Novel Antibody-Drug Conjugate Shows Efficacy in Advanced EGFR-Mutated NSCLC

SINGAPORE -- Treatment with the novel antibody-drug conjugate patritumab deruxtecan (HER3-DXd) after progression with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy resulted in "clinically meaningful and durable efficacy" in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC), according to the phase II HERTHENA-Lung01 trial.

Among the 225 patients included in the study, the confirmed objective response rate (ORR) was 29.8% (95% CI 23.9-36.2), with a median duration of response of 6.4 months, reported Helena A. Yu, MD, of Memorial Sloan Kettering Cancer Center in New York City, during the World Conference on Lung Cancer.

Results from the HERTHENA-Lung01 study were published simultaneously in the Journal of Clinical Oncology.

Treatment for EGFR-mutated advanced NSCLC will typically include one or more EGFR TKI regimens, Yu explained. "After progression on TKI therapy, currently the standard of care is platinum-based chemotherapy. Salvage therapies after EGFR TKI therapy and platinum-based chemotherapy provide only a limited and transient benefit."

Median progression-free survival (PFS) was 5.5 months, and among the 210 patients with baseline and post-baseline target lesion evaluation available, most had a reduction in tumor size. Median overall survival was 11.9 months.

The antibody-drug conjugate also had intracranial antitumor activity in patients with untreated brain metastases, with a confirmed ORR of 33.3% (95% CI 17.3-52.8), a disease control rate of 76.7% (95% CI 57.7-90.1), and a median duration of response of 8.4 months.

Real-world analyses of patients after treatment with the third-generation TKI osimertinib (Tagrisso) and platinum-based chemotherapy showed a PFS of 3.3 months, with an estimated ORR of 14.1%, "highlighting the unmet need in this treatment setting," Yu said.

Moreover, she noted that central nervous system (CNS) metastases are very common in this population, "and therapies to ensure CNS control, as well as systemic control, are needed for novel therapies."

HER3 is overexpressed in approximately 83% of NSCLC tumors, and in 85% to 100% of tumors harboring an activating EGFR mutation. The protein is implicated in resistance to EGFR TKI therapy and is associated with metastatic progression and shorter relapse-free survival.

A phase I dose-escalation/dose-expansion study in heavily pretreated patients with EGFR-mutated NSCLC showed that HER3-DXd 5.6 mg/kg administered intravenously every 3 weeks resulted in a confirmed ORR of 39% in patients previously treated with osimertinib and platinum-based chemotherapy, and the safety profile was manageable, thus leading to this phase II trial.

In the phase II study, patients had a median age of 64 years, 58.7% were women, and most were Asian (46.7%) or white (40.9%). A history of brain metastases was noted in 51.1% of patients, and 32% had radiologic evidence of brain metastases at baseline. Baseline radiologic evidence of bone and liver metastases was seen in 36.9% and 33.3% of patients, respectively.

Patients were heavily pretreated with a median of three prior lines of systemic therapy in the locally advanced/metastatic setting, with 93% of patients having received prior third-generation EGFR TKI therapy.

Patients received a fixed dose of HER3-DXd 5.6 mg/kg intravenously once every 3 weeks. Mean duration of treatment was 5.5 months.

Treatment-emergent adverse events (TEAEs) of grade ≥3 and ≥4 severity occurred in 64.9% and 28.9% of patients, respectively. The most common grade ≥3 TEAEs were hematologic toxicities, including thrombocytopenia (20.9%) and neutropenia (19.1%).

TEAEs were associated with dose interruption in 40.4% of patients, dose reduction in 21.3%, treatment discontinuation in 7.1%, and death in 1.8%.

An adverse event of particular interest was interstitial lung disease (ILD) due to concerns it could be a class effect. An independent adjudication committee determined ILD frequency to be 5.3%, Yu reported.

Clinical evaluation of HER3-DXd is ongoing in the phase III HERTHENA-Lung02 trial, which is comparing HER3-DXd with platinum-based chemotherapy in metastatic or locally advanced EGFR-mutated NSCLC after failure of EGFR TKI therapy.

Comment