Trastuzumab Deruxtecan Demonstrates Efficacy Reducing Brain Metastases in HER2m NSCLC

In patients with metastatic HER2 (ERBB2)-mutant (HER2m) non­–small cell lung cancer (NSCLC), the presence of brain metastases (BM) did not affect response to treatment with trastuzumab deruxtecan, according to results presented at ESMO Congress 2023, held October 20-24, both virtually and in Madrid, Spain.

Approximately one-fifth of patients with HER2m NSCLC have BM when they are diagnosed with metastatic disease. In a presentation, David Planchard, MD, PhD, Department of Cancer Medicine, Institut Gustave Roussy in Villejuif, France, presented the post hoc pooled analyses of trastuzumab deruxtecan efficacy and safety from DESTINY-Lung01 and DESTINY-Lung02.

In both trials, patients with and without BM were evaluated. In Destiny-Lung01, patients with unresectable/metastatic HER2m NSCLC were treated with trastuzumab deruxtecan 6.4 mg/kg (n = 91) and in Destiny-Lung02, patients with metastatic HER2m NSCLC were treated with trastuzumab deruxtecan 5.4 mg/kg (n = 102) or 6.4 mg/kg (n = 50). In Destiny-Lung02, patients had at least 1 prior line of anticancer therapy, including platinum-based chemotherapy.

Of the patients on the 5.4 mg/kg dose, 31.3% had detectable BM at baseline and of them 46.9% had untreated BM. Of the pooled analysis of all patients on the 6.4 mg/kg dose (n = 141), 38.2% had baseline BM and of them 55.6% had untreated BM. Across both groups, systemic objective response rates (ORRs) were similar.

Time since prior radiotherapy had been a median of 8.5 and 6.8 months for patients with BM and without BM, respectively, in the 5.4 mg/kg group, and 1.6 and 13.6 months for patients with BM and without BM, respectively, in the 6.4 mg/kg group. The patients with BM receiving 5.4 mg/kg had the longest time from NSCLC diagnosis to randomization with a median time of 22.4 months compared with 17.9 months for patients without BM receiving 5.4 mg/kg, and 17.9 and 16.2 months for patients with BM and without BM, respectively, receiving 6.4 mg/kg.

The median duration of response was 4.6 and 16.8 months for patients with and without BM, respectively, in the 5.4 mg/kg group and 7.2 and 14.1 months for patients with and without BM, respectively, in the 6.4 mg/kg group. The disease control rate was above 90% for all groups and the systemic confirmed ORR (cORR) was approximately 50% across all groups.

The median progression-free survival was 7.1 months for all patients with BM regardless of dose group, 18.0 months for patients without BM receiving 5.4 mg/kg, and 11.9 months for patients without BM receiving 6.4 mg/kg. The median overall survival was 13.6 months and 19.5 months for patients with and without BM, respectively, receiving 5.4 mg/kg and 13.8 and 27.9 months for patients with and without BM, respectively, receiving 6.4 mg/kg.

Looking at just the patient group with measurable BM at baseline, the intracranial cORR was 50.0% in the 5.4 mg/kg group and 30.0% in the 6.4 mg/kg group. Within the 5.4 mg/kg group, 21.4% of those patients had a complete response. Overall, 85.7% of patients receiving 5.4 mg/kg and 77.8% of patients in the pooled 6.4 mg/kg group had a reduction in brain lesion size from baseline as their best overall response.

Planchard noted that the limitations of the post hoc analyses included the small numbers of patients and the lack of a comparator arm.

Jessica Lin, MD

Image credit: Massachusetts General Hospital

However, in an invited discussion, Jessica Lin, MD, assistant professor of medicine at Harvard Medical School and attending physician at the Center for Thoracic Cancers and the Henri Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital, noted that despite the small numbers, the analysis offers informative data, which had been lacking, regarding central nervous system (CNS) activity of trastuzumab deruxtecan in this patient population.

“The findings, additionally, begin to address an area of critical unmet need,” Lin said. “We know that the cumulative incidence of brain metastasis in patients with HER2-mutatated non–small cell lung cancer reaches up to 47%. And yet, until today, there has been resounding paucity of data regarding the CNS activity of currently available HER2-targeted agents.”

She explained that, initially, the thought had been that due to the large size of antibody drug conjugates, as a class, would make them ineffective for crossing the blood-brain barrier and treating BM. Previous evidence has shown this assumption is untrue, and the findings of the Destiny-Lung01 and Destiny-Lung02 pooled analysis builds on that evidence.

“Based on these findings, together with accumulating CNS efficacy data from the breast cancer space, I would feel comfortable considering [trastuzumab deruxtecan] vs local therapy for a carefully selected subset of patients with asymptomatic clinically stable brain metastasis,” Lin concluded.