Tucatinib Plus T-DM1 Improves PFS in Previously Treated HER2+ Metastatic Breast Cancer

The combination of tucatinib (Tukysa) and ado-trastuzumab emtansine (Kadcyla; T-DM1) elicited an improvement in progression-free survival (PFS) compared with placebo plus T-DM1 in patients with HER2-positive metastatic breast cancer who received previous treatment with a taxane and trastuzumab (Herceptin) in any setting, meeting the primary end point of the phase 3 HER2CLIMB-02 trial (NCT03975647).¹

Data for overall survival (OS), which is a secondary end point, remain immature.

“We are encouraged by these results for [tucatinib] in combination with [T-DM1] in metastatic HER2-positive breast cancer, including in patients with brain metastases,” Roger Dansey, president of Research and Development and chief medical officer at Seagen, stated in a news release. “We plan to present the HER2CLIMB-02 data at an upcoming medical meeting and discuss the results with the FDA.”

The ongoing global, multicenter, randomized, double-blind, placebo-controlled HER2CLIMB-02 study is enrolling patients at least 18 years of age with HER2-positive metastatic or unresectable breast cancer who have had prior treatment with a taxane and trastuzumab, either separately or in combination, in any setting.² Other key inclusion criteria include measurable or non-measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1. Patients are allowed to have no evidence of brain metastases, untreated brain metastases not needing immediate local therapy, or previously treated brain metastases.

Patients are excluded if they received prior treatment with tucatinib, afatinib (Gilotrif), fam-trastuzumab deruxtecan-nxki (Enhertu), or any other investigational anti-HER2, anti-EGFR, or HER2 TKI agent; have any untreated brain lesions more than 2 cm in size; require ongoing use of corticosteroids for control of symptoms of brain metastases at a total daily dose of more than 2 mg of dexamethasone or an equivalent agent; have known or concurrent leptomeningeal disease; or have poorly controlled generalized or complex partial seizures.

Patients are being randomly assigned to receive 300 mg of oral tucatinib twice per day plus 3.6 mg/kg of intravenous T-DM1 once every 3 weeks, or oral placebo twice per day plus the same dose of T-DM1 every 3 weeks.

Investigator-assessed PFS per RECIST v1.1 criteria is the primary end point. Along with OS, other secondary end points include PFS as assessed by blinded independent central review, investigator-assessed PFS for patients with brain metastases at baseline, overall response rate, duration of response, clinical benefit rate, and safety.

Additional data showed that adverse effects leading to discontinuation were more common in the tucatinib arm. However, no new safety signals were reported with the combination.

In April 2020, the FDA approved tucatinib for use in combination with trastuzumab and capecitabine (Xeloda) for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, following at least 1 prior anti–HER2-based regimen in the metastatic setting.³

References

1. Seagen phase 3 trial of Tukysa (tucatinib) in combination with antibody-drug conjugate ado-trastuzumab emtansine meets primary endpoint of progression-free survival in patients with previously treated HER2-positive metastatic breast cancer. News release. Seagen. August 16, 2023. Accessed August 16, 2023. https://investor.seagen.com/press-releases/news-details/2023/Seagen-Phase-3-Trial-of-TUKYSA-tucatinib-in-Combination-with-Antibody-Drug-Conjugate-ado-trastuzumab-emtansine
2. A study of tucatinib vs. placebo in combination with ado-trastuzumab emtansine (T-DM1) for patients with advanced or metastatic HER2+ breast cancer. ClinicalTrials.gov. Updated August 15, 2023. Accessed August 16, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03975647
3. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. News release. FDA. April 17, 2020. Accessed August 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer