HER2-positive Metastatic Breast Cancer Patients Research Articles

Abstract PO4-04-06: Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study

Abstract Background Trastuzumab emtansine (T-DM1) is the established standard second-line treatment for HER2-positive metastatic breast cancer (MBC) patients who have previously received trastuzumab. However, there is ongoing debate regarding the subsequent therapeutic options following T-DM1 failure. This study aimed to evaluate the efficacy and safety of tyrosine kinase inhibitors (TKIs)-based therapy in HER2-positive MBC patients with resistance to T-DM1. Methods During the period from September 2018 to October 2021, a multicenter real-world study was conducted, enrolling a total of 53 patients diagnosed with HER2-positive metastatic breast cancer (MBC). These patients underwent TKIs-based therapy following the failure of T-DM1 treatment. The primary focus of the study was on evaluating progression-free survival (PFS) as the main endpoint. Secondary endpoints encompassed objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and safety assessments. Results A total of 53 patients received TKIs-based therapy as a second-line or later treatment. The median progression-free survival (PFS) for TKIs-based therapy was 11.9 months (95% CI 7.9-15.9). The objective response rate (ORR) and clinical benefit rate (CBR) were found to be 19.6% and 72.5%, respectively. Among patients with brain metastasis (n=12), a median PFS of 10.5 months (95% CI 7.5-13.5) and an intracranial ORR of 33.3% were observed. Patients treated with pyrotinib (n=21) showed improved PFS compared to those treated with lapatinib (n=30), as well as patients who had derived favorable benefit from T-DM1 (PFS ≥ 6 months). Hormone receptor status (HR) and response to T-DM1 were identified as independent factors affecting the effectiveness of TKIs-based therapy. The most frequently reported adverse events included thrombocytopenia (23.6%), diarrhea (15.7%), leucopenia (15.7%), and hand-foot syndrome (15.7%). Conclusion TKIs-based therapy demonstrated favorable effectiveness and safety in HER2-positive metastatic breast cancer (MBC) patients who had previously received T-DM1 but experienced treatment failure. This includes patients with brain metastases. Notably, individuals who derived favorable benefits from prior T-DM1 treatment displayed significantly prolonged progression-free survival (PFS) when undergoing subsequent TKIs-based therapy. Citation Format: Yongmei Yin, Chunxiao Sun, Yijia Hua, Nan Jin, Wei Li, Xiang Huang. Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world 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 PO4-04-06.

Abstract PO1-16-05: Matched multi-analyte and multi-omic liquid biopsy of cell-free DNA, circulating tumor cells and extracellular vesicles in HER2-positive metastatic breast cancer patients

Abstract Background: Liquid biopsy, specifically cell-free DNA (cfDNA) mutation analysis, has recently entered clinical practice for treatment decision-making in hormone receptor (HR)-positive (+)/HER2-negative (-) metastatic breast cancer (mBC) patients. However, we showed that the analysis of multiple liquid biopsy analytes in the course of treatment in this BC subgroup has additive value. Since no multi-analyte studies are currently available for the subgroup of HER2+ mBC patients, we here studied multiple analytes [cfDNA, circulating tumor cells (CTCs) and extracellular vesicles (EVs)] and utilized our multi-omics perspective (CpG island methylation, mutations and mRNA expression) to get insight into their utility in therapy management of HER2+ mBC. Methods: 2x 9 ml blood was drawn from 21 HER2+ (HR+ n=16 and HR- n=5) mBC patients at the time of disease progression and at two consecutive staging time points. CTCs and their mRNA were isolated from 2x5 ml blood by positive immunomagnetic selection targeting EpCAM, EGFR and HER2 (AdnaTest EMT2/StemCell Select/Detect). Plasma of CTC-depleted blood was used for cfDNA isolation, while mRNA from EVs was isolated from 4 ml pre-filtered plasma by affinity-based binding to a spin column (exoRNeasy) using the remaining blood. The mRNA purified from CTCs and EVs by Oligo-dT beads was reverse transcribed, pre-amplified and analyzed by a multi-marker (18 genes) qPCR panel. qPCR data was normalized to CD45 (for CTC analysis) and data of 20 healthy female donor controls to identify BC specific overexpression signals with a specificity of >90% for all targets. Variants in the cfDNA were analyzed with a customized QIAseq Targeted DNA Panel with unique molecular indices (UMIs) and high coverage (mean 22.000x), while CpG island methylation in the cfDNA was analyzed with a customized QIAseq Targeted Methyl Panel with UMIs covering 9786 CpG sites (mean 900x). Consumables: QIAGEN, Germany. Results: In general, substantial differences occurred between the CTC and EV mRNA profiles. Transcripts involved in the PI3K pathway (mTOR, AKT2, PIK3CA) as well as ERBB2 signals were significantly more prevalent in CTCs compared to EVs and mTOR, ERCC1, SRC, AKT2 und PIK3CA CTC overexpression signals were found in >50% of these patients. In contrast, PARP1, AURKA, SRC und ERCC1 signals were significantly more prominent in the EVs and detected in >50% of the patients. ERCC1 signals were present in EVs with highest prevalence whereas ERBB2 signals were only present in CTCs. ERBB3+ CTCs were only detected in patients showing disease progression. Currently, cfDNA mutations as well as cfDNA CpG island methylation are under evaluation and the complete multi-analyte and multi-omic data set as well as their relation to clinical outcome will have been finalized to be presented at the meeting. Conclusion: We successfully established a workflow for parallel isolation of multiple liquid biopsy analytes from a minimized blood volume in HER2+ mBC. Preliminary mRNA profile results for CTCs and EVs show the complementary nature of these two liquid biopsy analytes. Besides the multi-analyte nature of this workflow, the pending results for genomic and epigenomic information will show which one of the analytes, alone or in combination, will help to optimize therapy management in HER2+ mBC patients. Citation Format: Sabine Kasimir-Bauer, Markus Storbeck, Ioanna Andreou, Siegfried hauch, Oliver Hoffmann, Rainer Kimmig, Corinna Keup. Matched multi-analyte and multi-omic liquid biopsy of cell-free DNA, circulating tumor cells and extracellular vesicles in HER2-positive metastatic breast cancer patients [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 PO1-16-05.

Abstract PO1-04-02: ACE-Breast-03: A phase 2 study of ARX788, a novel next-generation anti-HER antibody-drug conjugate in HER2-positive metastatic breast cancer patients previously treated with trastuzumab deruxtecan

Abstract Background: HER2 overexpression and/or amplification confers aggressive tumor behavior and decreased survival in patients with breast cancer. Targeting of HER2 is a validated therapeutic strategy, and trastuzumab deruxtecan (T-DXd) has emerged as a preferred treatment in the second-line setting. However, effective treatment following progression on T-DXd remains a major unmet medical need. ARX788 is a next-generation antibody-drug conjugate (ADC) using a technology platform whereby a HER2-specific monoclonal antibody is conjugated to amberstatin 269 (AS269), a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to the slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells, at a lower effective dose compared with other HER2 ADCs. Methods: ACE-Breast-03 (NCT04829604) is a global, phase 2 study designed to assess anticancer activity and safety in approximately 40 patients with unresectable or metastatic HER2 positive breast cancer who have been previously treated with T-DXd. Eligibility criteria include measurable disease by RECIST v1.1, radiographically stable brain metastases, no more than three prior lines of treatment in the metastatic setting, and HER2 positivity as determined by central review. If recently progressed on T-DXd or trastuzumab emtansine (T-DM1), a new biopsy for HER2 status is required. Patients will be administered 1.5 mg/kg of ARX788 every three weeks. Efficacy will be assessed using RECIST v1.1 at nine-week intervals after starting ARX788 until progression or start of new cancer treatment. Objective response rate is the primary endpoint, with disease control rate, progression-free survival, overall survival, best overall response, duration of response, and time to response as additional endpoints. The safety and tolerability profile will also be evaluated. PK analysis will determine serum concentrations of ARX788, total antibody, and pAF-AS269. Potential predictive and/or prognostic biomarkers will be analyzed for exploratory purposes. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Citation Format: Kashif Ali, Laila Agrawal, Anu Thummala, Kevin Kalinsky, Sami Ali, Sibel Blau, Margaret Block, Michael Danso, Denise Yardley, Jay Andersen, Adrienne Gropper-Waks, Priya Jayachandran, Igor Makhlin, Petros Nikolinakos, Joyce O'Shaughnessy, Sandra Aung, Colin Hessel, Hope Rugo, William Gradishar, Debu Tripathy. ACE-Breast-03: A phase 2 study of ARX788, a novel next-generation anti-HER antibody-drug conjugate in HER2-positive metastatic breast cancer patients previously treated with trastuzumab deruxtecan [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 PO1-04-02.

Abstract PO4-04-04: A Multicenter, Retrospective, Real World Study of Inetetamab Combined with Pyrotinib and Vinorelbine as Treatment for HER2-positive Metastatic Breast Cancer

Abstract Background Inetetamab, a new human epidermal growth factor receptor 2 (HER2) targeted antibody to optimize the ADCC effect, has shown great effectiveness in treating HER2-positive metastatic breast cancer. Pyrotinib, another HER2 targeted drug, is a typical representative of TKI drugs, which not only has a strong HER2 antagonistic effect but also can synergize with monoclonal antibodies to amplify the ADCC effect. Here, we investigated the efficacy and safety of inetetamb combined with pyrotinib and vinorelbine as treatment or HER2-positive metastatic breast cancer. Methods From Jan 2020 to July 2023, 77 HER2-positive metastatic breast cancer patients received inetetamb combined with pyrotinib and vinorelbine were enrolled in this study. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety profiles were reported. Results The patients’ median age at enrollment was 53 years, 35 patients (45.5%) had hormone receptor-positive disease and 54 patients (70.1%) had visceral metastasis. The median PFS was 10.03 months (95% confidence interval [CI] 6.66 to 13.41 months). ORR was 62.3% (48/77) and CBR reached 77.9% (60/77). The most common adverse event (AE) was diarrhea, occurring in 36 patients (46.8%). While the most common grade III/IV AEs included neutropenia (9[11.7%]), leukopenia (8[10.4%]) and diarrhea (5[6.5%]). No treatment-related serious adverse events or treatment-related deaths occurred. Conclusion The combination regimen of inetetamab combined with pyrotinib and vinorelbine showed an encouraging efficacy and favorable safety in patients with HER2 positive metastatic breast cancer. Citation Format: Yongmei Yin, Wei Li, Xiang Huang, Nan Jin, Xinyu Wu, Chunxiao Sun, Yijia Hua. A Multicenter, Retrospective, Real World Study of Inetetamab Combined with Pyrotinib and Vinorelbine as Treatment for HER2-positive Metastatic 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 PO4-04-04.

Abstract PO3-16-09: Real-World Experience with Trastuzumab Deruxtecan at a Diverse NCI Comprehensive Cancer Center

Abstract Background: Trastuzumab Deruxtecan (T-DXd) is an antibody-drug conjugate originally approved for use in patients with HER2–positive metastatic breast cancer (MBC). In June 2022, data from the DESTINY-Breast04 trial revealed a near-doubling of progression-free survival (PFS) and significantly improved overall survival (OS) for patients with HER2-low MBC (immunohistochemistry [IHC] grade 1+ or IHC2+ in situ hybridization [ISH]-negative) treated with T-DXd versus standard-of-care chemotherapy. The data from this clinical trial led to the approval of T-DXd for use in patients with HER2-low MBC. However, the DESTINY-Breast studies completed to date have included < 5% black patients. This retrospective study of patients at a racially diverse NCI Comprehensive Cancer Center was designed to study whether T-DXd in a real-world population are comparable to published data. Methods: A retrospective chart review was conducted and identified 72 patients with HER2-low and HER2-positive MBC who received T-DXd between December 2019 and March 2023 at the Winship Cancer Institute at Emory University. Data collected for all patients included demographics, prior breast cancer history, T-DXd -specific and post-T-DXd treatment, and clinical outcomes where applicable. Results: Of the 103 patients who were dosed with T-DXd, 55 (53.4%) had HER2-positive disease, and 48 (46.7%) patients had HER2-low disease. 71 (68.9%) patients had hormone-receptor positive disease and 32 (31.1%) patients had hormone-receptor negative disease. The overall study population was 46% Caucasian; 38% African American; 13% Asian; 4% Unreported. The average number of cycles received was 11 (on treatment an average of 8 months). Pneumonitis occurred in 5 patients (4.9%). HER2-positive patients were typically on T-Dxd for a greater number of cycles than HER2-low patients (Table 1). Additionally, patients with brain metastases were, on average, treated with T-Dxd longer than patients without brain metastases, 14.5 versus 9 cycles. The number of cycles of T-Dxd received, the need for dose reduction, and incidence pneumonitis did not differ significantly between black and white patients. The data for this study is preliminary 48% of the patient population are still actively undergoing T-Dxd treatment. Conclusion: This study reviewed and analyzed T-Dxd treatment in a diverse population of both HER2-positive and HER2-low MBC patients, and in this study, outcomes of treatment did not differ by race. More attention to this topic is needed in future studies of larger populations, along with increased efforts to enroll diverse patient populations in clinical trials. Table 1. Citation Format: Jane Meisel, Maisey Ratcliffe. Real-World Experience with Trastuzumab Deruxtecan at a Diverse NCI Comprehensive Cancer Center [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 PO3-16-09.

NSABP FB-10: a phase Ib/II trial evaluating ado-trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer

BackgroundWe previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer patients. Patients with ERBB2 amplification in ctDNA had deeper and more durable responses. This study extends these observations with in-depth analysis of molecular markers and mechanisms of resistance in additional patients.MethodsForty-nine HER2-positive patients (determined locally) who progressed on-treatment with trastuzumab + pertuzumab were enrolled in this phase Ib/II study. Mutations and HER2 amplifications were assessed in ctDNA before (C1D1) and on-treatment (C2D1) with the Guardant360 assay. Archived tissue (TP0) and study entry biopsies (TP1) were assayed for whole transcriptome, HER2 copy number, and mutations, with Ampli-Seq, and centrally for HER2 with CLIA assays. Patient responses were assessed with RECIST v1.1, and Molecular Response with the Guardant360 Response algorithm.ResultsThe ORR in phase II was 7/22 (32%), which included all patients who had at least one dose of study therapy. In phase I, the ORR was 12/19 (63%), which included only patients who were considered evaluable, having received their first scan at 6 weeks. Central confirmation of HER2-positivity was found in 83% (30/36) of the TP0 samples. HER2-amplified ctDNA was found at C1D1 in 48% (20/42) of samples. Patients with ctHER2-amp versus non-amplified HER2 ctDNA determined in C1D1 ctDNA had a longer median progression-free survival (PFS): 480 days versus 60 days (P = 0.015). Molecular Response scores were significantly associated with both PFS (HR 0.28, 0.09–0.90, P = 0.033) and best response (P = 0.037). All five of the patients with ctHER2-amp at C1D1 who had undetectable ctDNA after study therapy had an objective response. Patients whose ctHER2-amp decreased on-treatment had better outcomes than patients whose ctHER2-amp remained unchanged. HER2 RNA levels show a correlation to HER2 CLIA IHC status and were significantly higher in patients with clinically documented responses compared to patients with progressive disease (P = 0.03).ConclusionsThe following biomarkers were associated with better outcomes for patients treated with T-DM1 + neratinib: (1) ctHER2-amp (C1D1) or in TP1; (2) Molecular Response scores; (3) loss of detectable ctDNA; (4) RNA levels of HER2; and (5) on-treatment loss of detectable ctHER2-amp. HER2 transcriptional and IHC/FISH status identify HER2-low cases (IHC 1+ or IHC 2+ and FISH negative) in these heavily anti-HER2 treated patients. Due to the small number of patients and samples in this study, the associations we have shown are for hypothesis generation only and remain to be validated in future studies.Clinical Trials registration NCT02236000

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial

DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline. Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR. As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1. Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.

A real-world study of treatment sequences and second-line clinical outcomes in patients with HER2-positive metastatic breast cancer in US community practice.

Standard-of-care for HER2-positive metastatic breast cancer (HER2 + mBC) patients consists of trastuzumab ± pertuzumab with chemotherapy in first-line (1L), and ado-trastuzumab emtansine (T-DM1) or the more recently approved trastuzumab deruxtecan (T-DXd) in second-line (2L). Contemporary data on treatment sequencing and real-world effectiveness is limited. This study aims to report 2L treatments and outcomes among HER2 + mBC patients in the United States (US). HER2 + mBC patients initiating 2L treatment (index date) between January 2014 and February 2021 were identified from the Syapse Learning Health Network (LHN) database. Summary statistics for patient characteristics, treatment received, reasons for 2L discontinuation and time to 2L-clinical outcomes are reported. Of the 312 patients initiating 2L treatment, had a median age of 59years (interquartile range [IQR], 50-66) at the start of 2L. The majority were white (69%) and had de novo mBC (62%). Top three 2L regimens included T-DM1 ± endocrine therapy (29%), trastuzumab/pertuzumab/taxane (10%) and T-DM1/trastuzumab (8%). Around 88% discontinued 2L and 63% received subsequent treatment. Median time-to-next-treatment was 10.6months (95% CI, 8.8-13.3) and real-world progression-free-survival was 7.9months (95% CI, 7.0-9.9). Among 274 patients who discontinued 2L, 47% discontinued due to progression and 17% because of intolerance/toxicity, respectively. This real-world US study showed that approximately two-thirds of 2L patients received subsequent therapy and disease progression was the most common reason for 2L discontinuation highlighting the need for timely 2L treatment with the most efficacious drug to allow patients to achieve longer treatment duration and delayed progression.

156 (PB-063) Poster - Safety of trastuzumab deruxtecan and radiation therapy combination in HER2-positive metastatic breast cancer patients

156 (PB-063) Poster - Safety of trastuzumab deruxtecan and radiation therapy combination in HER2-positive metastatic breast cancer patients

Prognostic value of baseline neutrophil/lymphocyte ratio in HER2-positive metastatic breast cancer: exploratory analysis of data from the CLEOPATRA trial

PurposeThis study aimed to evaluate the prognostic role of the baseline neutrophil/lymphocyte ratio (NLR) in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab/pertuzumab.Experimental designData from 780 patients from the CLEOPATRA trial and 248 local patients were collected. Patients were divided into the low and high NLR subgroups by the NLR cutoff value. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methods were used to control bias. Associations between the NLR and progression-free survival (PFS) and overall survival (OS) were analyzed.ResultsThe baseline characteristics of the subgroups were well balanced after PSM and IPTW. A low baseline NLR was associated with better PFS and OS in the trastuzumab and docetaxel (TH) group in the unadjusted, PSM and IPTW models. After IPTW, a low NLR, versus a high NLR, was associated with improved PFS (HR 1.35, 95% CI 1.07–1.70, P = 0.012) and OS (HR 1.47, 95% CI 1.12–1.94, P = 0.006) in the TH group. In patients undergoing treatment with trastuzumab and pertuzumab and docetaxel (THP), a low baseline NLR was also correlated with better PFS but not OS across the three models. After IPTW, a low NLR was associated with better PFS (HR 1.52, 95% CI 1.20–1.93, P = 0.001) than a high NLR in the THP group. Multivariate analyses showed that a low baseline NLR was a predictor for PFS and OS in the TH group and for PFS in the THP group in all three models. In the real-world setting, a low baseline NLR was a predictor of better PFS among patients treated with docetaxel plus trastuzumab without or with pertuzumab in the multivariate model (P = 0.015 and 0.008, respectively).ConclusionsA low baseline NLR is associated with better survival outcomes among HER2-positive MBC patients receiving docetaxel plus trastuzumab/pertuzumab as first-line therapy.

Third-line treatment patterns in HER2-positive metastatic breast cancer: a retrospective analysis of real-world data in Canada.

There is an increasing demand for real-world data pertaining to the usage of cancer treatments, especially in settings where no standard treatment is specifically recommended. This study presents the first real-world analysis of third-line treatment patterns in HER2-positive metastatic breast cancer (mBC) patients in Canada. The purpose was to assess evolution of clinical practice and identify unmet needs in post-second-line therapy. Retrospective data from medical records of 66 patients who received third-line treatment before 31st October 2018, and data from 56 patients who received third-line treatment after this date, extracted from the Personalize My Treatment (PMT) cancer patient registry, were analyzed. In the first cohort, the study revealed heterogeneity in the third-line setting, with trastuzumab, lapatinib, and T-DM1 being the main treatment options. Even though data were collected before the wide availability of tucatinib, neratinib and trastuzumab deruxtecan in Canada, the PMT cohort revealed the emergence of new therapeutic combinations and a shift from lapatinib usage to T-DM1 choice was observed. These findings underscore the evolving nature of third-line treatment strategies in Canada, a facet that is intrinsically tied to the availability of new drugs. The absence of a consensus on post-second-line treatment highlights the pressing need for more efficient therapeutic alternatives beyond the currently available options. This study not only offers valuable insights into the present landscape of third-line treatment in Canada but validates the significance and effectiveness of the PMT registry as a tool for generating pan-Canadian real-world evidence in oncology and its capacity to provide information on evolution of therapeutic practices.

Exploring the clinical outcomes and safety profile of inetetamab treatment in metastatic breast cancer patients: A multicenter assessment of a Chinese-origin recombinant Anti-HER2 monoclonal antibody

BackgroundInetetamab is a novel recombinant humanized anti-HER2 monoclonal antibody. This study aimed to evaluate the efficacy and safety of inetetamab and predictive factors for response in HER2-positive metastatic breast cancer (MBC) patients. MethodsA cohort of HER2-positive MBC patients who received inetetamab-based therapy between June 2020 and August 2021 was evaluated. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Adverse events (AEs) were graded according to the National Cancer Institute Common Toxicity Criteria. ResultsA total of 141 patients were included in the final analysis. The median PFS of the entire cohort was 7.1 months. The median number of treatment lines administered was three. The ORR was 36.9 %, and the DCR was 80.9 %. The most frequently employed treatment strategy was inetetamab + chemotherapy (49/141, 34.8 %), followed by inetetamab + HER2-tyrosine kinase inhibitors (HER2-TKIs) + chemotherapy, inetetamab + pertuzumab + chemotherapy, inetetamab + endocrine treatment and inetetamab + HER2-TKIs. Cox multivariate analysis revealed that PFS was associated with liver metastasis (hazard ratio [HR] 2.112, 95 % confidence interval [CI] 1.334–3.343, p = 0.001), previous HER2-TKI treatment (HR 2.019, 95 % CI 1.133–3.597, p = 0.017) and estrogen receptor positivity (HR 0.587, 95 % CI 0.370–0.934, p = 0.024). The toxicity was tolerable, with neutropenia being the most common treatment-related grade 3/4 AE (14.9 %). ConclusionInetetamab demonstrates effectiveness with a manageable safety profile, offering a promising therapeutic option for HER2-positive breast cancer patients who have shown resistance to prior anti-HER2 treatments.

72P Real-world data on the efficacy of T-DM1 biosimilar for the treatment of HER2-positive metastatic breast cancer patients: Outcomes from a single center retrospective study in India

72P Real-world data on the efficacy of T-DM1 biosimilar for the treatment of HER2-positive metastatic breast cancer patients: Outcomes from a single center retrospective study in India

Efficacy of anlotinib in Chinese patients with metastatic breast cancer: A retrospective observational study.

Anlotinib, a multitarget tyrosine kinase inhibitor, can inhibit tumour angiogenesis proliferation, metastasis, promote vascular normalization, increase T cell and NK cell activity and infiltration, remodel tumour microenvironment and synergistic immune enhancement. Our study aimes to evaluate the efficacy of anlotinib in the treatment of advanced metastatic breast cancer (MBC) after multiple lines of therapy. Patients included were treated with anlotinib for advanced MBC in the Affiliated Cancer Hospital of Zhengzhou University from 1 January 2019 to 30 June 2023. The objective remission rate, disease-free progression survival and adverse reactions were analysed. We compared and analysed the efficacy of anlotinib in the treatment of advanced metastatic breast cancer, which showed that ORR was 23.6% and DCR was 69.1%. The DCR of monotherapy was 66.7% and that of combination therapy was 69.6% in MBC patients. The combination therapy, combined with chemotherapy had the best effect (79.3%), combined with immunotherapy came second. In addition, the DCR (88.9%) was higher in MBC patients having received prior antiangiogenic therapy. According to the Kaplan-Meier (K-M) survival estimate analysis, the mPFS was 4.17 months (95% CI, 1.758-6.582 months) in Her-2 positive MBC patients, and 7.83 months (95% CI, 2.416-9.104) in Her-2 negative MBC patients. The mPFS was 5.76 months (95% CI, 3.231-8.298 m) in HR positive MBC patients, 7.83 months (95% CI, 3.182-12.478 m) in TNBC patients. Fatigue (20.0%), hypertension (21.8%) and liver dysfunction (18.2%) were common adverse reactions, followed by bone marrow suppression (16.4%), anorexia (14.5%), hypothyroidism (14.5%) and diarrhoea (14.5%). Altogether, Anlotinib monotherapy or combination therapy provides a viable third (or above)-line therapeutic strategy in patients with metastatic breast cancer. The adverse reactions of anlotinib are well tolerated and controllable.

Clinical Impact of New Treatment Strategies for HER2-Positive Metastatic Breast Cancer Patients with Resistance to Classical Anti-HER Therapies.

HER2-positive breast cancer accounts for 15-20% of all breast cancer cases. This subtype is characterized by an aggressive behavior and poor prognosis. Anti-HER2 therapies have considerably improved the natural course of the disease. Despite this, relapse still occurs in around 20% of patients due to primary or acquired treatment resistance, and metastasis remains an incurable disease. This article reviews the main mechanisms underlying resistance to anti-HER2 treatments, focusing on newer HER2-targeted therapies. The progress in anti-HER2 drugs includes the development of novel antibody-drug conjugates with improvements in the conjugation process and novel linkers and payloads. Moreover, trastuzumab deruxtecan has enhanced the efficacy of trastuzumab emtansine, and the new drug trastuzumab duocarmazine is currently undergoing clinical trials to assess its effect. The combination of anti-HER2 agents with other drugs is also being evaluated. The addition of immunotherapy checkpoint inhibitors shows some benefit in a subset of patients, indicating the need for useful biomarkers to properly stratify patients. Besides, CDK4/6 and tyrosine kinase inhibitors are also included in the design of new treatment strategies. Lapitinib, neratinib and tucatinib have been approved for HER2-positive metastasis patients, however clinical trials are currently ongoing to optimize combined strategies, to reduce toxicity, and to better define the useful setting. Clinical research should be strengthened along with the discovery and validation of new biomarkers, as well as a deeper understanding of drug resistance and action mechanisms.

Retrospective observational study of outcomes in HER2-positive metastatic breast cancer patients treated with trastuzumab emtansine in single center.

15 Background: Trastuzumab emtansine (T-DM1) was established as a standard second line treatment option for metastatic HER2 positive breast cancer (mBC). However, the EMILIA study did not include disease progression patients who received pertuzumab plus trastuzumab previously. After CLEOPATRA study, the dual blockade treatment was indicated for advanced breast cancer as first line treatment. In this study, we attempted to build the T-DM1 predictive model and to evaluate the association between dual blockade and T-DM1 for metastatic HER2-positive breast cancer. Methods: This retrospective cohort study was conducted in Taiwan. Consecutive patients with metastatic HER2-positive breast cancer who had received T-DM1 between January 2013 and December 2022 were enrolled. Those patients were divided to two groups based on strategy of trastuzumab only or dual-blockade as prior therapy. Demographic, clinical, and pre- and post-T-DM1 treatment characteristics were described. The swimmer plots were used to estimate time to treatment discontinuation (TTD) and overall survival (OS). Results: Of 32 patients treated with T-DM1, 12 (38%) had prior treatment with pertuzumab plus trastuzumab. The median age was 60 years. Most patients had visceral disease and 59% had two or more prior treatments for mBC before T-DM1 (range 1–8 lines). Most patients (63%) stopped T-DM1 due to disease progressed and followed by financial problem (22%). In dual-blockade group, median TTD with T-DM1 was 4.5 months; median OS from diagnosis day was 68.2 months (8 patients still alive in the end of study). In trastuzumab only group, median TTD with T-DM1 was 3.8 months; median OS from diagnosis day was 73.2 months (5 patients still alive in the end of study). In our swimmer plots we found a trend that the shorter interval between trastuzumab +/- pertuzumab and T-DM1 the longer TTD with T-DM1. Conclusions: Patients treated with T-DM1 in this study appeared to have more advanced disease than patients in clinical trials and were treated in later lines of therapy. We should prescribe T-DM1 once trastuzumab with or without pertuzumab failure for the longer TTD. The small patient number was a major limitation in our study. A multi-center analysis is needed and it will help us for treatment suggestion under the Taiwan’s National Health Insurance clinical practice.

Late-onset cardiotoxicity in patients with HER2-positive metastatic breast cancer receiving trastuzumab-based therapy.

Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) typically receive long-term trastuzumab treatment for several years. The aim of our study is to identify the incidence and characterize late-onset cardiotoxicity in patients with HER2-positive MBC receiving trastuzumab-based therapy. We retrospectively reviewed charts of HER2-positive MBC patients who received >1 year of trastuzumab-based therapy at the Massachusetts General Hospital Cancer Center over three-year period. The primary endpoint was development of trastuzumab-induced cardiotoxicity (TIC). Secondary endpoints included time to TIC development, incidence/duration of trastuzumab interruption due to TIC, incidence of permanent discontinuation of trastuzumab due to TIC, clinic visit, or hospitalization due to TIC. Thirty-seven patients were included. Mean age was 56 years (range: 33-78 years, SD 9.5). Seven patients received prior doxorubicin and 14 patients received previous or concurrent breast irradiation. Mean duration of trastuzumab-based therapy was 57 months (range: 14-140 months, SD 39.3). Seven patients (18.9%) experienced TIC resulting in treatment interruption for two patients (28 and 78 days). The median time from starting trastuzumab therapy to TIC was 14 months (interquartile range: 11-29.5 months). The mean number of left ventricular ejection fraction (LVEF) assessment completed per year was 2.7 (range: 1.2-6.6, SD 1.1). Cardiotoxicity occurred in a minority of patients with HER2-positive MBC receiving trastuzumab-based therapy for more than one year. LVEF reductions to below the institutional lower limit of normal and therapy modifications were uncommon.

Pyrotinib in combination with letrozole for hormone receptor-positive, human epidermal growth factor receptor 2-positive metastatic breast cancer (PLEHERM): a multicenter, single-arm, phase II trial

BackgroundHuman epidermal growth factor receptor 2 (HER2) targeted therapy combined with endocrine therapy has been recommended as an alternative treatment strategy for patients with hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (MBC). This study aimed to evaluate the role of pyrotinib, an oral pan-HER irreversible tyrosine kinase inhibitor, in combination with letrozole for patients with HR-positive, HER2-positive MBC.MethodsIn this multi-center, phase II trial, HR-positive and HER2-positive MBC patients who were not previously treated for metastasis disease were enrolled. Patients received daily oral pyrotinib 400 mg and letrozole 2.5 mg until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the clinical benefit rate (CBR) assessed by an investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsFrom November 2019 to December 2021, 53 patients were enrolled and received pyrotinib plus letrozole. As of August 2022, the median follow-up duration was 11.6 months (95% confidence interval [CI], 8.7–14.0 months). The CBR was 71.7% (95% CI, 57.7–83.2%), and the objective response rate was 64.2% (95% CI, 49.8–76.9%). The median progression-free survival was 13.7 months (95% CI, 10.7–18.7 months). The most common treatment-related adverse event of grade 3 or higher was diarrhea (18.9%). No treatment-related deaths were reported, and one patient experienced treatment discontinuation due to adverse event.ConclusionsOur preliminary results suggested that pyrotinib plus letrozole is feasible for the first-line treatment of patients with HR-positive and HER2-positive MBC, with manageable toxicities.Trial registrationClinicalTrials.gov, NCT04407988.

Anti-HER2 antibody inetetamab plus camrelizumab and utidelone for pretreated HER2-positive metastatic breast cancer: Final results from the phase 2 ICU trial.

1042 Background: We previously reported (Yan, ASCO 2022) promising efficacy and acceptable safety of anti-HER2 antibody inetetamab in combination with camrelizumab and utidelone regimen in preliminary 20 HER2-positive metastatic breast cancer (MBC) patients who progressed after at least two lines of HER2-directed therapies with trastuzumab and TKIs. Inetetamab is a novel anti-HER2 antibody. Camrelizumab is an anti-programmed death receptor 1 [PD-1] antibody. Utidelone, a genetically engineered epothilone analogue, has shown promising efficacy in heavily pretreated MBC. Here we report the final ICU study results. Methods: In the ICU study (NCT04681287), patients received intravenous camrelizumab (200 mg once every 3 weeks), inetetamab (initial dose of 8 mg/kg, then 6 mg/kg, once every 3 weeks), and utidelone (30 mg/m2, days 1-5, every 3 weeks) until disease progression or intolerable toxicity. The primary endpoint was 3-month progression-free survival (PFS) rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included objective response rate (ORR), PFS and safety. Simon’s two-stage design was adopted for this study. All AEs were graded according to the grading criteria in the Common Terminology Criteria for the Evaluation of Adverse Events, 5th edition. Results: From Apr 23 2021 to Sept 1 2022, a total of 46 HER2-positive MBC patients were enrolled with median age of 52 (range 43-57). As of Jan 18, 2023, the median follow-up was 11.37 months. There were 12 patients (26.09%) with ER+/PR+, 7 patients (15.22%) with ER+/PR-, one patient (2.17%) with ER-/PR+, 26 patients (56.52%) with ER-/PR-. The median number of previous systemic therapies for advanced disease was three. Previous HER2-targeted therapies included trastuzumab (46 [100%]), TKIs (46 [100%], of which pyrotinib 39 [84.78%] and lapatinib 12 [26.09%]), pertuzumab (13 [28.26%]), and margetuximab (3 [6.52%]), T-DM1 or other HER2-ADC (7 [15.22%]). The 3-month PFS rate in 46 patients was 71.84%. The confirmed ORR was 28% (13/46), include one (2.17%) patient achieved complete response. The median PFS was 5.59 months. The most common treatment-related adverse events (TRAEs) were peripheral neuropathy (40 [86.96%]), capillary proliferation (27 [58.7%]), and alopecia (17 [36.96%]). Grade ≥3 TRAEs included rash (3 [6.52%]), peripheral neuropathy (1 [2.17%]) and AST increase (1 [2.17%]). Moreover, there were no grade 4 or above TRAEs. No related treatment discontinuation or deaths occurred. Conclusions: Final efficacy and safety results were consistent with previous ICU study preliminary analyses. The ICU study showed a favorable benefit-risk profile and is an important option for Chinese patients with HER2-positive MBC after at least two lines of HER2-directed therapies with trastuzumab and TKIs. Clinical trial information: NCT04681287 .

Safety and efficacy study of oral metronomic capecitabine in combination with pyrotinib for HER2-positive metastatic breast cancer: A phase II trial.

e13038 Background: A single-arm prospective phase II trial to was conducted evaluate the efficacy and safety of oral metronomic capecitabine combined with pyrotinib in human epidermal growth factor receptor 2-positive (HER2 positive) metastatic breast cancer (MBC) patients. Methods: HER2-positive patients received oral metronomic capecitabine 500 mg three times daily and pyrotinib 400 mg. The primary endpoint was progression-free survival (PFS). Other endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Results: 50 patients with HER2-positive MBC were enrolled, and one was excluded due to medication irregularities. The median PFS and OS were 11.9 months (95%CI 8.8-14.6) and 29.3 months (95%CI 24.4-34.8) respectively. ORR was 34.7%, and CBR was 81.6% with 2 CR (4.1%), 15 PR (30.6%) and 23 SD (46.9%). The mPFS in first- or second-line treatment was 12.2 months. The most frequent treatment-related adverse complications included hand-foot syndrome, diarrhea, vomiting and nausea. Grade 3 adverse events occurred in 15 (30.6%) patients and included hand-foot syndrome (12.2%), diarrhea (12.2%), vomiting (4.1%), and nausea (2.0%). Grade 4 adverse event of diarrhea (2.0%) was observed in one case. Conclusions: The combination of metronomic capecitabine and pyrotinib is a promising regimen with competitive efficacy and improved tolerability in HER2-positive metastatic breast cancer patients. Clinical trial information: NCT03923166 .