-
Oncology and Therapy Dec 2023Many patients with human epidermal growth factor receptor-2-positive metastatic breast cancer (HER2+ mBC) require subsequent lines of therapy (LOTs) after being...
INTRODUCTION
Many patients with human epidermal growth factor receptor-2-positive metastatic breast cancer (HER2+ mBC) require subsequent lines of therapy (LOTs) after being treated with pertuzumab and trastuzumab-based regimens in the first line (1L). Although the efficacy of the second-line (2L) therapies has been demonstrated in clinical trials, the real-world effectiveness of these treatments is understudied. This retrospective cohort study assessed the real-world treatment patterns and outcomes for patients with HER2+ mBC following 1L therapy with pertuzumab and trastuzumab-based regimens in the United States (US) during 2015-2019.
METHODS
Adults with HER2+ mBC in the US who initiated 1L pertuzumab and trastuzumab-based regimens between 01/01/2015 and 09/30/2019 and had ≥ 60 days of follow-up after 1L initiation were identified from the IQVIA Oncology Electronic Medical Records database. The regimens utilized in 2L following 1L pertuzumab and trastuzumab-based regimens were described. Median treatment duration and time to treatment failure were reported for 2L based on Kaplan-Meier analyses.
RESULTS
Of the 710 eligible patients who received pertuzumab and trastuzumab-based regimens in 1L (median age: 57.0 years [interquartile range: 48.0-65.0]; median follow-up: 20.3 months; median 1L duration: 15.3 months), 222 (31.3%) initiated 2L. The most common regimens in 2L were ado-trastuzumab emtansine (T-DM1)-based regimens (n = 159 [71.6%]), followed by lapatinib-based (n = 21 [9.5%]) and neratinib-based (n = 18 [8.1%]) regimens. The median treatment duration and time to treatment failure were 5.9 (95% CI: 5.0, 8.7) and 8.6 (7.3, 11.5) months, respectively, among patients initiating 2L, and 5.7 (4.7, 7.8) and 7.9 (6.5, 10.0) months among those receiving 2L T-DM1.
CONCLUSIONS
Most patients with HER2+ mBC requiring additional treatments after 1L pertuzumab and trastuzumab-based regimens utilized T-DM1 in 2L during 2015-2019. The short median treatment duration and time to treatment failure highlight an unmet need that can potentially be fulfilled by recently approved treatment options.
PubMed: 37715853
DOI: 10.1007/s40487-023-00241-8 -
BMC Pharmacology & Toxicology Nov 2023Pertuzumab is widely used for the treatment of HER2 + breast cancer. But its safety in the real world should be continuously monitored. So, we evaluated the safety...
BACKGROUND
Pertuzumab is widely used for the treatment of HER2 + breast cancer. But its safety in the real world should be continuously monitored. So, we evaluated the safety of pertuzumab by pharmacovigilance analyze based on related adverse events (AEs) from the FDA Adverse Event Reporting System (FAERS) and find whether potential or uncertain adverse events were present.
METHODS
In disproportionality analysis, four algorithms were employed to detect the signals of pertuzumab from the FAERS between 2012 and 2022. In addition, we also used MYSQL 8.0, Navicat Premium 15, and Microsoft EXCEL 2019 to analyze the potential and high-ROR (reporting odds ratio) signals of pertuzumab. We also collected the onset times of pertuzumab-associated AEs.
RESULTS
From January 2012 to December 2022, there are 39,190,598 AEs reported from the FAERS database, of which 14,707 AEs listed pertuzumab as the 'primary suspected (PS)' drug. A total of 115 (46 potential) significant disproportionality preferred terms (PTs) conforming to the four algorithms were retained. Finally, we detected that the pertuzumab-induced AEs occurred in 12 organ systems. For pertuzumab, unexpected and significant PTs of AEs were found, including but not limited to below PTs: haematotoxicity, cardiotoxicity, cardiomyopathy, mitral valve incompetence, tachycardia, intestinal perforation, hemorrhoids, erysipelas, dehydration, pneumonitis, skin toxicity, onychomadesis, cyanosis, and circulatory collapse. We found there were 9 strong signals (5 potential safety signals) and 68 medium intensity signals (21 potential safety signals) according to IC (information component). The potential strong signals (IC > 3.0) were myelosuppression, cardiotoxicity, cardiac dysfunction, ejection fraction decreased, interstitial lung disease, and onychomadesis. Excluding unreported or unreasonable onset time reports, a total of 2016 AEs reported onset time and the median onset time was 117 days (4, 96), as median (Q1, Q3). Notably, most of the all AEs (n = 1133, 56%) and cardiac-related events (n = 405, 53%) all occurred within one month after pertuzumab therapy.
CONCLUSION
Analysis of FAERS data identified pertuzumab-associated AEs, and our findings supported continuous clinical monitoring, pharmacovigilance, and further studies of pertuzumab. A significant association was detected between pertuzumab and some potential adverse events which should be regarded with some care. We have to pay attention to the first month after pertuzumab therapy and prepare emergency measures, especially for the elderly and patients with cardiovascular diseases.
Topics: Humans; Aged; Female; Cardiotoxicity; Adverse Drug Reaction Reporting Systems; Antibodies, Monoclonal, Humanized; Pharmacovigilance; Breast Neoplasms
PubMed: 37957717
DOI: 10.1186/s40360-023-00702-w -
International Journal of Molecular... Jul 2023The binding affinity of trastuzumab and pertuzumab to HER2 has been studied using both experimental and in silico methods. The experiments were conducted using the...
The binding affinity of trastuzumab and pertuzumab to HER2 has been studied using both experimental and in silico methods. The experiments were conducted using the antibodies in their complete IgG form, as used in clinical therapy, and the extracellular domain of the HER2 protein in solution. This approach provides a precise, reproducible, and reliable view of the interaction between them in physicochemical conditions similar to those found in the tumoral environment. Dynamic light scattering and size exclusion chromatography coupled with tetra detection were utilized to characterize the protein complexes, measure their concentrations, and calculate the equilibrium-free binding energy, ΔG. In addition, PRODIGY, a QSAR-like model with excellent predictive ability, was employed to obtain in silico ΔG estimations. The results obtained indicate that pertuzumab exhibits a slightly higher binding affinity to HER2 than trastuzumab. The difference in binding affinity was explained based on the contribution of the different interfacial contact (IC) descriptors to the ΔG value estimated by the PRODIGY model. Furthermore, experiments revealed that the pertuzumab IgG antibody binds preferentially to two HER2 proteins, one per Fab fragment, while trastuzumab mainly forms a monovalent complex. This finding was interpreted based on a geometrical model that identified steric crowding in the trastuzumab-HER2 complex as compared with the pertuzumab-HER2 complex.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Receptor, ErbB-2; Trastuzumab
PubMed: 37569408
DOI: 10.3390/ijms241512031 -
Biomolecules Dec 2023Intact Transition Epitope Mapping-One-step Non-covalent force Exploitation (ITEM-ONE) analysis reveals an assembled epitope on the surface of Pertuzumab, which is...
Intact Transition Epitope Mapping-One-step Non-covalent force Exploitation (ITEM-ONE) analysis reveals an assembled epitope on the surface of Pertuzumab, which is recognized by the anti-Pertuzumab affimer 00557_709097. It encompasses amino acid residues NSGGSIYNQRFKGR, which are part of CDR2, as well as residues FTLSVDR, which are located on the variable region of Pertuzumab's heavy chain and together form a surface area of 1381.46 Å. Despite not being part of Pertuzumab's CDR2, the partial sequence FTLSVDR marks a unique proteotypic Pertuzumab peptide. Binding between intact Pertuzumab and the anti-Pertuzumab affimer was further investigated using the Intact Transition Epitope Mapping-Thermodynamic Weak-force Order (ITEM-TWO) approach. Quantitative analysis of the complex dissociation reaction in the gas phase afforded a quasi-equilibrium constant (KD m0g#) of 3.07 × 10. The experimentally determined apparent enthalpy (ΔHm0g#) and apparent free energy (ΔGm0g#) of the complex dissociation reaction indicate that the opposite reaction-complex formation-is spontaneous at room temperature. Due to strong binding to Pertuzumab and because of recognizing Pertuzumab's unique partial amino acid sequences, the anti-Pertuzumab affimer 00557_709097 is considered excellently suitable for implementation in Pertuzumab quantitation assays as well as for the accurate therapeutic drug monitoring of Pertuzumab in biological fluids.
Topics: Epitope Mapping; Epitopes; Antibodies, Monoclonal, Humanized; Thermodynamics
PubMed: 38254624
DOI: 10.3390/biom14010024 -
NPJ Breast Cancer Nov 2023The PATRICIA study (NCT02536339) examined the efficacy and safety of pertuzumab plus high-dose trastuzumab in patients with HER2-positive metastatic breast cancer (MBC)...
The PATRICIA study (NCT02536339) examined the efficacy and safety of pertuzumab plus high-dose trastuzumab in patients with HER2-positive metastatic breast cancer (MBC) with progressive central nervous system (CNS) metastases following radiotherapy. Primary analysis confirmed CNS objective response rate (ORR) was 11% (95% confidence interval [CI]: 3-25); clinical benefit rate (CBR) was 68% (4 months) and 51% (6 months). We report final efficacy data after a further 21-months of follow-up, updated safety, survival, and patient-reported outcomes (PROs). Patients received standard-dose pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Primary endpoint: confirmed ORR (CNS) per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary endpoints were response duration, CBR, progression-free survival (PFS), overall survival (OS), safety, and PROs. By clinical cut-off, 39 patients had completed or discontinued treatment. Confirmed ORR (CNS) was 11% (95% CI: 3.0-25.4). Median CNS-PFS was 4.6 months (95% CI: 4.0-8.9), as was median CNS-PFS or systemic PFS (95% CI: 4.0-8.9); median OS was 27.2 months (95% CI: 16.1-not reached). CBR in the CNS was 51% (19 patients, 95% CI: 34.4-68.1) at 6 months. Two patients remained on treatment until study closure, achieving stable disease for 4.1 and 4.8 years. Treatment-related grade 3/4 adverse events occurred in 7.7% of patients. Patients with confirmed partial response or stable disease (≥4 months) in the CNS had stable PROs over time. Pertuzumab plus high-dose trastuzumab represents a reasonable non-chemotherapeutic treatment option for selected patients with HER2-positive MBC with CNS metastases.
PubMed: 37978197
DOI: 10.1038/s41523-023-00587-2 -
Frontiers in Immunology 2022Human epidermal growth factor receptor 2 (HER2)-positive breast cancer has a high metastatic potential. Monoclonal antibodies (mAbs) that target HER2, such as... (Review)
Review
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer has a high metastatic potential. Monoclonal antibodies (mAbs) that target HER2, such as trastuzumab and pertuzumab, are the cornerstone of adjuvant therapy for HER2-positive breast cancer. A growing body of preclinical and clinical evidence points to the importance of innate immunity mediated by antibody-dependent cellular cytotoxicity (ADCC) in the clinical effect of mAbs on the resulting anti-tumor response. In this review, we provide an overview of the role of natural killer (NK) cells and ADCC in targeted therapy of HER2-positive breast cancer, including the biological functions of NK cells and the role of NK cells and ADCC in anti-HER2 targeted drugs. We then discuss regulatory mechanisms and recent strategies to leverage our knowledge of NK cells and ADCC as an immunotherapy approach for HER2-positive breast cancer.
Topics: Humans; Female; Breast Neoplasms; Antibody-Dependent Cell Cytotoxicity; Trastuzumab; Killer Cells, Natural; Antibodies, Monoclonal; Immunotherapy
PubMed: 36601109
DOI: 10.3389/fimmu.2022.1083462 -
Journal of Clinical Pharmacology Aug 2021PERJETA (pertuzumab), administered with Herceptin (trastuzumab), is used in the treatment of human epidermal growth factor receptor 2-positive breast cancer. Pertuzumab...
PERJETA (pertuzumab), administered with Herceptin (trastuzumab), is used in the treatment of human epidermal growth factor receptor 2-positive breast cancer. Pertuzumab is currently approved with an initial loading dose of 840 mg, followed by a 420-mg maintenance dose intravenously every 3 weeks. A reloading dose is required if there is a ≥6-week delay in treatment. In response to the potential treatment disruption due to COVID-19, the impact of dose delays and alternative dosing regimens on intravenous pertuzumab for human epidermal growth factor receptor 2-positive breast cancer treatment is presented. Simulations were conducted by using the validated population pharmacokinetic model for pertuzumab, and included (1) 4-, 6-, and 9-week dose delays of the 840 mg/420 mg every 3 weeks dosing regimen and (2) 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks alternative dosing regimens. Simulations were compared with the currently approved pertuzumab dosing regimen. The simulations in 1000 virtual patients showed that a dose reload (840 mg) is required following a dose delay of ≥6 weeks to maintain comparable C (lowest concentration before the next dose is given) levels to clinical trials. The 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks alternative dosing regimens decrease median steady-state C by ≈40% compared with the approved regimen, and <90% of patients will be above the target C . Thus, the alternative 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks pertuzumab dosing regimens are not recommended. Flexibility for intravenous PERJETA-based regimens is available with an alternative route of pertuzumab administration (subcutaneous vs intravenous).
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; COVID-19; Computer Simulation; Consolidation Chemotherapy; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Female; Humans; Infection Control; Maintenance Chemotherapy; Receptor, ErbB-2; SARS-CoV-2; Time-to-Treatment; Trastuzumab
PubMed: 33719071
DOI: 10.1002/jcph.1855 -
British Journal of Cancer Nov 2023Multiple drug treatments are approved for invasive breast cancer (IBC). We investigated uptake of NICE-recommended oncological drugs and variation by age, comorbidity...
BACKGROUND
Multiple drug treatments are approved for invasive breast cancer (IBC). We investigated uptake of NICE-recommended oncological drugs and variation by age, comorbidity burden and geographical region.
METHODS
Women (aged 50+ years) diagnosed with IBC from 2014 to 2019, were identified from England Cancer Registry data and drug utilisation from Systemic Anti-Cancer Therapy data. Interrupted time series analysis assessed national-level changes in drug use after publication of NICE recommendations. Regression models analysed variation in use.
RESULTS
This national cohort included 168,449 women. Use of drugs recommended for first-line treatment varied, from 26.6% for CDK 4/6 inhibitors to 63.8% for HER2-targeting therapies. Utilisation of drugs with a NICE recommendation published between 2014 and 2019, increased among patients diagnosed around the time of publication, except in the case of pertuzumab for metastatic breast cancer (MBC) which was previously accessible via the Cancer Drugs Fund (though use of pertuzumab for MBC increased from 34.1% to 75.0% across the study period). Use of trastuzumab and neoadjuvant/adjuvant pertuzumab varied by geographical region. Use was low for ribociclib (2.2%), abemaciclib (2.3%) and for drugs recommended beyond the first-line setting. For all drugs, use after NICE recommendation varied by age at diagnosis and increased as stage increased.
CONCLUSIONS
Use of NICE-recommended drugs for IBC in routine care is variable, with lowest use among women aged 70+ years. Improving access to effective treatments is an important step in improving outcomes.
Topics: Humans; Female; Breast Neoplasms; Cohort Studies; Receptor, ErbB-2; Trastuzumab; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37741900
DOI: 10.1038/s41416-023-02439-z -
JCI Insight Mar 2022Two HER2-specific mAbs, trastuzumab and pertuzumab (T+P), combined with chemotherapy comprise standard-of-care treatment for advanced HER2+ breast cancers (BC). While...
Two HER2-specific mAbs, trastuzumab and pertuzumab (T+P), combined with chemotherapy comprise standard-of-care treatment for advanced HER2+ breast cancers (BC). While this antibody combination is highly effective, its synergistic mechanism-of-action (MOA) remains incompletely understood. Past studies have suggested that the synergy underlying this combination occurs through the different mechanisms elicited by these antibodies, with pertuzumab suppressing HER2 heterodimerization and trastuzumab inducing antitumor immunity. However, in vivo evidence for this synergy is lacking. In this study, we found that the therapeutic efficacy elicited by their combination occurs through their joint ability to activate the classical complement pathway, resulting in both complement-dependent cytotoxicity and complement-dependent cellular phagocytosis of HER2+ tumors. We also demonstrate that tumor C1q expression is positively associated with survival outcome in HER2+ BC patients and that complement regulators CD55 and CD59 were inversely correlated with outcome, suggesting the clinical importance of complement activity. Accordingly, inhibition of C1q in mice abolished the synergistic therapeutic activity of T+P therapy, whereas knockdown of CD55 and CD59 expression enhanced T+P efficacy. In summary, our study identifies classical complement activation as a significant antitumor MOA for T+P therapy that may be functionally enhanced to potentially augment clinical therapeutic efficacy.
Topics: Animals; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Cell Line, Tumor; Complement C1q; Female; Humans; Mice; Phagocytosis; Receptor, ErbB-2; Trastuzumab
PubMed: 35167491
DOI: 10.1172/jci.insight.155636 -
Frontiers in Pharmacology 2022Breast cancer (BC) is caused by epigenetic modifications and genetic heterogeneity and exhibits various histological feature. HER2+ (Human epidermal growth factor... (Review)
Review
Breast cancer (BC) is caused by epigenetic modifications and genetic heterogeneity and exhibits various histological feature. HER2+ (Human epidermal growth factor receptor 2) is a more aggressive type of breast cancer, diagnosis and prognosis are difficult for HER2+ BC. Anti-HER2+ inhibitors have been effectively used for patient treatment. High mortality rate is reported in HER2+ BC, due to availability of limited therapeutic options. Despite advances in systemic medications to treat metastatic breast cancer (MBC), HER2-positive MBC is still challenging for patients and treating clinicians. The clinical characteristics of the disease have changed after treatment with HER2-targeted therapy. Various types of Tyrosine kinase inhibitors (TKIs) have been developed to treat patients with HER2+ BC including afatinib, lapatinib, neratinib, tucatinib, and pyrotinib, have been developed as HER2-targeted therapies. The antibody-drug conjugates adotrastuzumab, emtansine, famtrastuzumab, and deruxtecan, as well as the anti-HER2 monoclonal antibody pertuzumab are used in both early-stage and metastatic situations, either alone or in conjunction with chemotherapy and other HER2-targeting therapies. The emergence of drug resistance in anti-HER2 therapies has been observed. To overcome drug resistance and limited efficacy in current treatment options, nano formulations can be used in patients with HER2+ BC treatment. Anti-HER2 ligands can be used in various nano formulations to target HER2 receptors. Here we will discuss, targeted TKIs in patients with HER2+ BC, clinical studies of HER2+ targeted TKIs, mechanisms of resistance to HER2-directed therapies with new implications of TKIs in HER2+ MBC (metastatic breast cancer) and anti-HER2 ligand in various nano formulations to target HER2 receptors.
PubMed: 36578543
DOI: 10.3389/fphar.2022.1089066