First new drug approved under Project Orbis

WASHINGTON — The FDA approved tucatinib (Tukysa) in combination with trastuzumab/capecitabine chemotherapy to treat adult patients with advanced HER2-positive unresectable or metastatic breast cancer who have received at least one prior treatment.

This new approval makes tucatinib, a kinase inhibitor, the first new drug to gain approval under Project Orbis, an international collaboration that allows the FDA to work with other agencies around the globe to jointly review and approve oncology drugs. The FDA has previously worked with the Australian Therapeutic Goods Administration (TGA) and Health Canada via Project Orbis on two occasions — once in Sept. 2019 to approve combination lenvatinib/pembrolizumab for patients with advanced endometrial cancer, and once in Nov. 2019 to grant supplemental approval to acalabrutinib for adults with chronic lymphocytic leukemia.

For this approval, the FDA worked together with the TGA, Health Canada, Singapore’s Health Sciences Authority (HSA), and Switzerland’s Swissmedic (SMC). However, tucatinib has earned FDA approval, the drug is still under review at the other agencies.

In addition to Project Orbis, this review used the Real-Time Oncology Review pilot program, and the FDA granted it Priority Review, Breakthrough Therapy, Fast Track, and Orphan Drug designations.

“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,” said Richard Pazdur, MD, 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, in a statement. “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.”

The FDA’s approval of tucatinib was based on the results of a clinical trial of 612 patients with HER2-positive advanced unresectable or metastatic breast cancer who had previously been treated with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). “Patients with previously treated and stable brain metastases, as well as those with previously treated and growing or untreated brain metastases, were eligible for the clinical trial, and 48% of enrolled patients had brain metastases at the start of the trial,” the FDA explained.

“The primary endpoint was progression-free survival (PFS), or the amount of time when there was no growth of the tumor,” the agency wrote. “The median PFS in patients who received [tucatinib], trastuzumab, and capecitabine was 7.8 months compared to 5.6 months in those patients who received placebo, trastuzumab, and capecitabine. 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.”

The most common adverse effects reported in patients taking tucatinib included diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

The agency warned that the drug can cause severe diarrhea that can lead to dehydration, acute kidney injury, or even death. “Health care professionals should advise patients to notify their health care provider and start antidiarrheals as clinically indicated if diarrhea occurs. If patients are experiencing severe diarrhea, [tucatinib] should be interrupted or the dosage reduced,” the agency wrote. In addition, due to the risk for severe hepatoxicity, health care professionals should monitor liver tests in patients on the drug every three weeks during treatment, the FDA added.

“Women who are pregnant or breastfeeding should not take [tucatinib] because it may cause harm to a developing fetus or newborn baby,” they agency continued. “The FDA advises health care professionals to tell females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with [tucatinib] and for at least one week after the last dose. The FDA also advises patients refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.”

Tucatinib is manufactured by Seattle Genetics, Inc.

John McKenna, Associate Editor, BreakingMED™

Cat ID: 22

Topic ID: 78,22,730,22,192,725