Patritumab deruxtecan (HER3-DXd) in resistant EGFR -mutated ( EGFR m) advanced non-small cell lung cancer (NSCLC) after a third-generation EGFR TKI: The phase 3 HERTHENA-Lung02 study.

8506 Background: After disease progression on a 3rd-gen (3G) EGFR TKI for advanced EGFR m NSCLC, available therapies provide limited efficacy. HER3-DXd, an antibody-drug conjugate consisting of a fully human mAb to HER3 attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker, showed promising efficacy in HERTHENA-Lung01. Methods: HERTHENA-Lung02 (NCT05338970) is a phase 3, randomized, open-label study of HER3-DXd vs platinum-based chemotherapy (PBC) in patients (pts) with advanced EGFR m (Ex19del or L858R) NSCLC following disease progression on a 3G EGFR TKI. The primary endpoint is PFS by BICR, tested using a stratified log-rank test. The key secondary endpoint is OS. Results: 586 pts were randomized to HER3-DXd or PBC (median age, 64 y; 61% female; 60% Asian). At the 31 May 2024 data cutoff for primary analysis of PFS, median (range) study duration was 10.7 (5.2-21.9) mo, and treatment duration was 5.5 (0.7-16.8) mo and 4.6 (0.7-16.5) mo with HER3-DXd and PBC, respectively. HER3-DXd provided a significant improvement in PFS vs PBC (HR, 0.77; 95% CI, 0.63-0.94; P =.011). Median PFS (95% CI) with HER3-DXd vs PBC was 5.8 (5.5-6.8) mo vs 5.4 (5.0-5.6) mo. The PFS rate (95% CI) with HER3-DXd vs PBC was 0.50 (0.44-0.56) vs 0.38 (0.32-0.44) at 6 mo; 0.29 (0.23-0.35) vs 0.19 (0.14-0.25) at 9 mo; and 0.18 (0.12-0.25) vs 0.05 (0.01-0.13) at 12 mo. ORR (95% CI) was 35.2% (29.7%-40.9%) with HER3-DXd vs 25.3% (20.4%-30.6%) with PBC. Median DOR (95% CI) was 5.7 (5.1-7.3) mo with HER3-DXd vs 5.4 (4.1-5.6) mo with PBC. OS data were immature at this protocol-specified interim data cut. In pts with brain metastases at baseline (per CNS BICR), median (95% CI) intracranial PFS was 5.4 (4.0-5.9) mo with HER3-DXd (n=105) vs 4.2 (2.8-5.0) mo with PBC (n=95) (HR, 0.75; 95% CI, 0.53-1.06). TEAEs occurred in 100% of pts in the HER3-DXd arm and 99% in the PBC arm. TEAEs were associated with treatment discontinuation in 33 pts (11%) in the HER3-DXd arm and 27 (10%) in the PBC arm. The most common TEAEs (n %) in the HER3-DXd/PBC arms were nausea (168 57.9/118 42.1, thrombocytopenia (151 52.1/76 27.1), and fatigue (146 50.3/118 42.1). Grade G ≥3 TEAEs occurred in 73% (HER3-DXd) and 57% (PBC) of pts; the difference was driven by a higher rate of G≥3 thrombocytopenia with HER3-DXd (30% vs 7.9%). Each arm had 1 G≥3 bleeding event associated with G≥3 platelet count decreased. Adjudicated drug-related ILD occurred in 14 pts (5%; 11 G1/2, 1 G3, 2 G5) in the HER3-DXd arm. Conclusions: HER3-DXd demonstrated statistically significant improvement in PFS vs PBC in pts with EGFR m NSCLC post EGFR TKI therapy. The safety profile was manageable, consistent with prior reports. Most common TEAEs were hematologic and gastrointestinal. Follow-up is ongoing, along with further exploration of secondary/exploratory/biomarker endpoints from this data cut. Clinical trial information: NCT05338970 .