Tukysa (tucatinib)

Treatment of Ba/F3 or lung cells expressing MDK::ERBB2 with ERBB2 inhibitors (afatinib, poziotinib, tucatinib) blocked phosphorylation of ERBB2 and downstream effectors, and inhibited growth of both cell lines. ERBB2 fusions are rare oncogenic drivers that are candidates for targeted therapy. The subset of recurrent ERBB2 fusions with C-terminal/3' partners may represent an alternative mechanism of fusion oncogenicity.

P1/2, N=81, Not yet recruiting, Merck Sharp & Dohme LLC

The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.

P2, N=53, Active, not recruiting, UNICANCER | Recruiting --> Active, not recruiting

The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model.

Several TKIs, including lapatinib, neratinib, and tucatinib, have been developed and are currently used in clinical settings, often in combination with chemotherapy, endocrine therapy, or other targeted agents. TKIs have emerged as a promising therapeutic option for patients with breast cancer and hold potential for treating other breast cancer subtypes. The development of new TKIs and their integration into personalized treatment strategies will continue to shape the future of breast cancer therapy.

P2; Trial completion date: May 2029 --> Sep 2024 | Trial primary completion date: May 2025 --> Sep 2024

P2, N=3791, Recruiting, American Society of Clinical Oncology | Trial completion date: Dec 2025 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Jun 2026

P3, N=654, Active, not recruiting, Seagen Inc. | Trial completion date: Jun 2027 --> Oct 2027 | Trial primary completion date: Oct 2024 --> May 2025

Margetuximab plus chemotherapy was used as fourth- or later-line treatment in patients who had received multiple HER2-targeted agents, including trastuzumab, pertuzumab, ado-trastuzumab emtansine, trastuzumab deruxtecan, tucatinib, and neratinib. Patients responded to margetuximab plus chemotherapy with real-world progression-free survival (PFS) of 3, 4, and 7 months. Clinical outcomes from three heavily pretreated patients with metastatic HER2+/HR+ MBC demonstrated that margetuximab plus chemotherapy resulted in real-world PFS comparable to that reported in the controlled pivotal clinical trial and support use of this targeted therapy option in appropriately identified patients.

P1/2, N=40, Active, not recruiting, Seagen Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Mar 2025 --> Jul 2024

P1, N=279, Active, not recruiting, Jazz Pharmaceuticals | Trial completion date: Jul 2024 --> Oct 2024 | Trial primary completion date: Jun 2024 --> Oct 2024

Our data indicate that combination of TUC and IR could be more effective than single treatment strategies for BC. Thereby, treatment sequence seems to be an important factor. The lower sensitivity to TUC in NSCLC and particularly in CRC (compared to BC) implicates, that tumor promotion there might be less HER2-related. Combination with inhibitors of other driver mutations may aid in overcoming partial TUC resistance. These findings are of high relevance to improve long-time prognosis especially in brain-metastasized situations given the intracranial activity of TUC.

In this article, we report the case of a patient with HER2+ metastatic breast cancer who developed brain metastases, despite experiencing a durable effect on extracranial metastases after treatment with trastuzumab and pertuzumab. The patient exhibited intracranial progression while receiving treatment with trastuzumab deruxtecan monotherapy after secondary brain radiotherapy and multiple lines of therapy with anti-HER2 agents, such as pyrotinib, lapatinib, tucatinib, and ado-trastuzumab emtansine...The present case indicates that the combination of anlotinib and trastuzumab deruxtecan may be a promising treatment option for patients with HER2+ breast cancer with brain metastasis. Nevertheless, further studies are warranted to verify the present findings.

P2; N=30 --> 0 | Not yet recruiting --> Withdrawn | Trial primary completion date: May 2024 --> May 2025

P3, N=466, Active, not recruiting, Seagen Inc. | Recruiting --> Active, not recruiting

P3, N=654, Active, not recruiting, Seagen Inc. | Recruiting --> Active, not recruiting

P2/3, N=17, Completed, Seagen Inc. | Active, not recruiting --> Completed | Trial completion date: Mar 2027 --> Apr 2024 | Trial primary completion date: May 2025 --> Apr 2024

This is the case for EGFR-mutant or ALK-rearranged non-small cell lung cancer inhibitors, tucatinib and trastuzumab-deruxtecan for HER2-positive breast cancer and BRAF inhibitors for melanoma. The need for screening with an MRI in asymptomatic patients at risk of brain metastases is emphasized.

P1/2, N=245, Active, not recruiting, AstraZeneca | Trial completion date: Jul 2025 --> Jan 2025

P2, N=48, Recruiting, Carey Anders, M.D. | Trial completion date: Apr 2025 --> Oct 2027 | Trial primary completion date: Apr 2024 --> Oct 2026

P2, N=72, Not yet recruiting, Dana-Farber Cancer Institute

The unanimous consensus attained in this Delphi panel, particularly regarding tucatinib's efficacy and safety, underscores oncologists' recognition of its clinical significance based on existing trial data. These findings align closely with current literature, shedding light on areas necessitating further investigation, not thoroughly explored in prior studies. Moreover, the results underscore the scarcity of data on managing brain progression alongside stable extracranial disease, emphasizing the imperative for dedicated research to address these gaps and yield definitive insights.

Trastuzumab plus a tyrosine kinase inhibitor (4 tucatinib, 1 neratinib) were the most used first choice for HER2 therapy. In HER2-amplified CRC, post-treatment blood ctDNA analysis can detect genetic alterations associated with HER2 therapy failure. Additional research is warranted to examine the clinical utility of serial ctDNA monitoring to predict HER2 treatment response and failure.

P1/2, N=40, Recruiting, Seagen Inc. | N=120 --> 40 | Trial primary completion date: May 2024 --> Mar 2025

P1, N=25, Active, not recruiting, Merck Sharp & Dohme LLC | Trial primary completion date: Dec 2023 --> Jan 2025

P1/2, N=18, Recruiting, Jonsson Comprehensive Cancer Center | Phase classification: P1b --> P1/2 | Trial completion date: Apr 2025 --> Apr 2026 | Trial primary completion date: Apr 2024 --> Apr 2025

We postulate that telangiectasias may be a previously unreported dermatologic side effect of combination treatment with tucatinib and T-DM1. Electrocautery is a safe and effective procedure to reduce the appearance of telangiectasias and improve patient satisfaction during chemotherapy.

Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC)...The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure...In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness...While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors' preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting...These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.

P1, N=41, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed

P3, N=565, Recruiting, Seagen Inc. | Trial completion date: Apr 2024 --> Oct 2027

P1/2; Phase classification: P2 --> P1/2

P2, N=30, Recruiting, Criterium, Inc. | Trial completion date: May 2025 --> Aug 2027 | Trial primary completion date: Nov 2023 --> Jun 2027

P2, N=252, Completed, Genentech, Inc. | Active, not recruiting --> Completed

P2, N=70, Active, not recruiting, Seagen Inc. | Trial primary completion date: Jan 2024 --> Jul 2024

We also found that ErbB2's nuclear localization signal was not essential for LCR activity, but rather the cellular ErbB2 protein level and activation status that were inhibited by tucatinib and CP-724714...Expanding our investigation to directly assess the impact of ErbB2 on viral gene expression, quantitative analysis of E6 and E7 transcript levels in HPV16 and HPV18 transformed cell lines unveiled a noteworthy decrease in oncogene expression following ErbB2 depletion, concomitant with the downregulation of Akt and ERK signaling pathways. In light of these findings, we propose that ErbB2 holds promise as potential target for treating HPV infections and HPV-associated malignancies by silencing viral gene expression.

L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer.

P1/2, N=198, Recruiting, Seagen Inc. | Not yet recruiting --> Recruiting

P2, N=30, Recruiting, UNICANCER | Not yet recruiting --> Recruiting

P2, N=66, Recruiting, Institut Curie | Active, not recruiting --> Recruiting

We found that TH-4000E ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium) (1-1000 nM) had potent and highly selective toxic effects on HER2 breast cancer cells and inhibited the phosphorylation of HER family kinases at lower doses than that of Lapatinib and Tucatinib. The prodrug TH-4000 ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide) (50 mg/kg) effectively suppressed the tumor growth with less liver damage in mouse tumor models. This hypoxia-targeted strategy has possessed advantage in avoiding drug-induced liver damage, TH-4000 could be a promising drug candidate for the treatment of HER2 breast cancer.