Tucatinib-based therapy improves PFS and OS in heavily pretreated HER2-positive metastatic breast cancer

Adding the oral HER2-targeted tyrosine kinase inhibitor tucatinib to trastuzumab and capecitabine significantly improves progression-free survival (PFS) and overall survival (OS) in patients with heavily pretreated HER2-positive metastatic breast cancer (mBC), including those with brain metastases, results of the HER2CLIMB trial have shown.

The trial included 612 patients with HER2-positive mBC, with or without brain metastasis, who were previously treated with trastuzumab, pertuzumab and trastuzumab emtansine. At baseline, the patients had received a median of four previous lines of therapy. [N Engl J Med 2019, doi: 10.1056/NEJMoa1914609]

The primary endpoint of PFS, as well as secondary endpoints of OS, PFS in patients with brain metastases, and confirmed objective response rate (ORR), were all significantly improved among patients randomized to receive tucatinib in combination with trastuzumab and capecitabine (n=410), compared with those receiving placebo plus the trastuzumab-capecitabine combination (n=202).

“These results are unprecedented for late-line therapy in advanced breast cancer, and are a major advance for patients with a significant unmet medical need,” said first author Dr Rashmi Murthy of the University of Texas MD Anderson Cancer Center in Texas, US, who presented the findings at the 2019 San Antonio Breast Cancer Symposium. “Tucatinib in combination with trastuzumab and capecitabine should be the new standard of care for patients pretreated with multiple anti-HER2 agents, including those with brain metastases.”

After a median follow-up of 14 months, median PFS was 7.8 months in the tucatinib-combination group vs 5.6 months in the placebo-combination group, with estimated 1-year PFS rates of 33.1 percent and 12.3 percent, respectively (hazard ratio [HR], 0.54; 95 percent confidence interval [CI], 0.42 to 0.71; p<0.001).

Median OS was 21.9 months vs 17.4 months in the tucatinib-combination vs placebo-combination group, with estimated 2-year OS rates of 44.9 percent and 26.6 percent, respectively (HR, 0.66; 95 percent CI, 0.50 to 0.88; p=0.005).

Among patients with brain metastases, PFS was also significantly improved in the tucatinib-combination vs placebo-combination group, with estimated 1-year PFS rates of 24.9 percent vs 0 percent and median PFS of 7.6 months vs 5.4 months (HR, 0.48; 95 percent CI, 0.34 to 0.69; p<0.001).

In the primary endpoint analysis population, the median duration of exposure to treatment was 7.3 months for tucatinib and 4.4 months for placebo. The duration of exposure to the trastuzumab-capecitabine combination was shorter in the placebo-combination group.

Most adverse events (AEs) observed in the tucatinib-combination group were of grade 1 or 2. Grade ≥3 AEs most commonly observed with the tucatinib-based regimen were palmar-plantar erythrodysesthesia syndrome (13.1 percent vs 9.1 percent with placebo-combination), diarrhoea (12.9 percent vs 8.6 percent), elevated alanine aminotransferase (5.4 percent vs 0.5 percent) and aspartate aminotransferase (4.5 percent vs 0.5 percent) levels, and fatigue (4.7 percent vs 4.1 percent).

AEs led to discontinuation of tucatinib, placebo and capecitabine in 5.7 percent, 3 percent and 9.8 percent (10.1 percent in the tucatinib-combination group and 9.2 percent in the placebo-combination group) of the patients, respectively.

These positive results led to unblinding of the study, allowing all patients to benefit from the tucatinib-based regimen. While the trial is expected to be completed in September 2020, a New Drug Application was submitted to the US FDA in December 2019 based on these findings.