The FDA granted accelerated approval for tucatinib tablets in combination with trastuzumab and capecitabine as treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases who have received one or more prior anti-HER2-based regimens in the metastatic setting. The approval comes 4 months ahead of the targeted action date from the FDA’s Real-Time Oncology Review.
The FDA granted accelerated approval for tucatinib (Tukysa) tablets in combination with trastuzumab (Herceptin) and capecitabine as treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. The approval comes 4 months ahead of the targeted action date through the FDA’s Real-Time Oncology Review pilot program, according to a press release from Seattle Genetics, Inc.
Tucatinib, an oral, small molecule tyrosine kinase inhibitor (TKI) of HER2, received prior Breakthrough Therapy Designation from the FDA for this indication.1
"With highly significant and clinically important results for overall and progression-free survival, the addition of Tukysa to trastuzumab and capecitabine has the potential to become a standard of care for people with HER2-positive metastatic breast cancer after having received one or more previous anti-HER2 therapies in the metastatic setting," said Eric P. Winer, MD, chief of the Division of Breast Oncology, Susan F. Smith Center for Women's Cancers at Dana-Farber, in the press release. "Cancer spreads to the brain in up to half of patients with HER2-positive metastatic breast cancer; and this approval is based on a unique clinical trial that included patients with active brain metastases, either untreated or progressing. Tukysa is well tolerated by patients and is a valuable addition to the agents we have for HER2-positive metastatic breast cancer."
The approval was based on positive results from the phase II HER2CLIMB trial (NCT02614794), which were presented at the 2019 San Antonio Breast Cancer Symposium and published in the New England Journal of Medicine.
Tucatinib added to trastuzumab and capecitabine achieved a 46% reduction in the risk of progression or death in patients with heavily pretreated, unresectable, locally advanced or metastatic HER2-positive breast cancer. At 1 year, a 33.1% progression-free survival (PFS) rate was observed with the tucatinib combination versus 12.3% in the control arm, in which patients received placebo/trastuzumab/capecitabine (HR, 0.54; 95% CI, 0.42-0.71; P <.001). The median duration of PFS was 7.8 months in the tucatinib group versus 5.6 months in the placebo group.2
The tucatinib combination led to a 44.9% overall survival (OS) rate versus 26.6% for the placebo combination (HR, 0.66; 95% CI, 0.50-0.88; P = .005), at 2 years, and the median OS was 21.9 months and 17.4 months, respectively.
These findings varied among patients with brain metastases. The PFS at 1 year was 24.9% in the tucatinib group and 0% in the control group (HR, 0.48; 95% CI, 0.34-0.69; P <.001), with a median PFS of 7.6 months and 5.4 months, respectively.
Objective responses were seen in nearly twice the number of patients who received the tucatinib combination compared with those who received the control combination (40.6 percent (95% CI: 35.3, 46.0) vs. 22.8 percent (95% CI: 16.7, 29.8); P = .00008).1
The most common AEs observed in the tucatinib arm versus the control arms, respectively, were diarrhea (80.9% vs 53.3%), palmar-plantar erythrodysesthesia syndrome (63.4% vs 52.8%), nausea (58.4% vs 43.7%), fatigue (45.0% vs 43.1%), and vomiting (35.9% vs 25.4%).2
To be eligible for enrollment in the study, patients required a histological confirmation of HER2-positive breast cancer and previous treatment with trastuzumab, pertuzumab (Perjeta), and T-DM1 (ado-trastuzumab emtansine; Kadcyla), the progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy, an ECOG performance status of 0 or 1, and adequate hepatic and renal function were included in the study. For reasons related to prior treatments, previous and existing conditions, some individuals with HER2-positive breast cancer were excluded from the study.
In the double-blind, placebo-controlled HER2CLIMB trial, patients were randomized 2:1 to receive trastuzumab and capecitabine combined with either tucatinib (n = 410) or placebo (n = 202). The primary end point was PFS in the first 480 patients by blinded independent central review. Secondary end points included OS, PFS in patients with prior or present brain metastases, and objective response rate (ORR).
Key baseline characteristics were similar among the 2 treatment arms. The median age of patients was around 55, and the majority of patients were female (99%). There was about a 50/50 split in each arm of the study of patients with an ECOG performance score of either 0 or 1. There was a median of 4 prior lines of therapy overall in both arms and a median of 3 prior therapies in patients with metastatic disease.
Tucatinib is also under evaluation in clinical trials for other subsets of breast cancer, including a phase III study of tucatinib plus T-DM1 versus T-DM1 alone in patients with unresectable locally advanced or metastatic HER2-positive disease (NCT03975647). The phase II MOUNTAINEER study (NCT03043313) is evaluating this agent in combination with trastuzumab for the treatment of patients with HER2-positive, RAS wild-type metastatic or unresectable colorectal cancer.
The application for the tucatinib combination was reviewed under the FDA’s Project Orbis, an initiative of the FDA Oncology Center of Excellence, in collaboration with Australian Therapeutic Goods Administration, Health Canada, Health Sciences Authority of Singapore, and Swissmedic from Switzerland. Although approved for use in the United States, the application is still being reviewed by the other agencies.3
“This approval represents an additional targeted treatment option for patients with HER2-positive breast cancer. The clinical trial supporting this approval enrolled and specifically studied patients with active brain metastases in addition to the overall population enrolled, which also demonstrated benefit in this subgroup, said Richard Pazdur, MD, director of the FDA’s OCE and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in a statement.