Erika P. Hamilton, MD
Investigators are seeking to determine whether adding tucatinib (ONT-380), a novel small-molecule HER2 inhibitor, to standard therapies will improve outcomes for patients with progressive metastatic HER2-positive breast cancer, including those with brain tumors.
The HER2CLIMB trial (NCT02614794) is evaluating a triplet regimen that consists of a dual attack on HER2 with tucatinib and the monoclonal antibody trastuzumab (Herceptin) in combination with capecitabine in patients with unresectable locally advanced or metastatic HER2-positive disease with or without brain metastases (Figure)
The study is currently enrolling participants throughout the United States and Canada, and plans call for opening sites in Europe, Australia, and Israel.
So far, enrollment has exceeded expectations, according to principal investigator Erika P. Hamilton, MD, director of the Breast and Gynecologic Research Program at Sarah Cannon Research Institute in Nashville, Tennessee. In December, after meeting with the FDA, drug developer Cascadian Therapeutics amended the HER2CLIMB protocol to increase the sample size to 480 patients so that the phase II study could serve as a pivotal registration trial for tucatinib.1
This change stemmed from encouraging updated phase Ib findings demonstrating that heavily pretreated patients who received the triplet combination (n = 27) achieved a median progression-free survival of 7.8 months, an overall response rate of 61%, and a median duration of response of 10 months.2
Participants with brain metastases achieved outcomes including stable disease that were similar to results for patients without such tumors.
Figure. Tucatinib Triplet Therapy in HER2-Positive Metastatic Breast Cancer Phase II HER2CLIMB Trial
CBR indicates clinical benefit rate; CNS, central nervous system; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ORR, objective response rate; T-DM1, trastuzumab emtansine.
“Tucatinib in combination appears to be well tolerated, potentially making it a highly desirable HER2 therapy for a patient population that vitally needs new options,” Hamilton said in a statement. “An active agent showing systemic activity, with a tolerable safety profile and early signs of activity in HER2-positive brain metastases, would represent a meaningful advancement in treating metastatic breast cancer.” Tucatinib inhibits activity of the HER2 protein.
The other commonly used oral HER2 inhibitor, lapatinib (Tykerb), blocks not only HER2, but also HER1/EGFR, Hamilton explained in an interview with OncologyLive®
. “That is important because many of the adverse events [AEs] from lapatinib, such as rash and diarrhea, come from the fact that therapies are blocking EGFR, so what is unique about tucatinib is that it is effective in blocking HER2 but it does not block EGFR,” said Hamilton.
Prior research findings also have indicated that tucatinib is effective in the brain, which Hamilton said is particularly important for patients with HER2-positive breast cancer. She said that although only about 10% of patients with breast cancer will develop brain metastases, those with HER2-positive disease have a brain metastasis incidence rate close to 50%.
“Most of our therapies for this form of breast cancer do not cross into the brain well, so there is a high need for anti-HER2 agents that do cross into the brain,” said Hamilton. “This regimen was picked for that reason, because it is a standard HER2 regimen that also adds this drug that not only works in the body but also crosses into the brain for this population.
“The HER2CLIMB study can be used for patients with brain metastases who have never been treated before, who have not had brain irradiation or any of the usual treatment modalities that we use to treat brain metastases, or brain metastases that are currently progressing,” Hamilton added. “That is a unique offering in clinical trials at this time.
If successful, the triplet regimen including tucatinib would provide a standard of care for patients with HER2-positive breast cancer with brain metastases. “Most importantly, we would have a highly active drug that can combat brain metastases, which is currently not a common offering,” said Hamilton. “Secondly, irrespective of brain metastases, we could have a new treatment option in the third line for all HER2-positive patients.”