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Advanced Breast Cancer; Efficacy; Margetuximab Cáncer de mama avanzado; Eficacia; Margetuximab Càncer de mama avançat; Eficàcia; Margetuximab 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

Biosimilars have the potential to broaden patient access to biologics and provide cost savings for health care systems. During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. Such comparative data are generated in a stepwise hierarchical process that begins with extensive laboratory-based structural analyses and functional assays. This initial analytical phase serves as the foundation for the demonstration of biosimilarity and is followed by nonclinical in vivo testing (if required) and then clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics study that is usually conducted in healthy volunteers. The development program typically culminates with a comparative clinical efficacy study. The aim of this study is to confirm clinical equivalence of the potential biosimilar and reference product on the basis of prespecified margins, using a study population and efficacy end point that are sufficiently sensitive for detecting potential product-related differences. Such studies also include detailed analyses of safety as well as evaluation of immunogenicity. As biosimilars become more widely available in oncology, especially with recent regulatory approvals of rituximab, trastuzumab, and bevacizumab biosimilars, it is critically important that clinicians understand how the comparative clinical study differs from a traditional phase III efficacy and safety study in the development of a novel biologic originator product. Here, we review the role of comparative clinical studies in biosimilar development, with a focus on trials conducted to support approved trastuzumab biosimilars. We discuss the study populations and end points used, extrapolation of indications, and the confirmatory nature of these studies within the totality of evidence supporting biosimilarity.

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.

It has been over three decades since anthracyclines took their place as the standard chemotherapy backbone for breast cancer in the curative setting. Though the efficacy of anthracycline chemotherapy is not debatable, potentially life-threatening and long-term risks accompany this class of agents, leading some to question their widespread use, especially when newer agents with improved therapeutic indices have become available. Critically assessing when to incorporate an anthracycline is made more relevant in an era where molecular classification is enabling not only the development of biologically targeted therapeutics but also is improving the ability to better select those who would benefit from cytotoxic agents. This comprehensive analysis will present the problem of overtreatment in early-stage breast cancer, review evidence supporting the use of anthracyclines in the pre-taxane era, analyze comparative trials evaluating taxanes with or without anthracyclines in biologically unselected and selected patient populations, and explore published work aimed at defining anthracycline-sensitive tumor types.

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.

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 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.

Effective therapies are needed for the treatment of patients with HER2-positive MBC who develop brain metastases. In the open-label, phase II PATRICIA study (NCT02536339), 40 patients with HER2-positive MBC with CNS metastases and CNS progression post-radiotherapy (median age 48 years [range, 34–69]; prior CNS treatment [whole brain radiotherapy 71%, stereotactic radiosurgery 59%, both 31%]) were enrolled to receive pertuzumab plus high-dose trastuzumab (6-mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Following a median (range) treatment duration of 4.5 (0.3–37.3) months, the CNS-confirmed objective response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria (primary endpoint) was 11% (95% confidence interval: 3.03, 25.42), and the clinical benefit rate at 4 months was 68%, indicating sustained clinical stability. Patient-reported outcomes (PROs) were evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT), which includes sub-scales for symptom severity (average of 13 core symptom and 9 brain-tumor specific items) and symptom interference (average of 6 interference-with-life items representing overall symptom distress). Among 36 patients included in the PRO analyses, mean (standard deviation [SD]) symptom severity scores at baseline and weeks 12 and 28 were 1.65 (1.62), 2.24 (2.14), and 1.94 (2.55), respectively. Mean (SD) symptom interference scores at baseline and weeks 12 and 28 were 2.51 (2.63), 2.81 (3.39), and 1.76 (2.43), respectively. Mean (SD) changes in symptom severity and interferences scores from baseline to week 12 were 0.34 (1.54) and 0.33 (3.08), respectively. On average, patients who did not achieve stable disease or better in the CNS following treatment had worsened symptom severity and symptom interference scores over 12 weeks, while those with stable disease or better in the CNS exhibited stable or improving scores. Pertuzumab plus high-dose trastuzumab provided clinical benefit to the majority (68%) of patients in PATRICIA, without a decrement in quality of life.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; PCONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794. opens in new tab.)

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.

Background Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. Results Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p = 0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR = 0.23; p = 0.04). Conclusions These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting. Trial registration ClinicalTrials.gov, NCT00005970. Registered on July 5, 2000. Electronic supplementary material The online version of this article (10.1186/s13058-018-0989-8) contains supplementary material, which is available to authorized users.

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.

This paper deals with specific targeting of the prodrug/enzyme regimen, CNOB/HChrR6, to treat a serious disease, namely HER2+ human breast cancer with minimal off-target toxicity. HChrR6 is an improved bacterial enzyme that converts CNOB into the cytotoxic drug MCHB. Extracellular vesicles (EV) were used for mRNA-based HchrR6 gene delivery: EVs may cause minimal immune rejection, and mRNA may be superior to DNA for gene delivery. To confine HChrR6 generation and CNOB activation to the cancer, the EVHB chimeric protein was constructed. It contains high-affinity anti-HER2 scFv antibody (ML39) and is capable of latching on to EV surface. Cells transfected with EVHB-encoding plasmid generated EVs displaying this protein (“directed EVs”). Transfection of a separate batch of cells with the new plasmid, XPort/HChrR6, generated EVs containing HChrR6 mRNA; incubation with pure EVHB enabled these to target the HER2 receptor, generating “EXO-DEPT” EVs. EXO-DEPT treatment specifically enabled HER2-overexpressing BT474 cells to convert CNOB into MCHB in actinomycin D–independent manner, showing successful and specific delivery of HChrR6 mRNA. EXO-DEPTs—but not undirected EVs—plus CNOB caused near-complete growth arrest of orthotopic BT474 xenografts in vivo, demonstrating for the first time EV-mediated delivery of functional exogenous mRNA to tumors. EXO-DEPTs may be generated from patients' own dendritic cells to evade immune rejection, and without plasmids and their potentially harmful genetic material, raising the prospect of clinical use of this regimen. This approach can be used to treat any disease overexpressing a specific marker. Mol Cancer Ther; 17(5); 1133–42. ©2018 AACR.

Purpose: Management of breast cancer is a rapidly evolving field, and, although evidence-based guidelines are available for clinicians to provide direction on critical issues in patient care, clinicians often left to address these issues in the context of community practice situations with their patients. These include the patient’s comorbid conditions, actual versus perceived benefit of treatments, patient’s compliance as well as financial/reimbursement issues, and long-term tolerability of therapy. Methods: A meeting of global oncology experts was convened in January 2017 with the belief that there is a gap in clinical practice guidance on several fundamental issues in breast cancer care, particularly in the community setting, where oncologists may encounter multiple tumor types. The goal was to discuss some of the most important questions in this area and provide some guidance for practicing oncologists. Results: Topics addressed included risk of contralateral breast cancer recurrence in patients with estrogen receptor-positive early breast cancer who have undergone 5 years of adjuvant endocrine therapy, adverse events associated with endocrine therapy and their management, emergent data on adjuvant bisphosphonate therapy and its apparent benefit in reducing breast cancer recurrence, recent findings of extended adjuvant endocrine therapy trials, and the use of currently available genomic biomarker tests as a means of further informing treatment decisions. Conclusions: A summary of the discussion on these topics and several ‘expert opinion statements’ are provided herein in an effort to convey the collective insights of the panel as it relates to current standard practice.

The addition of trastuzumab to chemotherapy extends survival among patients with HER2+ breast cancer. Prior work showed that trastuzumab and chemotherapy augments HER2 extracellular domain (ECD)-specific antibodies. The current study investigated whether combination therapy induced immune responses beyond HER2-ECD and, importantly, whether those immune responses were associated with survival. Pretreatment and posttreatment sera were obtained from 48 women with metastatic HER2+ breast cancer on NCCTG (now Alliance for Clinical Trials in Oncology) studies, N0337 and N983252. IgG to HER2 intracellular domain (ICD), HER2-ECD, p53, IGFBP2, CEA, and tetanus toxoid were examined. Sera from 25 age-matched controls and 26 surgically resected HER2+ patients were also examined. Prior to therapy, some patients with metastatic disease had elevated antibodies to IGFBP2, p53, HER2-ICD, HER2-ECD, and CEA, but not to tetanus toxin, relative to controls and surgically resected patients. Treatment augmented antibody responses to HER2-ICD in 69% of metastatic patients, which was highly associated with improved progression-free survival (PFS; HR = 0.5, P = 0.0042) and overall survival (OS; HR = 0.7, P = 0.038). Augmented antibody responses to HER2-ICD also correlated (P = 0.03) with increased antibody responses to CEA, IGFBP2, and p53, indicating that treatment induces epitope spreading. Paradoxically, patients who already had high preexisting immunity to HER2-ICD did not respond to therapy with increased antibodies to HER2-ICD and demonstrated poorer PFS (HR = 1.6, P < 0.0001) and OS (HR = 1.4, P = 0.0006). Overall, the findings further demonstrate the importance of the adaptive immune system in the efficacy of trastuzumab-containing regimens. Cancer Res; 76(13); 3702–10. ©2016 AACR.

International audience; BACKGROUND: HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model. METHOD: Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16 mg kg(-1). Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set. RESULTS: A linear two-compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion. CONCLUSION: A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody.

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC→T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16% to 32% with NOV-002 plus AC→T (α=0.05, β=80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 16 achieved a pCR (40%), meeting the primary endpoint of the trial. Lower circulating levels of MDSCs at baseline and cycle 8 were associated with a pCR (P=0.02). Concurrent NOV-002 resulted in pCR rates for AC→T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (p=0.02). Further evaluation of NOV-002 in a randomized study is warranted.

SUMMARY: Besides surgery, radiation, chemotherapy, and endocrine treatment, immunotherapy has become an established part of systemic therapy in treating metastatic breast cancer. One of the most interesting targets for the design of anticancer therapeutics is the HER2/ErbB2 receptor which is overexpressed in about 20-25% of breast cancers. Given the poor prognosis of women whose tumors express ErbB2 (HER2) at high levels, accurate determination of the ErbB2 status should be routinely performed in women with newly diagnosed invasive breast cancer. Efficacy and safety data of numerous trials led to the approval of the monoclonal antibody trastuzumab as the first ErbB2-targeting therapy in ErbB2-positive breast cancer. However, the majority of patients who achieve an initial response to trastuzumab-based regimens for metastatic disease develop resistance within 1 year. This underlines the need for alternative or additional anti-ErbB2-targeting strategies.

PurposeCross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) –positive metastatic breast cancer (MBC).Patients and MethodsPostmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population.ResultsIn HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease ≥ 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable.ConclusionThis trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

Background In pre-clinical studies, the anti-tumor activity of T-DM1 was enhanced when combined with taxanes or pertuzumab. This phase 1b/2a study evaluated the safety/tolerability of T-DM1 + paclitaxel ± pertuzumab in HER2-positive advanced breast cancer. Methods In phase 1b (n = 60), a 3 + 3 dose-escalation approach was used to determine the maximum tolerated dose (MTD) of T-DM1 + paclitaxel ± pertuzumab. The primary objective of phase 2a was feasibility, with 44 patients randomized to T-DM1 + paclitaxel ± pertuzumab at the MTD identified in phase 1b. Results The MTD was T-DM1 3.6 mg/kg every three weeks (q3w) or 2.4 mg/kg weekly + paclitaxel 80 mg/m2 weekly ± pertuzumab 840 mg loading dose followed by 420 mg q3w. Phase 2a patients had received a median of 5.0 (range: 0–10) prior therapies for advanced cancer. In phase 2a, 51.2 % received ≥12 paclitaxel doses within 15 weeks, and 14.0 % received 12 paclitaxel doses by week 12. Common all-grade adverse events (AEs) were peripheral neuropathy (90.9 %) and fatigue (79.5 %). A total of 77.3 % experienced grade ≥3 AEs, most commonly neutropenia (25.0 %) and peripheral neuropathy (18.2 %). Among the 42 phase 2a patients with measurable disease, the objective response rate (ORR) was 50.0 % (95 % confidence interval (CI) 34.6–65.4); the clinical benefit rate (CBR) was 56.8 % (95 % CI 41.6–71.0). No pharmacokinetic interactions were observed between T-DM1 and paclitaxel. Conclusions This regimen showed clinical activity. Although there is potential for paclitaxel to be added to T-DM1 ± pertuzumab, peripheral neuropathy was common in this heavily pretreated population. Trial registration ClinicalTrials.gov NCT00951665. Registered August 3, 2009. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0691-7) contains supplementary material, which is available to authorized users.