Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial

Abstract

Purpose: Trastuzumab deruxtecan (T-DXd) 5.4 and 6.4 mg/kg showed robust antitumor activity in multiple cancer indications; however, T-DXd 5.4 mg/kg has not been evaluated in patients with previously treated human epidermal growth factor receptor 2-mutant (HER2m; defined as single-nucleotide variants and exon 20 insertions) metastatic non-small-cell lung cancer (mNSCLC).

Methods: DESTINY-Lung02, a blinded, multicenter, phase II study, investigated T-DXd 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with HER2m mNSCLC and further assessed T-DXd 6.4 mg/kg once every 3 weeks in this population. The primary end point was confirmed objective response rate (ORR) per RECIST v1.1 by blinded independent central review.

Results: One hundred fifty-two patients were randomly assigned 2:1 to T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. As of December 23, 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. Confirmed ORR was 49.0% (95% CI, 39.0 to 59.1) and 56.0% (95% CI, 41.3 to 70.0) and median duration of response was 16.8 months (95% CI, 6.4 to not estimable [NE]) and NE (95% CI, 8.3 to NE) with 5.4 and 6.4 mg/kg, respectively. Median treatment duration was 7.7 months (range, 0.7-20.8) with 5.4 mg/kg and 8.3 months (range, 0.7-20.3) with 6.4 mg/kg. Grade ≥ 3 drug-related treatment-emergent adverse events occurred in 39 of 101 (38.6%) and 29 of 50 (58.0%) patients with 5.4 and 6.4 mg/kg, respectively. 13 of 101 (12.9%) and 14 of 50 (28.0%) patients had adjudicated drug-related interstitial lung disease (2.0% grade ≥ 3 in each arm) with 5.4 and 6.4 mg/kg, respectively.

Conclusion: T-DXd demonstrated clinically meaningful responses at both doses. Safety profile was acceptable and generally manageable, favoring T-DXd 5.4 mg/kg.

Trial registration: ClinicalTrials.gov NCT04644237.

FIG 1.

Antitumor activity of T-DXd in patients with HER2-mutant metastatic non–small-cell lung cancer by HER2 mutation status and prior therapy. Best (minimum) percent change from baseline in the sum of diameters for all target lesions in (A) the T-DXd 5.4 mg/kg once every 3 weeks arm and (B) the T-DXd 6.4 mg/kg once every 3 weeks arm. The line at −30% indicates a partial response. Patients who had zero best percentage change from baseline in the sum of diameters for all target lesions are indicated with an asterisk (*). Numbers in the HER2 mutation row indicate in which exon the mutation occurred (8, 19, or 20). HER2 amplification was only assessed in patients who received T-DXd 5.4 mg/kg. HER2, human epidermal growth factor receptor 2; I, insertion; N, no; S, substitution; T-DXd, trastuzumab deruxtecan; TKI, tyrosine kinase inhibitor; Y, yes.

FIG 2.

PFS and OS in patients with human epidermal growth factor receptor 2–mutant metastatic non–small cell lung cancer receiving T-DXd. Kaplan-Meier curve and estimated median PFS for patients receiving (A) T-DXd 5.4 mg/kg once every 3 weeks and (B) T-DXd 6.4 mg/kg once every 3 weeks and Kaplan-Meier curve and estimated median OS for patients receiving (C) T-DXd 5.4 mg/kg and (D) T-DXd 6.4 mg/kg. PFS was assessed by blinded independent central review per RECIST version 1.1. Patients who were alive without objective documentation of radiographic disease progression by the PFS DCO date were censored at their last evaluable tumor assessment. For OS, if there was no death reported for a patient before the DCO, OS was censored at the last contact date at which the patient was known to be alive. DCO, data cutoff; NE, not estimable; OS, overall survival; PFS, progression-free survival; T-DXd, trastuzumab deruxtecan.