Positive tucatinib HER2CLIMB trial results in locally advanced or metastatic HER2-positive breast cancer published in the NEJM Seattle Genetics

Seattle Genetics, Inc. announced positive pivotal data from the HER2CLIMB trial evaluating tucatinib in patients with HER2-positive metastatic breast cancer (MBC) were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) and simultaneously published in the New England Journal of Medicine(NEJM).

The HER2CLIMB trial compared tucatinib in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with unresectable locally advanced or metastatic HER2-positive breast cancer . Patients had previously received trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1). Patients had received a median of four prior lines of therapy overall and three lines in the metastatic setting. Forty-seven percent of the patients enrolled in the trial had brain metastases at the time of enrollment. HER2CLIMB is the first randomized pivotal trial completed to enroll patients with metastatic HER2-positive breast cancer who have untreated or previously treated and progressing brain metastases.

Tucatinib is an oral, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2. Data presented at SABCS and published in NEJM include the primary endpoint of progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including overall survival (OS) as well as progression-free survival (PFS) in patients with brain metastases at baseline.

Pivotal HER2CLIMB Trial Results :Efficacy : The primary endpoint of PFS showed that the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46 percent reduction in the risk of disease progression or death (hazard ratio (HR)=0.54 [95% Confidence Interval (CI): 0.42, 0.71]; p<0.00001). estimated pfs at one year was 33 percent 95 ci: 27 40 in the tucatinib arm compared to 12 percent 95 ci: 6 21 in the trastuzumab and capecitabine arm control arm. median pfs was 7.8 months 95 ci: 7.5 9.6 in the tucatinib arm compared to 5.6 months 95 ci: 4.2 7.1 in the control arm. the addition of tucatinib to trastuzumab and capecitabine prolonged os a key secondary endpoint reducing the risk of death by 34 percent hr="0.66" 95 ci: 0.50 0.88 p="0.0048)," compared to the control arm. estimated os at two years was 45 percent 95 ci: 37 53 in the tucatinib arm compared to 27 percent 95 ci: 16 39 in the control arm. median os was 21.9 months 95 ci: 18.3 31.0 in the tucatinib arm compared to 17.4 months 95 ci: 13.6 19.9 in the control arm. for patients with brain metastases at baseline a key secondary endpoint the tucatinib arm also demonstrated superior pfs compared to trastuzumab and capecitabine alone. findings demonstrated that the tucatinib regimen resulted in a 52 percent reduction in the risk of disease progression or death compared to the control arm hr="0.48" 95 ci: 0.34 0.69 p><0.00001). the estimated pfs at one year was 25 percent 95 ci: 17 34 with the tucatinib regimen compared to zero percent in the control arm. median pfs was 7.6 months 95 ci: 6.2 9.5 in the tucatinib arm compared to 5.4 months 95 ci: 4.1 5.7 in the control arm. the confirmed objective response rate orr in the patient population with measurable disease at baseline 511 612 was 40.6 percent 95 ci: 35.3 46.0 in the tucatinib arm compared with 22.8 percent 95 ci: 16.7 29.8 for trastuzumab and capecitabine alone p="0.0008).">

Safety : Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated. The most common adverse events occurring in more than 20 percent of patients in the tucatinib arm vs. the control arm included: diarrhea (80.9 vs. 53.3 percent), palmar-plantar erythrodysaesthesia syndrome (PPE) (63.4 vs. 52.8 percent), nausea (58.4 vs. 43.7 percent), fatigue (45.0 vs. 43.1 percent) and vomiting (35.9 vs. 25.4 percent), which were primarily low grade. Discontinuation of tucatinib and placebo due to adverse events was 5.7 percent in the tucatinib arm and 3.0 percent in the control arm. Greater than or equal to Grade 3 diarrhea was seen in 12.9 percent of the patients in the tucatinib arm vs. 8.6 percent in the control arm. Antidiarrheal prophylaxis was not required per protocol. Antidiarrheals were used in less than half of all cycles where diarrhea was reported. In both treatment arms, when used, the duration of antidiarrheal treatment was short (median of 3 days/cycle). Greater than or equal to Grade 3 aspartate aminotransferase (AST) was seen in 4.5 percent of the patients in the tucatinib arm vs. 0.5 percent in the control arm, and alanine aminotransferase (ALT) elevation in 5.4 percent vs. 0.5 percent, respectively. Discontinuations due to liver transaminase elevations were infrequent in both arms (ALT: 1.0 vs. 0.5 percent; AST: 0.7 vs. 0.5 percent).

See- "Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer" Rashmi K. Murthy et al. NEJM December 11, 2019 DOI: 10.1056/NEJMoa1914609.