乌鸦传媒

More than half of patients with treatment-refractory HER2-positive non-small cell lung cancer (NSCLC) responded to an anti-HER2 antibody-drug conjugate, data from a preliminary trial showed.

Fifty of 91 patients responded to trastuzumab deruxtecan (T-DXd, Enhertu) and another 34 patients had stable disease, resulting in a disease control rate exceeding 90%. Responses were durable in many cases, reflected in a median duration of 9.3 months.

Toxicity was manageable, as reported by Bob T. Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center in New York City, at the European Society for Medical Oncology (ESMO) virtual meeting. The results were published simultaneously in the .

"T-DXd demonstrated robust and durable anticancer activity in patients with previously treated HER2-mutated non-small cell lung cancer," said Li. "Efficacy was consistently observed across subgroups including in those patients with stable central nervous system [CNS] metastases. Exploratory analyses demonstrated anticancer activity across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 gene amplification. Overall, the safety profile was consistent with previously reported studies."

" provides compelling evidence of a positive benefit/risk balance with T-DXd in the second-line setting and beyond and supports its establishment as a potential new treatment standard," he added.

About 3% of nonsquamous NSCLC arise from HER2 mutations. Affected patients tend to be younger, more likely female, and never smokers. The cancers have a poor prognosis and are associated with an increased incidence of brain metastases.

No FDA-approved HER2-targeted therapies are available for lung cancer, and HER2 mutation status is not routinely assessed, said Li. Patients are most often treated with chemotherapy and/or immunotherapy, which has limited activity beyond the first-line setting.

Several countries have approved T-DXd for metastatic HER2-positive breast and gastric cancers. The DESTINY-Lung01 trial extended investigation of T-DXd into the setting of relapsed/refractory HER2-positive NSCLC. An of 42 patients showed a high response rate and durable activity, justifying enrollment of an additional 49 patients in an expansion cohort. The primary endpoint was confirmed objective response rate (ORR).

The 91 patients had a median age of 60, women accounted for two-thirds of the population, a third of the patients were Asian, and a majority (57%) of the patients were never smokers. In 93.4% of cases, HER2 kinase domain mutations were present, and 36% of patients had brain metastases. The patients had received a median of two prior lines of treatment, including platinum-based therapy (94%), anti-PD-1/L1 agents (65.9%), or both (62.6%).

The data showed an ORR of 54.9%, and 84 of 91 (92.3%) patients achieved disease control during treatment with T-DXd. Among 85 patients with measurable tumor burden at baseline, almost all had some degree of tumor regression. With a median follow-up of 13.1 months, the cohort had a median progression-free survival of 8.2 months and median overall survival of 17.8 months.

The safety profile was consistent with observations from prior studies of T-DXd, said Li. A fourth of patients discontinued treatment, most often because of pneumonitis or interstitial lung disease (ILD). The most common grade ≥3 treatment-emergent adverse events were neutropenia (18.7%), anemia (9.9%), nausea (8.8%), and fatigue (6.6%). Drug-related ILD or pneumonitis occurred in 26.4% of patients, but was grade 1/2 in most cases. Four (4.4%) patients developed grade 3 lung effects and two patients died, both of whom had prior lung resection and had received immunotherapy shortly before enrollment, said Li.

The trial clearly showed that T-DXd is active in HER2-mutated NSCLC, and future studies should focus on optimizing the dose to improve the safety and identifying rational combinations to address on- and off-target resistance, said ESMO invited discussant Daniel Shao Weng Tan, MD, PhD, of the National Cancer Center of Singapore.

"The one concern, perhaps, remains the safety profile," said Tan. "That will require further evaluation in order to determine optimal dosing potential for combinations so that we can improve durability of response. Until we can properly characterize this and other important aspects, such as CNS activity, we need to be cautious about transition to the frontline setting.

"We also need to give due consideration to strategies to improve HER2 testing rates in order to expand on the clinical experience and really argues for the importance of broad upfront NGS [next generation sequencing] testing in non-small cell lung cancer," he stated.