Combination Of Trastuzumab Research Articles

Integrin β3 Reprogramming Stemness in HER2-Positive Breast Cancer Cell Lines.

HER2-positive breast cancer, characterised by overexpressed HER2 levels, is associated with aggressive tumour behaviour and poor prognosis. Trastuzumab is a standard treatment; however, approximately 50% of patients develop resistance within one year. This study investigates the role of ITGβ3 in promoting stemness and resistance in HER2-positive breast cancer cell lines (HCC1954 and SKBR3). The findings demonstrate that chronic exposure to trastuzumab upregulates stem cell markers (SOX2, OCT4, KLF4, NANOG, SALL4, ALDH, BMI1, Nestin, Musashi 1, TIM3, CXCR4). Given the documented role of RGD-binding integrins in drug resistance and stemness, we specifically investigated their impact on resistant cells. Overexpression of ITGβ3 enhances the expression of these stem cell markers, while silencing ITGβ3 reduces their expression, suggesting a major role for ITGβ3 in maintaining stemness and resistance. Further analysis reveals that ITGβ3 activates the Notch signalling pathway, known for regulating stem cell maintenance. The combination of trastuzumab and cilengitide, an integrin inhibitor, significantly decreases the expression of stem cell markers in resistant cells, indicating a potential therapeutic strategy to overcome resistance. These results identify the importance of ITGβ3 in mediating stemness and trastuzumab resistance through Notch signalling in HER2-positive breast cancer, offering new approaches for enhancing treatment efficacy.

Efficacy and safety of neoadjuvant trastuzumab, pyrotinib, and dalpiciclib without chemotherapy in early-stage HR-negative/HER2-positive breast cancer: An open-label, single-arm phase II trial.

e12613 Background: The chemotherapy-free neoadjuvant regimens of dual HER2 blockade has showed encouraging rates of pathological complete response (pCR) in patients with HER2-positive breast cancer. Additionally, combining cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with anti-HER2 therapy has shown synergistic effects in hormone receptor (HR)-positive and HER2-positive breast cancer. However, there is limited data regarding this combination strategy in HR-negative/HER2-positive settings. The objective of this study was to evaluate the efficacy and safety of a chemotherapy-free regimen consisting of the CDK4/6 inhibitor dalpiciclib, and dual anti-HER2 components of pyrotinib and trastuzumab in patients with HR-negative/HER2-positive early breast cancer (EBC). Methods: This open-label, single-arm, phase II study was designed using the Simon two-stage method (Registration number: Chi-CTR-2200060748). Patients with HR-negative/HER2-positive operable EBC (tumor stage T1-3 and nodal stage N0-2) were enrolled. Eligible patients received trastuzumab (HLX02, 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks intravenously) for 15 weeks, plus pyrotinib (240 mg daily orally) and dalpiciclib (125 mg daily orally for 3 weeks, followed by 1 week off) for 16 weeks. Surgery was performed 3-6 weeks after the completion of the last cycle of study treatment. The primary endpoint was pCR (ypT0/Tis ypN0) at surgery, and secondary endpoints included objective response rate (ORR), change of Ki-67 labeling index, biomarker analysis, survival and safety. Results: Between Jun 24, 2022, and Sept 14, 2023, a total of 30 patients with a median age of 54.5 years (range: 35-66) were enrolled and treated in this ongoing trial. As of the data cutoff date on Jan 20, 2024, 26 patients underwent surgery, and pCR was achieved in 18 (69.2%) cases. Out of the 29 patients with evaluable response, 26 achieved partial response and 3 achieved stable disease, resulting in an ORR of 89.7%. The most common grade 3 or more treatment-related adverse events (AEs) were diarrhea (66.7%), decreased neutrophil count (33.3%), and decreased white blood cell count (20.8%). Most AEs were tolerable, and no treatment-related deaths occur. Conclusions: In patients with HR-negative/HER2-positive EBC, a dual HER2-targeted combination of pyrotinib and trastuzumab, along with dalpiciclib in the absence of chemotherapy showed promising efficacy with encouraging pCR and ORR rates, as well as a favorable safety profile in the neoadjuvant setting. Clinical trial information: Chi-CTR-2200060748.

Phase II/III study of paclitaxel/carboplatin alone or combined with either trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma (NRG-GY026).

TPS5641 Background: Uterine serous carcinoma and uterine carcinosarcoma are rare, high-risk uterine cancer subtypes that overexpress HER2 in up to 40% and 10% of cases, respectively. Phase II data demonstrated a benefit in adding trastuzumab in HER2 positive advanced and recurrent uterine serous carcinoma. Dual anti-HER2 therapy has the potential for further improvement in survival. Methods: This is a non-blinded, three-arm randomized phase II/III study. The primary objective is to evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) or a fixed dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive uterine serous carcinoma or carcinosarcoma. The primary outcome of the phase II component is PFS. Depending on the phase II results, the study will progress to a phase III study of either two or three study arms. Patients in the control arm (Arm 1) receive carboplatin and paclitaxel every 3 weeks for 6 cycles. Patients on Arm 2 receive carboplatin and paclitaxel with trastuzumab and hyaluronidase-oysk every 3 weeks for 6 cycles plus one year of maintenance trastuzumab and hyaluronidase-oysk. Patients enrolled on Arm 3 receive carboplatin and paclitaxel with trastuzumab, pertuzumab, and hyaluronidase-zzxf every 3 weeks for 6 cycles plus one year of maintenance trastuzumab, pertuzumab, and hyaluronidase-zzxf . Those with an ongoing partial response may continue maintenance therapy for up to three years. Patients are eligible if they are diagnosed with chemo-naïve, non-recurrent stage IA-IVB myoinvasive uterine serous or carcinosarcoma. All tumors must be HER2 positive as defined by the ASCO/CAP Breast Cancer 2018 guidelines (testing performed locally). Tumors may also be HER2 positive based on next generation sequencing testing. Patients may have measurable, non-measurable, or no measurable disease and may have a plan for vaginal brachytherapy . Key exclusion criteria include severe heart disease or interstitial lung disease. The phase II portion of this study is open and enrolling. Clinical trial information: NCT05256225 .

Phase II clinical trial of docetaxel and trastuzumab for HER2-positive advanced extramammary Paget's disease (EMPD-HER2DOC).

No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD. In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period. All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated. The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073).

Efficacy of First-Line Treatment With Pertuzumab and Trastuzumab in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in Routine Clinical Practice.

The first-line treatment for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) involves a combination of trastuzumab, pertuzumab, and a taxane (TPH). This study assessed the efficacy of trastuzumab and pertuzumab (PH) in routine practice, following the treatment protocols of Uruguay's National Resources Fund (FNR), akin to clinical trials. Patients with advanced MBC treated with PH between 2008 and 2022 per FNR protocols were evaluated. The Kaplan-Meyer method and log-rank test were utilized for analyzing overall survival (OS). Demographic and clinical variables, including age, menopausal status, and hormone receptors (HR), were analyzed. The study included 318 PH-treated patients. The median age was 56 years, with 63.2% being postmenopausal and 60.4% HR and HER-2 positive. With a median follow-up of 17.2 months, the median OS was 29 months. OS varied based on HR status and the presence of metastases at different sites, significantly lower in patients with brain, cutaneous/subcutaneous, and pulmonary metastases. Additionally, OS was higher in patients treated at private institutions compared to public ones. This study demonstrates the disparity in oncological treatment efficacy between clinical trials and clinical reality in Uruguay, emphasizing the importance of authentic environment research for more representative and effective medicine in Latin America.

Characterization of MET Alterations in 37 Gastroesophageal Cancer Cell Lines for MET-Targeted Therapy.

Capmatinib and savolitinib, selective MET inhibitors, are widely used to treat various MET-positive cancers. In this study, we aimed to determine the effects of these inhibitors on MET-amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be MET-positive with copy number variation >10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Next, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the MET signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of MET and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in MET-amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in an MKN-45 GC cell xenograft model. Furthermore, a combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 (HER2)- and MET-positive OE33 cells. Targeting MET with savolitinib and capmatinib efficiently suppressed the growth of MET-amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on HER2- and MET-amplified GC cells.

HeredERA Breast Cancer: a phase III, randomized, open-label study evaluating the efficacy and safety of giredestrant plus the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with previously untreated HER2-positive, estrogen receptor-positive locally advanced or metastatic breast cancer

BackgroundHER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC.First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I–II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression.MethodsThis phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+ locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes.DiscussionheredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC.Trial registrationClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022). Sponsor: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland.

Efficacy and Satisfaction among HER2 Positive Breast Cancer Patients Undergoing Subcutaneous Injection of PHESGO along with Chemotherapy: A Case Series

Background: The prevalence of Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancer (BC) in India ranged from 11% to 17%. A combination of intravenous (IV) pertuzumab, trastuzumab and docetaxel in HER2+ BC reported a significant increase in the overall survival rate. However, the time taken for infusion of these drugs is lengthy. PHESGO, a combination of these two drugs along with hyaluronidase is provided subcutaneously and the time taken is 5-8 minutes. Despite patient preference for PHESGO, its efficacy and satisfaction levels in the Indian context remain unexplored. This case series investigates the efficacy of PHESGO with chemotherapy and assesses the level of satisfaction reported by HER2+ BC patients. Methods: HER2+ BC patients were identified retrospectively from January 2022 to November 2023. Interviews during follow-ups assessed patient satisfaction. Efficacy was evaluated based on Positron Emission Tomography (PET) scans for metastatic/adjuvant settings and pathological complete response (pCR) rate for neoadjuvant cases. Results: In total 27 HER2+ BC patients received PHESGO treatment with a median age of 54.5 years. Patients who received PHESGO with chemotherapy in neoadjuvant and metastatic settings were 44.4% and 51.9% respectively. The median cycle of PHESGO with chemotherapy was 5. Neoadjuvant patients showed an 83.3% pCR rate, while 85.7% of metastatic patients reported partial response after three cycles. Among 25 patients, 92% were satisfied with subcutaneous administration of PHESGO. Conclusion: The findings support the potential of PHESGO as an effective and convenient treatment option for HER2+ BC patients. However, further research, including larger prospective studies and long-term follow-ups, is warranted to comprehensively evaluate the safety profile, quality of life, and comparative effectiveness of PHESGO versus intravenous administration.

Bioinformatics and In Vitro Study Reveal ERα as The Potential Target Gene of Honokiol to Enhance Trastuzumab Sensitivity in HER2+ Trastuzumab-Resistant Breast Cancer Cells

Trastuzumab resistance presents a significant challenge in the treatment of HER2+ breast cancer, necessitating the investigation of combination therapies to overcome this resistance. Honokiol, a compound with broad anticancer activity, has shown promise in this regard. This study aims to discover the effect of honokiol in increasing trastuzumab sensitivity in HER2+ trastuzumab-resistant breast cancer cells HCC1954 and the underline mechanisms behind. A bioinformatics study performed to explore the most potential target hub gene for honokiol in HER2+ breast cancer. Honokiol, trastuzumab and combined treatment cytotoxicity activity was then evaluated in both parental HCC1954 and trastuzumab resistance (TR-HCC1954) cells using MTT assay. The expression levels of these hub genes were then analyzed using qRT-PCR and those that could not be analyzed were subjected to molecular docking to determine their potential. Honokiol showed a potent cytotoxicity activity with an IC50 of 41.05 μM and 69.61 μM in parental HCC1954 and TR-HCC1954 cell line respectively. Furthermore, the combination of honokiol and trastuzumab resulted in significant differences in cytotoxicity in TR-HCC1954 cells at specific concentrations. Molecular docking and the qRT-PCR showed that the potential ERα identified from the bioinformatics analysis was affected by the treatment. Our results show that honokiol has the potential to increase the sensitivity of trastuzumab in HER2+ trastuzumab resistant breast cancer cell line HCC1954 by affecting regulating estrogen receptor signaling. Further research is necessary to validate these findings.

Abstract PO2-04-07: Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials

Abstract Background: The numerous but conflicting first-line treatment regimens for Her-2 positive advanced breast cancer necessitate a comprehensive evaluation to inform clinical decision-making. In this study, we conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions. Methods: We systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts published by ASCO, SABCS. NMA was performed using R software, STATA and Review Manager 5.4 to calculate and analyze the primary endpoint progression free survival (PFS), as well as the secondary endpoints of overall survival (OS), objective response rate (ORR) and adverse events (AE) higher than grade 3. Results: Out of the 8,603 manuscripts retrieved, we included 30 RCTs involving 12,045 patients in our analysis. Regarding PFS, the combination of trastuzumab with TKI was more favorable than dual-target therapy (hazard ratio=0.54, 95% [CI]: 0.40–0.72), and combination chemotherapy was superior to monotherapy (HR=0.66, 0.53-0.83). It is important to note that the addition of anthracycline did not result in improved PFS (HR=1.27, 0.87-1.86). For the HR+HER2+ population, dual-target plus endocrine therapy was more effective than single-target plus endocrine therapy (HR=0.65, 0.53-0.80). Monotherapy combined with dual-target therapy significantly improved OS and ORR compared to monotherapy with single-target therapy (HR=0.69, 0.56-0.84; OR=1.89, 1.34-2.65). A comprehensive analysis of both PFS and AE higher than grade 3 indicated that monotherapy plus dual-target therapy struck a balanced approach between effectiveness and toxicity compared to other regimens. Conclusions: Monotherapy plus dual-target therapy remains the optimal choice among all first-line treatment options for advanced breast cancer. The combination of trastuzumab with TKI demonstrated a significant improvement in PFS, but further data are warranted to confirm the survival benefit. Figure 1. Network diagrams of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. Figure 2. Forest plot of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. (A): PFS of HER2+ for experimental arms. (B): PFS of HR+ and HER2+ for experimental arms. (C): OS of HER2+ for experimental arms. (D): ORR of HER2+ for experimental arms. (E): Adverse events higher than grade 3 of HER2+ for experimental arms. Figure 3. Each endpoint ranking for experimental arms. (SUCRA, surface under the cumulative ranking) (A): PFS ranking for experimental arms. (B): OS ranking for experimental arms. (C): ORR ranking for experimental arms. (D): Adverse events higher than grade 3 ranking for experimental arms. (E): Experimental arms ordered by their overall probability as the best treatment in terms of both efficacy and safety Citation Format: Junxiao Wang, Yushuai Yu, Jie Zhang, Chuangui Song. Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials [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 PO2-04-07.

Abstract RF02-04: A phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in older patients with metastatic HER2-positive breast cancer. (JCOG1607 HERB TEA study)

Abstract Background A combination of trastuzumab, pertuzumab, and docetaxel (HPD) is recommended as first-line treatment for patients with HER2-positive metastatic breast cancer. For older patients, it is difficult to maintain a relative dose intensity, which often impairs their quality of life. A new standard treatment option for older patients is required with less toxicity and non-inferior efficacy compared to HPD. Methods The eligibility criteria were as follows: age 65 years and older, HER2-positive metastatic breast cancer, no previous systemic treatment with chemotherapy and anti-HER2 targeted drugs, ECOG PS 0–2 for 65–74 years or 0–1 for 75 years or older, and adequate organ function. Treatment consisted of trastuzumab emtansine (T-DM1) 3.6 mg/kg every 3 weeks or HPD (trastuzumab 8 mg/kg, then 6 mg/kg, pertuzumab 840 mg, then 420 mg/body, and docetaxel 60 mg/m2, could be escalated to 75 mg/m2 if there were no unmanageable toxicity) every 3 weeks after a 1:1 ratio randomization. The trial was designed to achieve 70% power to confirm the non-inferiority of T-DM1 to HPD at a one-sided alpha of 5% with a non-inferiority margin of 1.35 in terms of the hazard ratio (HR) for overall survival (OS) as the primary endpoint. With a median OS of 30 months in both arms, 6.5 years of accrual, and 5 years of follow-up, the planned sample size was 250. Secondary endpoints were progression-free survival (PFS), response rate (RR), adverse events, cumulative breast cancer-specific mortality (BCSM), safety, and deterioration of activities of daily living. (Clinical Trial Information: UMIN000030783). Results In total, 148 patients were enrolled between January 2018 and March 2023. A total of 135 patients were assessed in the preplanned first interim analysis. The median patient age was 72 years (range 65-88) in the T-DM1 arm and 71 (65-84) in the HPD arm. The proportion of estrogen receptor-positive (10%) patients was well balanced between both arms (49.3 and 55.6%, respectively). Of these patients, 64.8% had stage IV disease and 35.2% had recurrent disease. T-DM1 was not non-inferior to HPD (HR 1.487; 99.9% CI, 0.288 to 7.678) in terms of OS. The median PFS was 9.8 months in the T-DM1 arm and 18.4 months in the HPD arm (HR 1.749; 95%CI, 1.124-2.723). Response rates were lower in the T-DM1 arm than that of the HPD arm (52.7% [95% CI, 38.8-66.4] and 76.8% [95% CI, 63.6-87.0], respectively) (p=0.099). BCSM was higher in the T-DM1 arm than that of the HPD arm (HR 1.617; 95% CI, 0.764-3.425). Grade 3 and higher neutropenia were less common in the T-DM1 arm than in the HPD arm (0 vs. 30.4%); however, thrombocytopenia was more common in the T-DM1 arm than in the HPD arm (16.9 vs. 0%). Grade 3 or more non-hematological adverse events were less common and lower in the T-DM1 arm (35.2%) than in the HPD arm (58.6%), including fatigue (5.6% vs. 22.9%), diarrhea (0% vs. 11.4%), appetite loss (8.5% vs. 11.4%), and febrile neutropenia (0% vs. 10.0%), which reduced the quality of life in older patients with HER2-positive metastatic breast cancer. Conclusion T-DM1 was not non-inferior to HPD in terms of OS. However, T-DM1 showed better tolerability in terms of frequency and severity of adverse events. HPD will continue to be the standard of care as the first-line treatment for older patients with HER2-positive metastatic breast cancer. Older patients with breast cancer have heterogeneous health conditions. A subset analysis according to age or geriatric assessment may identify the subpopulation of older patients with HER2-positive metastatic breast cancer for whom T-DM1 is an optional treatment. Citation Format: Akihiko Shimomura, Kenji Tamura, Keita Sasaki, Ryo Sadate, Akihiko Suto, Masataka Sawaki, Naohito Yamamoto, Tomoyuki Yoshiyama, Takako Hayashi, Eriko Tokunaga, Takashi Yamanaka, Chikako Shimizu, Tadahiko Shien, Hiroji Iwata. A phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in older patients with metastatic HER2-positive breast cancer. (JCOG1607 HERB TEA study) [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 RF02-04.

Abstract RF02-01: A Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab, and Pertuzumab in Hormone Receptor (HR)-Positive, HER2-Positive Metastatic Breast Cancer (ASPIRE)

Abstract Background: Among patients (pts) with HR-positive and HER2-positive breast cancer, crosstalk between HER2 and estrogen receptor (ER) signaling pathways may contribute to endocrine resistance but anti-HER2 agents in combination with endocrine therapy can restore endocrine sensitivity. Mechanistically, HER2/HER3 signaling promotes survival by way of PI3K-AKT activation whereas ER-CDK4/6-Rb signaling promotes cell cycle progression. The combination of anti-HER2 therapy with an aromatase inhibitor (AI) and a CDK 4/6 inhibitor would allow for blockade of both pathways and provide a novel, all biologic, and chemotherapy-free approach to the treatment of HR-positive, HER2-positive metastatic breast cancer (MBC). Methods: We conducted a phase I/II multi-institution trial in pts with previously untreated, HR-positive and HER2-positive MBC. In the Phase I portion, pts received escalating doses of palbociclib (100mg, 125mg) in conjunction with trastuzumab, pertuzumab and an AI anastrozole, using a 3+3 dose escalation trial design. In the phase II portion, pts received palbociclib at the maximum tolerated dose (MTD), anastrozole, trastuzumab, and pertuzumab. The primary endpoints of the Phase I and II portions were MTD and clinical benefit rate (CBR) defined as the sum of complete response, partial response, and stable disease for >/= 6 months, respectively. Secondary endpoints included progression free survival (PFS), objective response rate (ORR) and safety. The Phase II portion of this study was powered with 30 pts to show efficacy of palbociclib administered at the MTD in combination with anastrozole, trastuzumab and pertuzumab if the CBR achieved at 6 months exceeded 58%. The Clopper-Pearson method was used to calculate confidence intervals for ORR and CBR. The PFS distribution was estimated using the Kaplan-Meier method. Results: In the Phase I portion, a total of 9 pts were enrolled. No DLTs were observed at the 100mg dose (N=3) or the 125mg dose (N=6) level, and thus, 125mg was established as the MTD. An additional 24 pts were enrolled to the Phase II portion at the MTD, with a total of 30 pts in the modified intention-to-treat population included in the efficacy analysis. The median age of the population was 57.6 years (range 50.5-63.8) and 27% of pts were premenopausal and received ovarian function suppression as part of treatment. As shown in Table 1, the primary endpoint, CBR, was 97% (95% CI: 0.83-1.0, p<0.0001). ORR was 70% (95% CI: 0.51-0.85). Median time to objective response was 2.8 months with earliest response at 3 months. Median duration of response was not reached with range of 5.1-42.2 months. Median PFS was also not reached with range of 8-44.8 months. Safety data were consistent with known toxicity profiles of agents. Most common adverse events included diarrhea (80%), neutropenia (77%), leukopenia (70%), anemia (67%), and fatigue (60%). Grade 3-4 events occurred in 63% (19/30) of pts and included neutropenia (68%), leukopenia (32%), decrease in absolute neutrophil count (21%), and anemia (21%). Conclusions: The combination of anastrozole, palbociclib, trastuzumab, and pertuzumab was well tolerated and effective with a clinical benefit rate of 97% in pts with previously untreated HR-positive, HER2-positive MBC. The combination provides a chemotherapy-free alternative for pts with triple positive breast cancers. Further follow up will determine impact on PFS. Table 1. Results in Patients on Anastrozole, Palbociclib, Trastuzumab, and Pertuzumab Citation Format: Rima Patel, Krystal Cascetta, Paula Klein, Erin Moshier, Maryann Kwa, Julie Fasano, Anupama Goel, Melissa Accordino, Charles Shapiro, Rita Vaccaro, Gargi Atul Joshi, Joseph Sparano, Amy Tiersten. A Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab, and Pertuzumab in Hormone Receptor (HR)-Positive, HER2-Positive Metastatic Breast Cancer (ASPIRE) [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 RF02-01.

Abstract PO5-04-02: Combination of trastuzumab competing and non-competing fully human internalizing anti-Her2 monoclonal antibodies drug conjugates increases their inhibitory effect on the growth of HER2 positive metastatic breast cancer cells

Abstract The human epidermal growth factor receptor (HER) family of receptors plays a key role in proliferation stimulator for several human cancers. In particular, HER2 is overexpressed in 15-30% of breast cancers with or without gene amplification with prognostic and predictive implications. HER2 overexpression is associated with shorter disease-free and overall survivals, resistance to hormonal agents and increased risk of brain metastasis. Trastuzumab is a humanized anti-HER2 monoclonal antibody that binds to domain IV of HER2 extracellular domain and blocks its signaling. More recently, two antibody drug conjugates using trastuzumab have been approved: Ado-Trastuzumab-Emtansine (Kadcyla) consisting of trastuzumab conjugated to the drug mertansine DM1 and fam-trastuzumab-deruxtecan-nhki (Enhertu to deliver the topoisomerase inhibitor deruxtecan. We are reporting here the development of fully human internalizing anti-HER2 antibodies with distinct epitopes on the HER2protein which compete or not with trastuzumab for binding to HER2. These monoclonal antibodies have been developed by immunizing fully human (TC-Mab mouse) mice with recombinant HER2 protein. After production of hybridoma secreting fully human immunoglobulins, the screening process included competition with trastuzumab for binding to Her2 by enzyme linked immunoassay and Octet epitope binning and affinity determination as well as internalization assay. Several internalizing antibodies able to compete or not with trastuzumab and with high affinity (Kd ranging from 10−9 M to 10−12 M) were selected. Their ability to deliver a cytotoxic payload in HER2 overexpressing breast cancer cells such as SKBR3, BT474 and AU565 was next investigated. Two groups of antibodies: one competing with trastuzumab and the other one non-competing were further characterized. Data related to these antibodies’ biochemical characteristics as well as their ability to inhibit proliferation in vitro and in vivo in mouse xenografts studies will be presented here. In conclusion, the use of fully human mice to develop monoclonal antibodies provides a powerful and attractive approach to develop fully human monoclonal antibodies against cancer targets by-passing the need for humanization and affinity maturation of antibodies. This work is supported by 5R44CA224718 SBIR grant from the National Cancer Institute. Citation Format: Ginette Serrero, Binbin Yue, Jianping Dong, Jun Hayashi. Combination of trastuzumab competing and non-competing fully human internalizing anti-Her2 monoclonal antibodies drug conjugates increases their inhibitory effect on the growth of HER2 positive metastatic breast cancer cells [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 PO5-04-02.

Retrospective Analysis of Pyrotinib-Based Therapy for Metastatic Breast Cancer: Promising Efficacy in Combination with Trastuzumab.

To evaluate the efficacy and safety of a pyrotinib-based therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in the real world. Clinical data of 218 patients with HER2-positive MBC who received a pyrotinib-based therapy from January 2020 to March 2023 at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. Finally, 195 patients were included in the efficacy cohort. The median progression-free survival (PFS) in the total population is 12.4 months (95% CI, 9.8-15.0 months). More than half of the patients in the efficacy cohort received pyrotinib mono-targeted therapy (103 cases, 52.8%). Among the remaining patients, 74 (37.9%) patients chose a combined trastuzumab-targeted therapy and 17 (8.7%) chose to combine inetetamab. Median PFS in the pyrotinib group vs pyrotinib plus trastuzumab group was 10.5 months vs 20.1 months (P<0.001). The median PFS of primary trastuzumab resistance population reached to 20.1 months in pyrotinib plus trastuzumab group. Double-targets' advantage was also observed in the brain metastases subgroup (17.9 months vs 10.0 months, P=0.386). The patients who received pyrotinib plus inetetamab as second and higher-line treatment reached a median PFS of 7.9 months (95% CI, 4.0-11.8 months). Forty-one (19.8%) of 207 patients included in the safety cohort experienced grade 3 or higher diarrhea, the most common adverse event in safety analysis, and no adverse event-related deaths. The combination of pyrotinib and trastuzumab demonstrated promising efficacy in the treatment of HER2-positive metastatic breast cancer, including those who had primary resistance to trastuzumab and brain metastases. Pyrotinib plus trastuzumab is expected to be a potent option in the first-line. Additionally, the concurrent administration of pyrotinib and inetetamab could be an alternative to consider in the second and higher-line treatment for metastatic breast cancer. The adverse reactions of pyrotinib were tolerable in general.

Maitake Beta-Glucan Enhances the Therapeutic Effect of Trastuzumab via Antibody-Dependent Cellular Cytotoxicity and Complement-Dependent Cytotoxicity.

Trastuzumab, an anti-HER2 monoclonal antibody, is the mainstay treatment for of HER2-positive breast cancer. However, trastuzumab resistance is often observed during treatment. Therefore, new therapeutic strategies are needed to enhance the clinical benefits of trastuzumab. Maitake β-glucan MD-Fraction, isolated from Grifola frondosa, inhibits tumor growth by enhancing immune responses. In this study, we examined the effect of MD-Fraction on trastuzumab treatment of HER2-positive breast cancer. MD-Fraction did not directly inhibit the survival of HER2-positive breast cancer cells, alone or in the presence of trastuzumab in vitro. In HER2-positive xenograft models, the combination of MD-Fraction and trastuzumab was more effective than trastuzumab alone. Peripheral blood lymphocytes and splenic natural killer cells isolated from BALB/c nu/nu mice treated with MD-Fraction showed enhanced trastuzumab-induced antibody-dependent cellular cytotoxicity (ADCC) ex vivo. MD-Fraction-treated macrophages and neutrophils did not show enhanced trastuzumab cytotoxicity in the presence of heat-inactivated serum, but they showed enhanced cytotoxicity in the presence of native serum. These results suggest that MD-Fraction-treated macrophages and neutrophils enhance trastuzumab-induced complement-dependent cellular cytotoxicity (CDCC). Treatment of HER2-positive breast cancer cells with MD-Fraction in the presence of trastuzumab and native serum increased C3a release and tumor cell lysis in a dose-dependent manner, indicating that MD-Fraction enhanced trastuzumab-induced complement-dependent cytotoxicity (CDC) by activating the complement system. This study demonstrates that the combination of trastuzumab and MD-Fraction exerts a greater antitumor effect than trastuzumab alone by enhancing ADCC, CDCC, and CDC in HER2-positive breast cancer.

Neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy for human epidermal growth factor receptor 2 positive breast cancer: a real-world retrospective single-institutional study in China

IntroductionReal-world studies on neoadjuvant dual anti-HER2 therapy combined with chemotherapy for breast cancer (BC) are scarce in China. This study aimed to evaluate the efficacy and safety of neoadjuvant dual anti-HER2 therapy combined with chemotherapy in a real-world setting. Moreover, differences in estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation cell nuclear antigen (Ki-67) expression pre- and post-neoadjuvant therapy were analyzed.MethodsClinical and pathological data of patients with HER2-positive BC who received neoadjuvant dual anti-HER2 therapy combined with chemotherapy at Liaoning Cancer Hospital & Institute, China, between September 2021 and September 2023, were retrospectively reviewed.ResultsAmong 179 included patients, a pathologic complete response (pCR) was achieved in 109 patients (60.9%). The univariate analysis results indicated that the hormone receptor (HR) status (P = 0.013), HER2 status (P = 0.003), and cycles of targeted treatment (P = 0.035) were significantly correlated with pCR. Subsequent multivariable analysis showed that HR negative and HER2 status 3 + were independent predictive factors of pCR. Anemia was the most common adverse event (62.0%), and the most common grade 3–4 adverse event was neutropenia (6.1%). The differences in HER2 (34.5%) and Ki-67 (92.7%) expression between core needle biopsy and the residual tumor after neoadjuvant therapy were statistically significant, whereas the differences were insignificant in terms of ER or PR status.ConclusionsThe combination of neoadjuvant trastuzumab and pertuzumab with chemotherapy showed good efficiency, and the toxic side effects were tolerable in patients with BC. In cases where pCR was not achieved after neoadjuvant therapy, downregulation of HER2 and Ki-67 expressions was observed.

Targeting HER2 in Gastroesophageal Adenocarcinoma: Molecular Features and Updates in Clinical Practice.

Gastroesophageal adenocarcinoma (GEA) is one of the principal causes of death related to cancer globally. Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor which is found to be overexpressed or amplified in approximately 20% of GEA cases. In GEA, the identification of HER2-positive status is crucial to activate a specific anti-HER2 targeted therapy. The landmark ToGA trial demonstrated the superiority of adding trastuzumab to platinum-based chemotherapy, becoming the first-line standard of treatment. However, unlike breast cancer, the efficacy of other anti-HER2 drugs, such as lapatinib, pertuzumab, and T-DM1, has failed to improve outcomes in advanced and locally advanced resectable GEA. Recently, the combination of trastuzumab with pembrolizumab, along with chemotherapy, and the development of trastuzumab deruxtecan, with its specific bystander activity, demonstrated improved outcomes, renewing attention in the treatment of this disease. This review will summarise historical and emerging therapies for the treatment of HER2-positive GEA, with a section dedicated to the HER2 molecular pathway and the use of novel blood biomarkers, such as circulating tumour DNA and circulating tumour cells, which may be helpful in the future to guide treatment decisions.

HER2-Positive Metastatic Colorectal Cancer.

Targeted treatment strategies are available for human epidermal growth factor receptor 2 (HER2)-positive (amplified and/or overexpressed) metastatic colorectal cancer (mCRC), and HER2 testing is indicated in patients with mCRC. At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness. HER2-targeted agents should be considered for those with RAS/BRAF wild-type disease in subsequent-line treatment and in first-line treatment for patients not appropriate for intensive therapy. While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors' preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting. As T-DXd has demonstrated activity following treatment with other HER2-targeted regimens and carries an increased risk of high-grade toxicities, the authors favor reserving it for use after progression on prior anti-HER2 therapy. HER2-targeted therapies that inhibit signal transduction appear to have limited activity in those with RAS mutations, including trastuzumab-containing regimens. However, the antibody drug conjugate T-DXd has some data showing efficacy in this setting, and the authors would consider T-DXd in subsequent-line therapy for HER2-positive, RAS-mutated mCRC. Several areas of uncertainty remain regarding how to best utilize HER2-targeted therapies in mCRC. These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.

Abstract 1913: KD5005: HER-2 dependent strong potent anti-tumor activity of an anti-HER-2 mAb-TNFaimmunocytokine

Abstract Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with diverse biological functions, including apoptosis, cell survival, inflammation, and immunity. While recombinant human TNFα has demonstrated therapeutic efficacy in isolated limb perfusion for soft tissue sarcoma and melanoma, its systemic administration is limited by severe toxicities, including hypotension. Tumor-specific targeting and enhancement of TNFα's tumor cell killing activity hold promise for improving its therapeutic index. To address these challenges, we developed KD5005, a novel HER-2-targeted immunocytokine fusion protein comprising an anti-HER-2 IgG1 monoclonal antibody (trastuzumab) and human TNFα. Tissue distribution studies revealed that KD5005 specifically accumulated in HER-2-expressing tumors, demonstrating its tumor-targeting capability. In vitro, KD5005 exhibited reduced TNFα-mediated apoptosis in L929 cells compared to recombinant TNFα, indicating its lower non-specific toxicity. Notably, KD5005 induced apoptosis of HER-2-positive human gastric cancer NCI-N87 cells at significantly lower concentrations than trastuzumab, TNFα, or their combination, demonstrating its enhanced tumor cell killing activity. The potent apoptotic activity of KD5005 was HER-2-dependent, as it did not show increased apoptotic activity in WT mouse forestomach carcinoma (MFC) cells and had similar apoptotic activity compared to the combination of trastuzumab and TNFα. This HER-2 dependency further supports the tumor-specific targeting of KD5005.In vivo, KD5005 demonstrated superior anti-tumor efficacy compared to the combination of trastuzumab and TNFα in syngeneic tumor models using CT26 tumor cells transfected with the human HER-2 gene. KD5005 induced robust tumor regression and durable cure in 7 of 8 mice, while the combination of trastuzumab and TNFα elicited weaker therapeutic responses, resulting in tumor rejection in only 3 of 8 mice. Pharmacokinetic and toxicity studies of KD5005 were conducted in cynomolgus monkeys. KD5005 exhibited a significantly prolonged in vivo half-life compared to TNFα, indicating its improved pharmacokinetic profile. KD5005 was administered intravenously every two weeks to the same animal in a dose-escalation study at 0.3 mg/kg, 1.0 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg. The toxicity study results showed that the maximum tolerated dose for KD5005 in cynomolgus monkeys is 10 mg/kg, indicating its favorable toxicity profile. In summary, we have developed KD5005, a HER-2-targeted immunocytokine fusion protein with enhanced tumor-killing activity, improved pharmacokinetic properties, and a favorable toxicity profile. These preclinical findings support the further clinical development of KD5005 as a promising therapeutic agent for HER-2-positive cancers. Citation Format: YI CHEN, PENG LI, GUOBO FANG, HENG WU, CHI ZHANG, ZELING CAI. KD5005: HER-2 dependent strong potent anti-tumor activity of an anti-HER-2 mAb-TNFaimmunocytokine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1913.

A historical controlled study of domestic trastuzumab and pertuzumab in combination with docetaxel for the neoadjuvant treatment of early HER2-positive breast cancer.

HER2-positive molecular breast cancer subtypes are characterized by high aggressiveness and malignancy, and their metastasis and mortality rates are among the highest of all types of breast cancer. The use of anti-HER2-targeted agents in neoadjuvant therapy has significantly improved the prognosis of patients with HER2-positive breast cancer. In this study, we investigated the efficacy and safety of a neoadjuvant Chinese THP regimen (docetaxel, trastuzumab biosimilar TQB211 plus the pertuzumab biosimilar TQB2440 or pertuzumab) for ER/PR-negative and HER2-positive breast cancer in China. All enrolled patients received the THP regimen (T: docetaxel 75 mg/m2 per cycle; H: trastuzumab biosimilar TQB211 8 mg/kg in the first cycle and 6 mg/kg maintenance dose in cycles 2 to 4; P: pertuzumab biosimilar TQB2440 or pertuzumab 840 mg in the first cycle, maintenance dose 420 mg in cycles 2 to 4) every 3 weeks for 4 cycles. The biosimilar TQB2440 pertuzumab and pertuzumab were randomly assigned to patients. Docetaxel, TQB211, and TQB2440 were all developed by Chiatai Tianqing. The primary endpoint was the complete pathological response (pCR) in the breast, and the secondary endpoint was cardiac safety. Of the 28 eligible patients, 19 (67.9%) achieved tpCR. The tpCR rate was higher than in the NeoSphere trial (pCR63.2%) and the PEONY study (tpCR52.5%). The adverse events that occurred most frequently were leukopenia and neutropenia, with incidence rates of 82.1% and 75.0%, respectively. Of these, grade 3 leukopenia and neutropenia occupied 46.4% and 35.7%. Other grade 3 or higher adverse events were bone marrow suppression (7.1%), lymphopenia (3.6%), and anemia (3.6%). There were no events of heart failure in patients and no patient died during the neoadjuvant phase. Domestic dual-target HP has a more satisfactory efficacy and safety in the neoadjuvant phase of treatment. https://clinicaltrials.gov/study/NCT05985187, NCT05985187.