 64 years.

At the data cutoff date for PFS analysis (May 31, 2024), the median study duration was 10.7 months with treatment duration of 5.5 months with HER3-DXd and 4.6 months with chemotherapy.

Results showed that at 6, 9, and 12 months, HER3-DXd significantly improved PFS compared with chemotherapy. Overall median PFS was 5.8 months versus 5.4 months, respectively. The PFS rates with HER3-DXd and chemotherapy were, respectively, as follows: 0.50 versus 0.38 at 6 months, 0.29 versus 0.19 at 9 months, and 0.18 versus 0.05 at 12 months.

In addition, an objective response rate of 35.2% was observed with HER3-DXd compared with 25.3% with chemotherapy. The median duration of response was 5.7 months and 5.4 months, respectively. Overall survival data were immature at the data cutoff, the researchers said.

HER3-DXd also showed more benefit for patients with advanced cancer and brain metastases than chemotherapy at the start of treatment. The ADC delayed disease progression in the brain longer than chemotherapy (5.4 months vs 4.2 months).

On examination of HER3-DXd for safety, researchers found that patients in both arms experienced TEAEs (HER3-DXd, 100%; chemotherapy, 99%). The researchers determined that the most common TEAEs were hematologic and gastrointestinal, including nausea (HER3-DXd, 57.9%; chemotherapy, 42.1%), thrombocytopenia (HER3-DXd, 52.1%; chemotherapy, 27.1%), and fatigue (HER3-DXd, 50.3%; chemotherapy, 42.1%).

Grade 3 or higher TEAEs occurred in 73% of patients treated with HER3-DXd and 57% of patients treated with chemotherapy. HER3-DXd was associated with a higher rate of thrombocytopenia (30% vs 7.9%). Each arm had one grade 3 or higher bleeding event, and 14 patients in the HER3-DXd arm experienced adjudicated drug-related interstitial lung disease, most of which were grade 1 or 2 (n=11).

Overall, 33 patients in the HER3-DXd arm had to discontinue treatment because of TEAEs, as well as 27 patients in the chemotherapy arm.