General Information

Tukysa (tucatinib) is a kinase inhibitor.

Tukysa is specifically indicated:

in combination with trastuzumab and capecitabine for 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 antiHER2-based regimens in the metastatic setting.

in combination with trastuzumab for the treatment of adult patients with RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Tukysa is supplied as a tablet for oral administration.

The recommended dosage of Tukysa is 300 mg taken orally twice daily in combination with trastuzumab and capecitabine (breast cancer) or trastuzumab (colorectal cancer) until disease progression or unacceptable toxicity.

Advise patients to swallow Tukysa tablets whole and not to chew, crush, or split prior to swallowing. Advise patients not to ingest tablet if it is broken, cracked, or not otherwise intact.

Advise patients to take Tukysa approximately 12 hours apart and at the same time each day with or without a meal.

If the patient vomits or misses a dose of Tukysa, instruct the patient to take the next dose at its usual scheduled time.

Mechanism of Action

Tukysa (tucatinib) is a tyrosine kinase inhibitor of HER2. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells. In vivo, tucatinib 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 drug alone.

Indication 1 - advanced unresectable or metastatic HER2-positive breast cancer

approved April 2020

Clinical Trial Results

The FDA approval of Tukysa was based on the results of HER2CLIMB, 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 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 primary endpoint was progression-free survival (PFS). The median PFS in patients who received Tukysa, 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 Tukysa, 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 Tukysa, trastuzumab and capecitabine was 7.6 months compared to 5.4 months in patients who received placebo, trastuzumab and capecitabine.

Indication 2 - RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer
approved January 2023

Clinical Trial Results

Tukysa was approved under the FDA’s Accelerated Approval Program based on tumor response rate and durability of response from the phase 2 MOUNTAINEER clinical trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

MOUNTAINEER evaluated 84 patients with HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer following previous standard-of-care therapies. Patients evaluated in MOUNTAINEER had not received prior anti-HER2 therapy. Patients received Tukysa (300 mg) twice per day orally in combination with trastuzumab intravenously (8 mg/kg loading dose, then 6 mg/kg every three weeks thereafter) until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR)

Results from the MOUNTAINEER trial showed a 38% overall response rate (ORR) in the patients who received Tukysa in combination with trastuzumab (N=84 with a median age of 55.0 years [range: 24 to 77]). Complete responses were observed in 3.6% of patients (n=3), and partial responses were observed in 35% of patients (n=29). The median duration of response (DOR) per BICR was 12.4 months. At study entry, 64% and 70% of these patients had liver or lung metastases, respectively.