ABSTRACT
BACKGROUND: The Breast Cancer Index (BCI) test assay provides an individualized risk of late distant recurrence (5-10 years) and predicts the likelihood of benefitting from extended endocrine therapy (EET) in hormone receptor-positive early-stage breast cancer. This analysis aimed to assess the impact of BCI on EET decision-making in current clinical practice. METHODS: The BCI Registry study evaluates long-term outcomes, decision impact, and medication adherence in patients receiving BCI testing as part of routine clinical care. Physicians and patients completed pre-BCI and post-BCI test questionnaires to assess a range of questions, including physician decision-making and confidence regarding EET; patient preferences and concerns about the cost, side effects, drug safety, and benefit of EET; and patient satisfaction regarding treatment recommendations. Pre-BCI and post-BCI test responses were compared using McNemar's test and Wilcoxon signed rank test. RESULTS: Pre-BCI and post-BCI questionnaires were completed for 843 physicians and 823 patients. The mean age at enrollment was 65 years, and 88.4% of patients were postmenopausal. Of the tumors, 74.7% were T1, 53.4% were grade 2, 76.0% were N0, and 13.8% were HER2-positive. Following BCI testing, physicians changed EET recommendations in 40.1% of patients (P<.0001), and 45.1% of patients changed their preferences for EET (P<.0001). In addition, 38.8% of physicians felt more confident in their recommendation (P<.0001), and 41.4% of patients felt more comfortable with their EET decision (P<.0001). Compared with baseline, significantly more patients were less concerned about the cost (20.9%; P<.0001), drug safety (25.4%; P=.0014), and benefit of EET (29.3%; P=.0002). CONCLUSIONS: This analysis in a large patient cohort of the BCI Registry confirms and extends previous findings on the significant decision-making impact of BCI on EET. Incorporating BCI into clinical practice resulted in changes in physician recommendations, increased physician confidence, improved patient satisfaction, and reduced patient concerns regarding the cost, drug safety, and benefit of EET.
Subject(s)
Brain-Computer Interfaces , Breast Neoplasms , Humans , Female , Breast Neoplasms/pathology , Prospective Studies , Chemotherapy, Adjuvant/methods , Neoplasm Recurrence, Local/drug therapyABSTRACT
BACKGROUND: There is an increasing need for developing effective therapies for managing intracranial disease in patients with human epidermal growth factor receptor 2-positive (HER2 +) metastatic breast cancer and brain metastases (BM), as this population is growing and has historically been excluded from large clinical trials. In this systematic literature review, we aimed to provide a comprehensive overview of the epidemiology, unmet needs, and global treatment landscape for patients with HER2 + metastatic breast cancer and BM, with a particular focus on heterogeneity across clinical trial designs in this setting. METHODS: We conducted literature searches of PubMed and select congress websites up to March 2022 and filtered for publications with a significant focus on epidemiology, unmet needs, or treatment outcomes in patients with HER2 + metastatic breast cancer and BM. RESULTS: Key clinical trials of HER2-targeting treatments for HER2 + metastatic breast cancer had varying eligibility criteria relating to BM, with only two trials-HER2CLIMB and DEBBRAH-including patients with both active and stable BM. We also observed variance across assessed central nervous system (CNS)-focused endpoints (CNS objective response rate vs CNS progression-free survival vs time to CNS progression) and robustness of statistical analysis (prespecified vs exploratory). CONCLUSIONS: There is an unmet need for standardization of clinical trial design for patients with HER2 + metastatic breast cancer and BM, to aid the interpretation of the global treatment landscape and ensure patients with all types of BM can access effective treatments.
Subject(s)
Brain Neoplasms , Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Trastuzumab/therapeutic use , Receptor, ErbB-2/metabolism , Brain Neoplasms/drug therapyABSTRACT
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Final overall survival (OS) in SOPHIA (ClinicalTrials.gov identifier: NCT02492711), a study of margetuximab versus trastuzumab, both with chemotherapy, in patients with previously treated human epidermal growth factor receptor 2-positive advanced breast cancer, is reported with updated safety. Overall, 536 patients in the intention-to-treat population were randomly assigned to margetuximab (15 mg/kg intravenously once every 3 weeks; n = 266) plus chemotherapy or trastuzumab (6 mg/kg intravenously once every 3 weeks after a loading dose of 8 mg/kg; n = 270) plus chemotherapy. Primary end points were progression-free survival, previously reported, and OS. Final OS analysis was triggered by 385 prespecified events. The median OS was 21.6 months (95% CI, 18.89 to 25.07) with margetuximab versus 21.9 months (95% CI, 18.69 to 24.18) with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620). Preplanned, exploratory analysis of CD16A genotyping suggested a possible improvement in OS for margetuximab in CD16A-158FF patients versus trastuzumab (median OS, 23.6 v 19.2 months; HR, 0.72; 95% CI, 0.52 to 1.00) and a possible improvement in OS for trastuzumab in CD16A-158VV patients versus margetuximab (median OS, 31.1 v 22.0 months; HR, 1.77; 95% CI, 1.01 to 3.12). Margetuximab safety was comparable with trastuzumab. Final overall OS analysis did not demonstrate margetuximab advantage over trastuzumab. Margetuximab studies in patients with human epidermal growth factor receptor 2-positive breast cancer with different CD16A allelic variants are warranted.
Subject(s)
Breast Neoplasms , Humans , Female , Trastuzumab/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Receptor, ErbB-2 , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Several therapeutic monoclonal antibodies (mAbs), including those targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and CD20, mediate fragment crystallizable gamma receptor (FcγR)-dependent activities as part of their mechanism of action. These activities include induction of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which are innate immune mechanisms of cancer cell elimination. FcγRs are distinguished by their affinity for the Fc fragment, cell distribution, and type of immune response they induce. Activating FcγRIIIa (CD16A) on natural killer cells plays a crucial role in mediating ADCC, and activating FcγRIIa (CD32A) and FcγRIIIa on macrophages are important for mediating ADCP. Polymorphisms in FcγRIIIa and FcγRIIa generate variants that bind to the Fc portion of antibodies with different affinities. This results in differential FcγR-mediated activities associated with differential therapeutic outcomes across multiple clinical settings, from early stage to metastatic disease, in patients with HER2+ breast cancer treated with the anti-HER2 mAb trastuzumab. Trastuzumab has, nonetheless, revolutionized HER2+ breast cancer treatment, and several HER2-directed mAbs have been developed using Fc glyco-engineering or Fc protein-engineering to enhance FcγR-mediated functions. An example of an approved anti-HER2 Fc-engineered chimeric mAb is margetuximab, which targets the same epitope as trastuzumab, but features five amino acid substitutions in the IgG 1 Fc domain that were deliberately introduced to increase binding to activating FcγRIIIa and decrease binding to inhibitory FcγRIIb (CD32B). Margetuximab enhances Fc-dependent ADCC in vitro more potently than the combination of pertuzumab (another approved mAb directed against an alternate HER2 epitope) and trastuzumab. Margetuximab administration also enhances HER2-specific B cell and T cell-mediated responses ex vivo in samples from patients treated with prior lines of HER2 antibody-based therapies. Stemming from these observations, a worthwhile future goal in the treatment of HER2+ breast cancer is to promote combinatorial approaches that better eradicate HER2+ cancer cells via enhanced immunological mechanisms.
Subject(s)
Adaptive Immunity/immunology , Breast Neoplasms/genetics , Immunity, Innate/immunology , Receptor, ErbB-2/metabolism , Receptors, IgG/metabolism , Breast Neoplasms/mortality , Female , Humans , Retrospective Studies , Survival AnalysisABSTRACT
PURPOSE: HER2 mutations (HER2mut) induce endocrine resistance in estrogen receptor-positive (ER+) breast cancer. PATIENTS AND METHODS: In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/HER2mut, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n = 24) or fulvestrant-naïve cohort (n = 11). Patients with ER-negative (ER-)/HER2mut MBC received neratinib monotherapy in an exploratory ER- cohort (n = 5). RESULTS: The clinical benefit rate [CBR (95% confidence interval)] was 38% (18%-62%), 30% (7%-65%), and 25% (1%-81%) in the fulvestrant-treated, fulvestrant-naïve, and ER- cohorts, respectively. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease ≥24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2mut were detected in 5 of 23 patients at progression. CONCLUSIONS: Neratinib and fulvestrant are active for ER+/HER2mut MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2mut MBC.
Subject(s)
Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Fulvestrant , Humans , Quinolines , Receptor, ErbB-2/genetics , Receptor, ErbB-2/therapeutic useABSTRACT
Trastuzumab, a targeted anti-human epidermal-growth-factor receptor-2 (HER2) monoclonal antibody, represents a mainstay in the treatment of HER2-positive (HER2+) breast cancer. Although trastuzumab treatment is highly efficacious for early-stage HER2+ breast cancer, the majority of advanced-stage HER2+ breast cancer patients who initially respond to trastuzumab acquire resistance to treatment and relapse, despite persistence of HER2 gene amplification/overexpression. Here, we sought to leverage HER2 overexpression to engage antibody-dependent cellular phagocytosis (ADCP) through a combination of trastuzumab and anti-CD47 macrophage checkpoint immunotherapy. We have previously shown that blockade of CD47, a surface protein expressed by many malignancies (including HER2+ breast cancer), is an effective anticancer therapy. CD47 functions as a "don't eat me" signal through its interaction with signal regulatory protein-α (SIRPα) on macrophages to inhibit phagocytosis. Hu5F9-G4 (magrolimab), a humanized monoclonal antibody against CD47, blocks CD47's "don't eat me" signal, thereby facilitating macrophage-mediated phagocytosis. Preclinical studies have shown that combining Hu5F9-G4 with tumor-targeting antibodies, such as rituximab, further enhances Hu5F9-G4's anticancer effects via ADCP. Clinical trials have additionally demonstrated that Hu5F9-G4, in combination with rituximab, produced objective responses in patients whose diffuse large B cell lymphomas had developed resistance to rituximab and chemotherapy. These studies led us to hypothesize that combining Hu5F9-G4 with trastuzumab would produce an anticancer effect in antibody-dependent cellular cytotoxicity (ADCC)-tolerant HER2+ breast cancer. This combination significantly suppressed the growth of ADCC-tolerant HER2+ breast cancers via Fc-dependent ADCP. Our study demonstrates that combining trastuzumab and Hu5F9-G4 represents a potential new treatment option for HER2+ breast cancer patients, even for patients whose tumors have progressed after trastuzumab.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Breast Neoplasms/drug therapy , CD47 Antigen/immunology , Trastuzumab/administration & dosage , Animals , Antibody-Dependent Cell Cytotoxicity/drug effects , Breast Neoplasms/genetics , Breast Neoplasms/immunology , CD47 Antigen/antagonists & inhibitors , CD47 Antigen/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm , Drug Therapy, Combination , Female , Humans , Immunotherapy , Macrophages/drug effects , Macrophages/immunology , Mice , Mice, Inbred C57BL , Receptor, ErbB-2/genetics , Receptor, ErbB-2/immunologyABSTRACT
An array of isoforms of the nuclear estrogen receptor alpha (ER-α) protein contribute to heterogeneous response in breast cancer (BCa); yet, a single-cell analysis tool that distinguishes the full-length ER-α66 protein from the activation function-1 deficient ER-α46 isoform has not been reported. Specific detection of protein isoforms is a gap in single-cell analysis tools, as the de facto standard immunoassay requires isoform-specific antibody probes. Consequently, to scrutinize hormone response heterogeneity among BCa tumor cells, we develop a precision tool to specifically measure ER-α66, ER- α46, and eight ER-signaling proteins with single-cell resolution in the highly hetero-clonal MCF-7 BCa cell line. With a literature-validated pan-ER immunoprobe, we distinguish ER-α66 from ER-α46 in each individual cell. We identify ER-α46 in 5.5% of hormone-sensitive (MCF-7) and 4.2% of hormone-insensitive (MDA-MB-231) BCa cell lines. To examine whether the single-cell immunoblotting can capture cellular responses to hormones, we treat cells with tamoxifen and identify different sub-populations of ER-α46: (i) ER-α46 induces phospho-AKT at Ser473, (ii) S6-ribosomal protein, an upstream ER target, activates both ER-α66 and ER-α46 in MCF-7 cells, and (iii) ER-α46 partitions MDA-MB-231 subpopulations, which are responsive to tamoxifen. Unlike other single-cell immunoassays, multiplexed single-cell immunoblotting reports-in the same cell-tamoxifen effects on ER signaling proteins and on distinct isoforms of the ER-α protein.
Subject(s)
Estrogen Receptor alpha/metabolism , Single-Cell Analysis/methods , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Estrogen Receptor alpha/genetics , Female , Humans , Immunoblotting , Phosphorylation/drug effects , Principal Component Analysis , Protein Isoforms/genetics , Protein Isoforms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Single-Cell Analysis/instrumentation , Tamoxifen/pharmacologyABSTRACT
MEDI4276 is a biparatopic tetravalent antibody targeting two nonoverlapping epitopes in subdomains 2 and 4 of the HER2 ecto-domain, with site-specific conjugation to a tubulysin-based microtubule inhibitor payload. MEDI4276 demonstrates enhanced cellular internalization and cytolysis of HER2-positive tumor cells in vitro This was a first-in-human, dose-escalation clinical trial in patients with HER2-positive advanced or metastatic breast cancer or gastric cancer. MEDI4276 doses escalated from 0.05 to 0.9 mg/kg (60- to 90-minute intravenous infusion every 3 weeks). Primary endpoints were safety and tolerability; secondary endpoints included antitumor activity (objective response, progression-free survival, and overall survival), pharmacokinetics, and immunogenicity. Forty-seven patients (median age 59 years; median of seven prior treatment regimens) were treated. The maximum tolerated dose was exceeded at 0.9 mg/kg with two patients experiencing dose-limiting toxicities (DLTs) of grade 3 liver function test (LFT) increases, one of whom also had grade 3 diarrhea, which resolved. Two additional patients reported DLTs of grade 3 LFT increases at lower doses (0.4 and 0.6 mg/kg). The most common (all grade) drug-related adverse events (AEs) were nausea (59.6%), fatigue (44.7%), aspartate aminotransferase (AST) increased (42.6%), and vomiting (38.3%). The most common grade 3/4 drug-related AE was AST increased (21.3%). Five patients had drug-related AEs leading to treatment discontinuation. In the as-treated population, there was one complete response (0.5 mg/kg; breast cancer), and two partial responses (0.6 and 0.75 mg/kg; breast cancer)-all had prior trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). MEDI4276 has demonstrable clinical activity but displays intolerable toxicity at doses >0.3 mg/kg.
Subject(s)
Antibodies, Monoclonal , Antineoplastic Agents, Immunological , Breast Neoplasms , Immunoconjugates , Receptor, ErbB-2 , Stomach Neoplasms , Adult , Aged , Female , Humans , Male , Middle Aged , Antibodies, Monoclonal/chemistry , Antineoplastic Agents, Immunological/chemistry , Antineoplastic Agents, Immunological/pharmacokinetics , Antineoplastic Agents, Immunological/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/immunology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Follow-Up Studies , Immunoconjugates/chemistry , Immunoconjugates/pharmacokinetics , Immunoconjugates/pharmacology , Maximum Tolerated Dose , Prognosis , Receptor, ErbB-2/immunology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/immunology , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Survival Rate , Tissue DistributionABSTRACT
OBJECTIVE/BACKGROUND: We performed a retrospective analysis of longitudinal real-world data (RWD) from patients with breast cancer to replicate results from clinical studies and demonstrate the feasibility of generating real-world evidence. We also assessed the value of transcriptome profiling as a complementary tool for determining molecular subtypes. METHODS: De-identified, longitudinal data were analyzed after abstraction from records of patients with breast cancer in the United States (US) structured and stored in the Tempus database. Demographics, clinical characteristics, molecular subtype, treatment history, and survival outcomes were assessed according to strict qualitative criteria. RNA sequencing and clinical data were used to predict molecular subtypes and signaling pathway enrichment. RESULTS: The clinical abstraction cohort (n = 4000) mirrored the demographics and clinical characteristics of patients with breast cancer in the US, indicating feasibility for RWE generation. Among patients who were human epidermal growth factor receptor 2-positive (HER2+), 74.2% received anti-HER2 therapy, with â¼70% starting within 3 months of a positive test result. Most non-treated patients were early stage. In this RWD set, 31.7% of patients with HER2+ immunohistochemistry (IHC) had discordant fluorescence in situ hybridization results recorded. Among patients with multiple HER2 IHC results at diagnosis, 18.6% exhibited intra-test discordance. Through development of a whole-transcriptome model to predict IHC receptor status in the molecular sequenced cohort (n = 400), molecular subtypes were resolved for all patients (n = 36) with equivocal HER2 statuses from abstracted test results. Receptor-related signaling pathways were differentially enriched between clinical molecular subtypes. CONCLUSIONS: RWD in the Tempus database mirrors the overall population of patients with breast cancer in the US. These results suggest that real-time, RWD analyses are feasible in a large, highly heterogeneous database. Furthermore, molecular data may aid deficiencies and discrepancies observed from breast cancer RWD.
Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Sequence Analysis, RNA , Aged , Breast Neoplasms/therapy , Databases, Factual , Feasibility Studies , Female , Gene Expression Profiling , Humans , Longitudinal Studies , Male , Middle Aged , Receptor, ErbB-2/genetics , Receptors, Estrogen/genetics , Retrospective Studies , Sensitivity and Specificity , United StatesABSTRACT
IMPORTANCE: ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. OBJECTIVE: To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. DESIGN, SETTING, AND PARTICIPANTS: The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. INTERVENTIONS: Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. MAIN OUTCOMES AND MEASURES: Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. RESULTS: A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). Margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02492711.
Subject(s)
Antibodies, Monoclonal , Breast Neoplasms , Trastuzumab , Ado-Trastuzumab Emtansine , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms/drug therapy , Female , Humans , Middle Aged , Receptor, ErbB-2/analysis , Trastuzumab/adverse effects , Trastuzumab/therapeutic useABSTRACT
Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach.
Subject(s)
Copper/metabolism , Mitochondria/metabolism , Triple Negative Breast Neoplasms/pathology , Animals , Cell Death , Cell Line, Tumor , Chelating Agents/metabolism , Disease Models, Animal , Female , Humans , Mice , Oxidative Phosphorylation , Triple Negative Breast Neoplasms/metabolismABSTRACT
Trastuzumab and the related ADC, ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2+ breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload. Interestingly, in the clinic, T-DM1 cannot always replace the use of trastuzumab plus chemotherapy administered together as single agents. We hypothesize that this failure may be due, in part, to the limited systemic exposure achieved by T-DM1 relative to trastuzumab because of toxicity-related dosing constraints on the ADC. We have developed a trastuzumab-based ADC site specifically conjugated to maytansine through a noncleavable linker. This construct, termed CAT-01-106, has a drug-to-antibody ratio (DAR) of 1.8, approximately half the average DAR of T-DM1, which comprises a mixture of antibodies variously conjugated with DARs ranging from 0 to 8. The high DAR species present in T-DM1 contribute to its toxicity and limit its clinical dose. CAT-01-106 showed superior in vivo efficacy compared with T-DM1 at equal payload dosing and was equally or better tolerated compared with T-DM1 at equal payload dosing up to 120 mg/kg in Sprague-Dawley rats and 60 mg/kg in cynomolgus monkeys. CAT-01-106 also showed improved pharmacokinetics in rats relative to T-DM1, with 40% higher ADC exposure levels. Together, the data suggest that CAT-01-106 may be sufficiently tolerable to enable clinical dosing at trastuzumab-equivalent exposure levels, combining the functions of both the antibody and the payload in one drug and potentially improving patient outcomes.
Subject(s)
Ado-Trastuzumab Emtansine/administration & dosage , Breast Neoplasms/drug therapy , Immunoconjugates/administration & dosage , Maytansine/chemistry , Trastuzumab/chemistry , Ado-Trastuzumab Emtansine/adverse effects , Ado-Trastuzumab Emtansine/pharmacokinetics , Animals , Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Humans , Immunoconjugates/adverse effects , Immunoconjugates/chemistry , Immunoconjugates/pharmacokinetics , Macaca fascicularis , Maximum Tolerated Dose , Rats , Rats, Sprague-Dawley , Receptor, ErbB-2/metabolism , Trastuzumab/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Prodrugs are harmless until activated by a bacterial or viral gene product; they constitute the basis of gene-delivered prodrug therapies called GDEPT, which can kill tumors without major side effects. Previously, we utilized the prodrug CNOB (C16H7CIN2O4; not clinically tested) and enzyme HChrR6 in GDEPT to generate the drug MCHB (C16H9CIN2O2) in tumors. Extracellular vesicles (EVs) were used for directed gene delivery and HChrR6 mRNA as gene. Here, the clinical transfer of this approach is enhanced by: (i) use of CB1954 (tretazicar) for which safe human dose is established; HChrR6 can activate this prodrug. (ii) EVs delivered in vitro transcribed (IVT) HChrR6 mRNA, eliminating the potentially harmful plasmid transfection of EV producer cells we utilized previously; this has not been done before. IVT mRNA loading of EVs required several steps. Naked mRNA being unstable, we ensured its prodrug activating functionality at each step. This was not possible using tretazicar itself; we relied instead on HChrR6's ability to convert CNOB into MCHB, whose fluorescence is easily visualizable. HChrR6 mRNA-translated product's ability to generate fluorescence from CNOB vicariously indicated its competence for tretazicar activation. (iii) Systemic IVT mRNA-loaded EVs displaying an anti-HER2 single-chain variable fragment ("IVT EXO-DEPTs") and tretazicar caused growth arrest of human HER2+ breast cancer xenografts in athymic mice. As this occurred without injury to other tissues, absence of off-target mRNA delivery is strongly indicated. Many cancer sites are not amenable for direct gene injection, but current GDEPTs require this. In circumventing this need, a major advance in GDEPT applicability has been accomplished.
Subject(s)
Bacterial Proteins/genetics , Breast Neoplasms/therapy , Extracellular Vesicles/metabolism , Gene Transfer Techniques , Genetic Therapy , Prodrugs/pharmacology , RNA, Messenger/administration & dosage , Animals , Apoptosis , Bacterial Proteins/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Proliferation , Extracellular Vesicles/genetics , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, ErbB-2/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Efficacy data from the KATHERINE clinical trial, comparing the HER2-directed antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) to trastuzumab in patients with early-stage HER2-amplified/overexpressing breast cancer with residual disease after neoadjuvant therapy, demonstrates superiority of T-DM1 (HR for invasive disease or death, 0.50; P < 0.001). This establishes foundational precedent for ADCs as effective therapy for treatment of subclinical micrometastasis in an adjuvant (or post-neoadjuvant) early-stage solid tumor setting. Despite this achievement, general principles from proposed systems pharmacokinetic modeling for intracellular processing of ADCs indicate potential shortcomings of T-DM1: (i) C max limited by toxicities; (ii) slow internalization rate; (iii) resistance mechanisms due to defects in intracellular trafficking [loss of lysosomal transporter solute carrier family 46 member 3, (SLC46A3)], and increased expression of drug transporters MDR1 and MRP1; and (iv) lack of payload bystander effects limiting utility in tumors with heterogeneous HER2 expression. These handicaps may explain the inferiority of T-DM1-based therapy in the neoadjuvant and first-line metastatic HER2+ breast cancer settings, and lack of superiority to chemotherapy in HER2+ advanced gastric cancer. In this review, we discuss how each of these limitations is being addressed by manipulating internalization and trafficking using HER2:HER2 bispecific or biparatopic antibody backbones, using site-specific, fixed DAR conjugation chemistry, and payload swapping to exploit alternative intracellular targets and to promote bystander effects. Newer HER2-directed ADCs have impressive clinical activity even against tumors with lower levels of HER2 receptor expression. Finally, we highlight ongoing clinical efforts to combine HER2 ADCs with other treatment modalities, including chemotherapy, molecularly targeted therapies, and immunotherapy.
Subject(s)
Ado-Trastuzumab Emtansine/therapeutic use , Breast Neoplasms/drug therapy , Immunoconjugates/pharmacokinetics , Immunoconjugates/therapeutic use , Receptor, ErbB-2/biosynthesis , Antineoplastic Agents, Immunological/therapeutic use , Breast Neoplasms/enzymology , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Clinical Trials as Topic , Drug Development , Drug Resistance, Neoplasm , Female , Gene Amplification , Humans , Molecular Targeted Therapy/methods , Randomized Controlled Trials as Topic , Receptor, ErbB-2/genetics , Receptor, ErbB-2/immunology , Tissue DistributionABSTRACT
Introduction: Although many current cancer therapies are effective, the mortality rate globally is unacceptably high. Cancer remains the second leading cause of death worldwide after heart disease and has caused nearly 10 million deaths in 2018. Additionally, current preventive therapies for cancer are underdeveloped, undermining the quality of life of high-risk individuals. Therefore, new treatment options for targeting cancer are urgently needed. In a recent study, researchers adopted an autologous iPSC-based vaccine to present a broad spectrum of tumor antigens to the immune system and succeeded in orchestrating a strong prophylactic immunity towards multiple types of cancer in mice. Areas covered: In this review, we provide an overview of how cancer develops, the role of immune surveillance in cancer progression, the current status and challenges of cancer immunotherapy as well as the genetic overlap between pluripotent stem cells and cancer cells. Finally, we discuss the rationale for an autologous iPSC-based vaccine and its applications in murine cancer models. Expert opinion: The autologous iPSC-based vaccine is a promising preventive and therapeutic strategy for fighting various types of cancers. Continuing efforts and clinical/translational follow-up studies may bring an autologous iPSC-based cancer vaccination approach from bench to bedside.
Subject(s)
Cancer Vaccines/therapeutic use , Immunotherapy/methods , Induced Pluripotent Stem Cells/transplantation , Neoplasms/therapy , Animals , Antigens, Neoplasm/immunology , Cancer Vaccines/classification , Humans , Induced Pluripotent Stem Cells/cytology , Mice , Neoplasms/immunology , Quality of LifeABSTRACT
CanAssist-Breast (CAB) is an immunohistochemistry (IHC)-based prognostic test for early-stage Hormone Receptor (HR+)-positive breast cancer patients. CAB uses a Support Vector Machine (SVM) trained algorithm which utilizes expression levels of five biomarkers (CD44, ABCC4, ABCC11, N-Cadherin, and Pan-Cadherin) and three clinical parameters such as tumor size, grade, and node status as inputs to generate a risk score and categorizes patients as low- or high-risk for distant recurrence within 5 years of diagnosis. In this study, we present clinical validation of CAB. CAB was validated using a retrospective cohort of 857 patients. All patients were treated either with endocrine therapy or chemoendocrine therapy. Risk categorization by CAB was analyzed by calculating Distant Metastasis-Free Survival (DMFS) and recurrence rates using Kaplan-Meier survival curves. Multivariate analysis was performed to calculate Hazard ratios (HR) for CAB high-risk vs low-risk patients. The results showed that Distant Metastasis-Free Survival (DMFS) was significantly different (P-0.002) between low- (DMFS: 95%) and high-risk (DMFS: 80%) categories in the endocrine therapy treated alone subgroup (n = 195) as well as in the total cohort (n = 857, low-risk DMFS: 95%, high-risk DMFS: 84%, P < 0.0001). In addition, the segregation of the risk categories was significant (P = 0.0005) in node-positive patients, with a difference in DMFS of 12%. In multivariate analysis, CAB risk score was the most significant predictor of distant recurrence with hazard ratio of 3.2048 (P < 0.0001). CAB stratified patients into discrete risk categories with high statistical significance compared to Ki-67 and IHC4 score-based stratification. CAB stratified a higher percentage of the cohort (82%) as low-risk than IHC4 score (41.6%) and could re-stratify >74% of high Ki-67 and IHC4 score intermediate-risk zone patients into low-risk category. Overall the data suggest that CAB can effectively predict risk of distant recurrence with clear dichotomous high- or low-risk categorization.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/diagnosis , Adult , Aged , Algorithms , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Female , Humans , Kaplan-Meier Estimate , Lymphatic Metastasis , Middle Aged , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Staging , Prognosis , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Retrospective Studies , Risk Assessment/methods , Support Vector MachineABSTRACT
PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis. PATIENTS AND METHODS: Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort. RESULTS: Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months. CONCLUSION: 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Lymphoma/drug therapy , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/immunology , Antineoplastic Agents, Immunological/pharmacokinetics , Biopsy , CD47 Antigen/immunology , Cohort Studies , Female , Humans , Lymphoma/immunology , Lymphoma/metabolism , Lymphoma/pathology , Male , Middle Aged , Neoplasms/immunology , Neoplasms/metabolism , Neoplasms/pathologyABSTRACT
BACKGROUND: This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer. METHODS: Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review. RESULTS: The risk ratio for ORR was 0.940 (95% CI: 0.842-1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80-1.25. ORR was 62.5% (95% CI: 57.2-67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3-71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups. CONCLUSION: When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01989676.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Breast Neoplasms/drug therapy , Receptor, ErbB-2/genetics , Trastuzumab/administration & dosage , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biosimilar Pharmaceuticals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Disease-Free Survival , Double-Blind Method , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Metastasis , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Trastuzumab/adverse effects , Trastuzumab/chemistryABSTRACT
Metastatic breast cancer continues to be a life-threatening diagnosis that impacts hundreds of thousands of patients around the world. Targeted therapies are usually associated with less toxicity compared with cytotoxic chemotherapies and often induce response or durable disease control in estrogen receptor (ER) and/or HER2+ breast cancers. Drugs that target CDK 4/6 either alone or in combination with endocrine therapy have demonstrated substantial improvements in progression-free survival (PFS) compared with endocrine monotherapy. Most recently, PARP inhibitors have shown longer PFS compared with physician's choice of chemotherapy in BRCA-associated cancers, leading to the first U.S. Food and Drug Administration (FDA) approval of a targeted therapy with the potential to benefit a subgroup of patients with triple-negative breast cancer (TNBC). Finally, newer drug delivery strategies using antibody drug conjugates have also allowed a "targeted approach" to deliver moderate to extremely potent cytotoxins directly to sites of metastatic disease, with less toxicity.
Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/therapy , Antibody-Dependent Cell Cytotoxicity , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Combined Modality Therapy , Drug Resistance, Neoplasm/genetics , Female , Humans , Immunomodulation , Molecular Targeted Therapy , Mutation , Neoplasm Metastasis , Neoplasm Staging , Polymorphism, Genetic , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Signal Transduction/drug effects , Triple Negative Breast Neoplasms/diagnosis , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/therapyABSTRACT
In addition to canonical oncoproteins, truncated isoforms and proteolysis products are implicated in both drug resistance and disease progression. In HER2-positive breast tumors, expression of truncated HER2 isoforms resulting from alternative translation and/or carboxy-terminal fragments (CTFs) resulting from proteolysis (collectively, t-erbB2) have been associated with shortened progression-free survival of patients. Thus, to advance clinical pathology and inform treatment decisions, we developed a high-selectivity cytopathology assay capable of distinguishing t-erbB2 from full-length HER2 expression without the need for isoform-specific antibodies. Our microfluidic, single-cell western blot, employs electrophoretic separations to resolve full-length HER2 from the smaller t-erbB2 in each ~28 pL single-cell lysate. Subsequently, a pan-HER2 antibody detects all resolved HER2 protein forms via immunoprobing. In analysis of eight breast tumor biopsies, we identified two tumors comprised of 15% and 40% t-erbB2-expressing cells. By single-cell western blotting of the t-erbB2-expressing cells, we observed statistically different ratios of t-erbB2 proteins to full-length HER2 expression. Further, target multiplexing and clustering analyses scrutinized signaling, including ribosomal S6, within the t-erbB2-expressing cell subpopulation. Taken together, cytometric assays that report both protein isoform profiles and signaling state offer cancer classification taxonomies with unique relevance to precisely describing drug resistance mechanisms in which oncoprotein isoforms/fragments are implicated.