Impact of the Breast Cancer Index for Extended Endocrine Decision-Making: First Results of the Prospective BCI Registry Study.

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.

Pertuzumab plus high-dose trastuzumab for HER2-positive breast cancer with brain metastases: PATRICIA final efficacy data.

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.

Evolving perspectives on the treatment of HR+/HER2+ metastatic breast cancer.

Breast cancer (BC) with expression of the estrogen receptor (ER) and/or progesterone receptor (PR) protein and with overexpression/amplification of the human epidermal growth factor receptor 2 (HER2), termed hormone receptor-positive (HR+)/HER2+ BC, represents ∼10% of all BCs in the United States. HR+/HER2+ BC includes HER2+ BCs that are ER+, PR+, or both ER+ and PR+ (triple-positive BC). Although the current guideline-recommended treatment combination of anti-HER2 monoclonal antibodies plus chemotherapy is an effective first-line therapy for many patients with HER2+ advanced disease, intratumoral heterogeneity within the HR+/HER2+ subtype and differences between the HR+/HER2+ subtype and the HR-/HER2+ subtype suggest that other targeted combinations could be investigated in randomized clinical trials for patients with HR+/HER2+ BC. In addition, published data indicate that crosstalk between HRs and HER2 can lead to treatment resistance. Dual HR and HER2 pathway targeting has been shown to be a rational approach to effective and well-tolerated therapy for patients with tumors driven by HER2 and HR, as it may prevent development of resistance by blocking receptor pathway crosstalk. However, clinical trial data for such approaches are limited. Treatments to attenuate other signaling pathways involved in receptor crosstalk are also under investigation for inclusion in dual receptor targeting regimens. These include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, based on the rationale that association of CDK4/6 with cyclin D1 may play a role in resistance to HER2-directed therapies, and others such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway inhibitors. Herein, we will review the scientific and clinical rationale for combined receptor blockade targeting HER2 and ER for patients with advanced-stage HR+/HER2+ disease.

Incorporating clinicopathological and molecular risk prediction tools to improve outcomes in early HR+/HER2- breast cancer.

Stratification of recurrence risk is a cornerstone of early breast cancer diagnosis that informs a patient's optimal treatment pathway. Several tools exist that combine clinicopathological and molecular information, including multigene assays, which can estimate risk of recurrence and quantify the potential benefit of different adjuvant treatment modalities. While the tools endorsed by treatment guidelines are supported by level I and II evidence and provide similar prognostic accuracy at the population level, they can yield discordant risk prediction at the individual patient level. This review examines the evidence for these tools in clinical practice and offers a perspective of potential future risk stratification strategies. Experience from clinical trials with cyclin D kinase 4/6 (CDK4/6) inhibitors in the setting of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer is provided as an illustrative example of risk stratification.

Estrogen/HER2 receptor crosstalk in breast cancer: combination therapies to improve outcomes for patients with hormone receptor-positive/HER2-positive breast cancer.

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 13-22% of breast cancers (BC). Approximately 60-70% of HER2+ BC co-express hormone receptors (HRs). HR/HER2 co-expression modulates response to both anti-HER2-directed and endocrine therapy due to "crosstalk" between the estrogen receptor (ER) and HER2 pathways. Combined HER2/ER blockade may be an effective treatment strategy for patients with HR+/HER2+ BC in the appropriate clinical setting(s). In this review, we provide an overview of crosstalk between the ER and HER2 pathways, summarize data from recently published and ongoing clinical trials, and discuss clinical implications for targeted treatment of HR+/HER2+ BC.

Epidemiology, clinical outcomes, and unmet needs of patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases: A systematic literature review.

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.

Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial.

Importance: It is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs. Objective: To describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up. Design, Setting, and Participants: HER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed. Interventions: Patients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle). Main Outcomes and Measures: Evaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion-free survival in all patients. Only OS was prespecified before the primary database lock. Results: At baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI, 18.1-28.5) vs the placebo-combination group (12.5 months; 95% CI, 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS and ORR-IC compared with the placebo-combination group. The DOR-IC was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group vs the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]). Conclusions and Relevance: This subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs. Trial Registration: ClinicalTrials.gov Identifier: NCT02614794.

Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial.

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.

The Phase II MutHER Study of Neratinib Alone and in Combination with Fulvestrant in HER2-Mutated, Non-amplified Metastatic Breast Cancer.

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.

Role of Fcγ receptors in HER2-targeted breast cancer therapy.

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.

Research advances and new challenges in overcoming triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 receptor or harbor ERBB2 gene amplification. TNBC includes a collection of multiple distinct disease entities based upon genomic, transcriptomic and phenotypic characterization. Despite improved clinical outcomes with the development of novel therapeutics, TNBC still yields the worst prognosis among all clinical subtypes of breast cancer. We will systematically review evidence of the genomic evolution of TNBC, as well as potential mechanisms of disease progression and treatment resistance, defined in part by advances in next-generation DNA sequencing technology (including single cell sequencing), providing a new perspective on treatment strategies, and promise to reveal new potential therapeutic targets. Moreover, we review novel therapies aimed at homologous recombination deficiency, PI3 kinase/AKT/PTEN pathway activation, androgen receptor blockade, immune checkpoint inhibition, as well as antibody-drug conjugates engaging novel cell surface targets, including recent progress in pre-clinical and clinical studies which further validate the role of targeted therapies in TNBC. Despite major advances in treatment for TNBC, including FDA approval of 2 PARP inhibitors for metastatic TNBC, the crossing of the superiority boundary in a phase 3, placebo-controlled study of adjuvant olaparib in early-stage patients with germline BRCA-mutated high-risk HER2-negative early breast cancer, the FDA approval of 2 PD-(L)1 checkpoint antibodies for metastatic TNBC, and the FDA approval of the first antibody drug conjugate for TNBC, significant challenges remain. For example, despite the dawn of immunotherapy in metastatic TNBC, durable responses are limited to a small subset of patients, definitive biomarkers for patient selection are lacking, and the Oncology Drug Advisory Committee to the FDA has recently voted against approval of an anti-PD-1 checkpoint antibody high risk early-stage TNBC in the neoadjuvant setting. Also, despite early positive randomized phase 2 studies of AKT inhibition in metastatic TNBC, a recent phase 3 registration trial failed to validate earlier phase 2 data. Finally, we note that level one evidence for clinical efficacy of androgen receptor blockade in TNBC is still lacking. To meet these and other challenges, we will catalogue the ongoing exponential increase in interest in basic, translational, and clinical research to develop new treatment paradigms for TNBC.

A careful reassessment of anthracycline use in curable breast cancer.

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.

Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance.

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.

Single-cell immunoblotting resolves estrogen receptor-α isoforms in breast cancer.

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.

Biosimilars in an era of rising oncology treatment options.

New diagnostic technologies, including molecular profiling, have enabled advances in treatments of various cancers; this has significantly improved clinical outcomes, including overall survival. However, the high cost of biologic drugs may prevent patients from having access to optimal treatment. Introduction of lower priced biosimilar agents into the therapeutic armamentarium brings the potential to ease the burden on healthcare expenditure and facilitate better access to effective cancer treatments. Oncology biosimilars have shown comparable efficacy and safety based on clinical evidence and physicochemical quality data as well as in real-world settings. This paper aims to review changes in the management of oncology treatment and their implication with respect to biosimilars.

Pertuzumab Plus High-Dose Trastuzumab in Patients With Progressive Brain Metastases and HER2-Positive Metastatic Breast Cancer: Primary Analysis of a Phase II Study.

PURPOSE: Effective therapies are needed for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) with brain metastases. A trastuzumab radioisotope has been shown to localize in brain metastases of patients with HER2-positive MBC, and intracranial xenograft models have demonstrated a dose-dependent response to trastuzumab. METHODS: In the phase II PATRICIA study (ClinicalTrials.gov identifier: NCT02536339), patients with HER2-positive MBC with CNS metastases and CNS progression despite prior radiotherapy received pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. The primary end point was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary end points included duration of response, clinical benefit rate (complete response plus partial response plus stable disease ≥ 4 or ≥ 6 months) in the CNS, and safety. RESULTS: Thirty-nine patients were treated for a median (range) of 4.5 (0.3-37.3) months at clinical cutoff. Thirty-seven patients discontinued treatment, most commonly because of CNS progression (n = 27); two remained on treatment. CNS ORR was 11% (95% CI, 3 to 25), with four partial responses (median duration of response, 4.6 months). Clinical benefit rate at 4 months and 6 months was 68% and 51%, respectively. Two patients permanently discontinued study treatment because of adverse events (left ventricular dysfunction [treatment-related] and seizure, both grade 3). No grade 5 adverse events were reported. No new safety signals emerged with either agent. CONCLUSION: Although the CNS ORR was modest, 68% of patients experienced clinical benefit, and two patients had ongoing stable intracranial and extracranial disease for > 2 years. High-dose trastuzumab for HER2-positive CNS metastases may warrant further study.

First-in-Human, Phase 1 Dose-Escalation Study of Biparatopic Anti-HER2 Antibody-Drug Conjugate MEDI4276 in Patients with HER2-positive Advanced Breast or Gastric Cancer.

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.

Advances in Therapeutic Approaches for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), defined as breast cancer lacking expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), accounts for up to 20% of all breast cancer, and it occurs at a higher frequency in younger, African American, and Hispanic women. Compared to breast cancers that are hormone receptor and/or HER2 positive, TNBC has an aggressive clinical course and worse prognosis. Because TNBC is by definition unresponsive to endocrine therapy (eg, tamoxifen, aromatase inhibitors) and HER2-directed therapies (eg, trastuzumab), chemotherapy continues to play an important role. TNBC constitutes a molecularly heterogeneous group of tumors that can vary in response to treatment, and clinical management can be challenging, particularly for the practicing community oncologist, for whom breast cancer may be only one of many tumor types encountered. In January 2020, the Breast Cancer Therapy Expert Group (BCTEG) convened a roundtable discussion on the topic of advances in the treatment of TNBC. Topics discussed included histopathologic classification/definition of TNBC, neoadjuvant strategies, adjuvant chemotherapy (with special emphasis on management of patients who do not experience a pathologic complete response), and treatment of metastatic disease. Also reviewed was the wide range of emerging pathways and therapies currently under investigation to expand TNBC treatment options, including immunotherapies and poly(ADP-ribose) polymerase (PARP) inhibitors. This article summarizes the BCTEG discussion and highlights the key opinions relating to the treatment of patients with TNBC.