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The clinical benefit and tolerable safety profile of trastuzumab deruxtecan was maintained at 5.4 kg/mg vs 6.4 kg/mg in patients with HER2-mutated non–small cell lung cancer, confirming the benefit-risk ratio of the FDA-approved dose.
The clinical benefit and tolerable safety profile of fam-trastuzumab deruxtecan-nxki (Enhertu) was maintained at 5.4 kg/mg vs 6.4 kg/mg in patients with HER2-mutated non–small cell lung cancer (NSCLC), confirming the benefit-risk ratio of the FDA-approved dose. Findings from an interim analysis of the DESTINY-Lung02 trial (NCT04644237) were presented at the 2022 ESMO Congress.1
The confirmed overall response rate (cORR) in the prespecified early cohort (PEC) of the study was 53.8% (95% CI, 39.5%-67.8%) at the lower dose level (n = 52) and 42.9% (95% CI, 24.5%-62.8%) at the higher dose level (n = 28). The lower dose also showed superior safety and tolerability, including a lower rate of interstitial lung disease (ILD).
“The safety profile was generally consistent with the established safety profile of trastuzumab deruxtecan, [but] the patients in the 5.4 mg/kg arm experienced a lower frequency of grade 3 or more drug-related AEs [adverse events] and experienced lower drug discontinuation, dose reduction, and drug interruption,” Koichi Goto, MD, said in a presentation of the data.
The DESTINY-Lung01 trial (NCT03505710) showed efficacy of this agent at the 6.4 mg/kg dose in patients with previously treated HER2-mutant NSCLC.2
The DESTINY-Lung02 trial is investigating the benefit-risk profile of 2 dose levels. Investigators of the trial assessed trastuzumab deruxtecan at 5.4 mg/kg and 6.4 mg/kg every 3 weeks, randomly assigning patients 2:1 to receive the lower dose vs the higher dose. The primary end point was cORR by blinded independent central review, while the secondary end points included investigator-assessed cORR, duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, and safety and tolerability.1
Enrolled patients must have had metastatic NSCLC with a confirmed HER2 mutation. They needed to have undergone prior treatment including platinum-based chemotherapy and were excluded if they had prior or current noninfectious ILD.
At a data cutoff of March 24, 2022, 52 patients in the PEC assigned to receive 5.4 mg/kg of trastuzumab deruxtecan and 28 assigned to 6.4 mg/kg were assessed. This cohort was randomized 4.5 months or earlier before the interim analysis cutoff to provide a better efficacy assessment. In the safety analysis set, 101 were assigned to receive 5.4 mg/kg and 50 were assigned to receive 6.4 mg/kg.
In the 5.4 mg/kg arm of the PEC, there were 27 (51.9%) partial responses (PR), 1 (1.9%) complete response (CR), 19 (36.5%) patients with stable disease (SD), 2 (3.8%) with progressive disease (PD), and 3 (5.8%) who were not estimable (NE). In the 6.4 mg/kg arm, there were 11 (39.3%) PR, 1 (3.6%) CR, 14 (50.0%) SD, 1 (3.6%) PR, and 1 (3.6%) NE.
There were 47 patients (90.4%; 95% CI, 79.0%-96.8%) with a confirmed DCR for the lower-dose arm and 26 (92.9%; 95% CI, 76.5%-99.1%) in the higher-dose arm. The median DOR was NE (range, 4.2-NE) and 5.9 months (range, 2.8-NE) for the lower- and higher-dose arms, respectively.
An additional analysis of the response at a data cutoff of June 22, 2022, showed the median DOR was 8.7 months (95% CI, 7.1-NE) and the cORR was 57.7% (95% CI, 43.2%-71.3%) for the 5.4-mg/kg arm.
In terms of safety and tolerability, the rate of any-grade treatment-emergent adverse events (TEAEs) was 92.1% for the patients receiving the lower-dose and 100% for those receiving the higher dose. For grade 3 or higher TEAEs, it was 31.7% versus 58.0%, respectively. Dose reductions associated with TEAEs occurred in 9.9% of the patients in the lower-dose arm, dose discontinuation occurred in 7.9% of this arm, and dose interruption occurred in 13.9%. In the higher-dose arm, the rate of dose reductions due to TEAEs was 26.0%, the rate of dose discontinuations was 16.0%, and the rate of dose interruptions was 30.0%.
ILD, a TEAE of interest, occurred in 5.9% of the lower-dose arm versus 14.0% in the higher-dose arm. In addition, the median duration of treatment was shorter for the higher-dose arm: 4.7 months versus 5.5 months in the PEC and 3.3 months versus 3.7 months in the safety population.
Based on data from this trial, the FDA recently approved the 5.4 mg/kg dose for this patient population.3
“The totality of the evidence and positive benefit-risk balance supported the FDA’s approval of trastuzumab deruxtecan at 5.4 mg/kg, as the first HER2-targeted treatment for patients [with] previously treated HER2-mutated NSCLC and supports the establishment of trastuzumab deruxtecan as their new standard of care in this population,” Goto concluded.1