Tucatinib Research Articles

53. TUCATINIB VS PLACEBO ADDED TO TRASTUZUMAB AND CAPECITABINE FOR PATIENTS WITH PREVIOUSLY TREATED HER2+ METASTATIC BREAST CANCER (MBC) WITH BRAIN METASTASES (BM) (HER2CLIMB)

BACKGROUNDHER2CLIMB (NCT02614794) primary results have been reported previously (Murthy, NEJM 2019). We report results of exploratory efficacy analyses in pts with brain metastases (BM).METHODSAll HER2+ MBC pts enrolled had a baseline brain MRI. Pts with BM were eligible and randomized 2:1 to receive tucatinib (TUC) or placebo, in combination with trastuzumab and capecitabine. Efficacy analyses were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR-IC and DOR-IC were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy until second progression, and time from randomization to second progression or death was evaluated.RESULTSOverall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; P<0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of overall death was reduced by 42% in the TUC arm (OS HR: 0.58; P=0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%) vs the control arm (20.0%). Median DOR-IC was 6.8 mo vs 3.0 mo. In pts with isolated brain progression who continued study therapy after local treatment (n=30), risk of second progression or death was reduced by 71% (HR: 0.29), and median time from randomization to second progression or death was 15.9 mo vs 9.7 mo, favoring the TUC arm.CONCLUSIONSIn pts with previously treated HER2+ MBC with BM, TUC in combination with trastuzumab and capecitabine doubled the ORR-IC, reduced risk of IC progression or death by two-thirds and reduced risk of death by nearly half.

Management of adverse events in patients with HER2+ metastatic breast cancer treated with tucatinib, trastuzumab, and capecitabine (HER2CLIMB).

1043 Background: Tucatinib (TUC) is an investigational TKI, highly selective for HER2 without significant inhibition of EGFR. HER2CLIMB is a randomized trial of TUC vs placebo in combination with trastuzumab and capecitabine in patients (pts) with HER2+ breast cancer (NCT02614794, Murthy NEJM 2019). The most common G ≥3 adverse events (AEs) with higher incidence on the TUC arm (diarrhea, palmar-plantar erythrodysesthesia syndrome [PPE], and elevated liver enzymes) are described herein. Methods: Given that pts on the TUC arm had a longer duration of tx than those on the control arm, time-at-risk exposure-adjusted incidence rates of diarrhea, AST, ALT, and PPE were calculated as the number of pts with an event divided by the total exposure time-at-risk of an initial occurrence of the event among pts in the tx group. Time-to-event analyses were conducted for AST/ALT/bilirubin (in aggregate), diarrhea, and PPE. Results: Diarrhea and elevated AST/ALT/bilirubin on both the TUC and control arms were primarily G1/2 and manageable with dose modifications, and in some cases of diarrhea, with antidiarrheal tx. Median time to diarrhea onset was shorter on the TUC arm compared to control. For AST/ALT/bilirubin and PPE, median time to first onset was Cycles 1 and 2. On the TUC arm, antidiarrheals were used in 49.7% of cycles in which diarrhea was reported (39.8% on the control arm), and when used, the median duration of use on each arm was 3 days per cycle. Prophylactic antidiarrheals were not required per protocol. When adjusted for exposure (time-at-risk exposure-adjusted incidence rate per 100 person-years), the difference in G ≥3 events between tx arms becomes similar for diarrhea and PPE (21 vs 17 and 21 vs 19). The difference in G ≥3 events between arms is reduced for AST and ALT (7 vs 1 and 8 vs 1). Conclusions: TUC with trastuzumab and capecitabine was well-tolerated. Rates of G ≥3 diarrhea and PPE were similar between tx arms. Elevated liver enzymes were higher on the TUC arm, but were transient and reversible. Discontinuation of TUC due to AEs was rare. Clinical trial information: NCT02614794 . [Table: see text]

Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB).

1005 Background: Tucatinib (TUC) is an investigational, highly selective HER2 kinase inhibitor. HER2CLIMB (NCT02614794) showed clinically meaningful and statistically significant improvements in overall survival (OS) and progression free survival (PFS) in all pts, prolongation of PFS in pts with brain metastases (BM), and objective response rate (ORR) when TUC was added to trastuzumab (T) and capecitabine (C). Primary methods and outcomes have been reported previously (Murthy NEJM 2019). We report the results of exploratory efficacy analyses in pts with BM. Methods: All pts with HER2+ metastatic breast cancer (MBC) enrolled in HER2CLIMB had a baseline brain MRI. Pts with BM were eligible and classified as untreated, treated stable, or treated and progressing. Pts were randomized 2:1 to receive TUC or placebo, in combination with T and C. Efficacy analyses in pts with BM at baseline were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS (progression in the brain or death) and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR (ORR-IC) and IC duration of response (DOR-IC) were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy after local treatment until second progression, and time from randomization to second progression or death was evaluated. Results: Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; 95% CI: 0.22, 0.48; P &lt; 0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of death overall was reduced by 42% in the TUC arm (OS HR: 0.58; 95% CI: 0.40, 0.85; P = 0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%; 95% CI: 33.7, 61.2) vs the control arm (20.0%; 95% CI: 5.7, 43.7). Median DOR-IC was 6.8 mo (95% CI: 5.5, 16.4) vs 3.0 mo (95% CI: 3.0, 10.3). In pts with isolated brain progression who continued study therapy after local treatment (n = 30), risk of second progression or death was reduced by 67% (HR: 0.33; 95% CI: 0.11, 1.02), and median PFS from randomization was 15.9 mo vs 9.7 mo, favoring the TUC arm. Conclusions: In pts with heavily previously treated HER2+ MBC with BM, TUC in combination with T and C doubled the ORR-IC, reduced risk of IC progression or death by two thirds and reduced risk of death by nearly half. If approved, TUC in combination with T and C has the potential to become a new standard of care in pts with HER2+ MBC with and without BM. Clinical trial information: NCT02614794 .

137O Tucatinib vs placebo added to trastuzumab and capecitabine in previously treated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB)

Tucatinib (TUC) is an investigational oral TKI that is highly selective for HER2 with minimal EGFR inhibition. It has shown antitumor activity in preclinical models of HER2+ breast cancer (BC) and intracranial tumors.

Synthesis of Tucatinib

Synthesis of Tucatinib