Trastuzumab deruxtecan supported for pretreated HER2-mutant NSCLC
medwireNews: Trastuzumab deruxtecan (T-DXd) achieves durable responses in individuals who have received prior treatment for metastatic non-small-cell lung cancer (NSCLC) harboring HER2 mutations, suggests the DESTINY-Lung01 trial.
The results were presented at the ESMO Congress 2021 by Bob Li, from Memorial Sloan Kettering Cancer Center in New York, USA, and simultaneously published in The New England Journal of Medicine.
An interim analysis of the phase 2 study, which included 42 patients with unresectable or metastatic, nonsquamous, HER2-mutated NSCLC who had relapsed on or were refractory to standard therapy, “showed promising T-DXd activity,” he told the audience.
The current report provides data on the full cohort, comprising 91 patients aged a median of 60 years; 65.9% were women and the median number of prior regimens was two. The large majority (93.4%) had kinase domain HER2 mutations, while the remaining 6.6% had extracellular domain mutations.
Treatment with the antibody–drug conjugate T-DXd at a dose of 6.4 mg/kg every 3 weeks led to an objective response – as assessed by independent review – in just over half (54.9%) of the cohort. An additional 37.4% of patients had stable disease, giving a disease control rate of 92.3%.
Responses lasted for a median of 9.3 months and “were observed across HER2 mutation subtypes,” commented Li.
In this analysis, conducted at a median follow-up of 13.1 months, the median progression-free survival (PFS) and overall survival (OS) durations were 8.2 and 17.8 months, respectively.
“The safety profile was consistent with previously reported studies,” said the presenter. A total of 46.2% of participants experienced a drug-related treatment-emergent adverse event of at least grade 3, most commonly neutropenia, anemia, and nausea, in 18.7%, 9.9%, and 8.8%, respectively.
Drug-related interstitial lung disease (ILD) and pneumonitis, “which remains an important identified risk” of T-DXd treatment, occurred in 26.4% of patients, reported Li. The adverse event was of grade 1–2 in 18 of the 24 cases, but there were four grade 3 events and two grade 5.
The median time to onset was 141 days, but cases were observed as early as 14 days after treatment initiation and as late as 462 days after.
“Effective early detection and management are critical in preventing high-grade ILD and pneumonitis,” stressed the investigator, adding that “to further optimize the dosing regimen of T-DXd in patients with HER2-mutant lung cancers, the 5.4 mg/kg lower dose is currently being explored in the DESTINY-Lung02 clinical trial.”
And he concluded: “Overall, DESTINY-Lung01 provides compelling evidence of positive benefit–risk balance with T-DXd in the second-line or beyond settings, and supports its establishment as a potential new treatment standard for this patient population of unmet medical need.”
Daniel Tan, from the National Cancer Centre Singapore, who discussed the presentation, said that although the median PFS of 8.2 months “is somewhat more modest” compared with the 14.0 months observed in the interim analysis, the median PFS and OS times “are clinically meaningful” in the setting of refractory disease.
The discussant highlighted the need to further evaluate the safety profile of the agent in order to determine the optimal dosing and allow T-DXd to be used in combination with other therapies to improve the durability of response.
“Until we can properly characterize this and other important aspects such as [central nervous system] activity, we need to be cautious about transitioning to the front-line setting,” he commented.
Nevertheless, Tan believes due consideration needs to be given to strategies to improve HER2 testing rates “in order to expand on the clinical experience.”
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