HER2-targeted Agents Research Articles

OTHR-10. Diverse survival outcomes of HER2+ Breast Cancer Brain Metastases (BrCBM) presenting with isolated brain relapse compared to those with concurrent extracranial disease

BackgroundIn patients with isolated HER2+ BrCBM and no extracranial disease (ECD), there are no consensus guidelines on optimal treatment approaches following CNS-directed therapy. Our goal was to determine the implications of ECD at time of first HER2+ BrCBM on intracranial progression-free survival (PFS1) and overall survival (OS).MethodsRetrospective analysis was performed on 77 patients with HER2+ BrCBM who received 1st CNS radiation from 2006–2020. Demographics, dates of metastatic and intracranial diagnosis, ECD status at 1st BrCBM, and outcomes were collected. The primary endpoint was PFS1 defined as time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from 1st CNS radiation and 1st metastatic disease to date of death/last known alive. ECD status was defined by RECIST1.1 from staging scans within 30 days of 1st BrCBM.ResultsIn this patient cohort, 25% (19/77) had isolated brain relapse/no ECD. Median age was 50 years. Most patients (58%) developed first BrCBM during adjuvant or early-line metastatic therapy. All patients with no ECD presented with isolated brain relapse as first metastatic presentation. Patients with concurrent ECD presented with first BrCBM at a median of 16.6m (95% CI: 10.5 to 25.3) after initial metastatic presentation. Median OS from initial metastatic presentation to death was worse for patients with isolated brain relapse (25.3m, 95% CI: 16.8 to 35.3) compared to those with concurrent ECD (49.7m, 95% CI: 43.2 to 62; p=0.01). Median OS from first CNS involvement to death was not statistically different amongst groups.ConclusionsPatients with isolated HER2+ BrCBM as their initial metastatic event have substantially worse OS compared to patients with concurrent ECD developing CNS metastases later in their disease course. This population with isolated brain relapse deserves investigation of novel treatment algorithms, including earlier introduction of brain-penetrable HER2-targeted agents.

Preclinical evaluation of MRG002, a novel HER2-targeting antibody-drug conjugate with potent antitumor activity against HER2-positive solid tumors.

ERBB2 is a proto-oncogene of multiple cancers including breast and gastric cancers with HER2 protein overexpression or gene amplification and has been proven clinically as a valid target for these cancers. HER2-targeting agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA for the treatment of breast cancer, but these drugs still face the challenge of acquired resistance and/or severe adverse reactions in clinical use. Therefore, there is significant unmet medical need for developing new agents that are more effective and safer for patients with advanced HER2-positive solid tumors including breast and gastric cancers. We report here the making of MRG002, a novel HER2-targeted antibody drug conjugate (ADC), and preclinical characterization including pharmacology, pharmacodynamics and toxicology and discuss its potential as a novel agent for treating patients with HER2-positive solid tumors. MRG002 exhibited similar antigen binding affinity but much reduced antibody-dependent cellular cytotoxicity (ADCC) activity compared to trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor regression in both high- and medium-to-low HER2 expressing in vivo xenograft models. Furthermore, MRG002 showed enhanced antitumor activity when used in combination with an anti-PD-1 antibody. Main findings from toxicology studies are related to the payload and are consistent with literature report of other ADCs with monomethyl auristatinE. MRG002 has demonstrated a favorable toxicity profile and potent antitumor activities in the breast and gastric PDX models with varying levels of HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical study of MRG002 in patients with HER2-positive solid tumors is ongoing (CTR20181778).

Neoadjuvant Therapy with Trastuzumab Emtansine for HER2-Positive Breast Cancer

Chemotherapy with dual HER2-targeting agents (e.g., pertuzumab, trastuzumab) is considered optimal neoadjuvant therapy for patients with operable

Can Women With HER2-Positive Metastatic Breast Cancer Be Cured?

Breast cancer that is characterized by amplification or over expression of human epidermal growth factor receptor 2 (HER2) accounts for 15% to 20% of all forms of the disease. Although HER2 amplification has been associated with aggressive disease behavior and poor prognosis, the development and availability of a number of HER2-targeted agents has led to improved outcomes for patients with HER2-positive metastatic breast cancer, with data suggesting that overall survival has substantially improved in the past 2 decades. An increasing proportion of HER2-positive metastatic breast cancer is diagnosed as de novo stage IV disease. Patients with de novo metastases are traditionally classified in the general category of metastatic breast cancer and not analyzed as a distinct subgroup, though response to therapy and disease outcomes may differ from that of disease that recurred after early stage disease. Among patients with HER2+ de novo metastatic breast cancer, those who achieve a complete response have a prolonged progression‐free survival and overall survival. Moreover, the fact that some patients achieve a prolonged durable response has raised interest and renewed discussion about whether cure is feasible in the complex context of metastatic breast cancer. In this review, available data associated with the possibility of cure in the population of patients with HER2+ de novo metastatic breast cancer are presented and discussed in detail.

Abstract 337: p16INK4A-deficiency predicts for response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases

Abstract Approximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). To identify predictors of response and resistance to brain-penetrant, small molecule targeted therapies, we performed whole exome sequencing, RNAseq and quantitative immunohistochemistry of HER2+ BCBM tissues from 21 patients. We found that the tumor suppressor p16INK4A (p16) was deficient in the majority of HER2+ BCBMs. Orthotopic HER2+ BCBM patient-derived xenograft (PDX) models with p16 deficiency were resistant to the brain-penetrant HER2 inhibitor, tucatinib or the brain penetrant CDK4/6 inhibitor, abemaciclib, when used as single agents. However, p16-deficiency predicted response to combined tucatinib and abemaciclib in orthotopic HER2+ BCBM PDX models. These data establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2+ BCBM. Citation Format: Jing Ni, Sheheryar Kabraji, Shaozhen Xie, Yanzhi Wang, Peichen Pan, Xiaofang He, Zongming Liu, Henry Long, Myles Brown, Eric P. Winer, Deborah Dillon, Nancy Lin, Jean Zhao. p16INK4A-deficiency predicts for response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 337.

Where to Start and What to Do Next: The Sequencing of Treatments in Metastatic Esophagogastric Cancer.

Esophagogastric cancer is associated with rising incidence and high mortality. Nearly 40% of patients have metastatic disease at the time of diagnosis with poor 5-year overall survival. The treatment of squamous cell carcinoma of the esophagus and gastroesophageal adenocarcinoma has started to bifurcate in recent years, owing to the evolving understanding of the biologic and genomic characteristics of these tumors. Incorporation of HER2-directed therapy in the form of monoclonal antibody and antibody-drug conjugate is now standard of care for patients with HER2-positive disease. The addition of immune checkpoint inhibitors to the therapeutic landscape of metastatic esophagogastric cancer is associated with modest improvement in overall survival, and definition of predictive biomarkers of response to checkpoint inhibition remains imprecise. A number of therapeutic targets including FGFR2b, Claudin 18.2, DKK-1, and DNA repair defects are being explored in clinical trials. Similarly, combination immunotherapy and novel HER2-targeting agents, such as bispecific antibody and small-molecule inhibitors, are at various stages of clinical development. Despite the progress made in the field of targeted therapies and checkpoint inhibition, chemotherapy remains an integral part of treatment of metastatic esophagogastric cancer but is associated with considerable toxicity. Clinical trials focusing on minimizing toxicity of currently available therapeutic agents, development of novel biomarker-driven treatment strategies, and overcoming resistance to immune checkpoint inhibition will define the future of this traditionally indelible disease.

Establishment and Characterization of a HER2-Positive Cell Line Derived From the Pleural Effusion of a Drug-Resistant Breast Cancer Patient.

Drug resistance is a daunting challenge in the treatment of breast cancer, making it an urgent problem to solve in studies. Cell lines are important tools in basic and preclinical studies; however, few breast cell lines from drug-resistant patients are available. Herein, we established a novel HER2-positive breast cancer cell line from the pleural effusion of a drug-resistant metastatic breast cancer patient. This cell line has potent proliferative capability and tumorigenicity in nude mice but weak invasive and colony-forming capability. The molecular subtype of the cell line and its sensitivity to chemotherapeutics and HER2-targeting agents are different from those of its origin, suggesting that the phenotype changes between the primary and metastatic forms of breast cancer.

Impact of extracranial disease status on survival after initial central nervous system (CNS) involvement and radiation therapy in HER2+ breast cancer brain metastases (BCBM).

1041 Background: BCBMs are very common in metastatic HER2+ breast cancer. CNS-directed local therapy is the gold standard for treatment, followed by systemic HER2-targeted therapies. In patients with HER2+ BCBM and stable extracranial disease (ECD), consensus guidelines recommend continuing current systemic therapy after local therapy. Our goal was to determine the implications of ECD status at time of HER2+ BCBM first CNS involvement on outcomes including intracranial progression-free survival (PFS1) and overall survival (OS). Methods: Retrospective analysis was performed on data extracted from 77 patients with HER2+ BCBM who received CNS radiation at Duke between 2006 and 2020 following initial documentation of CNS involvement. Demographics, dates of metastatic and intracranial diagnosis, ECD status at first CNS involvement, systemic therapy, and outcomes were collected. The primary endpoint was PFS1 defined as the time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from first CNS radiation and first metastatic disease to date of death or last known alive. ECD status was defined by RECIST1.1 from systemic staging scans within 30 days of first CNS involvement. Results: In this patient cohort of HER2+ BCBMs undergoing CNS radiation at first CNS involvement, >50% of patients had extracranial disease control: no ECD (25%) or stable/responding disease (31%). 52% of patients’ tumors were ER+. Median age was 50 years (range 27 – 75). Most patients (58%) developed first CNS involvement during adjuvant or first/second line metastatic therapy. For first CNS radiation, 49% received SRS and 48% WBRT. All patients with no ECD presented with isolated CNS disease as first metastatic presentation. Median OS in this cohort from initial metastatic disease to death was markedly worse for patients with no ECD (25.3m, 95% CI: 16.8 to 35.3) compared to those with progressive or stable/responding ECD (48.8m, 95% CI: 28.1 to 65; and 52.9 months, 95% CI: 43.7 to 73.3, respectively; p=0.03). Median OS from first CNS involvement to death was not statistically different amongst groups. This analysis did not detect median PFS1 differences based on ECD after first CNS radiation: progressive ECD (6.3m), no ECD (8.7m), or stable/responding ECD (10.6m) (p=0.13), though clinically meaningful differences were observed. Conclusions: Patients with isolated HER2+ BCBM with no ECD at the time of their initial CNS involvement (25% of population) have substantially worse OS compared to patients who present with ECD and develop CNS metastases later in their disease course. This population with isolated CNS disease at metastatic presentation deserves investigation of novel treatment algorithms, including earlier introduction of brain penetrable HER2-targeted agents.

Prolonged Response to HER2-Directed Therapy in Three Patients with HER2-Amplified Metastatic Carcinoma of the Biliary System: Case Study and Review of the Literature.

HER2 amplification, which results in overexpression of the receptor tyrosine kinase HER2, has been described in a wide variety of malignancies. HER2-targeting agents have been incorporated into the treatment paradigms for HER2-overexpressing breast and gastric cancer. More recently, these agents have shown promise in other gastrointestinal malignancies, such as colon cancer and biliary tract tumors. This study discusses two patients with gallbladder carcinoma and a third with ampullary carcinoma who were able to achieve marked responses to HER2-directed therapy. These cases underscore the importance of molecular analysis for HER2 amplification/HER2 overexpression, irrespective of tumor histology, and highlight a need for further investigation of HER2-directed therapy beyond breast and gastroesophageal cancers. KEY POINTS: Current guidelines recommend molecular assessment for HER2 overexpression exclusively in breast and gastric adenocarcinoma. The focus of this report is on three cases (two biliary tract and one ampullary carcinoma) in which amplification of HER2 or overexpression of HER2 was detected and treatment with HER2-directed therapy resulted in robust responses. These cases exemplify responsiveness of non-breast/gastric histologies to HER2-directed therapies, highlighting several promising new settings for these agents. Testing for amplification of HER2 or overexpression of HER2 should be considered especially in rare diseases with limited treatment options.

The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2+ breast cancer.

Despite the availability of multiple human epidermal growth factor receptor 2–targeted (HER2-targeted) treatments, therapeutic resistance in HER2+ breast cancer remains a clinical challenge. Intratumor heterogeneity for HER2 and resistance-conferring mutations in the PIK3CA gene (encoding PI3K catalytic subunit α) have been investigated in response and resistance to HER2-targeting agents, while the role of divergent cellular phenotypes and tumor epithelial-stromal cell interactions is less well understood. Here, we assessed the effect of intratumor cellular genetic heterogeneity for ERBB2 (encoding HER2) copy number and PIK3CA mutation on different types of neoadjuvant HER2-targeting therapies and clinical outcome in HER2+ breast cancer. We found that the frequency of cells lacking HER2 was a better predictor of response to HER2-targeted treatment than intratumor heterogeneity. We also compared the efficacy of different therapies in the same tumor using patient-derived xenograft models of heterogeneous HER2+ breast cancer and single-cell approaches. Stromal determinants were better predictors of response than tumor epithelial cells, and we identified alveolar epithelial and fibroblastic reticular cells as well as lymphatic vessel endothelial hyaluronan receptor 1–positive (Lyve1+) macrophages as putative drivers of therapeutic resistance. Our results demonstrate that both preexisting and acquired resistance to HER2-targeting agents involve multiple mechanisms including the tumor microenvironment. Furthermore, our data suggest that intratumor heterogeneity for HER2 should be incorporated into treatment design.

Current treatment options for HER2-positive breast cancer patients with brain metastases.

Brain metastases (BMs) are frequently associated with HER2+ breast cancer (BC). Their management is based on a multi-modal strategy including both local treatment and systemic therapy. Despite therapeutic advance, BMs still have an adverse impact on survival and quality of life and the development of effective systemic therapy to prevent and treat BMs from HER2 + BC represents an unmet clinical need. Trastuzumab-based therapy has long been the mainstay of systemic therapy and over the last two decades other HER2-targeted agents including lapatinib, pertuzumab and trastuzumab emtansine, have been introduced in the clinical practice. More recently, novel agents such as neratinib, tucatinib and trastuzumab deruxtecan have been developed, with interesting activity against BMs. Further research is needed to better elucidate the best sequence of these agents and their combination with local treatment.

Systemic treatment of HER2-positive breast cancer patients with brain metastases: current status and exploratory case study in a Portuguese cohort

Over the last years, the incidence of brain metastases in HER2 breast cancer patients has increased. Surgery and radiotherapy are the current standard local therapies. Nevertheless, it is unclear which and when systemic treatment should be applied in addition to local treatment. This work aims to present an updated review of current systemic treatment options for patients with HER2+ metastatic breast cancer with brain metastases and to present a case study of clinical cases that occurred in a Portuguese population. The methodology of this work included a literature search in PubMed for the impact of HER2-targeting agents, such as pertuzumab, trastuzumab emtansine (T-DM1), lapatinib, neratinib, trastuzumab deruxtecan, and tucatinib in the treatment of patients with HER2+ breast cancer with brain metastases. Then, a cohort of Portuguese patients with HER2+ breast cancer (n=44) was analyzed. In this exploratory study, considering a follow-up of 23.9 months, three patients (6.8%) developed brain metastases despite having shown a complete pathological response. The role of systemic treatment for patients with HER2 breast cancer with brain metastases has rapidly evolved following recent successes in phase II and III clinical trials. The biggest challenge is how to integrate systemic and local treatment in the management of these patients.

Spatial proteomic characterization of HER2-positive breast tumors through neoadjuvant therapy predicts response.

The addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early-stage, HER2-positive breast cancer. Nonetheless, up to 50% of patients have residual disease after treatment, while others are likely overtreated. Here, we performed multiplex spatial proteomic characterization of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial sampled pre-treatment, after 14-21 d of HER2-targeted therapy and at surgery. We demonstrated that proteomic changes after a single cycle of HER2-targeted therapy aids the identification of tumors that ultimately undergo pCR, outperforming pre-treatment measures or transcriptomic changes. We further developed and validated a classifier that robustly predicted pCR using a single marker, CD45, measured on treatment, and showed that CD45-positive cell counts measured via conventional immunohistochemistry perform comparably. These results demonstrate robust biomarkers that can be used to enable the stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy, with implications for tailoring subsequent therapy.

Immunohistochemical HER2 score correlates with response to neoadjuvant chemotherapy in HER2-positive primary breast cancer.

The accuracy of biomarker assessment in breast cancer (BC) is paramount for therapy decisions and informs prognosis. We investigated neoadjuvant chemotherapy (NAC) response in HER2-positive BC with respect to immunohistochemistry (IHC) and in situ hybridization (ISH) results. We aimed to determine the role of HER2 protein expression in predicting NAC response and long-term outcome in two HER2-positive groups: IHC 3 + versus IHC 2 + ISH amplified groups. This retrospective study included 192 consecutive HER2 + primary BCs diagnosed from 2007 to 2019 treated with NAC and HER2-targeted agent (NACH). There were 158 HER2 3 + and 34 HER2 2 + ISH + cases. Clinicopathological parameters and long-term outcomes were analyzed. The Pathological Complete Response (pCR) rate was 85.7% (72/84) in ER-/HER2 + BCs and was lower in ER + /HER2 + BCs (42.6%, 46/108). The pCR was 55.1% (86/156) in the HER2 3 + group and was only 17.6% in HER2 2 + ISH + group (p < 0.001). Patients who achieved pCR in HER2 2 + ISH + group did not show a significantly higher HER2/CEP17 ratio or HER2 copy number. The overall survival (OS) and progression-free survival (PFS) were significantly higher in pCR compared to non-pCR cases (p = 0.011 and p = 0.015, respectively). There is significant heterogeneity in response to the NACH regimens in HER2 + cases. Our findings indicate that HER2 IHC score and ER expression determine NACH response in HER2 + BC. We recommend considering HER2 protein expression and ISH value to better select patients and assess the response for HER2-targeted therapy.

Abstract PS7-82: A real-world evidence study of treatment patterns among patients with HER2-positive metastatic breast cancer

Abstract Background Historically, the standard-of-care treatments for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC) have included targeted therapies, such as trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1), which have shown efficacy in clinical trials. Treatment choice and sequencing for patients with HER2+ mBC after first-line therapy have not been well delineated in the US real-world setting. Methods Patients who received at least two lines of therapy for HER2+ mBC diagnosed from January 2013 - April 2019 were selected from the Flatiron Health electronic health record-derived database. The Flatiron database is nationwide and comprises deidentified patient-level structured and unstructured data curated via technology-enabled abstraction in the US. The index date was the start date of the second line of therapy (2L). Treatment patterns from 2L onward were examined. Baseline information included disease stage at diagnosis and prior treatment for mBC. Duration of therapy was estimated using the Kaplan-Meier method. Results Among the 1390 patients with HER2+ mBC with a documented 2L therapy, the mean age at the initiation of 2L therapy was 60.4 years. Patients had one (n = 514; 37.0%), two (n = 390; 28.1%), or three or more (n = 461; 33.2%) metastatic sites by the start of 2L therapy. The most common metastatic sites were bone (n = 872; 62.7%), lung (n = 494; 35.5%), liver (n = 473; 34.0%), and brain (n = 223; 16.0%). The majority of patients (n = 1141; 82.1%) had positive hormone receptor status. Nearly half of patients (n = 601; 43.2%) had stage IV disease at their initial breast cancer diagnosis, 289 (20.8%) had stage III, and 277 (19.9%) had stage II. Before 2L therapy, 720 patients (51.8%) received a HER2-targeted combination therapy, 337 (24.2%) received hormone therapy alone, and 209 (15.0%) received HER2-targeted monotherapy. Among all included patients, 481 (34.6%) had two lines of systemic therapy for mBC, 359 (25.8%) had three, and 550 (39.6%) had four or more. Of these patients, 1290 (92.8%) had used a HER2-targeted agent (monotherapy or in combination) in at least one line of therapy, and 1108 (79.7%) had two or more lines of therapy containing a HER2-targeted agent. In 2L, the most frequently prescribed regimens were pertuzumab + trastuzumab + taxane (n = 246; 17.7%), T-DM1 monotherapy (n = 213; 15.3%), and trastuzumab monotherapy (n = 192; 13.8%). Overall, in 2L, 721 (51.9%) of all included patients received HER2-targeted combination therapy, 427 (30.7%) received HER2-targeted monotherapy, 82 (5.9%) received chemotherapy, and 118 (8.5%) received hormone therapy alone. Hormone therapy was combined with chemotherapy or targeted therapy in 622 patients (44.7%). Median (95% CI) duration of 2L therapy was 6 (6-6) months. Among the 909 patients who had third-line (3L) therapy, the most common regimens were T-DM1 (n = 170; 18.7%), pertuzumab + trastuzumab + taxane (n = 77; 8.5%), and hormone therapy alone (n = 59; 6.5%). Overall, in 3L, 446 patients (49.1%) had HER2-targeted combination therapy, 283 (31.1%) had HER2-targeted monotherapy, and 78 (8.6%) had chemotherapy, with hormone therapy added to chemotherapy or targeted therapy in 388 patients (42.7%). Median (95% CI) duration of 3L therapy was 5 (4-6) months. Conclusions The results of this real-world study of patients receiving care in community-based oncology clinics suggest that treatment patterns in later-line settings are variable, with no clear treatment approach for this patient population and patients often being re-treated with the same HER2-targeted therapies. As additional targeted therapies have recently been approved for HER2+ mBC with improvements in patient outcomes, future examination of the treatment landscape is warranted. Citation Format: Jenna Collins, Beth Nordstrom, Jackie Kwong, Brian Murphy, Melissa Pavilack. A real-world evidence study of treatment patterns among patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-82.

Abstract PS10-03: Interim safety and efficacy analysis of phase IB / II clinical trial of tucatinib, palbociclib and letrozole in patients with hormone receptor and HER2-positive metastatic breast cancer

Abstract Background: In hormone receptor-positive / HER2-positive (HR+/HER2+) breast cancer, the HER2 and estrogen receptor (ER) signals merge on the cyclin D1-CDK4/6-RB1 pathway. Thus, a combined pharmacological intervention with individual drugs targeting HER2, ER and CDK4/6 is warranted. Here, we present the safety and efficacy results of the combination of tucatinib with letrozole and palbociclib in patients (pts) with HR+/HER2+ metastatic breast cancer (MBC) (NCT03054363). Methods: Pts with HR+/HER2+ MBC previously treated with at least 2 HER2-targeted agents were enrolled in this phase IB/II clinical trial. Pts with untreated asymptomatic or stable treated brain metastasis (BM) were included. Pts with treated progressing BM were enrolled after local treatment and classified as treated stable. Treatment consisted of tucatinib 300mg PO BID and letrozole 2.5mg PO daily continuously, and palbociclib 125mg PO daily 21 days on, 7 days off. Due to drug-drug interaction issues found in the middle of the trial and not related to this study, the dose of sensitive CYP3A4 substrate palbociclib was reduced to 75mg for all study participants, as it became evident that tucatinib is a strong CYP3A4 inhibitor. The primary end-points were assessment of safety using CTCAE v.4.03 criteria, and progression free survival (PFS). Secondary end-points included pharmacokinetic evaluation (PKs) and objective response rate by RECIST 1.1. BM response was evaluated using RANO-BM criteria. All pts who received at least one cycle of therapy were assessed for safety. Results: Between 11.21.2017 and 04.20.2020, we enrolled 42 pts of whom 40 were evaluable. Median age was 52.5 years (range, 22 to 82) and the median number of prior lines of therapy for MBC was 2 (range, 0 to 7); 23 pts (58%) had visceral disease and 15 (38%) had BM. All pts had prior therapy with trastuzumab and pertuzumab and 18 pt (45%) had prior T-DM1. As of 06.15.2020 data cut off, 14 patients were on active therapy while 26 were off study (22 due to progressive disease [PD], 1 due to toxicity and 3 for other reasons). Median follow up time was 6 months. The combination was well tolerated with manageable and expected adverse events (AEs). The most common grade ≥3 AEs were neutropenia (25 pts, 60%), leukopenia (10 pts, 24%), diarrhea (8 pts, 19%), fatigue (6 pts, 14%), and infections (6 pts, 14%). One pt came off study due to asymptomatic grade 4 elevated LFTs that resolved without sequelae. There were no deaths due to AEs. Among 26 pts with measurable disease at the time of data cut-off, 8 pts (31%) had partial response, 16 pts (62%) had stable disease (SD) (7 pts [27%] had SD for ≥ 6 months and 6 pts [23%] have not yet reached 6 months of follow up) and 2 pts (8%) had PD. Among 14 patients with BM and evaluable disease by RANO-BM, 1 pt had complete response in the brain, 6 pts had SD in the brain for ≥6 months, and 7 pts had SD for 2-6 months (4 pts on active therapy have not yet reached 6 months of follow up). Median PFS is 8.7 months (10.1 months for pts without BM and 6.0 months for those with BM). Updated analysis including PKs, tumor response, and PFS will be presented. Conclusion: The combination of tucatinib with letrozole and palbociclib showed a tolerable and manageable safety profile and evidence of considerable anti-tumor activity that warrant further clinical investigation in pts with HR+/HER2+ MBC. Citation Format: Elena Shagisultanova, William Gradishar, Ursa Brown-Glaberman, Pavani Chalasani, Andrew J. Brenner, Alison Stopeck, Jose Mayordomo, Jennifer R. Diamond, Peter Kabos, Virginia F. Borges. Interim safety and efficacy analysis of phase IB / II clinical trial of tucatinib, palbociclib and letrozole in patients with hormone receptor and HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-03.

Abstract PS9-54: Healthcare costs for metastatic breast cancer patients treated with human epidermal growth factor receptor 2 targeted agents

Abstract Background: Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancer (BC) represents approximately 15% of early stage BC cases and is associated with a more aggressive clinical phenotype and poor prognosis with respect to most BC. Over the last decade new HER2-targeted therapies have become available that have prolonged survival for both early stage and metastatic breast cancer (mBC). However, the cost impact of these therapies has not been fully assessed in recent years. Given the evidence for major clinical benefit, it is imperative that health systems evaluate new treatments to maximize the value of health care expenditures. This study evaluated healthcare costs among mBC patients treated with HER2-targeted therapy. Methods: A retrospective cohort study using the IQVIA Real-World Data Adjudicated Claims Database (1/1/2015-7/31/2019) was conducted. Adult (≥18-years) female patients who initiated HER2-targeted therapy with evidence of mBC diagnosis in the prior year were identified. The study index date was the initiation date of the HER2-targeted agent after which, patients were required to have ≥12 months of follow-up. Annual all-cause and BC-related healthcare costs per patient (2019 USD) were computed using payer-paid amounts in the first and second year following the index date. BC-related costs were defined as costs for claims with a primary diagnosis for BC (ICD-9-CM: 174.% or ICD-10-CM: C50.%) or BC-related treatment (surgery – mastectomy or lumpectomy, HER2-targeted therapy, chemotherapy, hormone therapy, immunotherapy, and radiation). Results: 708 mBC patients treated with HER2-targeted therapy were included with a mean age (SD) of 53.2 (10.2) years and mean follow-up of about 2 years. During the follow-up period, trastuzumab (96.5%) and pertuzumab (81.2%) were the most common HER2-targeted therapies used followed by ado-trastuzumab (15.4%), neratinib (6.3%), and lapatinib (5.3%). Additionally, patients received other treatments including chemotherapy (88.0%), hormone therapy (56.6%), and radiation therapy (57.6%). Of note, 40.3% of patients underwent surgery (mastectomy or lumpectomy) following evidence of metastasis. Following initiation of HER2-targeted therapy, mean annual costs per patient in Year 1 and Year 2 were $330,784 and $196,139, respectively. Correspondingly, BC-related costs in Year 1 and Year 2 were $255,273 and $144,978, respectively. HER2-targeted therapies accounted for 72% of BC-related costs in both Year 1 and 2. Surgery patients incurred $37,822 higher BC-related costs in Year 1 compared to non-surgery patients. However, in Year 2, the opposite was noted with non-surgery patients having $70,885 higher BC-related costs, mainly due to a differences in BC treatment rates in Year 2 for HER2 targeted drugs, other BC drugs and radiation. Conclusion: Total BC-related costs of mBC patients treated with HER2-targeted therapy is highest in the first year following treatment initiation, with the main cost driver being the cost of HER2-targeted therapy. While total costs decreased in the subsequent year, the cost of HER2 targeted therapy remained the dominant component. Results of this study highlight the significant economic burden of treating HER2+ mBC and also the need for therapies that limit disease progression. Page 1 of 1 Citation Format: Reshma Mahtani, Deepa Lalla, Nina Oestreicher, Augustina Ogbonnaya, Vishal Saundankar, Joanne Willey, Anna Coutinho, Kelly McCann. Healthcare costs for metastatic breast cancer patients treated with human epidermal growth factor receptor 2 targeted agents [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-54.

A phase I open-label study to investigate safety and tolerability, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MT-5111 in patients with HER2-positive tumors.

TPS258 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action &amp; are capable of forcing internalization, self-routing through intracellular compartments to the cytosol &amp; inducing potent cell-kill via the enzymatic &amp; permanent inactivation of ribosomes. MT-5111 is a de-immunized ETB targeting HER2+ solid tumors. Its novel mechanism of action, via enzymatic ribosome inactivation, may not be subject to resistance mechanisms that exist for tyrosine kinase inhibitors, antibody-drug conjugates, or antibody modalities. MT-5111 binds an epitope on HER2, distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2-targeting agents. MT-5111 is a 55 kilodalton protein &amp; may have improved tumor penetration capability. The objective of this trial will be to determine the safety, tolerability, &amp; maximum tolerated dose (MTD) of MT-5111 in patients (pts) with advanced HER2+ solid tumors. Methods: This Phase 1, first-in-human, open-label, dose escalation &amp; expansion study will evaluate MT-5111 monotherapy in pts with HER2-positive solid tumors. The primary objective is to determine the MTD; secondary objectives include pharmacokinetics, tumor response &amp; immunogenicity. Part 1 consists of MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10µg/kg/dose) based on a modified 3+3 design (n≤42 pts); Part 2 (dose expansion) will evaluate MT-5111 at the MTD in ≤98 pts. All pts will be administered MT-5111 over 30 min via IV infusion on Days 1, 8, &amp; 15 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal of consent, or another reason for withdrawal. Part 1 will include pts with any HER2+ solid cancers. Part 2 will enroll 3 expansion cohorts: HER2+ breast (BC), HER2+ gastric or gastroesophageal junction adenocarcinomas (collectively referred as gastroesophageal adenocarcinomas [GEA]) &amp; other HER2+ solid cancers. Immunohistochemistry (IHC) status must be 2+ or 3+, regardless of in situ hybridization (ISH) results; if no IHC is available for pts with BC or GEA, ISH criteria per the American Society of Clinical Oncology College of American Pathologists guidelines will be used. In metastatic cases, HER2 positivity must be demonstrated on metastatic lesions. Pts with HER2+ BC should have had ≥2 lines of HER2-directed therapy; pts with HER2+ GEA should have received or been intolerant to trastuzumab. Pts with evaluable disease may be included in Part 1; in Part 2, all pts must have ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors v1.1. Further details can be found on clinicaltrials.gov (NCT04029922). Enrollment, which began in September 2019, is ongoing. Clinical trial information: NCT04029922.

Cardiotoxicity in HER2-positive breast cancer patients.

Due to the recent advances in diagnosis and management of patients with HER2-positive breast cancer, especially through novel HER2-targeted agents, cardiotoxicity becomes an emerging problem. Although chemotherapy significantly increases survival, the risk of cardiovascular disease development is high and still underestimated and could imply treatment discontinuation. Frequently, due to lack of rigorous diagnosis strategies, cardiotoxicity assessment is delayed, and, moreover, the efficacy of current therapy options in restoring heart function is questionable. For a comprehensive risk assessment, it is vital to characterize the clinical spectrum of HER2-targeted agents and anthracyclines, as well as their pathogenic pathways involved in cardiotoxicity. Advanced cardiovascular multimodal imaging and circulating biomarkers plays primary roles in early assessing cardiotoxicity and also in guiding specific preventive measures. Even though the knowledge in this field is rapidly expanding, there are still questions that arise regarding the optimal approach in terms of timing and methods. The aim of the current review aims to providean overview of currently available data.

Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway

HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.