Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer.

Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood-brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.

Enhanced anti-tumor effects by combination of tucatinib and radiation in HER2-overexpressing human cancer cell lines.

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.

Cost in the United States of FDA-approved small molecule protein kinase inhibitors used in the treatment of neoplastic and non-neoplastic diseases.

Because genetic alterations including mutations, overexpression, translocations, and dysregulation of protein kinases are involved in the pathogenesis of many illnesses, this enzyme family is the target of many drug discovery programs worldwide. The FDA has approved 80 small molecule protein kinase inhibitors with 77 drugs orally bioavailable. The data indicate that 69 of these medicinals are approved for the management of neoplasms including solid tumors such as breast and lung cancer as well as non-solid tumors such as leukemia. Moreover, the remaining 11 drugs target non-neoplastic diseases including psoriasis, rheumatoid arthritis, and ulcerative colitis. The cost of drugs was obtained from www.pharmacychecker.com using the FDA label to determine the dosage and number of tablets required per day. This methodology excludes any private or governmental insurance coverage, which would cover the entire cost or more likely a fraction of the stated price. The average monthly cost for the treatment of neoplastic diseases was $17,900 with a price of $44,000 for futibatinib (used to treat cholangiocarcinomas with FGFR2 fusions) and minimum of $5100 for binimetinib (melanoma). The average monthly cost for the treatment of non-neoplastic diseases was $6800 with a maximum of $17,000 for belumosudil (graft vs. host disease) and a minimum of $200 for netarsudil eye drops (glaucoma). There is a negative correlation of the cost of the drugs and the incidence of the targeted disease. Many of these agents are or were designated as orphan drugs meaning that there are fewer than 200,000 potential patients in the United States.

HER2-Positive Metastatic Colorectal Cancer.

OPINION STATEMENT: Targeted treatment strategies are available for human epidermal growth factor receptor 2 (HER2)-positive (amplified and/or overexpressed) metastatic colorectal cancer (mCRC), and HER2 testing is indicated in patients with mCRC. 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. HER2-targeted agents should be considered for those with RAS/BRAF wild-type disease in subsequent-line treatment and in first-line treatment for patients not appropriate for intensive therapy. 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. As T-DXd has demonstrated activity following treatment with other HER2-targeted regimens and carries an increased risk of high-grade toxicities, the authors favor reserving it for use after progression on prior anti-HER2 therapy. HER2-targeted therapies that inhibit signal transduction appear to have limited activity in those with RAS mutations, including trastuzumab-containing regimens. However, the antibody drug conjugate T-DXd has some data showing efficacy in this setting, and the authors would consider T-DXd in subsequent-line therapy for HER2-positive, RAS-mutated mCRC. Several areas of uncertainty remain regarding how to best utilize HER2-targeted therapies in mCRC. 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.

Tucatinib and stereotactic radiosurgery in the management of HER2 positive breast cancer brain metastases.

PURPOSE: HER2-positive breast cancer has a high risk of brain metastasis. Stereotactic radiosurgery (SRS) is standard of care for limited brain metastases. Tucatinib, a HER2-targeted tyrosine kinase inhibitor, has demonstrated intracranial efficacy in the HER2-CLIMB Trial. However, it is unknown whether tucatinib with SRS is safe or effective. METHODS: A retrospective analysis of HER2-positive breast cancer treated with SRS and tucatinib for brain metastases management was performed. All patients received tucatinib and SRS for the management of active brain metastases. The primary endpoint was local and distant brain tumor control. Secondary endpoints were intracranial progression free survival (CNS-PFS), systemic PFS, overall survival (OS), and neurotoxicity. RESULTS: A total of 135 lesions treated with SRS over 39 treatment sessions in 22 patients were identified. Median follow-up from tucatinib initiation was 20.8 months. Local brain control was 94% at 12-months and 81% at 24-months. Distant brain control was 39% at 12-months and 26% at 24-months. Median survival was 21.2 months, with 12- and 24-month OS rates of 84% and 50%, respectively. Median CNS-PFS was 11.3 months, with 12- and 24-month CNS-PFS rates of 44.9% at both time points. Median systemic PFS was not reached, with 12- and 24-month systemic PFS rates of 86% and 57%, respectively. Symptomatic radiation necrosis occurred in 6 (4%) lesions. No additional unexpected toxicities were noted. CONCLUSIONS: SRS in combination with tucatinib, capecitabine, and trastuzumab appears to be a safe and feasible treatment for HER2 + brain metastases. Further prospective evaluation of potential synergistic effects is warranted.

Synthesis and in vivo evaluation of [11C]tucatinib for HER2-targeted PET imaging.

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 (IC50 = 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.

Metastatic HER2-Positive Breast Cancer: Is There an Optimal Sequence of Therapy?

OPINION STATEMENT: Approximately 20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2+), conferring a particularly aggressive subtype of the disease with an increased risk for the development of systemic and brain metastases. However, the advent of trastuzumab and more recently several other HER2-targeting novel therapies has led to significant improvements in the prognosis, making the diagnosis a "double-edged sword." The current standard first-line therapy for patients with HER2+ metastatic breast cancer (MBC) is a taxane combined with trastuzumab and pertuzumab. Trastuzumab deruxtecan should be used preferentially in the second line, with the only caveat being patients with CNS involvement where the tucatinib, capecitabine, and trastuzumab regimen could be considered. In the third line setting, given the survival benefits demonstrated with the tucatinib regimen in patients with and without CNS metastases, this is the preferred strategy. In the fourth line and beyond, there is no clear standard. Options include margetuximab in combination with chemotherapy, neratinib + capecitabine, or trastuzumab + chemotherapy. There are several novel therapies under investigation reporting promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, with several active therapies being moved to the early-stage setting. Accordingly, it will be critical to identify biomarkers and mechanisms of resistance to optimize therapy selection and maximize patient outcomes and quality of life. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer and address the specific scenarios which may impact treatment selection including triple-positive breast cancer and the presence of brain metastases. Finally, we highlight promising novel treatments and ongoing trials that may impact future treatment sequencing.

Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

Efficacy and safety of HER2-targeted inhibitors for metastatic colorectal cancer with HER2-amplified: A meta-analysis.

OBJECTIVE: To systematically evaluate the efficacy and safety of human epidermal growth factor receptor 2 (HER2)-targeted inhibitors for metastatic colorectal cancer (mCRC) with HER2-amplified. METHOD: A systematic search of PubMed, Embase, Cochrane Library, Wan fang, VIP, and the CNKI database was conducted for literature published up to 28 February 2022 on the use of HER2-targeted inhibitors in the treatment of HER2-amplified mCRC. The retrieved articles were screened to determine the final inclusion of literature and extract relevant data, including the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of serious adverse events (SAEs) (grade ≥3AEs). In our study, we used merging ratios, means, and 95% confidence intervals (CIs) to describe the efficacy and safety of HER2-targeted inhibitors when treating HER2-amplified mCRC. RESULTS: The meta-analysis included 8 single-arm clinical trials comprising 258 patients with HER2-amplified mCRC who received second-line or above treatment. In our meta-analysis of mCRC treated with HER2-targeted inhibitors, the ORR and DCR were respectively 29% (95% CI 20-40) and 71% (95% CI 63-78). The median PFS (mPFS) and median OS (mOS) were respectively 4.89 months (95% CI 3.82-5.97) and 13.04 months (95% CI 9.45-16.62). The incidence of SAEs was 12% (95% CI 3-25). CONCLUSIONS: As the second-line or above treatment, HER2-targeted inhibitors have exhibited good antitumor efficacy and safety in HER2-amplified mCRC patients. Treatment patterns in clinically relevant subpopulations of mCRC patients can be possibly changed using HER2-targeted therapeutic strategies.

New anti-HER2 agents for brain metastasis: histology-agnostic weapons?

Besides predicting responsiveness to anti-HER2 agents, HER2 aberrations are associated with a high incidence of central nervous system (CNS) metastasis across several cancer types, including breast, lung, gastric and colorectal cancer. In this setting, several novel anti-HER2 agents with relevant CNS activity are emerging, including tucatinib and trastuzumab deruxtecan. Both agents are already FDA-approved for treating advanced breast cancer, but are also being tested for the treatment of other HER2-driven histologies. The confirmation of their activity in other cancer types may provide histology-agnostic weapons against HER2-driven brain metastasis, possibly improving the prognosis of a wide population of cancer patients.

Trastuzumab-induced cardiotoxicity: a review of clinical risk factors, pharmacologic prevention, and cardiotoxicity of other HER2-directed therapies.

PURPOSE: Despite great success as a targeted breast cancer therapy, trastuzumab use may be complicated by heart failure and loss of left ventricular contractile function. This review summarizes the risk factors, imaging, and prevention of cardiotoxicity associated with trastuzumab and other HER2-targeted therapies. FINDINGS: Cardiovascular disease risk factors, advanced age, and previous anthracycline treatment predispose to trastuzumab-induced cardiotoxicity (TIC), with anthracycline exposure being the most significant risk factor. Cardiac biomarkers such as troponins and pro-BNP and imaging assessments such as echocardiogram before and during trastuzumab therapy may help in early identification of TIC. Initiation of beta-adrenergic antagonists and angiotensin converting enzyme inhibitors may prevent TIC. Cardiotoxicity rates of other HER2-targeted treatments, such as pertuzumab, T-DM1, lapatinib, neratinib, tucatinib, trastuzumab deruxtecan, and margetuximab, appear to be significantly lower as reported in the pivotal trials which led to their approval. CONCLUSIONS: Risk assessment for TIC should include cardiac imaging assessment and should incorporate prior anthracycline use, the strongest risk factor for TIC. Screening and prediction of cardiotoxicity, referral to a cardio-oncology specialist, and initiation of effective prophylactic therapy may all improve prognosis in patients receiving HER2-directed therapy. Beta blockers and ACE inhibitors appear to mitigate risk of TIC. Anthracycline-free regimens have been proven to be efficacious in early HER2-positive breast cancer and should now be considered the standard of care for early HER2-positive breast cancer. Newer HER2-directed therapies appear to have significantly lower cardiotoxicity compared to trastuzumab, but trials are needed in patients who have experienced TIC and patients with pre-existing cardiac dysfunction.

Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update.

Owing to the dysregulation of protein kinase activity in many diseases including cancer, the protein kinase enzyme family has become one of the most important drug targets in the 21st century. There are 62 FDA-approved therapeutic agents that target about two dozen different protein kinases and eight of these were approved in 2020. All of the FDA-approved drugs are orally effective with the exception of netarsudil (a ROCK1/2 non-receptor protein-serine/threonine kinase antagonist given as an eye drop for the treatment of glaucoma) and temsirolimus (an indirect mTOR inhibitor given intravenously for the treatment of renal cell carcinoma). Of the approved drugs, ten target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), thirteen block non-receptor protein-tyrosine kinases, and 35 target receptor protein-tyrosine kinases. The data indicate that 55 of these drugs are prescribed for the treatment of neoplasms (52 against solid tumors including breast, lung, and colon, nine against non-solid tumors such as leukemias, and four against both solid and non-solid tumors: acalabrutinib, ibrutinib, imatinib, and midostaurin). A total of three drugs (baricitinib, tofacitinib, upadacitinib) is used for the treatment of inflammatory diseases including rheumatoid arthritis. Seven of the approved drugs form covalent bonds with their target enzymes and are classified as TCIs (targeted covalent inhibitors). Of the 62 approved drugs, eighteen are used in the treatment of multiple diseases. Imatinib, for example, is approved for the treatment of eight different disorders. The most common drug targets of the approved pharmaceuticals include BCR-Abl, B-Raf, vascular endothelial growth factor receptors (VEGFR), epidermal growth factor receptors (EGFR), and ALK. The following eight drugs received FDA approval in 2020 for the treatment of the specified diseases: avapritinib and ripretinib (gastrointestinal stromal tumors), capmatinib (non-small cell lung cancer), pemigatinib (cholangiocarcinoma), pralsetinib and selpercatinib (non-small cell lung cancer, medullary thyroid cancer, differentiated thyroid cancer), selumetinib (neurofibromatosis type I), and tucatinib (HER2-positive breast cancer). All of the eight drugs approved in 2020 fulfill Lipinski's rule of five criteria for an orally effective medicine (MW of 500 Da or less, five or fewer hydrogen bond donors, 10 or fewer hydrogen bond acceptors, calculated log10 of the partition coefficient of five or less) with the exception of three drugs with a molecular weight greater that 500 Da: pralsetinib (534), selpercatinib (526) and ripretinib (510). This review summarizes the physicochemical properties of all 62 FDA-approved small molecule protein kinase inhibitors.

Alliance A011801 (compassHER2 RD): postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer.

This report describes the rationale, purpose and design of A011801 (CompassHER2 RD), an ongoing prospective, multicenter, Phase III randomized trial. Eligible patients in the United States (US) and Canada with high-risk (defined as ER-negative and/or node-positive) HER2-positive (HER2+) residual disease (RD) after a predefined course of neoadjuvant chemotherapy and HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 and placebo, versus T-DM1 and tucatinib. Patients have also received adjuvant radiotherapy and/or endocrine therapy, if indicated per standard of care guidelines. The primary objective of the trial is to determine if the invasive disease-free survival (iDFS) with T-DM1 plus tucatinib is superior to iDFS with T-DM1 plus placebo; other outcomes of interest include overall survival (OS), breast cancer-free survival (BCFS), distant recurrence-free survival (DRFS), brain metastases-free survival (BMFS) and disease-free survival (DFS). Correlative biomarker, quality of life (QoL) and pharmacokinetic (PK) end points are also evaluated.

Lay abstract In this research study (A011801; CompassHER2 RD), patients with early stage HER2-positive breast cancer who already received treatment with chemotherapy and anti-HER2 targeted therapies followed by surgery are mainly enrolled. If cancer is still present in the breast and/or lymph nodes at the time of surgery, there is a higher risk of a recurrence in the future, and enrollment on A011801 is an option. Usually, if there is tumor remaining after chemotherapy and anti-HER2 targeted therapies, the main treatment is the use of an FDA-approved intravenous drug called T-DM1. Additional treatment may also include radiotherapy and/or medications to block the activity of estrogen. The usual treatment approach reduces the likelihood of breast cancer recurring in the future. This study has been performed to answer the following question: Is the combination of T-DM1 and a newer drug tucatinib better than usual treatment with T-DM1 alone at preventing cancer from returning? Study participants will receive treatment with T-DM1 and placebo (a pill that looks like the study drug but contains no medication) or T-DM1 and tucatinib, for up to 14 cycles, unless their breast cancer returns or the side effects become too severe. Research bloods are taken on study along with standard blood work, and we also request a stored tumor sample from the original biopsy and from the breast cancer surgery for research purposes. Optional Quality of Life Questionnaires are also included in the trial. After the study, participants finish T-DM1 and placebo, or T-DM1 and tucatinib, and their doctor will continue to follow their condition with clinic visits every 6 months for 10 years and watch for side effects and for signs of breast cancer recurring. Clinical Trial Registration: NCT04457596 (ClinicalTrials.gov).

Application of Tucatinib and Trastuzumab: Dual Anti HER2 Therapy Against HER2 Positive Breast Cancer.

Synergism in action of tucatinib and trastumab is reported in breast cancer management. However, its molecular basis is yet to be determined. In this context we attempted to provide an explanation at the molecular level by performing in silico experimentation and coupling its result with already available published observations. Our study will provide basis for planning further experimental study for unravelling the truth.

Novel HER2-targeted therapies for HER2-positive metastatic breast cancer.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of all breast cancers. Before the development of HER2-directed monoclonal antibodies, HER2-positive breast cancer was associated with a rather poor prognosis. With the advent of monoclonal HER2-targeting antibodies (trastuzumab and pertuzumab) and antibody-drug conjugates (trastuzumab emtansine [T-DM1] and trastuzumab deruxtecan), clinical outcomes for HER2-positive breast cancer have dramatically changed, and a greater proportion of patients in the nonmetastatic setting are cured. However, in the metastatic setting, resistance to anti-HER2 treatments still remains a major therapeutic challenge, underscoring the importance of developing novel HER2-directed therapies. Over the last year, there has been a dramatic shift in the current treatment paradigms for HER2-positive metastatic breast cancer, with recent U.S. Food and Drug Administration approvals of trastuzumab deruxtecan (DS-8201), neratinib, and tucatinib in combination with trastuzumab and capecitabine. The authors summarize recent phase 3 data with novel HER2-targeted therapies as well as phase 1 and 2 data with other novel HER2-targeting agents.

Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases.

BACKGROUND: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSION: The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. CLINICAL TRIAL REGISTRATION: NCT01921335.

Anti-HER2 therapy for breast cancer in older patients.

Older patients now form between 30 and 40% of breast cancer (BC) patients. Managing older patients with BC is particularly challenging due to the limited availability of high-quality evidence. In this review we discuss the available evidence on the efficacy and safety of anti-HER2 agents in older patients with HER2-positive BC is presented, with a particular look at the latest results of promising new agents such trastuzumab-deruxtecan. The data suggest that older patients can expect similar efficacy when using standard regimens, with higher toxicity, particular cardiac toxicity and diarrhea. Anti-HER2 agents should thus be used in most older patients most as per standard of care as long as adequate follow-up is available to manage toxicities.

Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases.

In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop metastases to the bone, liver, lung, or brain. Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative. Within the realm of chemotherapy, the last decade has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms. We provide a historical overview of BCBM chemotherapy, review the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM; tyrosine kinase inhibitors, antibodies, and conjugates for HER2+ BCBM; repurposed cytotoxic chemotherapy for triple negative BCBM; and the utilization of these new agents and formulations in ongoing clinical trials. The mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials are also discussed. These new treatments provide a promising outlook in the treatment of BCBM.

"Positioning of tucatinib in the new clinical scenario of HER2-positive metastatic breast cancer: An Italian and Spanish consensus paper".

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Telangiectasias induced by combination tucatinib and ado-trastuzumab emtansine in a patient with metastatic breast cancer.

BACKGROUND: Tucatinib is a tyrosine kinase inhibitor currently used in salvage therapy for human epidermal growth factor receptor 2 (HER2)-positive breast and colorectal cancer. The use of tucatinib alone or in combination with ado-trastuzumab emtansine (T-DM1) in the treatment of advanced HER2-positive cancers is rapidly expanding. OBJECTIVE/METHODS: We report the case of a 66-year-old female who presented to the dermatology clinic with a one-year history of widespread telangiectasias that began after initiation of combination chemotherapy with tucatinib and T-DM1 for metastatic HER2-positive invasive ductal carcinoma. RESULTS: The patient's lesions regressed upon cessation of combination therapy and reappeared in the setting of tucatinib re-initiation, with gradual improvement over the following four months following electrocautery to the affected regions. CONCLUSIONS: 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.