A phase 1b study of Plk1 inhibitor onvansertib in combination with paclitaxel in metastatic triple-negative breast cancer (mTNBC) patients.

Abstract

1100 Background: TNBC represents 15-20% of all breast cancer and is characterized by a more aggressive clinical course compared to other subtypes with response rate < 10% after 2-3 lines of chemotherapy. Onvansertib is an oral polo-like kinase 1 (PLK1) ATP-competitive inhibitor with preclinical data showing synergy when combined with paclitaxel (P) in TNBC models. Here, we report safety and outcome data for subjects enrolled in a phase 1b clinical trial of onvansertib and P for patients (pts) with mTNBC. Methods: Eligible pts received escalating doses of onvansertib, studied using a Bayesian Optimal Interval (BOIN) design, with a fixed dose of P to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of onvansertib. The primary objective was the characterization of dose-limiting toxicity (DLT). Onvansertib was tested at 9, 12, and 18 mg/m² dose levels (DL). Onvansertib was administered orally, once daily for 21 consecutive days, followed by 7 days off; P was administered intravenously at 80 mg/m 2 once on days 1, 8, and 15 of every 28-day cycle. Exploratory objectives included pharmacokinetic (PK) and circulating tumor DNA analyses. Results: 17 pts enrolled from September 2022 to August 2024. Median line of chemotherapy for mTNBC was 3 (range 1-11), 14/17 pts received prior taxane, 7/17 immunotherapy (IO), and 13/17 a prior antibody drug conjugate (ADC). There were 3 pts enrolled at DL0 (9 mg/m²), 4 at DL1 (12 mg/m²), and 10 at DL2 (18 mg/m²). One pt in DL2 remains on treatment, and 16 are off study (11 pts discontinued due to disease progression (PD) per RECIST 1.1; 3 due to clinical PD; 1 due to unacceptable toxicity; 1 death unrelated to the study drug). DLTs were observed in 0/3 pts at DL0, 1/4 (25%) at DL1, and 3/10 (30%) at DL2. Common adverse events were anemia (47% ≥ Grade 2, 12% Grade 3), decreased neutrophil count (47% ≥ Grade 2, 24% Grade 3-4), and fatigue (24% ≥ Grade 2, 6% Grade 3). Best responses included 24% partial response (PR, 2/4 confirmed) and 24% stable disease (2/4 SD ≥ 12 weeks) (Table 1). All 4 responders were treated in DL2 (18mg/m 2 ), 3/4 pts received prior P (2/4 in mTNBC setting) and IO (all in mTNBC), 2/4 received an ADC. The RP2D of onvansertib in combination with P is 18 mg/m². PKs and other biomarkers will be presented. Conclusions: The combination of onvansertib and P demonstrated a safe toxicity profile and promising clinical activity in pretreated mTNBC pts and warrant further exploration of the combination at the RP2D. Clinical trial information: NCT05383196 . Best response per RECIST 1.1 among different DL. Response All Pts (N=17) DL0 (N=3) DL1 (N=4) DL2 (N=10) PR 4 (23.5%) 0 (0.0%) 0 (0.0%) 4 (40.0%) Confirmed PR 2 (11.8%) 0 (0.0%) 0 (0.0%) 2 (20.0%) Unconfirmed PR 2 (11.8%) 0 (0.0%) 0 (0.0%) 2 (20.0%) SD 4 (23.5%) 2 (66.7%) 2 (50.0%) 0 (0.0%) SD > 12 wks 2 (11.8%) 2 (66.7%) 0 (0.0%) 0 (0.0%) SD < 12 wks 2 (11.8%) 0 (0.0%) 2 (50.0%) 0 (0.0%) PD 9 (52.9%) 1 (33.3%) 2 (50.0%) 6 (60.0%) By RECIST 1.1 8 (47.1%) 1 (33.3%) 1 (25.0%) 6 (60.0%) Clinical PD 1 (5.9%) 0 (0.0%) 1 (25.0%) 0 (0.0%)