The European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for tucatinib, in combination with trastuzumab (Herceptin®; Genentech/Roche) and capecitabine (Xeloda®; Genentech/Roche) for the treatment of adult patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least two prior anti-HER2 treatment regimens.
The EMA validation confirms that the submission is sufficiently complete to begin the formal review process.
Tucatinib is an investigational, oral, small-molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2 without significant inhibition of EGFR.
The inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. The investigational agent has shown activity as a single agent and in combination with both chemotherapy and other HER2 targeted agents, including trastuzumab. 
HER2-positive breast cancer
Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells.
An estimated 271,270 new cases of invasive breast cancer will be diagnosed in the U.S. in 2019. Between 15 and 20% of all breast cancer cases worldwide are HER2-positive. 
Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer. In patients with metastatic breast cancer, the most common site of first metastasis is in bone, followed by lung, brain, and liver.  Up to 50% of metastatic HER2-positive breast cancer patients develop brain metastases over time.
Despite recent treatment advances, there is still a significant need for new therapies that can impact metastatic disease, especially brain metastases. There are currently no approved therapies demonstrating progression-free survival or overall survival benefit for the treatment of patients with HER2-positive metastatic breast cancer after progression on ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche).
Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases.
HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, colorectal and gastric cancers and is known to mediate cell growth, differentiation, and survival.
The European Marketing Authorization Application for tucatinib was based on data from the pivotal HER2CLIMB clinical trial (NCT02614794). This study is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, a study designed and compared tucatinib in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer.
Patients had previously received trastuzumab, pertuzumab (Perjeta®; Genentech/Roche) and ado-trastuzumab emtansine.
These patients had received a median of four prior lines of therapy overall and three in the metastatic setting.
The HER2CLIMB study enrolled a total of 612 patients to support the analyses of key secondary endpoints, including overall survival, PFS per BICR in patients with brain metastases at baseline and confirmed objective response rate (ORR). Safety data were evaluated throughout the study. The primary endpoint of the trial was progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review (BICR) in the first 480 patients enrolled in the trial.
Forty-seven percent of the patients enrolled in the trial had brain metastases at the time of enrollment. Results of the pivotal HER2CLIMB trial were presented during an oral presentation at the 2019 San Antonio Breast Cancer Symposium (SABCS) and simultaneously published in the New England Journal of Medicine (NEJM).
Tucatinib is, in addition to the HER2CLIMB-study, being evaluated in other clinical studies.
One such study (NCT03975647) is a randomized, double-blind, placebo-controlled, multi-center phase III trial of tucatinib in combination with ado-trastuzumab emtansine compared to ado-trastuzumab emtansine alone, in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have had prior treatment with a taxane and trastuzumab. The primary endpoint is PFS per RECIST criteria. Secondary endpoints include overall survival, objective response rate and duration of response. This global trial is expected to enroll approximately 460 patients.
Another study designed to evaluate tucatinib is the multi-center, open-label, single-arm phase II MOUNTAINEER-trial. This study evaluates tucatinib in combination with trastuzumab in patients with HER2-positive, RAS wild-type metastatic or unresectable colorectal cancer. In this trial, the primary endpoint is ORR by RECIST criteria. PFS, duration of response, overall survival and safety and tolerability of the combination regimen are secondary objectives. Results for 26 patients were evaluated in an analysis and presented at the European Society for Medical Oncology (ESMO) 2019 Congress. Enrollment in this study is ongoing.
“Today, we achieved a significant milestone towards our goal of making tucatinib available to patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, around the world,” noted Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.
“We look forward to working with the EMA throughout the review process. If approved, tucatinib has the potential to be a clinically meaningful advance for patients in this disease setting.”
Breakthrough Therapy designation
The New Drug Application (NDA) for tucatinib was submitted to the U.S. Food and Drug Administration (FDA) on December 23, 2019, under the Real-Time Oncology Review Pilot Program.*
The review of the tucatinib NDA is also being conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence designed to create a framework for concurrent submission and review of oncology drugs among participating international partners.
Tucatinib was recently granted Breakthrough Therapy designation by the FDA in combination with trastuzumab and capecitabine, for the treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have been treated with trastuzumab, pertuzumab, and ado-trastuzumab emtansine.
This designation was also based on data from the HER2CLIMB trial.
A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB) – NCT02614794
Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer (MOUNTAINEER) – NCT03043313
A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Patients With Advanced or Metastatic HER2+ Breast Cancer – NCT03975647
* The Real-Time Oncology Review Pilot Program aims to explore a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible, while maintaining and improving review quality and balancing the review team’s workload through data and analysis standardization, and early iterative engagement with the applicant.
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