Prognostic and predictive implications of plasma ctDNA in guiding first-line targeted therapy for metastatic HER2-mutant non-small cell lung cancer (NSCLC).

Abstract

9052 Background: Trastuzumab deruxtecan (T-DXd) is the first HER2-targeted drug approved for NSCLC with human epidermal growth factor receptor 2 ( HER2, ERBB2) mutation in the second or later line settings. However, the optimal first-line treatment for these patients remains unclear. Access to rapid tissue sequencing is not always available, thus presenting challenges to first-line drug development. Circulating tumor DNA (ctDNA) analysis has the potential to overcome these obstacles to guide optimal first-line targeted therapy for patients with HER2-mutant NSCLC. Methods: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx Lung. Results: We identified 64 patients with metastatic HER2-mutant NSCLC who had received at least one line of systematic therapy. The median age was 63 years (range: 23–90), and there were more women (n = 38, 60%), and never-smokers (n = 38, 60%). The activating HER2 mutations included exon 20 insertions (73%), exon 8 (11%), 19 (11%), and 20 SNVs (5%). Plasma ctDNA was tested before initial therapy in 40 patients with a median overall survival (OS) of 28 months (95% CI 21-34), in whom 31 patients (78%) had at least one detectable ctDNA alteration by MSK-ACCESS and ctDx Lung. 55% (17/31) received chemoimmunotherapy with pembrolizumab as the first-line treatment. The median time to treatment discontinuation (TTD) was 6 months (95%CI 5.5-6.9). Additionally, 19% of patients (6/31) received a HER2-targeted antibody-drug conjugates (ADC) as first-line treatment with a median TTD of 6 months (95% CI 2-10), including 5 with T-DM1 and one who received first-line T-DXd treatment with a TTD of 9 months. Patients with baseline ctDNA alterations had significantly shorter OS (hazard ratio (HR), 5.25; 95% CI, 1–24; p = 0.019). Conclusions: Baseline plasma ctDNA has the potential to guide first-line targeted therapy for patients with HER2-mutant NSCLC. As an independent negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies to avoid underestimating the effects of therapy.