HER2-positive Advanced Breast Cancer Research Articles

Resistance mechanisms and prospects of trastuzumab

Breast cancer that overexpresses Human Epidermal Growth Factor Receptor 2 (HER2+) due to gene amplification or overexpression constitutes 15-20% of all breast cancer cases. Trastuzumab, the first FDA-approved monoclonal antibody targeting HER2, serves as the standard first-line treatment for HER2-positive advanced breast cancer, as recommended by multiple clinical guidelines.Currently, accumulated clinical evidence reveals a considerable degree of variability in the response of HER2+ breast cancer to trastuzumab treatment. Specifically, over 50% of patients either do not respond to or develop resistance against trastuzumab.The specific mechanisms of resistance to trastuzumab are currently unclear. This paper aims to review the existing research on the resistance mechanisms of trastuzumab, based on its target, from aspects such as genetic loci, molecular structure, signaling pathways, and the tumor microenvironment and to outline current research progress and new strategies.

Efficacy and safety of RC48-ADC in HER2-positive and HER2-low metastatic breast cancer: a multicenter, real-world study.

A standard treatment recommendation for third-line and subsequent treatments for advanced HER2-positive breast cancer is still missing, especially for low HER2 expression. Nevertheless, there is evidence that these patients might benefits from antibody-drug conjugates (ADCs) treatment. Therefore, this study aimed to evaluate the clinical efficacy, safety, and factors affecting efficacy of Disitamab Vedotin (RC48) for treating HER2-positive and HER2-low metastatic breast cancer (MBC) in the real-world setting. A retrospective study at five clinical sites was conducted in China, enrolling MBC patients treated with RC48 from July 01, 2021 and May 31, 2023. Patient demographics, treatment patterns, and adverse events (AEs) were recorded and analyzed. A total of 154 patients were included: 104 (67.53%) patients with HER2-positive and 50 (32.47%) patients with HER2-low MBC. The median progression-free survival (mPFS) was 5.06 months. The objective response rate (ORR) and disease control rate (DCR) were 36.36% and 68.83%, respectively. HER2-positive patients exhibited a mPFS of 5.93 and an ORR of 41.35%. In contrast, patients with low-HER2 had a mPFS of 4.28 months and an ORR of 26.00%. The most common AEs included neutropenia (54.55%), increased AST (53.25%), leukopenia (51.95%), and fatigue (43.51%), mostly graded mild to moderate (grade 1-2). This extensive study in China demonstrated that RC48 has excellent therapeutic potential for both HER2-positive and HER2-low MBC with a favorable safety profile. The study also suggests that combination therapy significantly boosts efficacy beyond monotherapy, indicating a promising avenue for future ADC development.

Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial.

The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance. RNA was extracted from metastasis biopsies obtained in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with transcriptomic data. Lesions were compared based on the level of [89Zr]trastuzumab uptake as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT. We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases. Genes and pathways involved in extracellular matrix (ECM) organization and glycosylphosphatidylinositol synthesis were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions showing no metabolic response to T-DM1, while immune-related processes were associated with high [89Zr]trastuzumab uptake and metabolic response. Gene signatures including differentially expressed genes according to [89Zr]trastuzumab uptake and metabolic response showed predictive value in an external cohort. To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings suggest a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, highlighting the potential of molecular imaging to depict tumor microenvironment features.

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial.

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2+ mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2+ mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 .

The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis.

Leptomeningeal disease (LMD) is associated with poor survival and diminished quality of life. Trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). The DEBBRAH trial was designed to evaluate its efficacy and safety in patients with HER2-positive and HER2-low ABC with a history of brain metastases (BMs) and/or LMD. Here, we report results from cohort 5, which specifically included patients with pathologically confirmed LMD. This single-arm, open-label, five-cohort, phase 2 trial enrolled seven patients in cohort 5 who received 5.4mg/kg T-DXd intravenously every 21days until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) and safety profile. At data cutoff (April 4, 2023), the median duration of follow-up was 12.0months (range, 2.5-18.6). The median OS was 13.3months (95% confidence interval [CI], 5.7-NA, p<0.001), meeting the primary endpoint. The median PFS was 8.9months (95% CI, 2.1-NA). Two (28.6%) of seven patients remained on treatment after 18.6 and 11.9months, respectively. Of the five patients who progressed and died, none had intracranial progression or clinical worsening of leptomeningeal symptoms. Notably, 71.4% (95% CI, 29.0-96.3) achieved prolonged stabilization (≥24weeks) by response evaluation criteria in solid tumors (RECIST) v.1.1. No unexpected safety signals and no treatment-related deaths were observed. T-DXd showed promising antitumor activity in patients with HER2-positive and HER2-low ABC with previously untreated, pathologically confirmed LMD. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.

331P Neoadjuvant intetamab in combination with standard chemotherapy for locally advanced HER2-positive breast cancer

331P Neoadjuvant intetamab in combination with standard chemotherapy for locally advanced HER2-positive breast cancer

HER-2 Receptor and αvβ3 Integrin Dual-Ligand Surface-Functionalized Liposome for Metastatic Breast Cancer Therapy.

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer metastasis remains the primary cause of mortality among women globally. Targeted therapies have revolutionized treatment efficacy, with Trastuzumab (Trast), a monoclonal antibody, targeting HER2-positive advanced breast cancer. The tumor-homing peptide iRGD enhances the intratumoral accumulation and penetration of therapeutic agents. Liposomes serve as versatile nanocarriers for both hydrophilic and hydrophobic drugs. Gefitinib (GFB) is a potential anticancer drug against HER2-positive breast cancer, while Lycorine hydrochloride (LCH) is a natural compound with anticancer and anti-inflammatory properties. This study developed TPGS-COOH-coated liposomes co-loaded with GFB and LCH, prepared by the solvent injection method, and surface-functionalized with Trast and iRGD. The dual surface-decorated liposomes (DSDLs) were characterized for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), surface chemistry, surface morphology, and their crystallinity during in-vitro drug release, drug encapsulation, and in-vitro cell line studies on SK-BR-3 and MDA-MB-231 breast cancer cells. The half-maximum inhibitory concentration (IC-50) values of single decorated liposomes (SDLs), iRGD-LP, and Trast-LP, as well as DSDLs (iRGD-Trast-LP) on SK-BR-3 cells, were 6.10 ± 0.42, 4.98 ± 0.36, and 4.34 ± 0.32 μg/mL, respectively. Moreover, the IC-50 values of SDLs and DSDLs on MDA-MB-231 cells were 15.12 ± 0.68, 13.09 ± 0.59, and 11.08 ± 0.48 μg/mL, respectively. Cellular uptake studies using confocal laser scanning microscopy (CLSM) showed that iRGD and Trast functionalization significantly enhanced cellular uptake in both cell lines. The wound-healing assay demonstrated a significant reduction in SDL and DSDL-treated MDA-MB-231 cell migration compared to the control. Additionally, the blood compatibility study showed minimal hemolysis (less than 5% RBC lysis), indicating good biocompatibility and biosafety. Overall, these findings suggest that TPGS-COOH-coated, GFB and LCH co-loaded, dual-ligand (iRGD and Trast) functionalized, multifunctional liposomes could be a promising therapeutic strategy for treating HER2-positive metastatic breast cancer.

Combination Therapy of Pyrotinib and Metronomic Vinorelbine in HER2+ Advanced Breast Cancer After Trastuzumab Failure (PROVE): A Prospective Phase 2 Study.

Approximately 50-74% of patients with metastatic HER2-positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients. In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cut-off date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% CI: 8.3-18.5). With all patients evaluated, an ORR of 38.9% (95% CI: 23.1-56.5%) and a DCR of 83.3% (95% CI: 67.2-93.6%) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs. Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.

Targeting ITGβ3 to Overcome Trastuzumab Resistance through Epithelial-Mesenchymal Transition Regulation in HER2-Positive Breast Cancer.

HER2-positive breast cancer, representing 15-20% of all breast cancer cases, often develops resistance to the HER2-targeted therapy trastuzumab. Unfortunately, effective treatments for advanced HER2-positive breast cancer remain scarce. This study aims to investigate the roles of ITGβ3, and Hedgehog signaling in trastuzumab resistance and explore the potential of combining trastuzumab with cilengitide as a therapeutic strategy. Quantitative gene expression analysis was performed to assess the transcription of EMT (epithelial-mesenchymal transition) markers Slug, Snail, Twist2, and Zeb1 in trastuzumab-resistant HER2-positive breast cancer cells. The effects of ITGβ3 and Hedgehog signaling were investigated. Additionally, the combination therapy of trastuzumab and cilengitide was evaluated. Acquired trastuzumab resistance induced the transcription of Slug, Snail, Twist2, and Zeb1, indicating increased EMT. This increased EMT was mediated by ITGB3 and Hedgehog signaling. ITGβ3 regulated both the Hedgehog pathway and EMT, with the latter being independent of the Hedgehog pathway. The combination of trastuzumab and cilengitide showed a synergistic effect, reducing both EMT and Hedgehog pathway activity. Targeting ITGβ3 with cilengitide, combined with trastuzumab, effectively suppresses the Hedgehog pathway and EMT, offering a potential strategy to overcome trastuzumab resistance and improve outcomes for HER2-positive breast cancer patients.

Olaparib plus trastuzumab in HER2-positive advanced breast cancer patients with germline BRCA1/2 mutations: The OPHELIA phase 2 study

PurposeTo evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm). MethodsOPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile. ResultsA total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4–99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7–94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified. ConclusionsThis study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive gBRCAm ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2-driven cancers.

Efficacy and safety of first-line regimens for advanced HER2-positive breast cancer: A Bayesian network meta-analysis.

The current standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is pertuzumab plus trastuzumab and docetaxel as first-line therapy. However, with the development of newer treatment regimens, there is a lack of evidence regarding which is the optimal treatment strategy. The aim of this network meta-analysis was to evaluate the efficacy and safety of first-line regimens for advanced HER2-positive breast cancer by indirect comparisons. A systematic review and Bayesian network meta-analysis were conducted. The PubMed, EMBASE, and Cochrane Library databases were searched for relevant articles published through to December 2023. The hazard ratio (HR) and 95% credible interval (CrI) were used to compare progression-free survival (PFS) between treatments, and the odds ratio and 95% CrI were used to compare the objective response rate (ORR) and safety. Twenty randomized clinical trials that included 15 regimens and 7094 patients were analyzed. Compared with the traditional trastuzumab and docetaxel regimen, PFS was longer on the pyrotinib and trastuzumab plus docetaxel regimen (HR: 0.41, 95% CrI: 0.22-0.75) and the pertuzumab and trastuzumab plus docetaxel regimen (HR: 0.65, 95% CrI: 0.43-0.98). Consistent with the results for PFS, the ORR was better on the pyrotinib and trastuzumab plus docetaxel regimen and the pertuzumab and trastuzumab plus docetaxel regimen than on the traditional trastuzumab and docetaxel regimen. The surface under the cumulative ranking curve indicated that the pyrotinib and trastuzumab plus docetaxel regimen was most likely to rank first in achieving the best PFS and ORR. Comparable results were found for grade ≥3 AE rates of ≥10%. Our results suggest that the pyrotinib and trastuzumab plus docetaxel regimen is most likely to be the optimal first-line therapy for patients with HER2-positive breast cancer.

Neoadjuvant inetetamab and pertuzumab with taxanes and carboplatin (TCbIP) In locally advanced HER2-positive breast cancer: a prospective cohort study with propensity-matched analysis

BackgroundInetetamab is the first domestically developed innovative anti-HER2 monoclonal antibody in China, proven effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remain to be validated.MethodsThis prospective cohort study aimed to evaluate the efficacy and safety of inetetamab combined with pertuzumab, taxanes, and carboplatin (TCbIP) in neoadjuvant therapy for HER2-positive LABC, comparing it to data from patients treated with the TCbHP regimen (trastuzumab combined with pertuzumab, taxanes, and carboplatin) using propensity score matching (PSM). The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints.ResultsForty-four patients with clinical stage IIA-IIIC HER2-positive LABC were prospectively enrolled and treated with the TCbIP regimen. The tpCR rate among 28 patients who completed surgery was 60.7%, comparable to and slightly higher than the TCbHP group in PSM (60.7% vs. 53.6%, P = 0.510). The ORR was 96.4%, and the DCR reached 100.0%. The most common ≥ grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs.ConclusionNeoadjuvant therapy with TCbIP showed good efficacy and safety in patients with HER2-positive LABC and might be another promising option for neoadjuvant treatment.Trial registrationNCT05749016 (registration date: Nov 01, 2021).

Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients

BackgroundDuring targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D.MethodsaHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1).ResultsAs expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009).ConclusionsHER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors.Trial registrationNCT05735392 retrospectively registered on January 31, 2023 https://www.clinicaltrials.gov/search?term=NCT05735392

Relative efficacy of antibody-drug conjugates and other anti-HER2 treatments on survival in HER2-positive advanced breast cancer: a systematic review and meta-analysis

BackgroundNovel antibody-drug conjugates (ADCs) drugs present a promising anti-cancer treatment, although survival benefits for HER2-positive advanced breast cancer (BC) remain controversial. The aim of this meta-analysis was to evaluate the comparative effect of ADCs and other anti-HER2 therapy on progression-free survival (PFS) and overall survival (OS) for treatment of HER2-positive locally advanced or metastatic BC.MethodsRelevant randomized controlled trials (RCTs) were retrieved from five databases. The risk of bias was assessed with the Cochrane Collaboration’s tool for RCTs by RevMan5.4 software. The hazard ratio (HR) and 95% confidence intervals (CIs) were extracted to evaluate the benefit of ADCs on PFS and OS in HER2-positive advanced BC by meta-analysis.ResultsMeta-analysis of six RCTs with 3870 patients revealed that ADCs significantly improved PFS (HR: 0.63, 95% CI: 0.49–0.80, P = 0.0002) and OS (HR: 0.79, 95% CI: 0.72–0.86, P < 0.0001) of patients with HER2-positive locally advanced or metastatic BC. Subgroup analysis showed that PFS and OS were obviously prolonged for patients who previously received HER2-targeted therapy. Sensitivity analysis and publication bias suggested that the results were stable and reliable.ConclusionStatistically significant benefits for PFS and OS were observed with ADCs in HER2-positive locally advanced or metastatic BC, especially for those who received prior anti-HER2 treatment.

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.

The subgroup analysis by age and geriatric assessment in a phase III study comparison of trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in older patients with advanced stage HER2-positive breast cancer (JCOG1607 HERB TEA study).

1031 Background: The JCOG1607, HERB TEA Study, is a phase III trial that compared trastuzumab emtansine (T-DM1) with the HPD regimen (trastuzumab, pertuzumab, docetaxel) in older patients with advanced HER2-positive breast cancer. The primary objective was to confirm the non-inferiority of T-DM1 to HPD in overall survival (OS), with a margin of 1.35 for hazard ratio (HR). The trial was terminated early due to futility at the planned first interim analysis. T-DM1 didn't show non-inferiority to HPD in OS (HR 1.263; 95% confidence interval [CI], 0.677-2.357). Median progression-free survival (PFS) was 11.3 months for T-DM1 and 15.6 months for HPD (HR 1.373; 95% CI, 0.917-2.056). However, the condition of older patients varies widely, and we conducted a subgroup analysis to investigate the subgroup that could benefit from T-DM1 with fewer side effects as a first-line treatment. Methods: Subgroup analysis for OS and PFS involved 148 patients enrolled in JCOG1607, considering age and PS (&lt;75 years old and PS 0,1 or &lt;75 years old and PS 2 or ≥75 years old), Geriatric 8 (G8) score (≥15 or &lt;15), Instrumental Activity of Daily Living (IADL) score (8 or &lt;8), visceral/brain metastasis presence (with or without), and other factors. Results: Subgroup of &lt;75 and PS 2 was not evaluable. For OS, HR of T-DM1 arm to HPD arm was 0.749 (95% CI: 0.310-1.808) in the group aged &lt;75 years, while 2.867 (95%CI: 1.018-8.069) in the group aged ≥75 years (Table). G8 score and the IADL score did not show significant differences in HR for OS, although low G8 score group and low IADL score group tended to have higher OS in HPD arm than T-DM1 arm: HR of T-DM1 arm to HPD arm of 1.541 (95% CI: 0.755-3.142) in low G8 score group and 2.147 (95% CI: 0.656-7.025) in low IADL score group. For PFS, patients with visceral/brain metastasis had HR of T-DM1 arm to HPD arm of 1.794 (95% CI: 1.092-2.948). No other subgroup showed a significant difference in HR for PFS. Conclusions: No subgroups benefiting from T-DM1 as first-line treatment were identified. HPD remains the standard for advanced HER2-positive breast cancer, regardless of age (even in ≥75 years) G8 score, or IADL. Clinical trial information: UMIN000030783. [Table: see text]

Imlunestrant, an oral selective estrogen receptor degrader (SERD), in combination with human epidermal growth factor receptor 2 (HER2) directed therapy, with or without abemaciclib, in estrogen receptor (ER) positive, HER2 positive advanced breast cancer (aBC): EMBER phase 1a/1b study.

1027 Background: Imlunestrant is a next-generation, oral SERD designed to deliver continuous ER-target inhibition. In the first-in-human Phase 1a/b EMBER study (NCT04188548), imlunestrant demonstrated favourable safety, PK, and clinical benefit when administered as monotherapy or with targeted therapy in ER+, HER2- aBC. Here we present clinical data of imlunestrant with HER2 targeted therapy, in patients (pts) with ER+, HER2+ aBC enrolled in EMBER. Methods: Pts were randomized to imlunestrant (400mg po daily) + trastuzumab (H), with or without (±) abemaciclib (Part C) or received maintenance treatment with imlunestrant + H + pertuzumab (P) (Part E), at standard doses in 21-day cycles. Key eligibility (Part C): ≥ 2 prior HER2 directed regimens, no prior CDK4/6i or fulvestrant; (Part E): received 1st line induction taxane chemotherapy (any duration) + H + P, without disease progression and ≤1 prior therapy for aBC. Key endpoints included safety, PK, ORR, CBR and PFS. Results: Overall, 45 pts with ER+/HER2+ aBC received the following combinations: imlunestrant + H (n=18), imlunestrant + H + abemaciclib (n=21; 1 pt received 800 mg imlunestrant), and imlunestrant + H + P (n=6). Baseline characteristics, safety, and preliminary efficacy are presented below (Table). Most TEAEs were grade 1-2. Common TEAEs with imlunestrant + H were fatigue (33%) and nausea (28%); with imlunestrant + H + abemaciclib were diarrhea (100%), neutropenia (57%), fatigue (52%) and nausea (48%); and with imlunestrant + H + P were diarrhea (50%) and arthralgia (50%). Imlunestrant PK was consistent with those previously reported with no drug-drug interactions observed with the combinations. From Part C, sequencing of baseline plasma ctDNA samples (n=37) identified prevalent mutations in TP53 (49%), PIK3CA (30%), ESR1 (24%), and GATA3 (14%). Clinical activity of imlunestrant in this ER+/HER2+ population, while based on small numbers, is promising. Conclusions: Imlunestrant in combination with trastuzumab ± abemaciclib or pertuzumab was well tolerated, showed no drug-drug interactions, and demonstrated preliminary antitumor activity in pts with ER+/HER2+ aBC. Clinical trial information: NCT04188548 . [Table: see text]

INAVO122: A phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients (pts) with PIK3CA-mutated, HER2-positive advanced breast cancer (HER2+ aBC).

TPS1124 Background: The PI3K pathway plays a crucial role in HER2 signaling. Somatic mutations of PIK3CA, the gene that encodes the PI3K p110α subunit, may induce resistance to HER2-targeted therapies and are associated with poorer clinical outcomes (Swain SM, et al. SABCS 2022; P2-11-07). Inavolisib, a potent p110α-selective inhibitor that induces degradation of mutant p110α, has shown antitumor activity in PIK3CA-mutated HER2+ BC and long-term tolerability with early intervention for common on-class toxicities, including hyperglycemia, diarrhea, and stomatitis (Jhaveri KL, et al. SABCS 2023; GS03-13, Bedard P, et al. ASCO 2022; 1052). The current study will assess the efficacy and safety of maintenance inavolisib + fixed-dose combination of pertuzumab + trastuzumab for subcutaneous injection (PH FDC SC) after first-line (1L) induction treatment in pts with PIK3CA-mutated, HER2+ aBC. Methods: INAVO122 (NCT05894239) is a multicenter, randomized, international, double-blind, placebo-controlled study. Pts will be enrolled for: 1L induction treatment if they are receiving/will receive PH + a taxane; or for maintenance treatment if they completed induction treatment per standard of care. In the maintenance phase, pts will be randomized 1:1 to receive inavolisib (9 mg orally once daily; 21-day cycles) + PH FDC SC (every 3 weeks), or placebo + PH FDC SC. Study treatment will continue until disease progression (PD), unacceptable toxicity, death, consent withdrawal, or at the investigator’s (INV) discretion. Enrolled pts must have centrally determined HER2+, PIK3CA-mutated tumors, with documented hormone receptor status per local assessment, and be disease-free for ≥6 months from completion of neoadjuvant/adjuvant HER2-targeted treatment. They must not have received any non-hormonal treatment for aBC prior to induction, and, at screening, fasting glucose must be &lt;126 mg/dL and HbA1c &lt;6.4%. To be randomized, pts must have completed induction therapy without PD and show left ventricular ejection fraction ≥50%. The primary endpoint is INV-assessed progression-free survival. Secondary endpoints are overall survival; INV-assessed objective response rate, duration of response, clinical benefit rate, and time to second disease progression; health-related quality of life; safety; and pharmacokinetics. The primary endpoint analysis will utilize a two-sided stratified log-rank test at a two-sided significance level of 5%. A stratified Cox proportional hazards model will be used to estimate the hazard ratio between the two treatment arms and its 95% confidence intervals. An independent data monitoring committee will be in place for safety. Target randomization is ~230 pts; this study is currently recruiting (15 pts enrolled). Encore from SABCS 2023 (PO2-19-09). Clinical trial information: NCT05894239 .

A propensity-matched analysis of the efficacy and safety of neoadjuvant inetetamab and pertuzumab with paclitaxel and carboplatin (TCbIP) on locally advanced HER2-positive breast cancer.

e12609 Background: Inetetamab is an Fc segment-modified innovative anti-HER2 monoclonal antibody. It has been proven to be effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in the neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remains to be validated. This study aimed to evaluate the efficacy and safety of Inetetamab-based neoadjuvant therapy (TCbIP). Methods: In this prospective cohort study, we investigated the efficacy and safety of TCbIP in neoadjuvant therapy for HER2-positive LABC, and compared with TCbHP regimen (trastuzumab combined with pertuzumab, paclitaxel, and carboplatin) with propensity score matching (PSM). Thirty-four patients (clinical stage IIA-IIIC, HER2-positive LABC) were prospectively enrolled in this study and treated with the TCbIP regimen. The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints. Results: The pCR rate of 28 patients who finished surgery was 60.7%, and was comparable and slightly higher (60.7% vs. 53.6%, P = 0.510) than the TCbHP group in PSM. The ORR was 96.4% and DCR reached 100.0%. The most common ≥grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs. Conclusions: Neoadjuvant therapy with TCbIP resulted in good efficacy and safety in patients with HER2-positive LABC, and might be another promising option for neoadjuvant treatment. Clinical trial information: NCT05749016 .

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.