Trastuzumab Deruxtecan in Patients with HER2-Mutated Advanced NSCLC

2020 Year in Review - Lung Cancer - Lung Cancer

Trastuzumab deruxtecan has a high overall response and durable responses in patients with HER2-mutated NSCLC.

[Fam-]trastuzumab deruxtecan (Enhertu; T-DXd) is an antibody–drug conjugate that comprises an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. In a small phase 1 trial, patients with HER2-mutated NSCLC who received T-DXd had a confirmed objective response rate (ORR) of 73%.1

DESTINY-Lung01 is an ongoing, multicenter, phase 2 study of T-DXd in patients with nonsquamous NSCLC who overexpress HER2 or have an HER2-activating mutation.2 Researchers reported data for the cohort of 42 patients with HER2 mutations after median follow-up of 8 months (range, 1-14).2

In DESTINY-Lung01, patients received T-DXd 6.4 mg/kg every 3 weeks. The primary end point was confirmed ORR (complete response plus partial response) by independent review. Additional end points were disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and safety.2

At the time of data cutoff, November 25, 2019, 42 patients (64% female) had received T-DXd.2 Their median age was 63 years (range, 34-83).2 Approximately half (45%) had central nervous system (CNS) metastases.2 Most (76%) patients had an European Cooperative Oncology Group performance status of 1.2 HER2 mutations were predominantly in the kinase domain (91%).2 Most (91%) patients had received platinum-based chemotherapy and 55% had received anti–programmed-cell death 1 (PD-1) or anti–programmed-cell death-ligand 1 (PD-L1) treatment.2 The median number of previous treatment lines was 2 (range, 1-6).2

Median duration of treatment with T-DXd was 7.8 months (range, 0.7-14) and 45% of patients remained on treatment.2 Confirmed ORR was 62% (95% confidence interval [CI], 46%-76%).2 Median DOR was not reached at data cutoff; 16 of 26 responders remained on treatment.2 The DCR was 91% (95% CI, 77%-97%).2 Estimated median PFS was 14.0 months (95% CI, 6.4-14.0).2

All 42 patients experienced treatment-emergent adverse events (AEs); 64% were grade ≥3 of which 52% were drug-related, including decreased neutrophil count and anemia.2 There were 5 (12%) cases of drug-related interstitial lung disease as adjudicated by an independent committee (all grade 2, no grade ≥3); 1 case of grade 1 interstitial lung disease is pending adjudication.2 Treatment-emergent AEs led to dose interruption in 60% of patients, dose reduction in 38% of patients, and treatment discontinuation in 24% of patients.2

Researchers concluded that T-DXd demonstrated promising clinical activity with high ORR and durable responses in patients with HER2-mutated NSCLC. The safety profile was generally consistent with previously reported studies.2

1. Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov. 2020;10:688-701.
2. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(15_suppl). Abstract 9504.


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Last modified: July 22, 2021