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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+ metastatic breast cancer. • Tucatinib combination shows continued prolongation of overall survival in patients with HER2+ metastatic breast cancer. • Overall survival benefit was consistent across all prespecified subgroups, including patients with brain metastases. • The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events (5.9%). [ABSTRACT FROM AUTHOR]

The introduction of trastuzumab and other subsequent human epidermal growth factor receptor 2 (HER2)–targeted therapies dramatically shifted the treatment landscape of HER2+ breast cancer, changing the natural history of the disease. There is no standard-of-care for patients with HER2+ metastatic breast cancer (MBC) in third and later lines of treatment; however, continued use of anti-HER2 therapies is recommended. Small-molecule tyrosine kinase inhibitors (TKIs) that target HER2 and other HER family receptors play a central role in this setting. TKIs have demonstrated various degrees of efficacy against central nervous system (CNS) metastases, which are a major clinical challenge for patients with HER2+ MBC. The TKIs lapatinib, neratinib, and tucatinib have received regulatory approval for the treatment of HER2+ MBC, while pyrotinib and afatinib have been evaluated in this setting. These TKIs vary by molecular weight, HER protein specificity and reversibility of binding and in turn have unique safety profiles. Toxicities reported in clinical trials of TKIs in HER2+ MBC that may require specific management strategies include diarrhoea, palmar–plantar erythrodysesthesia syndrome and rash. Here, we review the efficacy data, including CNS activity, and the safety profiles of the TKIs, and we provide guidance on adverse event management. Finally, we discuss how to incorporate the TKIs into the HER2+ MBC treatment algorithm. • TKIs that target HER proteins play a central role in the treatment of HER2+ MBC. • HER2-TKIs evaluated include lapatinib, neratinib, tucatinib, pyrotinib and afatinib. • The TKIs vary by molecular weight, HER specificity and reversibility of binding. • We review the efficacy and safety data for the TKIs. • We provide guidance on adverse event in the management of TKIs. [ABSTRACT FROM AUTHOR]

Advancements in monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates (ADCs) have notably enhanced outcomes for metastatic HER2-positive breast cancer patients. Despite the expanding treatment options and clinical complexities, determining the optimal sequence of HER2-targeted therapies remains partly uncertain, influenced by various factors. To refine HER2-positive metastatic breast cancer management, particularly regarding tucatinib's position, a Steering Committee of leading oncologists in breast cancer care devised a panel of statements via a Delphi approach, focusing on five key topics: general clinical management, therapeutic approaches for patients with HER2-positive breast cancer and brain metastases, treatment sequence, and tucatinib's safety and efficacy. A total of 29 statements were deliberated, with strong consensus achieved for most. However, no consensus emerged regarding the management of brain progression alongside stable extracranial disease: 48 % advocated for switching to tucatinib, while 53 % favored a stereotactic brain radiotherapy (SBRT) approach if feasible. 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. [ABSTRACT FROM AUTHOR]

In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB. Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3–9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit. Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm. HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases. NCT02614794 • HR-QoL was preserved in HER2+ metastatic breast cancer patients on a tucatinib regimen. • HR-QoL was preserved longer in patients with brain metastases taking tucatinib. • Preserved HR-QoL was in context of improved progression-free and overall survival. [ABSTRACT FROM AUTHOR]

Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. NCT01921335. • Phase I study of tucatinib and trastuzumab in patients with progressive HER2-positive breast cancer brain metastasis. • Two cohorts enrolled: cohort A, twice-daily (b.i.d.) tucatinib and cohort B, once-daily (q.d.) tucatinib. • The maximum tolerated dose of tucatinib was 300 mg p.o. b.i.d. in cohort A and 750 mg p.o. q.d. in cohort B. • The combination of tucatinib and trastuzumab was well tolerated. • We observed preliminary evidence of activity, including intracranial responses. [ABSTRACT FROM AUTHOR]

Approximately 30-50% of advanced HER2-positive breast cancer patients will develop central nervous system (CNS) metastases, with an annual risk of around 10%, and a half of them will die from brain progression. An increased risk of brain metastases is also seen in patients with early HER2-positive breast cancer administered curative therapy. Brain metastases in HER2-positive breast cancer patients usually constitute the first site of recurrence. The administration of anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, considerably delays the onset of symptomatic brain disease: however, the limited penetration of these compounds into the CNS hinders their efficacy. The small-molecule tyrosine kinase inhibitors of epidermal growth factor receptors family have established activity in HER2-positive breast cancer in both advanced disease and neoadjuvant setting. Favorable physico-chemical properties of these compounds allow them for a more efficient penetration through the blood-brain barrier, and hold the promise for more effective prevention and treatment of brain metastases. In this article we review the role of currently available or investigational HER2 tyrosine kinase inhibitors: lapatinib, neratinib, afatinib and tucatinib in the treatment of brain metastases in HER2-positive breast cancer patients. [ABSTRACT FROM AUTHOR]

• HER2 overexpression historically linked to poor prognosis in breast cancer. • However, the availability of active anti-HER2 compounds/combinations is evolving. • In HER2CLIMB, the tucatinib-containing combination improved overall survival. • The trial included patients with active brain metastases, an unmet need. • The review highlights tucatinib's journey from preclinical to clinical use. Approximately 20% of breast cancers (BCs) overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein with tyrosine kinase activity, encoded by ERBB2 gene. Historically, HER2 overexpression has been linked with increased disease recurrence and a worse prognosis. However, the increasing availability of different anti-HER2 compounds and combinations is progressively improving HER2-positive BC outcome, thus requiring expertise to prioritize both overall survival (OS) prolongation and quality of life, without neglecting the accessibility to further treatment lines with a low attrition rate. In this context, tucatinib, an oral tyrosine kinase inhibitor, has recently been granted approval by regulatory agencies based on evidence from the HER2CLIMB, a clinical trial which randomized patients with metastatic BC to receive trastuzumab and capecitabine with either tucatinib or placebo. A distinctive feature of this study was the inclusion of patients with new or active brain metastases (BMs) at study entry, a population traditionally excluded from clinical trials. Thus, HER2CLIMB provides the first solid evidence of an OS benefit in patients with BC and BMs, addressing a long standing unmet medical need, especially given the high incidence of central nervous system metastatic spread in patients with HER2-positive disease. This review provides an overview of the molecular and clinical landscape of tucatinib for the treatment of advanced BC. It focuses on the technological journey that drove the development of this therapeutic innovation, from preclinical data to clinical practice. [ABSTRACT FROM AUTHOR]

Tucatinib is known as a tyrosine kinase inhibitor (TKI), which has been commonly approved for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer. However, there haven't been systematic study about the inhibition of tucatinib on UDP-Glucuronosyltransferases (UGTs) and the potential risk of drug-drug interactions (DDIs). In present study, we aimed to systematically investigate the inhibition of tucatinib on recombinant human UGTs and pooled human liver microsomes (HLMs), and to quantitatively evaluate its potential risk of DDIs by in vitro-in vivo extrapolation (IVIVE). Our data indicated that tucatinib exhibited extensive inhibition on recombinant UGTs. Tucatinib was a weak inhibitor of UGT1A4, 2B4 and 2B7; tucatinib possessed a strong inhibitory effect on UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B15 and UGT2B17, with IC 50 values of 0.53 μM–15.50 μM. Especially, it also potently inhibited estradiol and SN-38 glucuronidation in HLMs with IC 50 values of 46.83 μM and 1.33 μM. The quantitative prediction of DDIs risk indicated that the co-administration of tucatinib with drugs mainly metabolized by hepatic or intestinal UGTs (UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B15 and UGT2B17) might result in potential DDIs risk through inhibition of glucuronidation. More attention should be paid to the influence of tucatinib on UGTs in liver and intestine to avoid unnecessary clinical DDIs risk. [Display omitted] • Tucatinib is an extensive inhibitor of UGTs. • Tucatinib may bring potential risk of DDIs via the inhibition of UGTs activities. • The combination of tucatinib and UGTs substrates might cause high risk of DDIs. [ABSTRACT FROM AUTHOR]

[Display omitted] • [11C]tucatinib was designed and synthesized as a HER2 PET imaging agent • The compound was obtained in a 12 steps synthetic route • [11C]tucatinib was obtained in good radiochemical yield and high radiochemical purity • [11C]tucatinib showed high liver and intestinal uptake and low tumor uptake • Modifications of [11C]tucatinib are required to obtain a successful HER2 PET tracer Tucatinib is a selective human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) in April 2020 for HER2-positive lesions in metastatic breast cancer patients, including CNS metastases. In this article, we attempted to develop the first small molecule, blood–brain-barrier (BBB) penetrant HER2 PET imaging probe based on tucatinib. [11C]tucatinib was synthesized via a Stille-coupling from the respective trimethylstannyl precursor and its biodistribution was evaluated in NMRI nude mice bearing HER2-overexpressing human ovarian cancer cells (SKOV-3). No significant tumor accumulation was observed despite its high affinity for HER-2 receptors (IC 50 = 6.9 nM). High liver and intestinal uptake indicate that [11C]tucatinib is too lipophilic to be used as a tumor targeting PET tracer. Therefore, chemical modifications of [11C]tucatinib are needed to increase the polarity for tumor imaging. Tucatinib as an FDA approved drug is still an interesting platform to develop the first small molecule HER2-selective PET tracer. The study highlights the differences between a drug, which needs to be effective, and an imaging agent, which is dependent on contrast. [ABSTRACT FROM AUTHOR]

[Display omitted] • Brain metastases are a frequent complication of HER2-positive breast cancer. • Treatment options include surgery, radiation and systemic therapy. • Trastuzumab plus pertuzumab, trastuzumab-emtansine and lapatinib are widely used. • Novel HER2-targeted agents recently showed promising activity against brain metastases. Brain metastases (BMs) are frequently associated with HER2+ breast cancer (BC). Their management is based on a multi-modal strategy including both local treatment and systemic therapy. Despite therapeutic advance, BMs still have an adverse impact on survival and quality of life and the development of effective systemic therapy to prevent and treat BMs from HER2 + BC represents an unmet clinical need. Trastuzumab-based therapy has long been the mainstay of systemic therapy and over the last two decades other HER2-targeted agents including lapatinib, pertuzumab and trastuzumab emtansine, have been introduced in the clinical practice. More recently, novel agents such as neratinib, tucatinib and trastuzumab deruxtecan have been developed, with interesting activity against BMs. Further research is needed to better elucidate the best sequence of these agents and their combination with local treatment. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 positive (HER2+) advanced breast cancer (ABC) accounts for about 15–20% of all ABC cases. Large randomized trials have determined the standard first- and second-line treatments for this subgroup of patients, namely dual blockade plus chemotherapy and TDM1. However, no standard treatment is specifically recommended after TDM1, and most of the subsequent therapeutic choices commonly rely on old trials not optimally reflecting the current patient population. The recent FDA-approval of three novel anti-HER2 compounds is revolutionizing the field. In particular, trastuzumab deruxtecan was approved after showing unprecedented activity in a phase 2 trial for highly pretreated HER2+ ABC patients; tucatinib and neratinib were approved based on the results of the randomized HER2CLIMB and NALA trial, respectively. With an increasing arsenal of treatment options, clinical decision-making will need to take into account a variety of aspects, including differences in clinical trial designs, outcomes and toxicity profile of each drug, patient's characteristics and preferences. [ABSTRACT FROM AUTHOR]