HER3-DXd Shows Efficacy In EGFR-Mutated NSCLC

This phase 2 open-label study included patients (pts) with advanced EGFR-mutated non-small cell lung cancer (NSCLC) previously treated with EGFR TKIs and platinum-based chemotherapy (PBC). Patients received one of two HER3-DXd (patritumab deruxtecan, U3-1402) dose regimens: 5.6 mg/kg IV every 3 weeks (Q3W) or an uptitration regimen (3.2-4.8-6.4 mg/kg). Enrollment in the uptitration arm was halted prematurely based on a benefit-risk evaluation of emerging phase 1 data, while enrollment in the 5.6 mg/kg arm was completed. The key endpoint was confirmed objective response rate (ORR) evaluated by blinded independent central review (BICR) following RECIST version 1.1 criteria.

In the 5.6 mg/kg arm, 225 pts received HER3-DXd. As of November 21, 2022, the median study duration was 13.1 months (range, 9.0-21.6), and the median treatment duration was 5.5 months (range, 0.7-18.2). The confirmed ORR by BICR was 28.4%, with a median duration of response (DOR) of 6.0 months, a median progression-free survival (PFS) of 5.5 months, and a preliminary median overall survival (OS) of 11.9 months. Patients with prior osimertinib treatment had similar outcomes. Clinically meaningful activity was observed across a wide range of pretreatment HER3 expression levels and various mechanisms of EGFR TKI resistance.

In patients with nonirradiated brain metastases at baseline (n=30), the confirmed central nervous system (CNS) ORR by BICR per CNS RECIST was 36.7% (95% CI, 19.9%-56.1%), with 10 complete responses and 1 partial response. Adverse events (AEs) were manageable and tolerable, consistent with prior observations: drug-related AEs led to discontinuation in 10 patients (4.4%) and death in 4 (1.8%); 45.3% of pts experienced grade ≥3 drug-related AEs; and 12 patients (5.3%) had independently adjudicated drug-related interstitial lung disease (grade 1/2, n=9; grade 3, n=2; grade 5, n=1).

In this patient population characterized by significant unmet needs and limited therapeutic alternatives, HER3-DXd demonstrated clinically meaningful efficacy. Additionally, this study presented the first evidence of HER3-DXd’s efficacy in the central nervous system (CNS).  The safety profile was manageable, and overall, HER3-DXd emerged as a promising therapy for pts with previously treated EGFR-mutated NSCLC. A phase 3 trial in EGFR-mutated NSCLC following EGFR TKI progression is currently ongoing (HERTHENA-Lung02; NCT05338970).

Source: https://cattendee.abstractsonline.com/meeting/10925/presentation/954

Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT04619004

Yu, H.A., Goto, Y., Hayashi, H., Felip, E., Yang, J.C-H., Reck, M., Yoh, K., Lee, S-H., Paz-Ares, L., Besse, B., Bironzo, P., Kim, D-W., Johnson, M.L., Wu, Y-L., Vigliotti, M., Dong, Q., Fan, P-D., Shrestha, P., Sternberg, D.W., Sellami, D., Jänne, P.A. Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC Following EGFRTKI and Platinum-Based Chemotherapy: HERTHENA-Lung01