Efficacy and safety of tucatinib (TUC) vs placebo (PBO) combined with trastuzumab and pertuzumab (HP) as maintenance therapy for HER2+ metastatic breast cancer by stratified subgroups.

1005 Background: In the phase 3 HER2CLIMB-05 study (NCT05132582), TUC + maintenance HP demonstrated a statistically significant improvement in progression-free survival (PFS) vs control treatment (Tx) (hazard ratio: 0.641, P < 0.0001) in patients (pts) with HER2+ locally advanced or metastatic breast cancer (MBC). Here we report additional efficacy and safety outcomes by stratified subgroups. Methods: Pts with centrally confirmed HER2+ MBC without evidence of progression following chemotherapy-based induction Tx (taxane + HP) were randomly assigned 1:1 to TUC (300 mg) or PBO BID + HP. Randomization was stratified by diagnosis ( de novo /recurrent), hormone receptor (HR) status (positive/negative), and presence or history of brain metastases (BM; yes/no). Endocrine therapy (ET) is permitted for pts with HR+ disease. The primary endpoint is investigator-assessed PFS. Confirmed objective response rate (cORR), duration of response (DOR), and safety were evaluated in stratified subgroups. Results: Among pts assigned to TUC + HP (n = 326) or PBO + HP (n = 328), ∼69% had de novo MBC, ∼53% had HR+ status with ∼45% having received concurrent ET, and ∼12% had baseline BM. At data cutoff (Sep 5, 2025), median PFS was longer with TUC than PBO + HP in all stratified subgroups; TUC + HP consistently improved cORR vs PBO + HP (Table). Safety outcomes in subgroups aligned with the overall population. Conclusions: TUC + HP demonstrated clinically meaningful efficacy vs PBO + HP in pts with de novo or recurrent disease, HR+ or HR− disease, and baseline BM or not, with no new safety signals identified. Results were consistent with the overall population and support TUC + HP as a potential new maintenance therapy across pts with HER2+ MBC. Clinical trial information: NCT05132582 . Efficacy outcomes. Overall De novo Recurrent HR+ (± ET) † HR− BM (yes) BM (no) TUC+HP(n=326) PBO+HP(n=328) TUC+HP(n=227) PBO+HP(n=226) TUC+HP(n=99) PBO+HP(n=102) TUC+HP(n=168) PBO+HP(n=176) TUC+HP(n=158) PBO+HP(n=152) TUC+HP(n=41) PBO+HP(n=40) TUC+HP(n=285) PBO+HP(n=288) Median PFS, mos (95% CI) 24.9(21.3−NE) 16.3(12.6−18.7) 28.9(22.7−NE) 16.8(12.9−19.2) 21.3(15.6−27.2) 12.7(8.3−18.1) 25.0(16.5−NE) 18.1(13.0−20.8) 24.9(19.4−NE) 12.6(9.4−16.8) 8.5(4.2−16.5) 4.2(2.2−8.1) 27.2(24.3−NE) 18.1(14.8−20.7) cORR*, % (95% CI) 22.6(18.0−27.8) 15.2(11.3−19.7) 26.1(20.2−32.7) 18.5(13.5−24.4) 15.1(8.5−24.0) 7.0(2.6−14.6) 20.1(14.0−27.5) 12.9(8.2−19.0) 25.2(18.4−33.0) 17.9(11.8−25.5) 15.0(5.7−29.8) 8.3(1.8−22.5) 23.8(18.7−29.5) 16.1(11.9−12.1) Median DOR*, mos (95% CI) 20.9(16.4−NE) 16.9(12.3−NE) NR(16.4−NE) 16.3(10.4−NE) 17.9(8.3−NE) NR(7.2−