Lower Trastuzumab Deruxtecan Dose Reduces Toxicity Without Impacting Efficacy in HER2-mutated NSCLC

Author: By Laura Cowen, Senior medwireNews Reporter 

medwireNews: Trastuzumab deruxtecan 5.4 mg/kg has “clinically meaningful” activity in people with previously treated HER2-mutant non-small-cell lung cancer (NSCLC), show data from the phase II DESTINY-Lung02 trial presented at the ESMO Congress 2022 in Paris, France. 

The HER2-targeting antibody–drug conjugate previously “showed durable activity” in the DESTINY-Lung01 trial, but more than a quarter of patients experienced drug-related interstitial lung disease (ILD), reported Koichi Goto, from the National Cancer Center Hospital East in Kashiwa, Japan. 

In DESTINY-Lung02, patients with previously treated HER2-mutant metastatic NSCLC were randomly assigned to receive trastuzumab deruxtecan at a lower dose of 5.4 mg/kg (n=102) or at the original 6.4 mg/kg (n=50) every 3 weeks. The data were analysed in two sets: a prespecified early cohort that included patients who had at least 4.5 months of follow-up and three post-baseline assessments, and a safety analysis set that included all patients who received at least one dose of the study drug. 

At data cutoff, with a mean 5.6 months of follow-up, the objective response rate (ORR), confirmed by blinded independent central review, was 53.8% among 52 patients in the prespecified early cohort who received trastuzumab deruxtecan 5.4 mg/kg. 

The confirmed ORR was lower, at 42.9%, after a median 5.4 months of follow-up among the 28 patients in the prespecified early cohort who received trastuzumab deruxtecan 6.4 mg/kg, but the presenter noted that the study was not powered for statistical comparisons. 

Confirmed disease control rates were 90.4% and 92.9% with the 5.4 and 6.4 mg/kg doses, respectively, while the median response duration was not reached among the people who received the lower dose and 5.9 months among those who received the higher dose. 

In the safety analysis set, which included a median 3.8–3.9 months of follow-up data, treatment-emergent adverse events (TEAEs) of any grade occurred among 92.1% of participants who received trastuzumab deruxtecan 5.4 mg/kg and among all participants who received the 6.4 mg/kg dose. 

This included 5.9% of participants in the 5.4 mg/kg group and 14.0% of those in the 6.4 mg/kg group who experienced any-grade treatment-related ILD. 

Koichi Goto pointed out that the majority of ILD was grade 1 or 2 but stressed that it “remains an important identified risk, and effective early detection and management are critical in reducing […] severity.” 

TEAEs of grade 3 or higher occurred in 31.7% and 58.0% of patients in the lower and higher dose arms, respectively, while a corresponding 9.9% and 26.0% required a dose reduction as a result of an AE. 

Dose interruptions and discontinuations due to AEs were needed by a respective 13.9% and 7.9% of people in the 5.4 mg/kg group, and by 30.0% and 16.0% of those in the 6.4 mg/kg group. 

Koichi Goto concluded that trastuzumab deruxtecan 5.4 mg/kg demonstrated “clinically meaningful responses in previously treated HER2-mutated non-small-cell lung cancer.” 

He added: “The totality of the evidence and a positive benefit–risk balance supported the FDA’s approval of [trastuzumab deruxtecan] 5.4 mg/kg as the first HER2-targeted treatment for patients with previously treated HER2-mutant non-small-cell lung cancer and support the establishment of [trastuzumab deruxtecan] as a new standard of care in this population.” 

Session discussant Laura Mezquita, from the University of Barcelona in Spain, focused on the rates of ILD and said that although they were lower than in the DESTINY-Lung01 trial, the follow-up in DESTINY-Lung02 was much shorter. She also noted that baseline characteristics were not available for the study population and it was not possible to determine whether any of the toxic effects were associated with overlap with immunotherapy. 

Laura Mezquita concluded that “we need longer follow-up to confirm the activity” of trastuzumab deruxtecan and also to identify vulnerable populations.  

Reference 

LBA55 - Goto K, Sang-We K, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small cell lung cancer (NSCLC): Interim results from the phase 2 DESTINY-Lung02 trial. Ann Oncol 2022; 33 (suppl_7): S808–S869. Doi: 10.1016/annonc/annonc1089