Trastuzumab Deruxtecan Addresses an Important Need in HER2-Positive Lung Cancer

Objective responses occurred in 34.1% of patients receiving trastuzumab deruxtecan at 5.4 mg/kg and 26.5% receiving 6.4 mg/kg.

In relapsed or refractory, unresectable and/or metastatic HER2-overexpressing non-small cell lung cancer (NSCLC) patients, trastuzumab deruxtecan showed efficacy in a phase 2 trial.

The DESTINY-Lung01 results appeared in The Lancet Oncology .

HER2 Alterations and Their Importance in Cancer

The HER (human epidermal growth factor receptor) family consists of receptor tyrosine kinases influencing key pathways that regulate cell growth, differentiation and survival. It plays a central role in cancer development and progression. HER2, one of its best-studied members, can cause uncontrolled cell division and growth when overexpressed. HER2 is an important target in several cancers, particularly breast and lung cancer.

Three important HER2 alterations in cancer are overexpression, mutation and amplification. HER2 overexpression means the gene produces more protein than normal. Mutations are structural changes that may affect gene function. Amplification increases gene copy number and may make it overactive. Each can affect cancer-cell growth and spread, making it an important treatment target.

On August 11, 2022, trastuzumab deruxtecan for HER2-mutated lung cancer received US Food and Drug Administration (FDA) accelerated approval . This approval for HER2-mutated lung cancer was an important step, but similar approval has not yet been granted for other HER2 alterations. It highlights ongoing research into effective treatments for HER2-overexpressing and/or amplified cancers.

Details of DESTINY-Lung01

DESTINY-Lung01 enrolled HER2-overexpressing or HER2-mutated NSCLC, but this analysis included only HER2-overexpressing disease (immunohistochemistry scores 3+ or 2+).

Patients had standard-treatment-resistant or recurrent and/or unresectable, nonmetastatic, nonsquamous NSCLC, or had no available standard treatment.

Patients received trastuzumab deruxtecan every 3 weeks at 6.4 mg/kg (cohort 1) or 5.4 mg/kg (cohort 1A).

Between August 27, 2018, and January 28, 2020, 49 patients received 6.4 mg/kg (cohort 1). Between June 16, 2020, and December 9, 2020, 41 received 5.4 mg/kg (cohort 1A). In total, 90 patients.

Results

• Median treatment duration was 4.1 months in cohort 1 and 5.5 months in cohort 1A; median follow-up was 12 and 10.6 months, respectively.
• The independently confirmed objective response rate in cohort 1 was 26.5% and in cohort 1A, 34.1% . All responses in cohort 1 were partial, while in cohort 1A, 2 patients had complete responses .
• The disease control rate in cohort 1 was 69.4% and in cohort 1A, 78% .
• Median response duration was 5.8 months in cohort 1 and 6.2 months in cohort 1A.
• Median progression-free survival was 5.7 and 6.7 months, respectively.
• Median overall survival was 12.4 months and 11.2 months, respectively.
• Treatment-related adverse events occurred in 90% of cohort 1 and 93% of cohort 1A. Grade 3 or higher events occurred in 53% and 22%, respectively.

The most common grade 3 or higher events in cohorts 1 and 1A, respectively, were neutropenia (24% versus 0%) and fatigue (10% versus 7%). The most common serious events were pneumonitis (8% versus 2%) and nausea (4% versus 0%), again in cohorts 1 and 1A, respectively. Cohort 1 had 1 fatal event (interstitial lung disease or pneumonitis); there were none in cohort 1A.

Given the low antitumor activity of available treatments in this population, trastuzumab deruxtecan may address a substantial unmet need in HER2-overexpressing NSCLC.