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Antibody–Drug Conjugate Shows Promising Activity in Patients with Advanced or Metastatic EGFR Mutation–Positive NSCLC

TOP - January 2022 Vol 15, No 1 – Online Only

Patritumab deruxtecan (HER3-DxD), an investigational antibody–drug conjugate targeting the HER3 growth factor receptor, showed promising activity in patients with locally advanced or metastatic EGFR mutation–positive non–small-cell lung cancer (NSCLC) who had received previous EGFR tyrosine kinase inhibitor (TKI) therapy, according to interim results from a phase 1 dose-escalation and dose-expansion trial. These findings were presented at the American Society of Clinical Oncology 2021 virtual annual meeting.

“HER3-DxD meets an unmet medical need. EGFR tyrosine kinase inhibitor [TKI] resistance is often difficult to treat and has diverse resistance mechanisms,” said lead investigator Pasi Jänne, MD, PhD, Scientific Director, Belfer Center for Applied Cancer Science, and Director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA. “Efficacy [of HER3-DxD] is clinically meaningful and durable. Efficacy is also observed across EGFR TKI resistance mechanisms and in those without known resistance mechanisms. Antitumor efficacy was also observed across a wide range of baseline HER3 expression.”

Study Details

The study included 57 patients with EGFR mutation–positive NSCLC who were treated with 5.6 mg/kg of HER3-DxD in dose-escalation (N = 12) and dose-expansion cohort 1 (N = 45). All patients were heavily pretreated; the median number of previous lines of therapy was 4 (range, 1-9). All patients had received previous treatment with a TKI (86% received previous osimertinib), 91% had received previous treatment with platinum-based chemotherapy, and 40% had received previous treatment with a checkpoint inhibitor. Forty-seven percent of patients had central nervous system metastasis.

The confirmed objective response rate (ORR) was 39%, and the disease control rate was 72%. Sixteen percent of patients had progressive disease and 12% were not evaluable at the time of data cutoff.

The ORR rates for patients with and without previous central nervous system metastases were 32% and 41%, respectively. Overall, durable responses were observed regardless of previous treatments or history of brain metastases. In addition, clinical responses were observed across the spectrum of baseline HER3 expression.

Cell-free (cf)DNA was collected before and after treatment with HER3-DxD and was evaluable in 40 patients. Those with cfDNA clearance at 3 or 6 weeks had an ORR of 68% compared with 19% in patients who did not clear cfDNA. Patients with cfDNA clearance also had longer progression-free survival, Dr Jänne noted.

A safety analysis of 81 patients treated at all dose levels of HER3-DxD showed manageable side effects and low rates of treatment discontinuations. The incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was 64%, with the most prevalent TEAEs including a decrease in platelet and neutrophil counts, fatigue, and anemia. There were 4 (5%) cases of interstitial lung disease, none of which were grade 4 or 5 severity. Overall, 7 (9%) patients discontinued treatment due to TEAEs, which included 2 cases of fatigue and 1 each of nausea, decreased appetite, interstitial lung disease, decreased neutrophil count, pneumonitis, and upper respiratory tract infection.

“Additional studies of HER3-DxD are under way, including a phase 2 pivotal study [HERTHENA-Lung01] in locally advanced or metastatic NSCLC that progressed on treatment with TKIs and platinum-based chemotherapy, and a phase 1 study of osimertinib in combination with HER3-DxD in locally advanced or metastatic EGFR-mutated NSCLC that progressed after treatment with osimertinib and platinum-based chemotherapy,” Dr Jänne said.

Expert Commentary

Invited discussant Nicolas Girard, MD, PhD, Professor, Respiratory Medicine, Versailles Saint Quentin University, and Head of the Curie-Montsouris Thorax Institute, Paris, France, said, “A major challenge is what happens when osimertinib [EGFR] resistance develops. New drugs are being developed to combat EGFR TKI resistance, and HER3 activation is one of the known resistance mechanisms.”

“The efficacy of HER3-DxD was high in the setting of heavily pretreated patients [with EGFR resistance]. Remaining questions include the impact of previous treatment sequences on efficacy and the clinical activity in patients with intracranial metastases. The striking finding of this study is the reported activity of HER3-DxD across all reported resistance mechanisms, including EGFR-related and EGFR/MET-related. Predictive biomarkers need to be assessed,” he added.

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