T-DXd shows meaningful and durable responses in previously treated HER2-mutant mNSCLC

Trastuzumab deruxtecan (T-DXd) at both 5.4 mg/kg and 6.4 mg/kg doses provides clinically meaningful and durable responses in patients with previously treated HER2-mutant (HER2m) metastatic non-small-cell lung cancer (mNSCLC), with the 5.4 mg/kg dose showing a more favourable benefit/risk profile, according to primary results of the phase II DESTINY-Lung02 trial.

The blinded, multicentre trial included 152 patients with HER2m mNSCLC previously treated with platinum-containing therapy, who were randomized to receive T-DXd at 5.4 mg/kg Q3W (n=102; median age, 59.4 years; female, 63.7 percent; from Asia, 61.8 percent; ≤2 prior lines of therapy, 63.7 percent) or 6.4 mg/kg Q3W (n=50; median age, 61.3 years; female, 68 percent; from Asia, 60 percent; ≤2 prior lines of therapy, 62 percent). As of data cut-off on 23 December 2022, the median duration of follow-up was 11.5 months in the 5.4 mg/kg arm and 11.8 months in the 6.4 mg/kg arm. [J Clin Oncol 2023;doi:10.1200/JCO.23.01361]

The primary endpoint of confirmed objective response rate (ORR) was 49 percent with the 5.4 mg/kg dose, with complete response (CR) achieved in 1 percent of patients and partial response (PR) achieved in 48 percent of patients. With the 6.4 mg/kg dose, confirmed ORR was 56 percent, with CR and PR achieved in 4 percent and 52 percent of patients, respectively.

“Responses were observed across treatment arms regardless of the number or type of prior systemic anticancer therapy and baseline central nervous system metastasis,” the investigators reported. “At both doses, patients had a reduction in tumour size from baseline that was sustained over time.”

The median duration of response was 16.8 months with the 5.4 mg/kg dose and not estimable with the 6.4 mg/kg dose, while median time to initial response was 1.8 months and 1.6 months, respectively.

At 12 months, 54.4 precent of responders in the 5.4 mg/kg arm and 64.1 percent of responders in the 6.4 mg/kg arm were estimated to maintain a response.

Median progression-free survival (PFS) was 9.9 months in the 5.4 mg/kg arm and 15.4 months in the 6.4 mg/kg arm, while estimated 12-month PFS rate was 45 percent and 53 percent, respectively.

Median overall survival (OS) was 19.5 months with the 5.4 mg/kg dose and not estimable with the 6.4 mg/kg dose, while estimated 12-month OS rate was 67 percent and 73 percent, respectively.

“The safety profile was acceptable and generally manageable with both doses, but a lower incidence of drug-related treatment-emergent adverse events [TEAEs] and interstitial lung disease [ILD]/pneumonitis was observed with the lower dose,” the investigators noted.

Grade ≥3 drug-related TEAEs were reported in 38.6 percent of patients receiving T-DXd 5.4 mg/kg and 58 percent of those receiving T-DXd 6.4 mg/kg, after a median treatment duration of 7.7 months and 8.3 months, respectively. Adjudicated drug-related ILD occurred in 12.9 percent and 28 percent of the patients, respectively, with grade ≥3 events reported in 2 percent of patients in each arm.

“The more favourable benefit/risk profile observed with T-DXd 5.4 mg/kg supports the use of this dose for patients with previously treated HER2m mNSCLC and reinforces T-DXd as the standard of care in this population,” the investigators concluded.