HER2-positive Metastatic Breast Cancer Research Articles

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.

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial

Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24–0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56–0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110.

Phase 2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 (trastuzumab imbotolimod) +/- pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan (T-DXd).

TPS1121 Background: Therapies to manage pts with HER2+ MBC have significantly improved, but better agents are still needed. BDC-1001 (trastuzumab imbotolimod) is being studied for MBC and other HER2+ cancers. The ISAC BDC-1001 consists of a trastuzumab biosimilar conjugated to a cell membrane impermeable TLR7/8 agonist via a non-cleavable linker and is given IV every 2 wks. Designed to trigger the innate immune system, BDC-1001 causes a durable tumor-targeted adaptive immune response. Early studies show that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, and tumor regression, in a TLR- and Fc receptor-dependent manner (1). Preclinical studies with a murine surrogate of BDC-1001 (trastuzumab-T785 ISAC) show better efficacy with trastuzumab-T785 compared to trastuzumab + P. In the BDC-1001 dose-escalation trial (BBI-20201001), 6 PRs and 12 SDs ≥ 24 weeks in 8 tumor types were observed, particularly in 20mg/kg q2w dose cohorts. The most frequent drug-related AE was low grade (grade 1/2) infusion-related reactions (29%) (2). We showed the combination of a surrogate ISAC (trastuzumab-T785) + P significantly enhances efficacy in multiple HER2-expressing tumors, including those with lower HER2 expression (1). The addition of P lowered the quantity of ISAC required for anti-tumor activity in the JIMT-1 HER2 IHC2+ model. The combination of P with the ISAC significantly increased the tumor cytokine and chemokine concentration compared to monotherapy or antibody-alone, indicating enhanced tumor myeloid activation suggesting this combination may enhance the clinical activity of trastuzumab-based ISACs. Methods: The Phase 2 multicenter, open-label, randomized study (BBI-20231001) is enrolling up to 66 patients with HER2-positive (ASCO/CAP 2018) MBC previously treated with 2 or more anti-HER2 therapies including T-DXd. Patients must be > 18 years, have measurable disease, and have ECOG performance status of 0 or 1. Patients will be randomized 1:1 to receive BDC-1001 20mg/kg every 2 weeks with or without P (840mg initial dose, followed by 420mg IV q 3w). Each arm has a Simon 2 stage design. The primary objective is anti-tumor activity of BDC-1001 alone and in combination with P. Secondary objectives will evaluate safety, PK, and immunogenicity of BDC-1001 alone and in combination with P. Exploratory objectives will include PD biomarkers in tumor tissue and in peripheral blood to elucidate the MOA and biomarkers associated with BDC-1001 activity with or without P. This study began accrual in Nov 2023. 1. Ackerman S, et al. Nature Cancer. 2021. 2. Li B, et al. ASCO 2023, Abstract 2538. Clinical trial information: NCT05954143 .

Pyrotinib plus taxanes or vinorelbine for human epidermal growth factor receptor 2-positive metastatic breast cancer: A prospective study.

e13004 Background: Pyrotinib in combination with capecitabine is recommended as the second-line treatment for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC) in China. The efficacy and safety of pyrotinib combined with non-capecitabine chemotherapy regimens remain unclear. Thus, we conducted this study to evaluate the efficacy and safety of pyrotinib combined with taxanes or vinorelbine in HER2-positive MBC. Methods: Patients with HER2-positive MBC were included to receive pyrotinib combined with taxanes or vinorelbine in Jiangsu Cancer Hospital. Patients received pyrotinib 400mg orally once daily plus taxanes (docetaxel 75-100 mg/m2 on day1, or nab-paclitaxel 125 mg/m2 on days 1 and 8, paclitaxel 80 mg/m2 on days 1 and 8, every 3 week) or vinorelbine 25 mg/m2 on days 1 and 8, every 3 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS) and safety. Results: Between Nov 20, 2018, and Jan 11, 2023, a total of 101 patients were assigned to pyrotinib plus taxanes group (n=83) and pyrotinib plus vinorelbine group (n=18). The median number of pyrotinib therapy lines was 2 (IQR 1-7), the first line accounted for 23.8%, the second line, and third line and above was 34.6%, 41.6%, respectively. As of May 24, 2023, the median PFS in the total was 11.5 months (95% confidence interval [CI], 8.8-15.7). The median PFS was significantly longer in the pyrotinib plus taxanes group than in the pyrotinib plus vinorelbine group, with median PFS being 12.2 months (95% CI, 9.2-18.6) and 8.4 months (95% CI, 5.5-13.7) (HR=2.2 [95% CI, 1.2-3.9]; P=0.005), respectively. The median PFS in the first-line, second-line, and third-line and above treatment was 28.6 (95% CI, 10.6-NA), 12.2 (95% CI, 8.5-16.3), and 8.3 months (95% CI, 6.3-14.5), respectively. The most common grade 3 or 4 adverse events were diarrhea (22.8%), leukopenia (19.5%), and neutropenia (18.2%). Conclusions: The median PFS of pyrotinib plus taxanes or vinorelbine, especially taxanes, was not inferior even superior to that of pyrotinib combined capecitabine. No increase treatment-related side effects was reported. Thus, the combination of pyrotinib and taxanes or vinorelbine regimen can be an option for HER2-positive MBC. Clinical trial information: ChiCTR2000041217.

Comparative survival analysis of patients with HER2-low and HER2-positive metastatic breast cancer with or without brain metastases treated with trastuzumab deruxtecan.

1036 Background: Breast cancer outcomes vary among HER2-amplified and HER2 low-expression patients, particularly in the presence of brain metastases (BM). Trastuzumab deruxtecan (T-DXd) is FDA approved for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low and HER2-positive (HER2+) patients (pts). This study aims to evaluate the impact of T-DXd treatment on overall survival among HER2 low and HER2-positive metastatic breast cancer (MBC) patients with and without brain metastases (BM). Methods: A retrospective analysis was conducted by using de-identified data available from seven US-based health systems part of Guardian Research Network (GRN). Patients treated with T-DXd from December 2019 to December 2023 with a diagnosis of HER2 low (immunohistochemistry [IHC] 1 + or IHC 2+/negative with HER2 FISH non-amplified) and HER2+ (IHC 3+ or HER2+ and FISH amplified MBC were included. Median overall survival (mOS), calculated from the initiation of T-DXd treatment, was assessed using Kaplan-Meier Curve analysis and Log-rank test. Results: A total of 380 MBC pts were identified. Among these 231 (61.1%) were stratified as having HER2 low and 149 (38.9%) HER2+ MBC. Pts with HER2+ disease had a higher prevalence of BM (n=70; 47%) compared to HER2-low pts (n=55;23.8%). The median age at BM diagnosis was 60.5 years, range: 21.6 to 87.1 years. Within the entire BM group (n=125), there were more pts with ER+ disease (81.9%) in the HER2 low group compared to HER2+ group (55.8%, p=0.01). The majority of these patients had multiple prior lines of therapy. HER2+ BM pts had a median overall survival (mOS) of 9.3 months [CI: 6.79-11.88, log rank p <0.001], compared to 4.3 months [CI: 1.89-6.82, log rank p <0.001] in the HER2-low pts. Without BM, HER2+ pts had a mOS of 10.7 months [CI: 0.71-20.82, log rank p <0.001], compared to 6 months [CI: 3.47-8.67, log rank p <0.001] in the HER2-low pts. Conclusions: In this retrospective study of heavily pretreated MBC patients with multiple prior lines of therapy, pts with HER2+ MBC with and without BM had a longer mOS compared to those with HER2- low disease, suggesting HER2 expression as a key determinant of T-DXd efficacy. Poor survival in MBC patients without BM was attributed to pre-treatment with multiple lines of therapy. Future research should explore combination therapies and predictive biomarkers while conducting clinical trials to optimize treatment strategies for HER2+ metastatic breast cancer patients.

The efficacy and safety of trastuzumab biosimilar HLX02 compared with reference trastuzumab plus pertuzumab in combination with chemotherapy as the first-line treatment for HER2 positive metastatic breast cancer: A real-world study in China.

e13016 Background: Dual-targeted anti-HER2 therapy with trastuzumab (H) and pertuzumab (P) significantly improves outcomes in HER2-positive breast cancer and has become the first-line standard treatment for patients with advanced HER2-positive breast cancer in China in 2019 based on the results of the CLEOPATRA and PUFFIN study. HLX02 (Zercepac) was the first trastuzumab biosimilar manufactured in China. Here, we present the first real-world comparison of HLX02 versus reference trastuzumab (RTZ) and pertuzumab with chemotherapy as the first-line treatment for HER2-positive metastatic China.Between January 2019 and August 2023, 121 patients with HER2-positive MBC patients were enrolled at Beijing Cancer Hospital in China. These patients received HLX02 or RTZ in combination with pertuzumab and various chemotherapies as first-line treatment. We retrospectively analyzed survival outcomes, efficacy, and adverse events. Methods: Between January 2019 and August 2023, 121 patients with HER2-positive MBC patients were enrolled at Beijing Cancer Hospital in China. These patients received HLX02 or RTZ in combination with pertuzumab and various chemotherapies as first-line treatment. We retrospectively analyzed survival outcomes, efficacy, and adverse events. Results: Both groups, 68 received RTZ and 53 received HLX02, showed similar characteristics of age, disease status (de novo or recurrent), metastatic sites (visceral or non-visceral), and treatment history. A total of 118 (97.5%) received trastuzumab plus pertuzumab combined with chemotherapy as the first-line palliative therapy, with a median number of 6 cycles in each group. Taxanes were the most commonly used chemotherapy regimen in both groups (91.2 vs. 92.5%), including nab-paclitaxel (44.1 vs. 45.3%), docetaxel (41.2 vs. 17.0%), paclitaxel (5.9 vs. 30.2%). With a median follow-up of 15.0 months (range 1.0 - 58.0), the results showed no significant difference in PFS between the RTZ and HLX02 arms (median PFS: 22.0 vs. 19.0 months, p=0.900). Additionally, the efficacy outcomes, including objective response rate (ORR), disease control rate (DCR), and safety profiles did not show significant differences between the two groups. Among 121 patients, 20 patients (16.5%) experienced CNS progression. For these patients, the median time from the first-line therapy to the CNS progression was 15.0 months (95% CI 12.8 - 17.2). Conclusions: The real-world data suggest similar efficacy and safety of HLX02 and RTZ plus pertuzumab with different chemotherapy regimens as the first-line treatment for patients with HER2-positive advanced breast cancer patients in China. Overall, the PFS was consistent with the CLEOPATRA trial in both groups, and there was no new safety signal.

Real-world data comparison of time to next treatment for patients with HER2 positive metastatic breast cancer treated in the second line of therapy with fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine.

Real-world data comparison of time to next treatment for patients with HER2 positive metastatic breast cancer treated in the second line of therapy with fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine.

A randomized study comparing electronic patient-reported outcome (ePRO) monitoring with routine follow-up during trastuzumab deruxtecan treatment in patients with metastatic breast cancer (PRO-DUCE study).

1504 Background: Trastuzumab deruxtecan (T-DXd) is a highly effective agent for HER2-positive metastatic breast cancer (MBC), but is associated with adverse events such as nausea, fatigue, and interstitial lung disease. Based on recent studies showing that symptom monitoring and alert notifications via ePROs could improve patient quality of life (QoL) and prognosis, we hypothesized that employing this method may diminish the treatment burden for patients receiving T-DXd. Methods: In this multicenter, randomized controlled exploratory study (jRCTs031200387), we randomized patients with HER2-positive MBC eligible for T-DXd to either the ePRO monitoring (ePROm) group or the usual care (UC) group. ePROm involved weekly symptom and daily body temperature/SpO2 reports via a smartphone or computer at home. If any symptoms exceeded the predetermined thresholds, an email alert was sent to the medical staff, the ePRO was evaluated, and, if necessary, a phone consultation was provided. The primary endpoint was the change in the Global QoL score of EORTC QLQ-C30 from baseline at week 24. Secondary endpoints included score changes in the functional and symptom scales of EORTC QLQ-C30, and the time to deterioration of Global QoL (defined as a 10-point decrease from baseline). For a score difference between groups of 10 points and a standard deviation of 24, the required number of patients was 55 in each group, with a two-sided alpha error of 10% and a power of 87%. We analyzed the primary endpoint using a mixed-effects model for repeated measures. Results: Between March 2021 and January 2023, 111 patients were enrolled at 38 hospitals in Japan, with 56 assigned to ePROm and 55 to UC; the full-analysis set for QoL assessment included 54 and 52 patients, respectively. During the 24-week period, there were 1223 ePRO reports (95% compliance rate) in the ePROm group, including 427 alert notifications (7.9 per patient) to healthcare providers. Overall compliance with the questionnaire for QoL was 97%. Mean changes from baseline scores in Global QoL at week 24 showed that ePROm was significantly better than UC (mean difference 8.0 [90% CI 0.2, 15.8]; p=0.091). Role, cognitive, and social functioning were better in ePROm, with mean differences of 10.0 (95% CI 1.1, 18.9; p=0.028), 6.3 (1.1, 11.5; p=0.017), and 10.9 (3.9, 18.0; p=0.003), respectively. There was no difference in nausea/vomiting (0.5 [- 6.2, 7.1]; p=0.889), while fatigue was significantly better in ePROm (-8.4 [-16.1, -0.6]; p=0.034). Median time to first deterioration in Global QoL score was 3.9 months (95% CI 2.5, 13.9) in ePROm and 3.0 months (95% CI 1.6, 6.7) in UC (hazard ratio 0.73 [95% CI 0.45, 1.17]; p=0.159). Conclusions: ePROm systems, especially for symptom and SpO2 tracking in HER2-positive MBC patients treated with T-DXd, are promising to enhance patient QoL. Clinical trial information: jRCTs031200387 .

Outcome with pertuzumab, docetaxel, and trastuzumab (PTH) regimen in patients with HER2 positive metastatic breast cancer: Real-world data from a single center in India.

e13037 Background: Pertuzumab, Docetaxel and Trastuzumab (PTH) regimen constitutes one of the standard treatment regimens in human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC). The real-world outcomes of its use from the Indian sub-continent are lacking. Methods: We retrospectively reviewed the medical records of HER2-positive MBC treated with an upfront PTH regimen at the All India Institute of Medical Sciences, New Delhi, India, between Aug 2016 to July 2023. A total of six cycles of PTH [pertuzumab (840 mg loading followed by 420 mg), docetaxel (75 mg/m2), trastuzumab (8 mg/kg loading followed by 6 mg/kg) q21 days] were planned along with granulocyte-colony stimulating factor (GCSF) prophylaxis. Patients were continued on maintenance trastuzumab after 6 cycles (till disease progression) and hormonal agent if indicated. The primary outcome was progression-free survival (PFS). The secondary outcome was overall survival (OS), overall response rate (ORR) rates, and toxicity. Results: Eighty-seven were included with a median age of 48 years (range, 25-73). Overall, 38 (43.6%) patients had hormone-positive (estrogen receptor and or progesterone receptor) disease and 48 (55.17%) were premenopausal. Thirty-five (40.2%) patients had received prior adjuvant and neoadjuvant treatment. Eighty patients (91.5%) had visceral metastasis and the most common site was the liver followed by the lung. After a median follow-up of 36 months, the median PFS was 15 months and OS was 42 months. The ORR was 85.3% and complete response (CR) was observed in 14(16.09%) patients. The survival outcomes were significantly better among those with hormone-negative disease and among those who achieved CR after 6 cycles of PTH. Grade 3/4 toxicity was seen in 12% of patients which led to dose modification, interruption, and change in chemotherapy. Two patients developed reversible left asymptomatic ventricular systolic dysfunction. None of the patients developed congestive heart failure. The most common grade 3/4 toxicities were diarrhea in 8 (9.1%) patients, cutaneous rash in 2 (2.2%) patients and thrombocytopenia in 2 (2.2%) patients. There were two cases of febrile neutropenia. Conclusions: In a real-world context, PTH is an effective and well-tolerated regimen for in patients with HER2-positive MBC in India. Hormone-positive disease has poor survival compared with hormone negative disease.

Efficacy and safety of inetetamab-containing regimens in patients with HER2-positive metastatic breast cancer in first-line/second-line setting.

e13013 Background: Inetetamab is a novel recombinant humanized anti-human epidermal growth factor receptor-2 (HER-2) monoclonal antibody. This real-world retrospective study assessed the efficacy and safety of inetetamab-based combination regimens in first-line/second-line treatment of HER2-positive metastatic breast cancer (MBC). Methods: This study retrospectively recruited HER2-positive MBC patients who received inetetamab-based combination regimens from June 2020 to May 2023. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Results: A total of 329 patients were enrolled and included in the efficacy analysis. The most frequently used treatment strategy was inetetamab plus pyrotinib-contained regimens (205/329, 62.3%). Patients treated with first-line regimens benefited the most, with a median PFS of 14.5 versus (vs.) 10.0 months (first-line- vs. second-line combination therapy of inetetamab, pyrotinib and chemotherapy, p <0.001), 18.0 vs. 17.0 months (first-line- vs. second-line combination therapy of inetetamab, pertuzumab and chemotherapy, p=0.096), and 14.0 vs. not applicable months (first-line- vs. second-line inetetamab plus chemotherapy, p=0.229). The complete response (CR) was observed in 14 (4.3%) patients. The ORR was 54.4% (95%CI, 49.0%-59.7%), and the DCR was 99.4% (95%CI, 97.8%-99.8%). Diarrhea (39.2%) and white blood cell count decreased (33.0%) were the most common adverse events (AEs). The grade 3 and higher AEs were observed in 29.5% of the whole study cohort. Conclusions: Inetetamab-based combinations therapy demonstrated promising clinical activity and a manageable safety profile in patients with HER2-positive MBC, especially in the first-line setting.

Safety and preliminary efficacy of GQ1001, a next generation HER2-targeting ADC, combined with pyrotinib in pretreated patients with HER2-positive metastatic breast cancer: A phase 1b clinical trial.

Safety and preliminary efficacy of GQ1001, a next generation HER2-targeting ADC, combined with pyrotinib in pretreated patients with HER2-positive metastatic breast cancer: A phase 1b clinical trial.

Trastuzumab-induced cardiotoxicity in patients with metastatic HER2-positive breast cancer treated at a reference hospital in Mexico.

e13032 Background: In Mexico, breast cancer represents the leading cause of cancer-related death in women, and up to 52% is diagnosed at a metastatic stage. Up to 20-25% of women with breast cancer have overexpression of the human epidermal growth factor receptor 2 (HER2) which is associated with an aggressive behavior. The most relevant adverse effect associated with therapy targeting this receptor is an increase of up to 4 times in the rate of myocardial dysfunction. There is limited research in the Mexican population, especially in the metastatic context. This review is intended to be conducted in the national population, including patients with HER2-positive metastatic breast cancer who have received trastuzumab treatment, to determine the main characteristics of such myocardial dysfunction using the definition of cardiac dysfunction proposed by the International Cardio-Oncology Society (ICOS) in 2021, as well as its current prevalence. Methods: Observational, descriptive, cross-sectional, retrospective study. Medical records of patients diagnosed with metastatic HER2-positive breast cancer between January 2017 and December 2022, who received trastuzumab and had a determination of left ventricular ejection fraction (LVEF) before treatment and at least two LVEF determinations during treatment to determine the presence or absence of cardiotoxicity. LVEF could have been determined by MUGA (Multigated Acquisition Scan) or by echocardiogram. Results: A total of 103 patients were included, with a mean age of 55 years. The found prevalence of cardiotoxicity was 30.09%. Among the most frequent clinical characteristics of these patients were obesity in 32.2% [n= 10], smoking habit in 12.9% [n= 4], and type 2 diabetes in 9.7% [n= 3]. The diagnosis of de novo metastatic disease was 48.4% [n= 15]. A history of ischemic heart disease was present in 3.2% [n= 1], and a frequency of 12.9% [n= 4] of patients with borderline LVEF (50-54%) was reported at baseline, with only 3.2% [n= 1] documented with a baseline LVEF < 50%. The median number of trastuzumab cycles administered during follow-up was 14 cycles, anthracycline therapy was documented in most patients, and previous exposure to thoracic and/or mediastinal radiotherapy with a dose exceeding 30 Gy was found in 35.5% [n= 11]. Referral to cardiology and/or cardio-oncology service was 51.6% [n= 16]. Discontinuation of anti-HER2 treatment was carried out in 3 patients (2.9%). Conclusions: We demonstrated a prevalence of cardiotoxicity from anti-HER2 agents in our population similar to that reported in the international literature. Multicenter studies are necessary to define the prevalence more accurately in the Mexican population, as well as prospective studies to demonstrate the association between cardiovascular risk factors and clinical characteristics with the development of cancer therapy-related cardiac dysfunction.

Real-world efficacy and safety of inetetamab-based therapy in patients with HER2-positive metastatic breast cancer with prior trastuzumab exposure: A multi-center retrospective study.

Real-world efficacy and safety of inetetamab-based therapy in patients with HER2-positive metastatic breast cancer with prior trastuzumab exposure: A multi-center retrospective study.

T-DM1 in Chinese patients with Her2-positive metastatic breast cancer: A multi-center, retrospective, real world study.

T-DM1 in Chinese patients with Her2-positive metastatic breast cancer: A multi-center, retrospective, real world study.

Real-world analysis of inetetamab combined with pyrotinib plus chemotherapy for the treatment of HER2-positive advanced breast cancer: A multi-center retrospective study.

e13012 Background: Inetetamab combined with tyrosine kinase inhibitors exhibited stronger antitumor effects than inetetamab alone. At present, there was few studies on the efficacy and safety of inetetamab combined with pyrotinib in the treatment of advanced breast cancer (ABC) patients. The study aims to investigate the efficacy and safety of inetetamab combined with pyrotinib plus chemotherapy for HER2-positive ABC patients. Methods: We retrospectively investigated the medical records of eligible women who aged 18 years or older with pathologically confirmed HER2-positive recurrent or metastatic invasive breast cancer, and received at least two cycles of inetetamab combined with pyrotinib plus chemotherapy treatment regimens in multicenters in China between July 2020 and December 2022. The primary endpoint was progression-free survival (PFS) estimated by the Kaplan-Meier method. The secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and safety. Cox regression model was used to identify predictive factors for PFS. Results: A total of 99 patients were included. Overall patient's median PFS was 12.3 (95% CI: 10.9-13.6) months. Of 99 evaluable patients, 53 (53.5%) patients achieved objective response, including 9 (9.1%) complete response and 44 (44.4%) partial response. The remaining 45 patients achieved stable disease as the best response, thus, the DCR was 99.0%. Patients who received Inetetamab combined with pyrotinib plus chemotherapy as first-line treatment (15.0 months [95% CI: 13.6-15.8]) provided longer median PFS than that as second-line treatment (10.3 months [95% CI:9.6-10.9], p<0.001). Furtherly, the Cox multivariate regression analysis indicated that patients who received inetetamab combined with pyrotinib plus albumin-bound paclitaxel for first-line treatment achieved longer median PFS. Grade 1-2 diarrhea (59.6%), vomiting (29.3%) and nausea (28.3%), hand-foot syndrome (23.2%) were the top four most common adverse events (AEs). The most common grade ≥3 AEs were leukopenia (19.2%), diarrhea (18.2%), myelosuppression (7.1%) and neutromenia (4.0%). Conclusions: The first-line treatment of inetetamab combined with pyrotinib plus chemotherapy was an effective and safe treatment for HER2-positive ABC patients. Inetetamab combined with pyrotinib plus albumin-bound paclitaxel might be the most effective combination therapies. All AEs were controllable and tolerable.

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 .

Unraveling the synergistic mechanisms of pyrotinib in combination with trastuzumab: Insights from the PHILA trial.

e13015 Background: There are many options for the treatment of advanced HER2-positive breast cancer. The results of PHILA study suggest that pyrotinib, trastuzumab and docetaxel may be considered as a potential first line treatment for patients with untreated HER2-positive metastatic breast cancer. We aimed to investigate the synergistic mechanisms of pyrotinib plus trastuzumab and compare them to trastuzumab plus pertuzumab, providing further insights for the PHILA trial. Methods: The efficacy of combination treatments was detected by cell vitality assay, Western blot and immunohistochemistry. The relevant mechanism was examined by flow cytometry and co-immunoprecipitation. Cell-derived xenografts and TUBO tumor model were utilized to evaluate the anti-tumor activity of rational combinations. Next-generation sequencing of circulating tumor DNA from a cohort of 18 patients in the PHILA trial was performed to evaluate molecular alterations associated with clinical response. Results: We demonstrated that pyrotinib plus trastuzumab superiorly inhibited cell growth than trastuzumab plus pertuzumab in models of HER2-dependent breast cancer. In addition to inhibiting HER family phosphorylation, pyrotinib plus trastuzumab synergistically reduced membrane HER2 levels by inducing receptor ubiquitination and internalization via HSP90 dissociation, which resulted in a comprehensive blockade of HER signaling pathway. Moreover, TUBO tumor model was utilized to further confirm the synergistic effects of pyrotinib and anti-neu antibody on HER2 signaling cascade. In both treatment groups of PHILA study, patients with aberrant mutations in HER2 signaling cascade showed a significantly shorter median progression-free survival compared to individuals with wild-type pathway. Correspondingly, in models of HCC1954 breast cancer cell harboring PIK3CA H1047R mutation, we did not observe a synergy between pyrotinib and trastuzumab. Conclusions: Pyrotinib and trastuzumab synergistically achieve the comprehensive blockade of HER signaling pathway in HER2-dependent breast cancer. Patients with advanced HER2-positive breast cancer, who are addicted to HER2 signaling cascade, could be considered for pyrotinib in combination with trastuzumab and docetaxel as an alternative first line treatment.

Efficacy of first-line dual oral pyrotinib plus capetabine therapy in HER2-positive metastatic breast cancer: A real-world retrospective study.

The combination of dual-targeted human epidermal growth factor receptor 2 (HER2) therapy and chemotherapy is the standard first-line regimen for recurrent/metastatic breast cancer (mBC). However, the toxicity of such combination therapy can lead to some patients being unable to tolerate adverse events or bear treatment costs. As a novel irreversible pan-ErbB receptor TKI (pyrotinib), can the dual oral administration of pyrotinib plus capetabine (PyroC) provide first-line survival benefits and serve as a more affordable treatment option? This real-world retrospective study included patients diagnosed with HER2-positive mBC who received PyroC as a first-line treatment at West China Hospital between May 2018 and July 2023. The survival data and toxicity profiles were reported in this study. A total of 64 patients received PyroC as first-line therapy. The median progression-free survival (PFS) was 19.6 months (95% CI 15.0-27.2), while overall survival (OS) has not yet been reached. Kaplan-Meier analysis indicated that age (≥60, p = 0.03) and metastasis sites (p = 0.004) were related to poor efficacy of PyroC, while there was no relationship between effectiveness and menstrual status, hormone receptor (HR) status or previous treatment with anti-HER2 therapy. Furthermore, the objective response rate (ORR) and disease control rate (DCR) were 79.7% and 98.4%, respectively. Of the patients, 78.1% reported treatment-related adverse events (TRAEs). The predominant adverse events were diarrhea (n = 46, 71.9%) and hand-foot syndrome (n = 10, 15.6%). The dual oral administration regimen (PyroC) has a promising ORR or PFS in HER2-positive mBC patients, with an acceptable safety profile and convenience.

Trastuzumab-emtansine versus other anti-HER2 regimens in early or unresectable or metastatic HER-2 positive breast cancer: systematic review and network meta-analysis.

Motivation for the study. Treatment options for HER2-positive breast cancer were evaluated, focusing on the efficacy and safety of trastuzumab-emtansine (T-DM1) compared to other anti-HER2 therapies. Main findings. Trastuzumab-deruxtecan (T-DXd) and PyroCap emerged as promising alternatives, showing substantial improvements in progression-free survival for locally advanced or metastatic breast cancer. T-DM1 showed superior efficacy to the other treatments. Implications. Our findings could inform healthcare decision-making processes to optimize strategies for HER2-positive breast cancer, and potentially improve health outcomes and quality of life. We aimed to study the efficacy and safety of trastuzumab-emtansine (T-DM1) versus other anti-HER2 therapies in HER2+ breast cancer (BC). We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs). Our study focused on patients undergoing treatment for unresectable locally advanced breast cancer (LABC) or metastatic breast cancer (mBC), which included regimens involving trastuzumab and taxanes. Additionally, we considered cases within the first 6 months of treatment for HER2+ early breast cancer (EBC). A total of 23 RCTs and 41 reports were included in our analysis. LABC and mBC showed no statistically significant difference in any of the comparisons of T-DM1 versus the other anti-HER2+ therapies. When assessing progression-free survival (PFS), trastuzumab-deruxtecan (T-DXd) and PyroCap demonstrated greater efficacy compared to other treatments (Hazard Ratio [HR]: 3.57; 95% confidence interval [CI]: 2.75-4.63 and HR: 1.82; 95% CI: 1.35-2.44; respectively), while T-DM1 alone exhibited superior effectiveness compared to LapCap (HR: 0.65; 95% CI: 0.55-0.77), TrasCap (HR: 0.65; 95% CI: 0.46-0.91), LapCapCitu (HR: 0.60; 95% CI: 0.33-1.10), Nera (HR: 0.55; 95% CI: 0.39-0.77), and Cap (HR: 0.37; 95% CI: 0.28-0.49). NMA allows a ranking based on the comparative efficacy and safety among the interventions available. Although superior to other schemes, T-DM1 showed a lower efficacy performance in PFS and overall response rate and a trend towards worse overall survival than T-DXd.

Clinical benefit of post-trastuzumab deruxtecan treatment in patients with HER 2-positive unresectable or metastatic breast cancer: A single-institution retrospective observational study.

Trastuzumab deruxtecan (T-DXd) can improve the prognosis of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, data on treatment recommendations after T-DXd are lacking. Thus, this study aimed to evaluate the treatment options after T-DXd and their effectiveness. Patients with HER2-positive MBC were included in this study. Data from clinical records were retrospectively analyzed. The primary outcome was time to treatment failure (TTF). Secondary endpoints were TTF of each treatment and first-line treatment after interstitial lung disease (ILD) and overall survival (OS). A total of 29 patients were included. Among them, 18 (62%) were hormone receptor-positive. All patients had a median TTF (mTTF) of 3.5months (95% confidence interval (CI) 2.1-10.03). The mTTF of each treatment, including HER2 tyrosine kinase inhibitor (HER2 TKI), other anti-HER2 treatments, and other treatments, was 2.6, 8.8, and 3.8months, respectively. No significant differences were observed between treatments, but regimens that include trastuzumab showed a longer TTF than TKI. However, the mTTF among patients who developed T-DXd-related ILD was 2.33months (95% CI 0.7-not reached), which was shorter than that among those who did not develop ILD (3.83months, 95% CI 2.1-10.03, hazard ratio: 2.046, 95% CI 0.760-5.507, p = 0.258). The median OS was 14.9months (95% CI 11.07-29.17). Treatments after T-DXd showed a shorter mTTF. Regimens that include trastuzumab may be more effective post-T-DXd treatment than HER2 TKI. Further data are needed to establish the best sequential treatment after T-DXd.