HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy

Abstract

Purpose: Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC).

Methods: This phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced EGFR-mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data.

Results: Enrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations.

Conclusion: After tumor progression with EGFR TKI therapy and PBC 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 TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).

FIG 1.

CONSORT diagram (patient disposition). HER3, human epidermal growth factor receptor 3; PD, progressive disease.

FIG 2.

Kaplan-Meier plots of (A) PFS and (B) DOR, both by BICR per RECIST 1.1. Snapshot data cutoff, May 18, 2023. BICR, blinded independent central review; DOR, duration of response; PFS, progression-free survival.

FIG 3.

Waterfall plot of best percentage change in the sum of diameters from baseline (n = 225). Snapshot data cutoff, May 18, 2023. Below the waterfall plot, categories of genomic alterations before treatment with HER3-DXd are flagged for each patient (more details on genomic alterations can be found in the Data Supplement, Fig S4) and pretreatment HER3 IHC membrane H-score is shown as a heatmap. Two hundred and ten patients had evaluable target lesion measurements at both baseline and post baseline and are included. ^aT790M was not included as an EGFR-dependent mechanism of EGFR TKI resistance. ^bPretreatment (within 3 months before baseline) tumor HER3 membrane IHC H-score. BICR, blinded independent central review; CR, complete response; EGFR, epidermal growth factor receptor; HER3, human epidermal growth factor receptor 3; IHC, immunohistochemistry; MET, MET proto-oncogene, receptor tyrosine kinase; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.

FIG 4.

Outcomes by CNS BICR in patients with brain metastases at baseline with no previous radiotherapy. (A) Best change from baseline in the sum of diameters of measurable target brain lesions. (B) Intracranial antitumor activity in all patients with brain metastasis at baseline (including nontarget lesions). (C) Contrast-enhanced CT series for the patient with a measurable target lesion who had a confirmed complete intracranial response. ^aCR + PR. ^bEight patients had only nontarget lesions. BICR, blinded independent central review; BOR, best overall response; cORR, confirmed objective response rate; CR, complete response; CT, computed tomography; LD, longest diameter; NE, not estimable/not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; T, target. Snapshot data cutoff, May 18, 2023.

FIG 5.

Most common TEAEs occurring in ≥10% of patients (n = 225). Primary data cutoff, November 21, 2022. ^aPlatelet count decreased, thrombocytopenia. ^bNeutropenia, neutrophil count decreased. ^cAnemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased. ^dLeukopenia, white blood cell count decreased. ^eAbdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper. ^fAphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, stomatitis. PT, preferred term; TEAE, treatment-emergent adverse event.