Patritumab deruxtecan (HER3-DXd) in resistant <i>EGFR</i> -mutated ( <i>EGFR</i> m) advanced non-small cell lung cancer (NSCLC) after a third-generation EGFR TKI: The phase 3 HERTHENA-Lung02 study.
Tony Mok, Helena A. Yu, Sun Min Lim, Isamu Okamoto, M. Pérol, Silvia Novello, Christophe Alfons Dooms, Jong‐Mu Sun, Steven Kao, Pasi A. Jänne, Martin Reck, Conor Steuer, Makoto Nishio, Yi‐Long Wu, Xiaofang Li, Ronan Fougeray, Ragini R. Kudchadkar, Jianyu Wu, Stephen Esker, Antonio Passaro
Abstract
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 .