Patritumab deruxtecan may improve survival in EGFR-mutated NSCLC

Treatment with patritumab deruxtecan (HER3-DXd) confers survival benefits on patients with epidermal growth factor receptor (EGFR)-mutated nonsmall-cell lung cancer (NSCLC) following EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy, results of a phase I study have shown.

“Human epidermal growth factor receptor 3 (HER3) is broadly expressed in NSCLC and is the target of HER3-DXd, an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker,” according to the investigators, led by Helena A Yu from the Memorial Sloan Kettering Cancer Center in New York, US.

Yu and her team evaluated the overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and performed an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd.

The investigators then assessed safety in EGFR-mutated NSCLC patients previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg and efficacy in those treated with platinum-based chemotherapy.

The safety population consisted of 102 patients, who had a median treatment duration of 5.5 months. Of the patients, 76.5 percent had grade ≥3 adverse events. The overall safety profile supported that of previous reports. [Ann Oncol 2024;35:437-447]

In 78 patients treated with third-generation EGFR TKI and platinum-based chemotherapy, the confirmed objective response rates (as per RECIST v1.1) was 41.0 percent (95 percent confidence interval [CI], 30.0‒52.7), the median progression-free survival was 6.4 months (95 percent CI, 4.4‒10.8), and the median OS was 16.2 months (95 percent CI, 11.2‒21.9).

“Patients had diverse mechanisms of EGFR TKI resistance at baseline,” Yu said. “At tumour progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified.”

Survival benefit

In previous studies, available therapies provided a median OS from 7.5‒10.6 months in patients with EGFR-mutated NSCLC who have been treated with EGFR TKI therapy and platinum-based chemotherapy. However, the investigators stressed the need for caution when interpreting cross-trial comparisons of single-arm OS data. [BMC Pharmacol Toxicol 2017;18:21; Cancer Res 2023;83:6754]

“HER3-DXd resulted in clinically meaningful antitumour activity in patients with diverse baseline disease characteristics, including those with a variety of EGFR TKI resistance-associated mutations and a broad range of pretreatment tumour HER3 membrane expression,” Yu said.

“Moreover, efficacy was observed in patients with and without a history of central nervous system metastasis (intracranial responses were not assessed as serial brain imaging was not protocol mandated),” she added.

Further research is required to explore the potential benefits of HER3-DXd in EGFR-mutated NSCLC, according to the investigators.

Currently, a phase II study (HERTHENA-Lung01; NCT04619004) of HER3-DXd is being conducted in patients with EGFR-mutated NSCLC after disease progression with EGFR TKI therapy and platinum-based chemotherapy. [J Clin Oncol 2023;41:5363-5375]

In addition, a phase III trial (HERTHENA-Lung02; NCT05338970) is in full swing to compare HER3-DXd with platinum-based chemotherapy in this population following disease progression with a third-generation EGFR TKI.