tucatinib
Regulatory sources consulted
Approved indications
- With trastuzumab and capecitabine: advanced unresectable or metastatic HER2-positive breast cancer, including brain metastases, after at least one anti-HER2 regimen in metastatic disease. With trastuzumab: HER2-positive, RAS-wild-type unresectable or metastatic colorectal cancer after fluoropyrimidine, oxaliplatin, and irinotecan.
Contraindications
Absolute
- CIMA: hypersensitivity to tucatinib or excipients; the FDA label establishes no formal contraindications.
Clinical warnings
- It can cause severe diarrhea with dehydration, hypotension, acute kidney injury, and death. Treat, investigate other causes, and withhold, reduce, or discontinue according to severity. — OpenFDA, set_id f27eb1b9-b7fc-424e-988f-84dd7bb195a3
- It can cause severe hepatotoxicity. Monitor ALT, AST, and bilirubin before starting, every 3 weeks, and as indicated; withhold, reduce, or discontinue according to severity. — OpenFDA, set_id f27eb1b9-b7fc-424e-988f-84dd7bb195a3
Drug interactions
- HighStrong CYP3A or moderate CYP2C8 inducers and strong CYP2C8 inhibitors
Mechanism: Inducers decrease and CYP2C8 inhibitors increase tucatinib exposure.
Recommendation: Avoid; if a strong CYP2C8 inhibitor cannot be avoided, reduce tucatinib according to the label.
OpenFDA, set_id f27eb1b9-b7fc-424e-988f-84dd7bb195a3
- HighNarrow-therapeutic-index CYP3A or P-gp substrates
Mechanism: Tucatinib may increase their exposure.
Recommendation: Avoid sensitive CYP3A substrates; consider reducing P-gp substrates and monitor toxicity.
OpenFDA, set_id f27eb1b9-b7fc-424e-988f-84dd7bb195a3
Adverse events
Common (≥1%)
diarrhea · palmar-plantar erythrodysesthesia · nausea · hepatotoxicity · vomiting · stomatitis · decreased appetite · rash
Pregnancy and lactation
It may cause fetal harm. Women and men with partners who can become pregnant must use contraception during treatment and for 1 week afterward. Do not breastfeed during treatment or for 1 week afterward. Also consult the partner-drug labels.
Recent literature (PubMed)
The HER2CLIMB-05 study (ClinicalTrials.gov identifier: NCT05132582) is investigating the efficacy and safety of adding tucatinib to trastuzumab and pertuzumab as first-line (1L) maintenance therapy in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC). Patients with centrally confirmed HER2+ MBC without evidence of progression post induction therapy and no or asymptomatic brain metastases (BM) were enrolled. Patients were randomly assigned 1:1 to tucatinib (300 mg) or placebo twice a day combined with trastuzumab/pertuzumab. The primary end point is investigator-assessed progression-free survival (PFS); secondary end points include overall survival (OS), PFS per blinded independent central review, CNS-PFS, and safety. Between March 2022 and July 2024, 654 patients were randomly assigned to tucatinib (n = 326) and placebo (n = 328) arms. All patients were female (median age, 54 years), 69.3% had de novo MBC, 52.6% were hormone receptor-positive, and 12.4% had presence/history of baseline BM. In this primary analysis, PFS was statistically significantly improved with addition of tucatinib versus placebo (hazard ratio, 0.641 [95% CI, 0.514 to 0.799]; P < .0001; median PFS: 24.9 v 16.3 months); a PFS benefit was seen regardless of the presence/absence of BM or hormone receptor status. OS data remain immature. The most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (ALT: 28.2%; AST: 25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1%, respectively, were grade ≥3. In the tucatinib arm, 13.5% discontinued tucatinib because of TEAEs. Tucatinib addition to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for 1L maintenance therapy in patients with HER2+ MBC. Tucatinib is tyrosine kinase inhibitor that targets the human epidermal growth factor receptor 2 (HER2) and is used in
The availability of HER2-targeted therapy has dramatically improved patient outcome in HER2-positive (HER2+) early breast cancer (EBC) as recently demonstrated by the EBCTCTG metaanalysis on trastuzumab in HER2+ EBC: Adding trastuzumab to chemotherapy has reduced recurrence rates and breast-cancer related mortality by a third [1]. Today, neoadjuvant therapy has become standard of care for women with stage II or III tumors as pathological complete response (pCR) status after surgery can be used to individualize adjuvant systemic therapy. pCR is correlated with favorable patient outcome, particularly in hormone receptor (HR) negative HER2+ EBC, as demonstrated by the FDA meta-analysis. Moreover, for patients with non-pCR, 14 cycles of adjuvant T-DM1 have become a new adjuvant therapy standard based on the results of the KATHERINE trial. Primary surgery can be offered to patients with low tumor burden (cN0 cT1). For this low-risk subgroup, 12 weeks of adjuvant paclitaxel + trastuzumab for one year are correlated with excellent outcome based on the APT trial results. A multidisciplinary team is essential right from the beginning for optimal locoregional and systemic therapy in such a complex neoadjuvant - adjuvant continuum of care. Clinical trials in HER2+ EBC are currently evaluating further therapy de-escalation in low-risk disease or patients with pCR whereas for patients with non-pCR, escalation trials are also ongoing. Newly approved drugs for HER2+ MBC like tucatinib or trastuzumab-deruxtecan or even immunotherapy combinations are being evaluated to improve upon efficacy of T-DM1 alone in the non-pCR setting. Regarding de-escalation, the WSG ADAPT trial demonstrated feasibility of avoiding overtreatment and individualizing neoadjuvant therapy without compromising outcome. Further de-escalation trials (e.g. DECRESCENDO, COMPASS-HER2) are currently ongoing.
It is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs. To describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up. HER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed. Patients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle). Evaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion-free survival in all patients. Only OS was prespecified before the primary database lock. At baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median
In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB. HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized. Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events. With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ me