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Patients diagnosed with metastatic colorectal cancer (mCRC) have a poor prognosis with survival ranging 2–3 years. The prevalence of human epidermal growth factor receptor 2 (HER2) amplification is approximately 3–4% in mCRC and increases up to 8% in patients with KRAS/NRAS/BRAF wild-type (WT) CRC tumors. Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor that, in combination with trastuzumab, has demonstrated clinically meaningful activity in patients with chemotherapy-refractory, HER2-positive (HER2+), RAS WT mCRC in the MOUNTAINEER trial. The MOUNTAINEER-03 phase III trial is designed to investigate the efficacy and safety of first-line tucatinib in combination with trastuzumab and modified FOLFOX6 (mFOLFOX6) versus standard of care (mFOLFOX6 plus bevacizumab or cetuximab) in patients with untreated HER2+, RAS WT locally advanced unresectable or mCRC. MOUNTAINEER-03 will include two arms of approximately 400 patients randomized 1:1 to either treatment arm. The primary endpoint is progression-free survival per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate (according to RECIST v1.1 per BICR). Safety assessments will include surveillance and recording of adverse events, physical examination findings, vital signs, cardiac assessments, Eastern Cooperative Oncology Group performance status, concomitant medications, and laboratory tests. Clinical trial registration: NCT05253651 (ClinicalTrials.gov). Plain Language Summary Colorectal cancer is a common and leading cause of cancer deaths worldwide. Patients who have colorectal cancer that has spread to other parts of the body (metastasized) only live for 2 to 3 years after their diagnosis. Tucatinib is a medicine that has shown promising anti-tumor activity when it is given in combination with trastuzumab in patients with metastatic colorectal cancer that is of a certain type, called HER2-positive. HER2 is a protein that, when present in amounts above normal in cancer cells, can cause them to grow more and survive longer. The MOUNTAINEER-03 study is a trial in progress of patients with HER2-positive metastatic colorectal cancer. In this trial, researchers are investigating if tucatinib in combination with trastuzumab and chemotherapy increases the length of time patients live before their cancer grows or spreads (also called progression-free survival) and how long a person is alive after the start of treatment (also called overall survival) compared to standard of care treatment (chemotherapy combination). Researchers are also investigating whether this new tucatinib combination treatment makes the colorectal cancer shrink and stop spreading and if it is safe to use in patients with HER2-positive metastatic colorectal cancer. If the findings of the MOUNTAINEER-03 phase III trial are positive, the tucatinib combination treatment could be a new option for the first-line treatment of a patient population with a high unmet medical need. This paper describes the study design of the MOUNTAINEER-03 trial. [ABSTRACT FROM AUTHOR]

A profound understanding of the binding dynamics of drugs with plasma proteins is highly important as it determines its therapeutical potential. Herein, we have investigated the molecular interaction of Tucatinib (TUC), a novel, primitive and highly selective drug for treatment of HER2+ advanced unresectable breast cancer, with bovine serum albumin (BSA) using multi‐pronged spectroscopic techniques and molecular docking. TUC considerably quenched the intrinsic fluorescence of BSA via static quenching mechanism, and it binds to the hydrophobic cleft of subdomain IIA of BSA with a moderate binding affinity. The thermodynamic analysis revealed the major interplay of van der Waals forces and hydrogen bonding interactions in stabilising the binding. The Förster distance 'r' signifies feasible energy transfer between BSA and TUC. The conformational analyses indicate some alterations in the protein secondary structure as a consequence of some changes in the protein polar environment due to complex formation. The experimental results are supported by docking analyses. [ABSTRACT FROM AUTHOR]

Abstract Background Tucatinib (TUC), a HER2-directed tyrosine kinase inhibitor, is the first targeted drug demonstrating intracranial efficacy and significantly prolonged survival in metastatic HER2-positive breast cancer (BC) patients with brain metastases. Current treatments for brain metastases often include radiotherapy, but little is known about the effects of combination treatment with TUC. Therefore, we examined the combined effects of irradiation and TUC in human HER2-overexpressing BC, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) cell lines. For the latter two, a standard therapy successfully targeting HER2 is yet to be established. Methods Nine HER2-overexpressing (BC: BT474, ZR7530, HCC1954; CRC: LS411N, DLD1, COLO201; NSCLC: DV90, NCI-H1781) and three control cell lines (BC: MCF7, HCC38; NSCLC: NCI-H2030) were examined. WST-1 assay (metabolic activity), BrdU ELISA (proliferation), γH2AX assay (DNA double-strand breaks (DSB), Annexin V assay (apoptosis), and clonogenic assay (clonogenicity) were performed after treatment with TUC and/or irradiation (IR). The relevance of the treatment sequence was analyzed exemplarily. Results In BC, combinatorial treatment with TUC and IR significantly decreased metabolic activity, cell proliferation, clonogenicity and enhanced apoptotis compared to IR alone, whereby cell line-specific differences occurred. In the PI3KCA-mutated HCC1954 cell line, addition of alpelisib (ALP) further decreased clonogenicity. TUC delayed the repair of IR-induced DNA damage but did not induce DSB itself. Investigation of treatment sequence indicated a benefit of IR before TUC versus IR after TUC. Also in CRC and NSCLC, the combination led to a stronger inhibition of metabolic activity, proliferation, and clonogenic survival (only in NSCLC) than IR alone, whereby about 10-fold higher concentrations of TUC had to be applied than in BC to induce significant changes. Conclusion 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.

Background: Tucatinib (TUC), a HER2-directed tyrosine kinase inhibitor, is the first targeted drug demonstrating intracranial efficacy and significantly prolonged survival in metastatic HER2-positive breast cancer (BC) patients with brain metastases. Current treatments for brain metastases often include radiotherapy, but little is known about the effects of combination treatment with TUC. Therefore, we examined the combined effects of irradiation and TUC in human HER2-overexpressing BC, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) cell lines. For the latter two, a standard therapy successfully targeting HER2 is yet to be established. Methods: Nine HER2-overexpressing (BC: BT474, ZR7530, HCC1954; CRC: LS411N, DLD1, COLO201; NSCLC: DV90, NCI-H1781) and three control cell lines (BC: MCF7, HCC38; NSCLC: NCI-H2030) were examined. WST-1 assay (metabolic activity), BrdU ELISA (proliferation), γH2AX assay (DNA double-strand breaks (DSB), Annexin V assay (apoptosis), and clonogenic assay (clonogenicity) were performed after treatment with TUC and/or irradiation (IR). The relevance of the treatment sequence was analyzed exemplarily. Results: In BC, combinatorial treatment with TUC and IR significantly decreased metabolic activity, cell proliferation, clonogenicity and enhanced apoptotis compared to IR alone, whereby cell line-specific differences occurred. In the PI3KCA-mutated HCC1954 cell line, addition of alpelisib (ALP) further decreased clonogenicity. TUC delayed the repair of IR-induced DNA damage but did not induce DSB itself. Investigation of treatment sequence indicated a benefit of IR before TUC versus IR after TUC. Also in CRC and NSCLC, the combination led to a stronger inhibition of metabolic activity, proliferation, and clonogenic survival (only in NSCLC) than IR alone, whereby about 10-fold higher concentrations of TUC had to be applied than in BC to induce significant changes. Conclusion: 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. [ABSTRACT FROM AUTHOR]