Tucatinib regimen provides ‘unprecedented’ benefit in heavily pretreated HER2-positive breast cancer
SAN ANTONIO — The addition of tucatinib to trastuzumab and capecitabine significantly extended survival among heavily pretreated patients with HER2-positive metastatic breast cancer, according to results of an interim analysis of the randomized phase 3 HER2CLIMB trial presented at San Antonio Breast Cancer Symposium.
The findings — simultaneously published in The New England Journal of Medicine — showed even patients with brain metastases derived PFS and OS benefits from the combination.
The results will support a new drug application that likely will be submitted to the FDA in the first quarter of 2020.
“I hope it’s going to be the next standard of care,” Rashmi K. Murthy, MD, assistant professor of breast medical oncology at The University of Texas MD Anderson Cancer Center, told Healio. “No clinical trial has shown an OS benefit for patients who are this heavily pretreated, and also for a patient population that included those with untreated and progressing brain metastases, so I would say these are unprecedented results.”
Patients with HER2-positive metastatic breast cancer whose disease progressed after receiving multiple HER2-targeted agents have limited treatment options. The unmet need is particularly high for the approximately 50% of patients who develop brain metastases, who typically are excluded from clinical trials.
Tucatinib (Seattle Genetics) — an investigational oral tyrosine kinase inhibitor that is highly selective for HER2 — has demonstrated antitumor activity in preclinical models of HER2-positive breast cancer, as well as intracranial tumor models.
The global, double-blind, placebo-controlled HER2CLIMB trial included 612 patients with locally advanced or metastatic HER2-positive breast cancer who received prior treatment with trastuzumab (Herceptin, Genentech), pertuzumab (Perjeta, Genentech) and ado-trastuzumab emtansine (Kadcyla, Genentech).
Eligibility criteria allowed patients with untreated, treated stable or treated progressive brain metastases to enroll.
Researchers randomly assigned patients 2:1 to tucatinib 300 mg or placebo twice daily in combination with trastuzumab — dosed at 6 mg/kg once every 21 days, with a loading dose of 8 mg/kg on day 1 of the first cycle — and capecitabine, dosed at 1,000 mg/m² twice daily on days 1 to 14 of each 21-day cycle.
Investigators stratified randomization by brain metastases, ECOG status and geographic region.
The two treatment groups were well-balanced for demographics and disease characteristics, including percentage of patients with brain metastases (47.5%), median number of prior treatments (n = 4) and median number of treatments in the metastatic setting (n = 3).
PFS among the first 480 patients as assessed by blinded independent central review served as the primary endpoint. Multiplicity-adjusted secondary endpoints in the entire cohort included OS, PFS among those with brain metastases, and confirmed overall response rate among patients with measurable disease.
Median follow-up for the entire cohort was 14 months.
Results showed the addition of tucatinib to trastuzumab and capecitabine conferred a statistically significant improvement in PFS (median, 7.8 months vs. 5.6 months; HR = 0.54; 95% CI, 0.42-0.71). A higher percentage of patients in the tucatinib group remained progression free at 1 year (33% vs. 12%).
The PFS benefit extended to patients with brain metastases (median, 7.6 months vs. 5.4 months; HR = 0.48; 95% CI, 0.34-0.69). In this subgroup, 25% of those assigned tucatinib remained progression free at 1 year, compared with 0% in the control group.
Researchers reported a 34% reduction in risk for death among tucatinib-treated patients (median OS, 21.9 months vs. 17.4 months; HR = 0.66; 95% CI, 0.5-0.88). A higher percentage of those assigned tucatinib remained alive at 2 years (45% vs. 27%).
Results showed similar outcomes across all subgroups for all endpoints.
Researchers reported a significantly higher ORR rate in the tucatinib group (41% vs. 23%; P = .00008).
“I consider these results very clinically meaningful,” Murthy told Healio. “It also is important to point out that this is a very safe and tolerable regimen. There was not much added toxicity due to the addition of tucatinib, and this allows for patients to receive this treatment for a prolonged duration until they have disease progression. That is extremely important for a heavily pretreated population with limited options.”
The most common adverse events observed among tucatinib-treated patients included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue and vomiting.
Grade 3 or higher adverse events that occurred at higher frequency in the tucatinib group included diarrhea (12.9% vs. 8.6%), increased aspartate transaminase level (4.5% vs. 0.5%) and increased alanine transaminase level (5.4% vs. 0.5%). A higher percentage of patients in the placebo group experienced increased bilirubin (2.5% vs. 0.7%).
Adverse events led to treatment discontinuation for 5.7% of patients assigned tucatinib and 3% of those assigned placebo.
These results prompted investigators to unblind the study to allow patients assigned placebo to cross over to tucatinib treatment.
The HER2CLIMB trial is ongoing but no longer recruiting patients. The trial is expected to reach completion in September.
The phase 3 HER2CLIMB-02 clinical trial — designed to investigate the combination of tucatinib and ado-trastuzumab emtansine as second-line treatment for patients with locally advanced or metastatic HER2-positive breast cancer — began in October.
“We still need clinical trials to show benefit in earlier-line settings, but it’s very promising that we’re seeing an OS benefit in these heavily pretreated patients,” Murthy told Healio. “Certainly, there would be significant interest in trying to see if this drug is active in earlier settings and could even potentially prevent brain metastases.” – by Mark Leiser
Murthy RK, et al. Abstract GS1-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: Seattle Genetics sponsored the study. Murthy reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.