Abstract LBO1-04: Primary results from a phase 2a study of zanidatamab (zani) + palbociclib (palbo) + fulvestrant (fulv) in HER2+/HR+ metastatic breast cancer (mBC)

Abstract Background: HER2+ mBC remains incurable, thus novel HER2-directed therapies including chemotherapy-free options are needed. Approximately 50% of HER2+ mBC is also HR+, making the estrogen pathway an additional therapeutic target. The CDK4/6 inhibitor palbo + endocrine therapy fulv is approved for HER2−/HR+ mBC. Targeting all 3 pathways may further improve outcomes in pts with HER2+/HR+ mBC. Zani is a bispecific HER2-targeted antibody that binds HER2 in a unique trans configuration, driving multiple mechanisms of action. A prior analysis of the current single-arm, phase 2a study (NCT04224272) demonstrated antitumor activity and a tolerable safety profile for zani + palbo + fulv in heavily pretreated pts with HER2+/HR+ mBC. Enrollment has been completed; here we report the primary endpoint of PFS at 6 mo (PFS6) and other endpoints. Methods: Eligible pts had HER2+ (by local HER2 testing) and HR+, unresectable, locally advanced or mBC; ECOG PS ≤1; prior treatment with at least trastuzumab, pertuzumab, and T-DM1; and no prior CDK4/6 inhibitor. Pts received zani (20 mg/kg Q2W) + palbo + fulv (standard doses)—recommended doses determined in Part 1 assessment. The Part 2 primary endpoint was PFS6. Other endpoints included median PFS (mPFS), confirmed objective response rate (RECIST v1.1), disease control rate, and duration of response. PAM50 analysis was exploratory. A centrally confirmed HER2+ (ccHER2) subset was analyzed post hoc. Results: As of August 3, 2023, 51 pts (median age [range] 54 yr [36-77]) received zani + palbo + fulv treatment with a median follow-up time of 16.1 mo. Of the 51 pts, 32 (63%) were ccHER2+. Nine pts (18%) remained on treatment; median (range) duration of zani treatment was 8.4 (1.0-29.5) mo. In the metastatic setting, pts received a median (range) of 4 (1-12) prior systemic regimens, 3 (1-10) prior different HER2-targeted therapies, and 1 (0-5) prior endocrine therapy; 12 (24%) pts had prior T-DXd and 11 (22%) had prior fulv. The primary endpoint of PFS6 was 67% (69% in ccHER2+ subset). The mPFS was 11.7 mo (14.9 mo in ccHER2+ subset). See Table 1 for other efficacy endpoints. PAM50 subtyping was available for 29 pts (57%; 1 basal like; 16 HER2 enriched; 12 luminal B). Compared with HER2 enriched, luminal B was associated with numerically, but not statistically, longer mPFS (11.7 vs 9.3 mo; P=0.74) and similar PFS6 (66.7% vs 62.5%). The most common (>20%) treatment (zani, palbo, and/or fulv)-related adverse events (TRAEs) were diarrhea (80%), neutrophil count decrease/neutropenia (59%), nausea (39%), stomatitis (37%), anemia (29%), vomiting (25%) and asthenia (24%). Grade ≥3 TRAEs in ≥2 pts were neutrophil count decrease/neutropenia (53%), diarrhea (14%), anemia (10%), thrombocytopenia (6%), hypokalemia (4%), and hypomagnesemia (4%). One serious TRAE (transaminases increased) was reported. AEs of special interest: 6 pts with cardiac events (all LVEF decrease; 5 pts with grade 1 or 2 events, 1 pt with a grade 3 event) and 2 pts with infusion-related reactions (both grade 1). Three pts discontinued palbo due to an AE; 1 pt discontinued zani and fulv due to an AE. No treatment-related deaths were reported. Conclusions: Zani + palbo + fulv showed a promising PFS6 and mPFS with durable responses. The safety profile was manageable. These results support further development of a novel chemotherapy-free treatment regimen for heavily pretreated pts with HER2+/HR+ mBC. Table 1. Efficacy of Triplet Regimen (Zani + Palbo + Fulv) for HER2+/HR+ mBC a Patients with measurable disease (n=46 all pts; n=29 ccHER2+ subset). b Defined as best response of CR, PR, non-CR/non-PD (for patients who have only non-target lesions) or SD per RECIST 1.1. c Patients with DOR (n=16 all pts; n=14 ccHER2+ subset). cBOR, confirmed best overall response; ccHER2+, centrally confirmed HER2+; CI, confidence interval; cORR, confirmed objective response rate; CR, complete response; DCR, disease control rate; DOR, duration of response; HER2+, human epidermal growth factor receptor 2 positive; HR+, hormone receptor positive; mBC, metastatic breast cancer; mo, month; PD, progressive disease; PFS, progression-free survival; PFS6, progression-free survival at 6 months; PR, partial response; RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SD, stable disease. Citation Format: Santiago Escrivá-de-Romani, Juan Miguel Cejalvo, Emilio Alba, Jennifer Friedmann, Álvaro Rodríguez Lescure, Marie-France Savard, Rossanna C. Pezo, Maria Gion, Manuel Ruíz - Borrego, Erika Hamilton, Timothy Pluard, Marc Webster, Muralidhar Beeram, Hannah Linden, Cristina Saura, Diana Shpektor, Bob Salim, Phoebe Harvey, Sara Hurvitz. Primary results from a phase 2a study of zanidatamab (zani) + palbociclib (palbo) + fulvestrant (fulv) in HER2+/HR+ metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr LBO1-04.

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