HER2-positive Breast Cancer Research Articles

Preliminary safety and efficacy of TQB2930, a HER2-targeted bispecific antibody in patients with advanced breast cancer: Results from a phase 1b study.

1026 Background: TQB2930 is a HER2-targeted bispecific antibody, binding to two distinct HER2 epitopes, the same domain as trastuzumab (ECD4) and pertuzumab (ECD2). This study aims to evaluate the safety and efficacy of TQB2930 for patients with advanced breast cancer after failure of standard therapy. Methods: This phase 1b, dose-escalation and expansion trial included patients preferred HER2-expressing or HER2-amplified breast cancer who had received standard therapy. In the dose-escalation phase, TQB2930 was given weekly (10mg/kg, QW), biweekly (20mg/kg, Q2W), or triweekly (30mg/kg, Q3W). After the dose-escalation phase, eligible patients were enrolled and dosed biweekly or triweekly in the expansion cohort. The primary endpoints were safety, maximum tolerated or maximum administered dose, and the secondary endpoints were immunogenicity, pharmacokinetics, and tumor response per RECIST v1.1. Results: As of Dec 20, 2023, 34 patients(pts) have received TQB2930 weekly (n=3), biweekly (n=16), and triweekly (n=15). All pts were female, the median age was 59. 22 pts had HER2 expression of ICH3+ or ICH2+ with FISH+, and the others had ICH2+ with FISH- or ICH1+. The median prior lines of therapies were 3 (range: 0-8), with one pt intolerance to first-line treatment enrolled, and the median prior lines of HER2-targeted therapies were 2 (range: 0-8). No dose-limited toxicity was observed. The main treatment-related adverse events (TRAEs) were infusion reaction, occult blood of urine, leukopenia, and neutropenia. 3 pts were reported grade≥3 TRAEs, including neutropenia, anemia, and hypokalemia. Of 31 response-evaluable pts, the objective response rate (ORR) was 25.8% with 8 partial responses (PRs) were observed (including 5 confirmed PRs and 3 PRs awaiting confirmation). The disease control rate was 80.6%. Moreover, 5 pts achieved PR at 30mg/kg (ORR 41.7%), including one with prior exposure to trastuzumab, pyrotinib, tucatinib, ARX788, and the other one prior to trastuzumab, pertuzumab, lapatinib, MRG002. The median progression-free survival for all pts was 5.5 months (95%CI 3.58-NE). Additionally, Pharmacokinetic analysis showed exposure (Cmax and AUC0-t) of TQB2930 increased linearly with doses within 10~30mg/kg. After dosing, the mean peak concentration reached at 2.5-4.3 h, and the elimination half-life of TQB2930 was 109-161 h. Conclusions: TQB2930 is well tolerated and has demonstrated promising single-agent anti-tumor activity in HER2-positive breast cancer who have failed standard anti-HER2 therapies, including multiple lines of prior HER2 targeted agents. These early signs of activity support the further exploration of combination therapy of TQB2930 and the study is ongoing. Clinical trial information: NCT06202261 .

A pilot study of early PET and biomarker dynamics in patients with stage 2 and 3 triple negative breast cancer treated with neoadjuvant response-adapted chemotherapy with pembrolizumab (NeoADAPT).

TPS624 Background: In patients with triple negative breast cancer (TNBC) the addition of pembrolizumab to neoadjuvant chemotherapy has improved pathologic complete response rates (pCR) and 5-year event free survival (EFS). Patients with TNBC who achieve a pCR have a significantly lower risk of recurrence compared to those with residual disease (RD). However, pCR can only be assessed at the time of surgery after completion of 6 months of intensive chemo-immunotherapy, associated with up to 77% high-grade treatment-related toxicity. Identifying pCR early on is imperative in developing optimized and individualized treatments, however, there are no predictive biomarkers. Studies in HER2-positive breast cancer have shown that early fluorodeoxyglucose positron emission tomography (FDG-PET) changes soon after initiation of neoadjuvant treatment can help predict the pathological outcomes at the time of surgery and also the risk of recurrence. Emerging data also support that clearance of circulating tumor DNA (ctDNA) during neoadjuvant treatment may be associated with higher rates of pCR. We thus designed a study to determine the association of early FDG-PET changes and ctDNA clearance with pCR in early-stage TNBC. Methods: NeoADAPT is a phase 2, open label, single center clinical trial including adult patients with previously untreated clinical stage 2 or 3 TNBC. Participants will receive 4 cycles of neoadjuvant paclitaxel/carboplatin with pembrolizumab (TC/pembro), per standard-of-care (SOC). An FDG-PET will be performed at baseline and after 1 cycle. A breast MRI will be performed at baseline and after completion of 4 cycles of treatment. Patients with a complete clinical response (cCR) will proceed to surgery and will forgo more neoadjuvant treatment. Patients with clinical RD on MRI will complete SOC neoadjuvant therapy with 4 cycles of doxorubicin/cyclophosphamide (AC) with pembro prior to surgery. If RD is identified after surgery, adjuvant therapy will be determined by the treating oncologist, which may include pembro with AC (if not given prior), capecitabine, etc. The primary objective is to evaluate if lack of decrease in maximum FDG-PET standard uptake value of lean body mass (SULmax) by less than 40% after 1 cycle of neoadjuvant treatment correlates with RD at the time of surgery (i.e. determining the negative predictive value of FDG-PET). Additional key endpoints include ctDNA clearance, evaluation of pCR and cCR rates in the treatment population and EFS. Distributions of percent reduction in SULmax will be compared between pCR and no-pCR groups using the Wilcoxon rank sum test. Receiver operating characteristic (ROC) curve analysis will be performed to estimate the ability of FDG-PET SULmax reduction and cCR by MRI in predicting pCR at surgery. Clinical trial information: NCT06245889 .

Pathological and clinical outcomes following neoadjuvant dual HER2 therapy for early-stage breast cancer: An Australian institutional real-world experience.

There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non-metastatic HER2-positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long-lasting toxicity. Hence, de-escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real-world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre. This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non-metastatic HER2-positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post-surgical prescribing patterns and also undertook survival analyses for invasive disease-free survival (iDFS) as well as exploratory analyses for correlations between pre-specified clinicopathologic factors and pathological response at surgery. Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease-free at 3 years of follow-up. Only 3 events of recurrence or death were recorded at a median follow-up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery. This study demonstrates that de-escalated adjuvant treatment for HER2-positive early breast cancer achieved favourable pathological and long-term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components.

Role of NEDD9 expression in non-metastatic HER2-positive breast cancer.

e12645 Background: Neural Precursor Cell Expressed Developmentally Downregulated Protein 9 (NEDD9) is a member of the associated substrate family. Our previous studies demonstrated the role of NEDD9 overexpression in early tumorigenesis in HER2-positive (HER2+) breast cancer in vivo. Tissue microarray-based analysis showed a strong correlation between NEDD9 mRNA and relapse-free survival (RFS) and pathologic complete response (pCR) rate in HER2+ breast cancers. In this study, NEDD9 expression in non-metastatic HER2+ breast cancer was evaluated by tissue microarray. Methods: A total of 64 patients with non-metastatic HER2+ cancer of the breast who had received neoadjuvant chemotherapy and had sufficient pathology specimens were included in the study. NEDD9 was stained by tissue microarray, and the expression was subclassified as low, intermediate, and high based on the NEDD9 expression score. The correlations of NEDD9 expression with the clinical/biological characteristics, treatment, and treatment response were analyzed by Fisher Exact test. Results: A total of 64 patients were included in the study, with a medium follow-up duration of 4.6 years. The median age was 54, 1 patient was male, 79.3% of patients had stage 2 disease, 1 patient had inflammatory breast cancer, and 37.5% of patients had ER/PR negative disease. The most common neoadjuvant chemotherapy regimen was TCHP (82.5%), 44.4% of patients underwent lumpectomy, and 67.7% of patients underwent axillary lymph node dissection (ALND). 54% of patients achieved complete pathologic response (pCR), all patients received adjuvant anti-HER2 treatment, 85.7% received adjuvant radiotherapy, and 74.6% received adjuvant endocrine therapy. The NEDD9 expression distribution for low, intermediate, and high were 37.5%, 50.0%, and 12.5%, respectively. NEDD9-high patients had higher tumor stage and grade than NEDD9-low/ intermediate patients (p = 0.004, p= 0.041). More NEDD9-high patients underwent ALND compared to NEDD9- low/intermediate patients (p = 0.09). There is no statistically significant difference in pCR rate between NEDD9 expression groups, although numerically more NEDD9-high patients achieved pCR (75%, 56.2%, and 43.5% in NEDD9-high, intermediate, and low patients). Conclusions: In non-metastatic HER2+ breast cancer, NEDD9 expression is associated with more advanced tumor grade and stage. There is no statistically significant difference in pCR rate between groups, although more patients achieved pCR with a higher level of NEDD9 expression. The sample size limits our study. Additional study is needed to evaluate the correlation between NEDD9 expression and pCR rate following neoadjuvant chemotherapy in HER2+ breast cancer.

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 .

Is HER2-negative breast cancer really negative? Clinical implication of novel assessment method using inPROBE technology.

e13030 Background: IHC/FISH is currently the gold standard method of HER2 expression assessment on breast cancer (BC) cells. Recent studies regarding HER2-low category show that the semi-quantitative methods are inaccurate. False-negative results may have a negative impact on the prognosis and treatment outcomes. Methods: To determine the correlation between HER2 receptor levels assessed quantitatively with the use of an innovative diagnostic probe and traditional standard IHC/FISH we conducted an interventional, open-label, single-arm safety and efficacy part I/II clinical trial. In total 22 female patients aged 18 to 75 years with BC and known HER2 status were enrolled. We have developed a novel microprobe merging molecular biology with photonics technology for real-time, in vivo assessment of HER2 expression on BC. The concentration of the HER2 was measured using a diagnostic microprobe inserted in the tumor under ultrasound guidance. To assess the optimal puncture site the second probe examination was additionally performed at the same time in the immediate vicinity of the tumor. Results: Finally, 18 pts. were included in statistical analysis (6 pts. with HER2-positive and 12 pts. with HER2-negative BC). Neither baseline patients’ characteristics nor medical history or concomitant medications did include any potential factors that could affects efficacy or safety analysis. The primary endpoint was initial determination of HER2 receptor concentration ranges detected with microprobe corresponding to HER2 receptor status (positive/negative) identified by IHC/FISH. The study met its primary endpoint. Microprobe mean values in tumor ranged between 4.893 (SD ±10.125) (min) and 8.782 (SD ±12.509) (max), with mean value 6.497 (SD ±10.939) for HER2 IHC positive status and between -3.634 (SD ±6.360) (min) and 5.012 (SD ±2.685) (max), with mean value 1.178 (SD ±2.387) for HER2 IHC negative status. The difference was significant with use of Wilcoxon rank sum exact test. i.e. showed lower values for HER2-negative BC than for HER2-positive BC, p=0.041 for min values. For the remaining comparisons the p-values were not statistically significant; however, the analysis detected reasonable numerical tendency toward higher values in HER2-positive BC as compared to HER2-negative BC. It has been confirmed in analysis performed using linear mixed models for repeated measures. We suspect that HER2-negative group is heterogenous and possibly includes patients with truly HER2-negative (0), but also patients with HER2-low, which could falsely overvalue concentrations range in this group. Conclusions: The current standard IHC/FISH method for HER2 expression assessment could be questioned and challenged as too imprecise and advances in targeted therapy may require more detailed technologies. False negative results can have particularly important clinical and prognostic implications. Clinical trial information: NCT05415943 .

Impact of hormone receptor status and tumor subtypes on clinical behavior and outcomes of breast cancer in young BRCA carriers.

504 Background: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer (BC). Among young patients harboring germline BRCA1or BRCA2 (BRCA) pathogenic variants (PVs), most of the tumors arising in BRCA2carriers express hormone receptors, while most BC cases in BRCA1 carriers do not; however, limited evidence exists on the impact of hormone receptor status on clinical behavior and outcomes in young patients harboring BRCA PVs. Methods: This is an international, multicenter, hospital-based, retrospective cohort study including young patients (≤40 years) diagnosed with invasive BC between January 2000 and December 2020, harboring germline PVs in BRCA genes. Our analysis investigates the impact of hormone receptor status on clinical behavior and outcomes of BC. The type and pattern of recurrence and survival outcomes (disease-free survival [DFS], BC specific survival [BCSS] and overall survival [OS]) were first investigated according to hormone receptors expression (positive vs. negative), and then according to BC subtype (luminal A-like vs. luminal B-like vs. triple-negative vs. HER2-positive BC). Results: From 78 centers worldwide, 4,709 BRCA carriers were included in this analysis, of whom 2,143 (45.5%) had hormone receptor-positive and 2,566 (54.5%) hormone receptor-negative BC. Patients with hormone receptor-positive BC were more likely to harbor BRCA2 PVs while less frequently had grade 3 tumors and nodal involvement. Median follow-up was 7.88 (IQR 4.47-12.61) years. The rate of distant recurrences was higher in patients with hormone receptor-positive BC (13.1% vs. 9.6%, p<.001), while the rate of second primary BC was lower (9.1% vs. 14.7%, p<.001) when compared to patients with hormone receptor-negative disease. The 8-years DFS was 65.8% in patients with hormone receptor-positive and 63.4% in those with hormone receptor-negative BC. No differences in terms of OS nor BCSS were observed. The hazard ratio of hormone receptor-positive vs. negative disease changed over time for DFS, BCSS, and OS (p<.05 for interactions of hormone receptor status and survival time). Among the 4,363 patients eligible for subtypes analysis, 612 had luminal A-like, 1,038 luminal B-like, 2,373 triple-negative and 340 HER2-positive BC. Patients with Luminal A-like BC had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-years DFS: 60.8% in luminal A-like vs. 63.5% in triple-negative vs. 65.5% in HER2-positive and 69.7% in luminal B-like subtype). Conclusions: In young BRCAPVs carriers with early BC, hormone receptor status did not appear to be a positive prognostic factor. The differences in pattern of recurrence and second primary BC among hormone receptor-positive vs. negative disease warrants consideration in counseling patients on treatment, follow-up strategies and indication for risk-reducing surgery.

Prognostic significance of ctDNA mutation analysis in patients with HER2-positive breast cancer undergoing neoadjuvant chemotherapy.

e12654 Background: Neoadjuvant chemotherapy (NACT) combined with dual anti-HER2 agents followed by surgical resection is the standard treatment for stage II-III HER2- positive breast cancer (BC). Despite the availability of effective therapies such as ado-trastuzumab emtansine (T-DM1) and neratinib, identifying patients at high risk of disease recurrence remains challenging. To evaluate whether circulating tumor DNA (ctDNA) can be used as a biomarker to assess treatment response in patients with HER2-positive EBC treated with neoadjuvant anti-HER2 therapy. ctDNA burden can serve as a useful determinant for escalating or de-escalating (neo)adjuvant strategy in EBC patients. This study aimed to assess the role of ctDNA mutation analysis using low-pass whole-genome sequencing (lpWGS) and whole exome sequencing (WES) in evaluating blood copy-number burden (bCNB), genomic alterations, mutational signatures, blood tumor mutational burden (bTMB), and minimal residual disease (MRD) monitoring. Methods: A total of 46 HER2-positive BC patients who underwent NACT combined with dual anti-HER2 agents and surgical resection were enrolled, including 28 clinical stage II and 17 III patients. Plasma samples were collected at four time points: before NACT, after 3 cycles, at the completion of NACT, and after surgery. lpWGS was utilized to assess bCNB, while WES was performed to evaluate genomic alterations, mutational signatures, and bTMB. Mutations selected from the baseline sample were monitored for MRD. In cases where lpWGS yielded negative results, targeted NGS sequencing was conducted. Somatic mutations are identified by whole exome sequencing across 20,000 genes (with boosted sequencing coverage for 600 cancer-related genes). Between 4-50 personalized somatic mutations or fusions are selected for each patient. This personalized panel together with a fixed MRD core panel is utilized for MRD detection and monitoring. Results: Among the enrolled patients, nodal metastasis was observed in 29 patients and 29 were hormone receptor-positive, and 36 achieved pCR (78.2%). Positive ctDNA was detected 58.8% of patients. Higher nodal stage was associated with ctDNA positivity at baseline. MRD positivity after chemotherapy was observed in 4 patients and 2 patients achieved pCR TP53 was the most frequently altered gene, followed by PIK3CA, MAP3K1, REV3L, MYC, MAP2K4, ERBB3, ATRX, ATM and ALK. This pattern is comparable to that observed in previous studies on BC. Non-PCR patients commonly exhibit MAP3K1 and MAP2K4 alteration is their ctDNA. Conclusions: The identification of MRD, regardless of pCR status, can be valuable for risk stratification and personalized treatment decision-making. Further studies are warranted to validate these findings and explore the clinical implications of ctDNA mutation analysis in HER2-positive BC management.

Therapeutic response and outcomes with less common breast cancer subtypes in the I-SPY trial 2011-2022.

582 Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients (1). We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized. EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCs. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. 1. Wolf et al, Cancer Cell 2022. Clinical trial information: NCT01042379 . [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]

Personalized neoadjuvant strategy in ER positive and HER2 negative breast cancer to increase BCS rate (PLATO): A prospective, multicenter, phase II clinical trial.

595 Background: Neoadjuvant therapy significantly enhances the likelihood of breast-conserving surgery (BCS) in breast cancer patients. However, in ER-positive and HER-2 negative breast cancer, the response to neoadjuvant chemotherapy (NCT) is not as good as HER-2 positive or triple-negative breast cancer. In addition, with the evolution of multi-gene assays, many patients of this subtype may not require adjuvant chemotherapy. This study explores the potential of tailored neoadjuvant treatments (NCT or endocrine therapy (NET)) guided by 70-gene assay (Mammaprint, Agendia) to improve BCS rates in ER-positive/HER-2 negative breast cancer. Methods: A prospective, multicenter cohort study was conducted across four Korean centers from 2019 to 2023. Participants were clinical stage II-IIIA, ER-positive/HER2-negative breast cancer patients deemed unsuitable for BCS. Suitability was further verified by an independent three-surgeon panel using mammography or MRI. Out of 130 screened patients, 100 were enrolled. We analyzed 90 patients, excluding 10 cases; 2 with a basal type or HER2 type result in the blueprint, 7 who refused neoadjuvant therapy, and 1 who underwent surgery at another hospital. Before initiation of therapy, each surgeon recorded a target tumor size at which the surgeon would be able to do BCS considering location of the tumor and patient’s breast size. Based on the 70-gene assay results from core needle biopsies, high-genomic-risk patients received NCT (anthracycline + cyclophosphamide for 4 cycles, followed by 4 cycles of docetaxel), while low-risk patients underwent 16 weeks of NET with letrozole (±leuprolide for premenopausal women). Results: Out of the patients, 66 (73%) were high-genomic-risk and underwent NCT, while 24 (27%) received NET. Median tumor size was 3.7cm (85.6% clinical T2 and 14.4% T3/4). The primary endpoint, achieving the pre-established target tumor size for BCS, was reached by 70.0% (95% CI: 59.4-79.2%) of patients, significantly surpassing the set goal of 50.8% (a 15% increase from historical control). The rates were 74.2% for NCT and 58.3% for NET. The actual BCS rate was 58.9% overall (63.6% for NCT and 45.8% for NET). Clinically, 5.6% exhibited complete response (CR), 74.4% partial response (PR), 18.8% stable disease (SD), and 1.1% progressive disease (PD). Pathologic complete response (pCR) was achieved in 2.2% (all in the NCT group). No severe adverse events beyond expectations were observed. No pre-treatment clinical or pathological factor was significantly predictive for the BCS conversion. Conclusions: For ER positive, HER2 negative breast cancer patients initially ineligible for BCS, the use of pre-treatment multi-gene assays to guide selective NCT or NET could substantially increase BCS rates and reduce unnecessary chemotherapy. Clinical trial information: NCT03900637 .

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.

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.

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.

Population pharmacokinetics of trastuzumab deruxtecan (T-DXd) in subjects with HER2-mutant and HER2-overexpressing non-small cell lung cancer (NSCLC).

e20537 Background: T-DXd is a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, approved globally at the dose of 5.4 mg/kg in HER2-positive or HER2-low breast cancer (BC) and HER2-mutant (HER2m) NSCLC1,2. The aim of the analysis was to characterize the populaton pharmacokinetics (PopPK) of T-DXd and its released payload, deruxtecan (DXd), in HER2m or HER2-overexpressing (HER2-OE) NSCLC subjects using data across tumor types (BC, NSCLC and others) from 12 Phase 1 to 3 studies with T-DXd doses ranging from 0.8-8.0 mg/kg. Methods: Analysis wasperformed using nonlinear mixed-effects modeling methods in NONMEM (version 7.4.3), similar to the previous analysis in HER2-positive BC1. Covariate effects were explored on the PK parameters of T-DXd and DXd. Results: Analysis included data across 1822 subjects, including 346, 1128, and 348 subjects with NSCLC, BC, and other cancers, respectively. The PK of T-DXd and DXd were adequately described by a PopPK model, judging by standard model diagnostics3. Covariate effects on T-DXd and DXd steady-state area under the concentration-time curve (AUC) were not clinically meaningful (within 0.8 to 1.25 AUC ratio interval for tested covariate level versus reference), except for subjects with high body weight (e.g., 90 kg; 95th percentile) showing a 31% and 37% higher T-DXd and DXd AUC, respectively, relative to typical subject with 58 kg body weight (median).The T-DXd and DXd AUC were also similar across subjects with BC, HER2m or HER2-OE NSCLC, with the same T-DXd dose. T-DXd and DXd AUC in NSCLC subjects were similar across subjects with mild hepatic or mild or moderate renal impairment (vs. normal counterparts), region (Asia, North America, Europe, and rest of the world), and race-country (Asian-Japan, Asian-Non-Japan, and Non-Asian) groups. Conclusions: T-DXd and DXd exposures were similar across subjects with BC and HER2m or HER2-OE NSCLC, as well as across hepatic function, renal function, region, and race-country groups within NSCLC supporting the use of 5.4 mg/kg dose (approved dose in BC) in HER2m or HER2-OE NSCLC from PK perspective. Reference: Enhertu [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2022. Enhertu [summary of product characteristics]. Daiichi Sankyo Europe GmbH, Munich; 2022 Yin O et al. Clin Pharmacol Ther. 2021;109(5):1314-1325. Clinical trial information: NCT04644237 , NCT03505710 .

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 .

Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study.

3038 Background: JSKN003 is a biparatopic HER2-directed ADC conjugated to a topoisomerase I inhibitor with an average DAR 4. Preclinical studies showed that JSKN003 had a good serum stability and strong anti-tumor activity. Hence JSKN003 could be effective in HER2 expressing tumors with a potentially broader therapeutic window. Methods: JSKN003-101 is a first-in-human, dose-escalation and -expansion study in Australian pts with advanced solid tumors. Pts (ECOG 0-1) with histologically documented HER2-expressing (HER2-positive defined as IHC 2+ or 2+/ISH+, HER2 low defined as IHC 1+ pr 2+/ISH-) or HER2-mutation by local testing who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, tolerability, MTD or RP2D, PK, and preliminary antitumor activity. Here the results from dose-escalation part were reported. Results: As of 15 Dec 2023, 32 pts were enrolled and received JSKN003 across 7 dose levels (1.0-8.4 mg/kg, Q3W). Among the 32 pts, 9 were IHC 1+, 16 were IHC 2+, and 7 were IHC 3+. Most pts (22/32, 68.8%) received ≥ 3 prior lines of therapy. The median duration of treatment was 15.8 (range, 6-54) weeks, and 19 pts (59.4%) remain on treatment. TRAEs occurred in 27 pts (84.4%) and 2 pts (6.3%) in 4.2mg/kg and 7.3mg/kg experienced grade 3 TRAE (anemia and fatigue); the most common TRAEs were diarrhea (62.5%) and nausea (50.0%), which were all grade 1-2. Only 1 pt experienced ILD/pneumonia (7.3mg/kg, grade 2). To date, no DLT events were found yet, and no TRAE led to death or treatment discontinuation. MTD has not been reached in 8.4 mg/kg. Following a single dose, exposures (Cmax and AUC) of JSKN003 and released TOP1i increased proportionally over a dose range of 4.2 mg/kg to 8.4 mg/kg. T1/2 of JSKN003 is approximately 5-6 days for 6.3 mg/kg and higher doses and increases with dose escalation. Accumulation of JSKN003 was minimal within the range of 1.1-1.5. The exposure of released payload was significantly lower than JSKN003 ADC, demonstrating the stability of the JSKN003 in circulation. All pts had at least one post-baseline tumor assessment. 16 pts achieved PR per RECIST 1.1 by investigator. Thus, ORR and DCR was 50.0% (95%CI: 31.9%, 68.1%) and 90.6% (95%CI: 75.0%, 98.0%), respectively. The ORR in pts with IHC 1+, 2+ and 3+ was 55.6% (5/9), 37.5% (6/16), and 71.4% (5/7), respectively. As for the efficacy of the HER2-positive and HER2-low breast cancer, the ORR was 80% (4/5) and 40.0% (4/10), respectively. Conclusions: JSKN003 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2 expressed tumors. As of the cut-off date, no DLT was observed, MTD has not been reached yet. Clinical trial information: NCT05494918 .

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 .

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 <126 mg/dL and HbA1c <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 .

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 .