The U.S. Food and Drug Administration (FDA) has approved tucatinib (Tukysa™; Seattle Genetics), an oral small molecule medicine, for the treatment of patients with advanced unresectable or metastatic HER2-Positive breast cancer who have at least received one prior treatment.
The drug, a highly selective HER2-directed tyrosine kinase inhibitor (TKI) of HER2, was approved in combination with trastuzumab (Herceptin®; Genentech/Roche) plus capecitabine (Xeloda®; Genentech/Roche). 
In vitro studies demonstrated that tucatinib inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and proliferation, and showed anti-tumor activity in HER2-expressing tumor cells. In vivo, the drug inhibited the growth of HER2-expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone. 
The approval was part of Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE), providing a framework for concurrent submission and review of oncology products among international regulators. The approval process for tucatinib, which included the Australian Therapeutic Goods Administration (TGA) and Health Canada, also, for the first time, included a Project Orbis partnership with the Health Sciences Authority (HSA; Singapore) and Swissmedic (SMC; Switzerland).
Although the FDA has approved tucatinib, other regulators are still reviewing the dossier. The collaboration between international regulators makes it possible that patients with cancer may receive earlier access to products in other countries where there may be significant delays in regulatory submissions, regardless of whether the product has received FDA approval.
Facilitating global collaboration
Early availability of new therapies and adoption as a standard of care around the world may have an impact on the increasingly international conduct of cancer clinical trials, potentially accelerating the development of anticancer products. With a framework for concurrent submission and review of oncology drugs, Project Orbis facilitates a collaborative review to identify any regulatory divergence across review teams.
“The FDA’s Project Orbis provides a framework for concurrent submission and review of oncology drug applications among the FDA’s international collaborators. We are pleased to work with our Singapore and Switzerland colleagues for the first time, and to continue working alongside our Australian and Canadian colleagues as we facilitate new treatment options for patients – like today’s first new molecular entity under Project Orbis,” noted Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.
“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,” he added.
HER2-positive breast cancer
HER2-positive breast cancer, which makes up approximately one-fifth of breast cancers, has too much of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. An estimated 279,100 new cases of breast cancer will be diagnosed in the U.S. in 2020.
Between 15% and 20% of breast cancer cases are HER2-positive. Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer. Up to 50% of women diagnosed with metastatic HER2-positive breast cancer will develop brain metastases over time. 
“We recognize that patients with cancer constitute a vulnerable population at risk of contracting the coronavirus (COVID19) disease,” Pazdur said.
“In this critical time, we remain steadfast in our commitment to patients with cancer and doing everything we can to expedite oncology product development. Tucatinib was approved four months prior to the FDA goal date, providing an example of this commitment and showing how our regular work in reviewing treatments for patients with cancer is moving forward without delay,” he concluded.
Clinical trials results
Tucatinib was approved for the treatment of patients who had received one or more anti-HER2-based regimens in the metastatic setting. The decision was based on the results of the HER2CLIMB study (NCT02614794), a randomized (2:1), double-blind, placebo-controlled trial enrolling 612 patients who had HER2-positive advanced unresectable or metastatic breast cancer and had prior treatment with trastuzumab, pertuzumab (Perjeta®; Genentech/Roche) and ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche).
Forty-eight percent of patients in the study had a presence or history of brain metastases. These patients, as well as patients with previously treated and stable brain metastases and those with previously treated and growing or untreated brain metastases, were eligible for the clinical trial.
The primary efficacy outcome measure or endpoint was progression-free survival (PFS) or the amount of time when there was no growth of the tumor, as assessed by blinded independent central review (BICR) in the first 480 randomized patients.  Additional efficacy outcome measures were evaluated in all randomized patients and included overall survival (OS), PFS in patients with a history or presence of brain metastases, and confirmed objective response rate (ORR).
Overall survival and PFS in patients with brain metastases at baseline were key secondary endpoints. The median overall survival in patients who received tucatinib, trastuzumab, and capecitabine was 21.9 months compared to 17.4 months in patients who received placebo, trastuzumab, and capecitabine. The median PFS in patients with brain metastases at baseline who received tucatinib, trastuzumab, and capecitabine was 7.6 months compared to 5.4 months in patients who received placebo, trastuzumab, and capecitabine.
Furthermore, patients who received tucatinib in combination with trastuzumab and capecitabine had a 46% reduction in the risk of cancer progression or death (PFS) compared to patients who received trastuzumab and capecitabine alone (hazard ratio (HR)=0.54 [95% Confidence Interval (CI): 0.42, 0.71]; p<0.00001).
The addition of tucatinib reduced the risk of death (OS) by 34% compared to trastuzumab and capecitabine alone (HR=0.66 [95% CI: 0.50, 0.87]; p=0.0048). Nearly twice the number of patients who received tucatinib in combination with trastuzumab and capecitabine had a confirmed objective response compared to those who received trastuzumab and capecitabine alone (40.6% (95% CI: 35.3, 46.0) vs. 22.8% (95% CI: 16.7, 29.8); p=0.00008).
For patients with brain metastases, the addition of tucatinib reduced the risk of cancer progression or death (PFS) by 52% compared to trastuzumab and capecitabine alone (HR=0.48 [95% CI: 0.34, 0.69]; p<0.00001).
Significant clinical improvement
“With highly significant and clinically important results for overall and progression-free survival, the addition of tucatinib 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.
“Cancer spreads to the brain in up to half of the 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. Tucatinib is well tolerated by patients and is a valuable addition to the agents we have for HER2-positive metastatic breast cancer.”
“We’re pleased to have collaborated with the FDA on our second expedited real-time oncology review, enabling us to rapidly bring this new targeted medicine to patients,” said Clay Siegall, Ph.D., Chief Executive Officer at Seattle Genetics.
“[Tucatinib] has shown impressive results in people with HER2-positive metastatic breast cancer, including in patients with active brain metastases, and offers patients an effective medicine following previous treatment with other anti-HER2 agents in the metastatic setting.”
In the trial, serious adverse reactions occurred in 26% of patients who received tucatinib. Serious adverse events were reported in 2% or more of patients who received the drug, included diarrhea (4%), vomiting (2.5%), nausea, abdominal pain, and seizure (2% each).
The most common adverse reactions occurring in 20% or more of patients who received tucatinib were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity (liver damage), vomiting, stomatitis (inflammation of the mouth and lips), decreased appetite, abdominal pain, headache, anemia, and rash. Adverse reactions leading to treatment discontinuation occurred in 6% of patients who received tucatinib; adverse reactions leading to treatment discontinuation of tucatinib (in 1 percent or more of patients) were hepatotoxicity (1.5%) and diarrhea (1%).
According to the highlights of prescribing information, women who are pregnant or breastfeeding should not take tucatinib because it may cause harm to a developing fetus or newborn baby.
Real-time oncology Review
In addition to the international collaboration between the FDA and TGA, Health Canada, HSA Singapore, and SMC Switzerland, this review used the Real-Time Oncology Review (RTOR) pilot program, which can streamline the submission of data prior to the completion and submission of the entire clinical application. RTOR, as well as the Assessment Aid, facilitated discussions among the regulatory agencies and regulatory review.
The FDA granted this application Priority Review and Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies. Tucatinib was also granted Fast Track designation, which expedites the review of drugs to treat serious conditions and fill an unmet medical need.
Tucatinib received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB) – NCT02614794
A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Patients With Advanced or Metastatic HER2+ Breast Cancer – NCT03975647
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