Trastuzumab deruxtecan induces high rates of tumour control in heavily pretreated, HER2-overexpressing advanced non-small cell lung cancer patients
Interim results of the phase II DESTINY-Lung01 trial demonstrate promising clinical activity of the antibody drug conjugate trastuzumab deruxtecan (T-DXd) in non-small cell lung cancer (NSCLC) patients with HER2 overexpression. In this heavily pretreated cohort, T-DXd induced a complete or partial response in a quarter of patients, with disease control in close to 70%. Although the drug was generally well-tolerated, the three fatal cases of treatment-related interstitial lung disease (ILD) warrant close monitoring for this adverse event in the further development of this agent.
T-DXd is an antibody–drug conjugate consisting of an anti-HER2 antibody, a cleavable, tetrapeptide-based linker, and a topoisomerase I inhibitor payload. Previously, results of an open label phase I study including 60 heavily pretreated patients with different HER2-overexpressing or -mutant solid tumors, T-DXd was associated with an overall response rate (ORR) of 55.6% in a cohort of 18 HER2-overexpressing or mutant NSCLC. The median progression-free survival (PFS) and duration of response (DoR) in this cohort was 11.3 and 10.7 months, respectively. Based on these results, T-DXd was subsequently tested in a dedicated phase II trial including patients with HER2-overexpressing or -mutant, previously treated, unresectable or metastatic non-squamous NSCLC. Interim results of this trial, focusing on the 49 patients with HER2 overexpression were presented at WCLC 2020.
Treatment response in a quarter of patients
The median age of patients in this cohort was 63 years, with 55% of patients being younger than 65 years of age. About 70% of patients had an ECOG performance status of 1. The vast majority of patients (91.8%) previously received platinum-based chemotherapy, three quarters was previously exposed to anti-PD(L)1 therapy and 25% was previously treated with docetaxel. Patients received a median of 3 prior lines of therapy (ranging from 1 to 8). Overall, T-DXd was associated with an ORR of 24.5% with an additional 44.9% of patients experiencing disease stabilization for a disease control rate of 69.4%. Responses were durable, with a median DoR of 6.0 months. The median PFS among the 49 HER2-overexpressing patients was 5.4 months, with a median overall survival (OS) of 11.3 months.
All patients experienced adverse events (AEs) of which 89.8% were believed to be treatment related. Grade ≥3 treatment related AEs were reported in 55.1% with 16.3% experiencing serious drug-related AEs. Treatment discontinuations and reductions due to treatment-related AEs were required in 12.2% and 32.7% of patients, respectively. The most common grade ≥3 treatment-related AE consisted of a decreased neutrophil count which was seen in 20.4% of patients. Overall, 16.3% experienced some form of drug-related interstitial lung disease (ILD). in three patients this ILD was grade 5 (cause of death disease progression in 2, pneumonitis in 1).
T-DXd showed promising evidence of antitumor activity in patients with HER2-overexpressing NSCLC. In a cohort of extensively pretreated patients who had previously received a median of 3 treatment lines of therapies T-DXd was associated with a confirmed ORR of 24.5%, with no apparent difference in ORR in function of the level of HER2 overexpression (IHC 3+ or 2+). A DCR of 69.4% and median OS of almost one year was reported. In general, the drug was well-tolerated, but physicians need to be vigilant for the occurrence of drug related ILD. In this trial, 16.3% of patients developed ILD with fatal outcomes in 6.1% of patients. Overall, these encouraging early efficacy results support the continued exploration of T-DXd in patients with HER2-overexpressing NSCLC.
Nakagawa K, et al. Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic Non–Small Cell Lung Cancer (NSCLC): Interim Results of DESTINY-Lung01. Presented at WCLC 2020; Abstract OA04.05.