Trastuzumab Deruxtecan in Patients with HER2-Mutated Advanced NSCLC

[Fam-]trastuzumab deruxtecan shows promising clinical activity with a high and durable response rate in patients with <em>HER2-</em>mutated NSCLC.

The antibody–drug conjugate [fam-]trastuzumab deruxtecan (T-DXd) comprises an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. According to results from a limited scope phase 1 trial, patients with HER2-mutated non–small-cell lung cancer (NSCLC) treated with T-DXd had a confirmed objective response rate (ORR) of 73%.¹

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

In the study, patients received T-DXd 6.4 mg/kg every 3 weeks.² The primary end point was independently confirmed ORR (complete response [CR] + partial response [PR]).² Other end points included duration of response, progression-free survival (PFS), disease control rate (DCR; CR + PR + stable disease), and safety.²

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

Median duration of treatment with T-DXd was 7.8 months (range, 0.7-14 months) and 45% of patients remained on treatment at the time of data cutoff.² Confirmed ORR was 62% (95% confidence interval [CI], 46%-76%).² Median duration of response was not reached at the data cutoff and 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 months).²

Treatment-emergent adverse events (TEAEs) were experienced by all 42 patients, nearly two-thirds (64%) of which were grade ≥3. Slightly more than half (52%) of the grade ≥3 TEAEs were drug-related, including anemia and decreased neutrophil count.² Researchers reported 5 (12%) independently determined grade 2 cases of drug-related interstitial lung disease. There is 1 case of grade 1 interstitial lung disease pending adjudication.² TEAEs contributed 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

References
1. Tsurutani J, et al. Cancer Discov. 2020;10:688-701.
2. Smit EF, et al. J Clin Oncol. 2020;38(suppl 15). Abstract 9504.