HER2-targeted Monoclonal Antibody Research Articles

Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer

BackgroundTrastuzumab and pertuzumab combination has been approved for the treatment of patients with HER2-positive metastatic breast cancer. However, trastuzumab and pertuzumab combination did not show improvement in overall survival in patients with HER2-positive metastatic gastric cancer.MethodsWe developed a new HER2-targeted monoclonal antibody, HLX22, targeting HER2 subdomain IV as trastuzumab but with non-overlapping epitopes. We examined the antitumor effects of this novel HER2-antibody in gastric cell lines and cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models.ResultsHLX22 in combination with HLX02 (trastuzumab biosimilar) induced enhancement of HER2/HER2 homodimers and HER2/EGFR heterodimers internalization, which ultimately led to the reduction in signal transductions involving STAT3, P70 S6, and AKT; gene expressions of FGF-FGFR-PI3K-MTOR, EGF-EGFR-RAS, TGF-β-SMAD, PLCG and cell cycle progression related pathways that favor tumor development, proliferation, progression, migration and survival in gastric cancer cell line NCI-N87 were also reduced. These differing but complementary actions contributed to the synergistic antitumor efficacy of the HLX22 and HLX02 combination in gastric cancer cell lines, CDX and PDX. In addition, HLX22 in combination with HLX02 demonstrated stronger antitumor efficacy than HLX02 and HLX11 (a potential pertuzumab biosimilar) combination treatment both in vitro and in vivo.ConclusionsThese results suggested that the application of non-competing antibodies HLX22 and HLX02 targeting HER2 subdomain IV together may be of substantial benefit to gastric cancer patients who currently respond suboptimal to trastuzumab therapy.

Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer

BackgroundTrastuzumab and pertuzumab combination has been approved for the treatment of patients with HER2-positive metastatic breast cancer. However, trastuzumab and pertuzumab combination did not show improvement in overall survival in patients with HER2-positive metastatic gastric cancer.MethodsWe developed a new HER2-targeted monoclonal antibody, HLX22, targeting HER2 subdomain IV as trastuzumab but with non-overlapping epitopes. We examined the antitumor effects of this novel HER2-antibody in gastric cell lines and cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models.ResultsHLX22 in combination with HLX02 (trastuzumab biosimilar) induced enhancement of HER2/HER2 homodimers and HER2/EGFR heterodimers internalization, which ultimately led to the reduction in signal transductions involving STAT3, P70 S6, and AKT; gene expressions of FGF-FGFR-PI3K-MTOR, EGF-EGFR-RAS, TGF-β-SMAD, PLCG and cell cycle progression related pathways that favor tumor development, proliferation, progression, migration and survival in gastric cancer cell line NCI-N87 were also reduced. These differing but complementary actions contributed to the synergistic antitumor efficacy of the HLX22 and HLX02 combination in gastric cancer cell lines, CDX and PDX. In addition, HLX22 in combination with HLX02 demonstrated stronger antitumor efficacy than HLX02 and HLX11 (a potential pertuzumab biosimilar) combination treatment both in vitro and in vivo.ConclusionsThese results suggested that the application of non-competing antibodies HLX22 and HLX02 targeting HER2 subdomain IV together may be of substantial benefit to gastric cancer patients who currently respond suboptimal to trastuzumab therapy.

Mechanisms of action and resistance to anti-HER2 antibody-drug conjugates in breast cancer

Human epidermal growth factor 2 (HER2)-positive breast cancer (BC) represents nearly 20% of all breast tumors. Historically, these patients had a high rate of relapse and dismal prognosis. The advent of HER2-targeting monoclonal antibodies such as trastuzumab followed by pertuzumab had improved the prognosis of HER2-positive metastatic BC. More recently, antibody-drug conjugates (ADCs) are now reshaping the treatment paradigm of solid tumors, especially breast cancer. Tratsuzumab emtansine (T-DM1) was one of the first ADC developed in oncology and was approved for the management of HER2-positive metastatic BC. In a head-to-head comparison, trastuzumab deruxtecan (T-DXd) defeated T-DM1 as a second-line treatment. The efficacy of ADCs is counterbalanced by the appearance of acquired resistance to these agents. In this paper, we summarize the mechanisms of action and resistance of T-DM1 and T-DXd, as well as their clinical efficacy. Additionally, we also discuss potential strategies for addressing resistance to ADC.

Neoadjuvant pyrotinib and inetetamab in combination with chemotherapy for locally advanced HER2-positive breast cancer (NeoPICD study): A prospective, multicenter, open-label, single-arm study.

e12627 Background: Inetetamab, a novel monoclonal antibody targeting HER2, alters the Fc region amino acids, which induces ADCC stronger than trastuzumab. Pyrotinib is a small chemical inhibitor of pan-HER receptor tyrosine kinase. The globally recommended first-line neoadjuvant treatment for HER2-positive breast cancer is chemotherapy and two large-molecule monoclonal antibodies, which have unsatisfactory benefits for 50% of patients. This study aims to investigate the effectiveness and safety of targeted medicines, specifically inetetamab and pyrotinib, in conjunction with chemotherapy for patients diagnosed with locally advanced HER2-positive breast cancer. Methods: The trial was structured as a multicenter, open-label, single-arm, prospective study. 143 treatment-naive HER2-positive locally advanced breast cancer patients were planned for the trial. Eligible patients will be administered six cycles of neoadjuvant treatment, including carboplatin (AUC=6mg/mL×min, ivgtt), doxorubicin (75mg/m2, ivgtt), inetetamab (initial loading dosage of 8mg/kg, maintenance dose of 6mg/kg), and pyrotinib (400mg/day, po). The surgery was conducted after the neoadjuvant phase, subsequent to a one-year course of targeted therapy with inetetamab and pyrotinib. The primary endpoint of the study is the total pathologic complete response (tpCR). The secondary endpoints include event-free survival (EFS), disease-free survival (DFS), distant metastasis-free survival (DMFS), neurologic disease-free survival (NDFS), overall survival (OS), and safety. Results: A cohort of 70 patients was enrolled between Nov. 27, 2021 and Feb. 1, 2024. Most patients completed the six-cycle neoadjuvant therapy with inetetamab, pyrotinib, and chemotherapy. The pathological findings of 49 patients who had radical surgery revealed that 65.3% (32/49, 95% CI, 0.515-0.791) of them achieved tpCR (ypT0/Tis ypN0). The initial subgroup analysis revealed that among patients with negative hormone receptors, the rate of tpCR was 80.0% (24/30, 95% CI, 64.8-95.2). Moreover, hormone receptor was statistically determined to be an independent factor influencing the effectiveness of the new treatment regimen ( p=0.032). The prevailing grade 3 or more severe adverse events included anemia (12.8%), diarrhea (10.0%), leukopenia (4.2%), liver dysfunction (4.2%) and renal dysfunction (4.2%). As of now, no treatment-related deaths have been documented. Conclusions: The ongoing study is actively enrolling participants. Preliminary findings from the study indicate that the combination of neoadjuvant inetetamab and pyrotinib with chemotherapy has demonstrated satisfactory effectiveness and manageable side effects. This offers a promising alternative for patients with locally advanced breast cancer that is HER2-positive. Clinical trial information: NCT06234137 .

An open-label, multicenter, phase 2 study to evaluate the safety and efficacy of BB-1701, a novel antibody drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2), in previously treated patients with HER2-positive (HER2+) or HER2-low unresectable or metastatic breast cancer (BC).

TPS1122 Background: Treatment options for patients (pts) with unresectable or metastatic BC have improved with the development of novel targeted therapies including trastuzumab deruxtecan (T-DXd), an ADC directed against HER2 with a cytotoxic topoisomerase I inhibitor as a payload. Currently, there are limited treatment options for pts with HER2+ or HER2-low metastatic BC that has progressed on T-DXd. BB-1701 is an ADC consisting of a monoclonal antibody targeting HER2 with eribulin (microtubule inhibitor) as a payload that is capable of exerting a bystander effect. A first-in-human dose-finding Study 101 of BB-1701 is ongoing. Here we describe Study 205, an open label, multicenter, phase 2 study of BB-1701 in pts with HER2+ or HER2-low unresectable or metastatic BC who have disease progression after treatment with T-DXd. Methods: Study 205 (NCT06188559) includes dose-optimization and dose-expansion parts for BB-1701. Eligible pts must have histologically confirmed HER2+ or HER2-low, unresectable or metastatic BC, with measurable disease per RECIST v1.1. Prior treatment must include 1–3 prior chemotherapy-based regimens for unresectable or metastatic BC, including T-DXd. The primary objectives of the dose-optimization part include determining the recommended dose (RD) and evaluating safety and tolerability of BB-1701. The RD will be assessed by randomly assigning ~50 pts into 1 of 3 dosing cohorts (1.6 mg/kg on day 1 Q3W, 0.8 mg/kg on days 1 and 8 Q3W, and 1.2 mg/kg on day 1 Q3W; IV) in a 2:2:1 ratio. Randomization will be stratified by HER2 status (HER2+ vs. HER2-low) documented prior to T-DXd treatment. The dose-expansion part will enroll ~85 pts at RD; the primary objective includes evaluating the efficacy of BB-1701 at the RD. In both study parts, secondary objectives include assessment of additional efficacy measures (i.e., duration of response [DOR], progression free survival [PFS], overall survival [OS], disease control rate [DCR], clinical benefit rate [CBR], and time to response [TTR]), and pharmacokinetics. Efficacy endpoints will be assessed per RECIST v1.1 by the investigator during the dose-optimization part or by Blinded Independent Central Review during the dose-expansion part. Safety assessments will consist of recording, monitoring, and grading of adverse events (AEs) based on CTCAE v5.0, AEs of special interest, and serious AEs. In both study parts, exploratory objectives will include evaluation of biomarkers of response to BB-1701 and BB-1701 immunogenicity; other efficacy measures (i.e., PFS on the next line of therapy) and population pharmacokinetics will be analyzed in the dose-expansion part only. Pt enrollment is currently open. Clinical trial information: NCT06188559 .

Abstract PO2-18-12: Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive Breast Cancer

Abstract Background: Inetetamab is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity effect. However, robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) for neoadjuvant therapy is still lacking. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy for patients with locally advanced HER2-positive breast cancer. We now present the updated results of this trial. Methods: This phase II trial included female patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients received TCbIP treatment every three weeks for a maximum of six cycles followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease < 1cm) rate, objective response rate (ORR) and safety. Results: From November 2021 to July 2023, 40 patients were enrolled in the trial. One patient received one cycle of the study treatment but was lost to follow-up without surgery, and five patients received one cycle of the study treatment and were still undergoing treatment, leaving 34 patients in the intention-to-treat (ITT) population. Among these 34 patients (82.4% in stage III), 22 patients completed the study treatment and surgery (per-protocol [PP] population) and 12 patients were still undergoing neoadjuvant treatment. The ORR was 91.2% (31/34) in the ITT population and 86.4% (19/22) in the PP population. Among the 22 patients in the PP population, 12 patients (54.5%) achieved pCR, and18 patients (81.8%) achieved npCR. The pCR rates for patients with hormone receptor (HR) negative and positive tumors were 80.0% (8/10) and 33.3% (4/12), respectively. The most common grade 3 adverse event was neutropenia (17.6%). No significant reduction in the left ventricular ejection fraction was observed in any patient. Conclusions: Neoadjuvant therapy with TCbIP demonstrated promising efficacy and manageable toxicity in patients with HER2-positive locally advanced breast cancer. Registration number: NCT05749016 (www.clinicaltrials.gov). Citation Format: Yue Chai, Jiaxuan Liu, Mingxia Jiang, Maiyue He, Xin Wang, Yipeng Wang, Xue Yang, Jing Wang, Binghe Xu, Qiao Li. Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-18-12.

An Antibody-CRISPR/Cas Conjugate Platform for Target-Specific Delivery and Gene Editing in Cancer.

The CRISPR/Cas system has been introduced as an innovative tool for therapy, however achieving specific delivery to the target has been a major challenge. Here, an antibody-CRISPR/Cas conjugate platform that enables specific delivery and target gene editing in HER2-positive cancer is introduced. The CRISPR/Cas system by replacing specific residues of Cas9 with an unnatural amino acid is engineered, that can be complexed with a nanocarrier and bioorthogonally functionalized with a monoclonal antibody targeting HER2. The resultant antibody-conjugated CRISPR/Cas nanocomplexes can be specifically delivered and induce gene editing in HER2-positive cancer cells in vitro. It is demonstrated that the in vivo delivery of the antibody-CRISPR/Cas nanocomplexes can effectively disrupt the plk1 gene in HER2-positive ovarian cancer, resulting in substantial suppression of tumor growth. The current study presents a useful therapeutic platform for antibody-mediated delivery of CRISPR/Cas for the treatment of various cancers and genetic diseases.

Evidence for cytoprotective autophagy in response to HER2-targeted monoclonal antibodies.

The advent of HER2-targeted monoclonal antibodies such as trastuzumab has significantly improved the clinical outcomes for patients with breast cancer overexpressing HER2, and more recently also for gastric cancers. However, the development of resistance, as is frequently the case for other antineoplastic modalities, constrains clinical efficacy. Multiple molecular mechanisms and signaling pathways have been investigated for their potential involvement in the development of resistance to HER2-targeted therapies, among which is autophagy. Autophagy is an inherent cellular mechanism whereby cytoplasmic components are selectively degraded to maintain cellular homeostasis via the generation of energy and metabolic intermediates. Although the cytoprotective form of autophagy is thought to predominate, other forms of autophagy have also been identified in response to chemotherapeutic agents in various tumor models; these include cytotoxic, cytostatic, and non-protective functional forms of autophagy. In this review, we provide an overview of the autophagic machinery induced in response to HER2-targeted monoclonal antibodies, with a focus on trastuzumab and trastuzumab-emtansine, in an effort to determine whether autophagy targeting or modulation could be translated clinically to increase their effectiveness and/or overcome resistance development. Significance Statement This manuscript is one in a series of papers that investigate the different roles of the autophagic machinery induced in response to versatile anti-neoplastic agents in various cancer models. This series designed in an attempt to build a conclusion whether autophagy targeting or modulation is an effective adjuvant strategy to increase the efficacy of chemotherapeutic agents. In this review, we shed the light on the relationship between the autophagic machinery and HER2 targeted therapies.

Next-Generation HER2-Targeted Antibody-Drug Conjugates in Breast Cancer.

Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic payload, which is attached by a linker, forming the basic structure of an ADC. Novel combinations and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd. Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal dosing regimens, understanding resistance mechanisms, and identifying patient populations that would derive the most benefit from these treatments. These novel ADCs are at the forefront of a new era in targeted cancer therapy, holding the potential to improve outcomes for patients with HER2-positive and HER2-Low breast cancer.

Standard-of-Care Treatment for HER2+ Metastatic Breast Cancer and Emerging Therapeutic Options.

Prior to the advent of the HER2-targeted monoclonal antibody trastuzumab, HER2+ breast cancer (BC) was considered an aggressive disease with a poor prognosis. Over the past 25 years, innovations in molecular biology, pathology, and early therapeutics have transformed the treatment landscape. With the advent of multiple HER2-directed therapies, there have been immense improvements in oncological outcomes in both adjuvant and metastatic settings. Currently, 8 HER2-targeted therapies are approved by the Food and Drug Administration (FDA) for the treatment of early-stage and/or advanced/metastatic disease. Nonetheless, approximately 25% of patients develop recurrent disease or metastasis after HER2-targeted therapy and most patients with HER2+ metastatic breast cancer (MBC) die from their disease. Given the many mechanisms of resistance to HER2-directed therapy, there is a pressing need to further personalize care for patients with HER2+ MBC, by the identification of reliable predictive biomarkers, and the development of novel therapies and combination regimens to overcome therapeutic resistance. Of particular interest are established and novel antibody-drug conjugates, as well as other novel therapeutics and multifaceted approaches to harness the immune system (checkpoint inhibitors, bispecific antibodies, and vaccine therapy). Herein, we discuss standard-of-care treatment of HER2+ MBC, including the management of breast cancer brain metastases (BCBM). Furthermore, we highlight novel treatment approaches for HER2+ MBC, including endeavors to personalize therapy, and discuss ongoing controversies and challenges.

A study of human epidermal growth factor receptor 2 overexpression by immunohistochemistry in patients with gastric adenocarcinoma.

Gastric cancer is one of the leading causes of cancer-related deaths across the world and in the Middle East. Human epidermal growth factor receptor 2 (HER2) overexpression has been observed in gastric cancers. Trastuzumab, a recombinant monoclonal antibody targeting HER2 protein, is being used for treatment of metastatic gastric cancer. To study the frequency and association of HER2 overexpression with age, gender, histopathological subtype and grade of differentiation in patients with gastric adenocarcinoma from Basra, Iraq. This cross-sectional single-center study collected demographic (age, gender), histopathological (histological subtype, grade of differentiation) and immunohistochemical (HER2 overexpression status) data from 100 consenting adult patients (male: 56) with histopathologically confirmed gastric adenocarcinoma from samples obtained through endoscopy or surgery. HER2 overexpression (ToGA score 3+) was observed in 6/100 (6%) of patients, with another 6 showing 'equivocal' HER2 expression (2+). Out of 20 patients with moderately differentiated gastric cancer, 4 (20%) showed HER2 overexpression (p=0.008). Other factors considered (age, gender, histological subtype) did not show statistically significant correlation with HER2 overexpression. More females showed HER2 overexpression than males (4 vs. 2), and more patients with intestinal type gastric cancer showed HER2 overexpression than diffuse gastric cancer (5 vs. 1), but the difference was not statistically significant in both variables. HER2 overexpression was 6% in this population; statistically significant correlation was found with histological grade. Statistically non-significant correlations were observed between HER2 overexpression and gender, age, and histological subtype.

Neoadjuvant inetetamab combined with pertuzumab, paclitaxel, and carboplatin (TCbIP) for locally advanced HER2-positive breast cancer: Primary analysis of a phase II study.

e12597 Background: Inetetamab (Cipterbin) is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity (ADCC) effect. Unfortunately, no robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) exists for neoadjuvant therapy. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy of patients with locally advanced (LA) HER2-positive breast cancer. Methods: This phase II trial included patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients receive TCbIP treatment every 3 weeks for a maximum of 6 cycles, followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease < 1cm) rate, objective response rate (ORR) and safety. Efficacy was analyzed in the intention-to-treat (ITT) and per-protocol (PP) populations. The ITT population included patients who received at least 2 cycles of TCbIP treatment but excluded those who were lost to follow-up without surgery and those who received other targeted therapy. The PP population included patients who met all the trial criterias, complianted with the protocol, and did not violate any major protocol. The safety population included all patients who received at least one dose of the study drugs and had available safety data. Results: A total of 24 patients were enrolled from November 2021 to February 2023. Of 24 patients, 1 patient received 1 cycle of study treatment and was lost to follow-up without surgery, and 4 patients received 1 cycle of study treatment and were still in treatment, leaving 19 patients in the ITT population. Among 19 patients in the ITT population (median age, 50 years; 78.9% in stage III), 12 patients completed the study treatment and surgery (PP population) and 7 patients were still in neoadjuvant treatment. ORR was achieved 78.9% in the ITT population (15 of 19 patients) and 91.7% in the PP population (11 of 12 patients). Among 12 patients of PP population, 8 patients (66.7%) achieved pCR and 10 patients (83.3%) achieved npCR. For patients with hormone receptor negative and positive tumors, the pCR rates were 71.4% (5/7) and 60.0% (3/5) ( P = 0.771), and the npCR rates were 85.7% (6/7) and 80.0% (4/5) ( P = 0.793), respectively. The most common grade ³3 adverse events were hair loss (41.7%) and neutropenia (12.5%). No significant reduction in the left ventricular ejection fraction was observed in any patient. No patients withdrew from the treatment due to adverse drug reactions. Conclusions: TCbIP displays a promising efficacy (pCR rate of 66.7%) and manageable toxicity in patients with HER2-positive LA breast cancer in the neoadjuvant setting. Clinical trial information: NCT05749016 .

A phase II study of concurrent WOKVAC vaccination with neoadjuvant chemotherapy and HER2-targeted monoclonal antibody therapy.

TPS636 Background: HER2+ breast cancer (BCa) is an aggressive breast cancer subtype. The treatment of Stage I-III HER2+ BCa with neoadjuvant chemotherapy and HER2 monoclonal antibodies (trastuzumab and pertuzumab) induces a pathologic complete response in 43-67% of patients. Residual HER2+ disease (i.e. residual cancer burden) after neoadjuvant therapy is associated with a significantly higher risk of recurrence. Evidence supports that HER2 immunity is progressively lost in HER2 oncogenesis and that restoration of HER2 specific CD4+ Th1 immunity is associated with a lower risk of recurrence. Trastuzumab can partially restore HER2 specific immunity, but only in a minority of patients. We have demonstrated that HER2 specific vaccination can augment HER2 specific immunity. While taxane chemotherapy can deplete immunosuppressive cells (MDSCs) 13 – 17 days after treatment creating an optimal time for vaccination. The WOKVAC vaccine is a plasmid vaccine encoding Th1 selective epitopes from HER2 and two other high-risk cancer antigens IGFBP-2 and IGF-1R. The Phase I trial of this vaccine reported that it is safe and all doses induced antigen specific Type I immune responses. We hypothesize that addition of WOKVAC to neoadjuvant chemo/HER2 targeted therapy will induce a significant increase in the number of patients with Th1 CD4+ and CD8+ T cells after neoadjuvant vaccine/chemo/HER2 therapy. Methods: Trial Design: Phase II single arm trial of WOKVAC vaccination with concurrent neoadjuvant taxane based chemotherapy, trastuzumab, and pertuzumab in patients with Stage I-III HER2+ (HR+/-) breast cancer. Enrolled patients will receive WOKVAC vaccine 150mcg on day 13 of cycles 1-3. WOKVAC vaccination may be given with either TCHP or THP. A maximum of 16 patients will be enrolled in this study. Objectives: The primary objective is to evaluate whether concurrent WOKVAC vaccine with chemotherapy and HER2 antibody therapy can significantly increase T-bet+ CD4+ and CD8+ TIL. Secondary objectives are to determine: (1) whether concurrent WOKVAC with neoadjuvant chemo/HER2 therapy is safe, (2) if the magnitude of vaccine induced antigen specific Th1 immunity after neoadjuvant therapy is associated with pathologic response. Statistical Methods: (1) In order to detect a 30% increase in the number of patients with Tbet+ CD4+ and CD8+ TIL in the enrolled patients with 80% power and a one-side alpha of 0.05, our enrollment goal for this study will be 16 patients. (2) Safety will be assessed per CTCAE v5.0, Benchmarks for safety needed to advance this trial concept to a Phase III study will be a grade 3 toxicity rate of ≤13% and a grade 4 toxicity rate of ≤ 7%. (3) The induction of Th1 immunity will be compared against the presence or absence of a complete pathologic response to determine if there is a significant correlation using Pearson r correlation analysis. Targeted Accrual: The study will accrue up to 16 patients. Clinical trial information: NCT04329065 .

Interaction between Radiation Therapy and Targeted Therapies in HER2-Positive Breast Cancer: Literature Review, Levels of Evidence for Safety and Recommendations for Optimal Treatment Sequence.

Purpose: Over the past twenty years, anti-HER2 targeted therapies have proven to be a revolution in the management of human epidermal growth receptor 2 (HER2)-positive breast cancers. Anti-HER2 therapies administered alone or in combination with chemotherapy have been specifically studied. Unfortunately, the safety of anti-HER2 therapies in combination with radiation remains largely unknown. Thus, we propose a literature review of the risks and safety of combining radiotherapy with anti-HER2 therapies. We will focus on the benefit/risk rationale and try to understand the risk of toxicity in early-stage and advanced breast cancer. Methods: Research was carried out on the following databases: PubMed, EMBASE, ClinicalTrial.gov, Medline, and Web of Science for the terms "radiotherapy", "radiation therapy", "radiosurgery", "local ablative therapy", and "stereotactic", combined with "trastuzumab", "pertuzumab", "trastuzumab emtansine", "TDM-1", "T-Dxd", "trastuzumab deruxtecan", "tucatinib", "lapatinib", "immune checkpoint inhibitors", "atezolizumab", "pembrolizumab", "nivolumab", "E75 vaccine", "interferon", "anti-IL-2", "anti-IL 12", and "ADC". Results: Association of radiation and monoclonal antibodies such as trastuzumab and pertuzumab (with limited data) seems to be safe, with no excess risk of toxicity. Preliminary data with radiation and of antibody-drug conjugate of trastuzumab combined cytotoxic (trastuzumab emtansine, trastuzumab deruxtecan), given the underlying mechanism of action, suggest that one must be particularly cautious with the association. The safety of the combination of a tyrosine kinase inhibitor (lapatinib, tucatinib) and radiation remains under-studied. The available evidence suggests that checkpoint inhibitors can be safely administrated with radiation. Conclusions: HER2-targeting monoclonal antibodies and checkpoint inhibitors can be combined with radiation, apparently with no excess toxicities. Caution is required when associating radiation with TKI and antibody drugs, considering the limited evidence.

Abstract OT3-25-02: Inetetamab combined with pyrotinib and Chemotherapy in Pretreated Patients with HER2-positive metastatic breast cancer, a single arm, multicenter phase II clinical trial

Abstract Background: The HER2-targeted drugs selection after trastuzumab failure has become a challenging issue for HER2-positive metastatic breast cancer (MBC) patients. Inetetamab is a neotype of HER2-targeted monoclonal antibody with an engineered Fc segment that optimizes the antibody-dependent cell-mediated cytotoxicity (ADCC) effect, which was important for disease control. Moreover, HER2-targeted tyrosine kinase inhibitors, as pyrotinib, were found to further improve the ADCC effect of monoclonal antibodies in pre-clinical researches, indicating that the combination of pyrotinib and inetetamab could achieve complementarity and synergy effects in terms of short-term tumor killing effect and long-term immunotherapy benefits. Therefore, the combined treatment pattern of the two drugs has potential clinical benefits. Methods: This is a prospective, multi-center, single-arm clinical study designed to evaluate the efficacy and safety of pretreated patients with HER2-positive MBC. We recruited patients with pathologically confirmed HER2-positive MBC who had received 1-3 prior regimens for metastatic disease, which must include trastuzumab. The enrolled patients received 6 cycles of Inetetamab combined with pyrotinib and chemotherapy, subsequent maintenance therapy should be considered according to tolerability. The chemotherapy drugs were decided by physicians’ choice, and could be microtubules, anthracyclines, or antimetabolites. The primary endpoint was objective response rate (ORR) after 6 cycles of treatment, secondary endpoints included progression-free survival (PFS), overall survival (OS), and clinical benefit rate (CBR) and adverse events (AEs). Results: 57 patients were enrolled from October 2020 to July 2022. And 45 patients were available for response evaluation. The ORR and DCR were 53.5 % (24/45) and 86.7 % (39/45), respectively after 6 cycles treatment. The median PFS was 7.3 months. The incidence of grade Ⅲ-Ⅳ AEs was 15.8 %. The most common treatment-related AEs were diarrhea, anemia, neutropenia, leukopenia, hand and foot syndrome. No patient’ s left ventricle ejection fraction (LVEF) decreased to < 50% or decreased by >15%. And no significant decline in quality of life score was reported. Conclusion: Inetetamab combined with pyrotinib and chemotherapy showed a promising efficacy and a good tolerance in patients with HER2-positive metastatic breast cancer, confirming the synergistic effect between the ADCC optimized monoclonal antibodies and TKIs, which brings more treatment options for HER2-positive metastatic breast cancer. Citation Format: Jianli Zhao, Yangyang Cai, Linxiaoxiao Ding, Yaping Yang, Guorong Zou, Herui Yao, Ying Wang. Inetetamab combined with pyrotinib and Chemotherapy in Pretreated Patients with HER2-positive metastatic breast cancer, a single arm, multicenter phase II clinical trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-25-02.

Tailoring the Treatment of Early-stage HER2-positive Breast Cancer: One Size Does Not Fit All

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer accounts for 15% of all breast cancers and this cancer subtype was historically associated with poor outcomes. The development of HER2-directed therapies has dramatically improved outcomes for patients with early and advanced HER2+ disease. Trastuzumab is a HER2-targeted monoclonal antibody first approved for the treatment of advanced breast cancer in the late 1990s. Since then, it has been shown to improve long-term outcomes for patients with early-stage disease, particularly when given in combination with chemotherapy in the (neo)adjuvant setting. Pertuzumab is another monoclonal antibody that targets a different domain of the HER2 receptor from trastuzumab and prevents HER2–HER3 dimerization. The addition of pertuzumab to trastuzumab and chemotherapy improved long-term outcomes for patients with advanced disease; this drug has also been studied in the (neo)adjuvant setting and proved to improve long-term outcomes for patients with lymph node involvement. Neratinib and trastuzumab emtansine in the adjuvant setting have been shown to improve outcomes for selected high-risk patients. As more effective treatment options have been developed for the treatment of HER2+ breast cancer, we have progressively moved from a one-size-fits-all approach towards a tailored paradigm. In this narrative review, we summarize the diagnosis and prognosis of early-stage HER2+ breast cancer, as well as current treatment approaches.

Systemic Therapy for HER2-Positive Metastatic Breast Cancer: Current and Future Trends

Approximately 20% of breast cancers (BC) overexpress human epidermal growth factor receptor 2 (HER2). This subtype of BC is a clinically and biologically heterogeneous disease that was associated with an increased risk for the development of systemic and brain metastases and poor overall survival before anti-HER2 therapies were developed. The standard of care was dual blockade with trastuzumab and pertuzumab as first-line followed by TDM-1 as second-line. However, with the advent of new HER2-targeted monoclonal antibodies, tyrosine kinase inhibitors and antibody- drug conjugates, the clinical outcomes of patients with HER2-positive BC have changed dramatically in recent years, leading to a paradigm shift in the treatment of the disease. Notably, the development of new-generation ADCs has led to unprecedented results compared with T-DM1, currently establishing trastuzumab deruxtecan as a new standard of care in second-line. Despite the widespread availability of HER2-targeted therapies, patients with HER2-positive BC continue to face the challenges of disease progression, treatment resistance, and brain metastases. Response rate and overall life expectancy decrease with each additional line of treatment, and tumor heterogeneity remains an issue. In this review, we update the new-targeted therapeutic options for HER2-positive BC and highlight the future perspectives of treatment in this setting.

Antibody-Drug Conjugates for the Treatment of HER2-Positive Breast Cancer.

Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20-30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted monoclonal antibodies with the potent cytotoxic effects of various small molecules, such as tubulin inhibitors and topoisomerase inhibitors. To date, two HER2-targeting ADCs have been approved by the FDA for the treatment of HER2-positive breast cancer: Ado-trastuzumab emtansine (T-DM1; Kadcyla®) and fam-trastuzumab deruxtecan-nxki (T-Dxd; Enhertu®). Kadcyla and Enhertu are approved for use as a second-line treatment after trastuzumab-taxane-based therapy in patients with HER2-positive breast cancer. The success of ADCs in the treatment of HER2-positive breast cancer provides novel therapeutic advancements in the management of the disease. In this review, we discuss the basic biology of HER2, its downstream signaling pathways, currently available anti-HER2 therapeutic modalities and their mechanisms of action, and the latest clinical and safety characteristics of ADCs used for the treatment of HER2-positive breast cancer.

184 (PB-097) Poster - A Phase III, Randomized, Multicenter, Double-blind Study to Compare Efficacy and Safety of EG12014 (EirGenix Trastuzumab) with Herceptin® as Neoadjuvant Treatment in Combination with Anthracycline/Paclitaxel-based Systemic Therapy in Patients with HER2-positive Early Breast Cancer

Background: Amplification and/or overexpression of HER2 in breast cancer (BC) patients is associated with aggressive disease and poor prognosis. Herceptin® (trastuzumab), a monoclonal antibody targeting HER2 in combination with anthracycline- and taxane-based neoadjuvant treatment in women with HER2-positive BC has resulted in improvements in pathological complete response (pCR), event-free survival (EFS) and overall survival (OS). This study was designed to compare efficacy (pCR) and safety between the originator Herceptin® and the proposed trastuzumab biosimilar EG12014.

The financial impact of reducing drug waste with biosimilar transition of trastuzumab in the Oncology Care Model for the U.S. Oncology Network.

11 Background: The Oncology Care Model (OCM), a 6-year long Medicare value-based care program, rewards practices for decreasing total cost of care (TCOC) compared to a benchmark price, while maintaining high quality cancer care. Care services for enrolled patients are divided into 6-month episodes within 1-year time intervals called Performance Periods (PP). One approach to reducing TCOC is reducing the expenditure for drug waste. In mid-2017, trastuzumab (HER2-targeted monoclonal antibody) 420 mg multi-dose vial (MDV) was discontinued and replaced with a 150 mg single-dose vial (SDV), leading to wastage of the remaining partial quantities of the SDV after preparation of a patient-defined dose. The increased drug waste led to an increase in the total drug cost of trastuzumab and TCOC. Late 2019, MDV and SDV biosimilar trastuzumab products were introduced, and The US Oncology Network (The Network) practices adopted the MDV biosimilar as a strategy to reduce drug waste and TCOC. This study highlights the impact of trastuzumab drug waste on TCOC. Methods: Claims data for 14 Network practices, participating in OCM, were assessed. The financial impact of drug waste and TCOC for The Network’s transition from MDV trastuzumab to SDV trastuzumab in 2017, and from SDV trastuzumab to the MDV biosimilar trastuzumab in 2020 was evaluated. Results: With the use of MDV trastuzumab during OCM PP1, drug waste accounted for 0.05% of the total dose of trastuzumab. After having to shift from MDV to SDV during PP2, as a result of the packaging change, trastuzumab drug waste increased to 10.25% of the total dose, with an increase in TCOC by 0.25% ($2M) per PP during PPs 3-7. As The Network practices adopted the use of MDV biosimilar trastuzumab starting in PP8, drug waste declined 57% to 4.4% of the total dose in PP9, reducing the drug waste component of TCOC by $1.4M (0.16%). Had all SDV trastuzumab doses been transitioned to the MDV biosimilar, an additional $600K (0.09%) in TCOC could have been reduced in PP9. Conclusions: TCOC fluctuations can be driven by not just increasing costs or increased utilization, but also by drug packaging and increasing drug waste. The discontinuation of MDV trastuzumab resulted in a substantial financial impact on drug waste, TCOC, and cost for patients. Swift transition to biosimilar MDV trastuzumab within The Network helped to significantly reduce drug waste and its impact on TCOC in the OCM. Trastuzumab biosimilars, in addition to being cost-effective alternatives to biological therapeutics, offer significant cost savings via drug waste reduction.