In the phase II HERTHENA-Lung01 trial reported in the Journal of Clinical Oncology, Helena Yu, MD, and colleagues found that patritumab deruxtecan (HER3-DXd), a new anti-HER3 antibody-drug conjugate, showed activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC) previously treated with an EGFR tyrosine kinase inhibitor and platinum-based chemotherapy.

Helena Yu, MD

Study Details

The current analysis involved 225 patients enrolled between February 2021 and February 2022 at sites in North America, Europe, East Asia, Southeast Asia, and Australia who received HER3-DXd at 5.6 mg/kg once every 3 weeks. All patients had received prior EGFR tyrosine kinase inhibitor therapy and platinum-based chemotherapy. All 209 patients who received third-generation tyrosine kinase inhibitors received osimertinib. The primary endpoint of the study was confirmed objective response rate on blinded independent central review, with a null hypothesis of 26.4% on the basis of historical data.

Responses

Median follow-up was 18.9 months (range = 14.9–27.5 months). Confirmed objective response was observed in 67 (29.8%, 95% confidence interval [CI] = 23.9%–36.2%) of 225 patients, with complete response in 1. An additional 99 patients (44.0%) had stable disease. Median response duration was 6.4 months (95% CI = 4.9–7.8 months), with 43% of responders having a response lasting ≥ 6 months. Median progression-free survival was 5.5 months (95% CI = 5.1–5.9 months) and median overall survival was 11.9 months (95% CI = 11.2–13.1 months).

Among the 209 patients who had received prior osimertinib, objective response was observed in 61 (29.2%, 95% CI = 23.1%–35.9%). Median response duration was 6.4 months (95% CI = 5.2–7.8 months). Among 115 patients with a history of brain metastasis, objective response was observed in 33 (28.7%, 95% CI = 20.6%–37.9%) and median response duration was 5.5 months (95% CI = 4.2–7.8 months). Among 110 patients without a history of brain metastasis, objective response occurred in 34 (30.9%, 95% CI = 22.4%–40.4%) and median response duration was 6.9 months (95% CI = 4.4–10.6 months). Among 30 patients with nonirradiated brain metastases at baseline, central nervous system (CNS) objective response was observed in 10 (33.3%, 95% CI = 17.3%–52.8%), with a median duration of CNS response of 8.4 months (95% CI = 5.8–9.2 months).

Responses were observed across a range of pretreatment tumor HER3 membrane expression levels and diverse mechanisms of EGFR tyrosine kinase inhibitor resistance.

Adverse Events

Grade ≥ 3 adverse events occurred in 65% of patients, most commonly thrombocytopenia (in 21%), neutropenia (in 19%), and anemia (in 14%). Adverse events led to discontinuation of treatment in 7% of patients. Adjudicated interstitial lung disease occurred in 12 patients (5%); all were considered drug-related (1 grade 1 case, 8 grade 2 cases, 2 grade 3 cases, and 1 grade 5 case). Treatment-related death occurred in four patients (2%), due to pneumonitis, pneumonia, gastrointestinal perforation, and respiratory failure, all of which occurred in one patient each.

The investigators concluded, “After tumor progression with EGFR tyrosine kinase inhibitor therapy and platinum-based chemotherapy in patients with EGFR-mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR-mutated NSCLC after progression on an EGFR tyrosine kinase inhibitor is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier NCT05338970).”

Dr. Yu, of the Department of Medicine, Medical Oncology, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Daiichi Sankyo, Inc. For full disclosures of the study authors, visit ascopubs.org.