HER2-negative Metastatic Breast Cancer Research Articles

HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.

10616 Background: Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with BRCA1- or BRCA2- ( BRCA1/2) associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC. Methods: A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in BRCA1/2, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response. Results: Eight treated pts (s BRCA1:1 ;g BRCA2:6; s BRCA2:1 ) had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in >1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in >50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts. Conclusions: MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331 .

Differential genomic profiling of the progesterone receptor (PR) negative and estrogen receptor (ER) low metastatic breast cancer subtypes through circulating tumor DNA: A TNBC-like disease subtype?

1039 Background: ER positive/HER2 negative metastatic breast cancer (MBC) is typically regarded as a single entity, although significant clinical differences are often observed, especially in the ER low subgroup (ER<10% regardless of PR status). This study aims to investigate genomic differences among HER2 negative subtypes (i.e., ERlow, PRpos [ER >10%/PRpositve], PRneg [ER >10%/PRnegative], triple negative [TNBC]) through circulating tumor DNA (ctDNA) next-generation sequencing (NGS). Methods: The study analyzed a retrospective cohort of 879 patients (pts) with HER2 negative MBC with ctDNA testing using the Guardant360 NGS panel within a large multicenter academic consortium. ER, PR and HER2 status was defined based on the most updated biopsy. Associations across single nucleotide and copy number variations (SNVs and CNVs) and ER/PR status were tested by multinomial logistic regression in terms of Relative Risk Ratio (RRR), adjusting for significant clinical characteristics (i.e., lines of treatment, metastatic sites, histology). Oncogenic pathway was defined based on reference (1). Prognosis was analyzed through Cox regression for overall survival (OS) defined from time of ctDNA collection. Results: Among the 879 analyzed pts, PRpos was the most prevalent subtype (N:420, 48%), followed by PRneg (N:216, 24%), TNBC (N:209, 24%), and ERlow (N:34, 4%). Compared to PRpos, lobular MBC was less common in TNBC (RRR: 0.33, P=0.001), while lung involvement was more frequent in TNBC (RRR: 1.53, P=0.019), and liver involvement in PRneg (RRR: 1.44, P=0.035). In contrast, bone metastases were less common in TNBC and ERlow (RRR: 0.26, P<0.001 and RRR: 0.45, P=0.03, respectively). After multivariable analysis, ERlow and TNBC were associated with a higher incidence of TP53 SNVs (RRR: 5.42, P<0.001 and RRR: 3.08, P=0.007, respectively) and a lower incidence of ESR1 SNVs (RRR: 0.23, P=0.025 and not detected, respectively). TNBC exhibited significantly fewer PIK3CA SNVs (RRR: 0.41, P=0.005) and CCND1 CNVs (RRR: 0.20, P=0.009), along with a higher frequency of CCNE1 CNVs (RRR: 6.47, P<0.001). PRneg had a lower incidence of ESR1 SNVs (RRR: 0.52, P=0.013) and more frequent FGFR1 CNVs (RRR: 2.61, P=0.004). Similar results were observed across oncogenic pathways. Compared to PRpos, OS analysis indicated poorer outcomes across all subgroups (PRneg HR: 1.29 P = 0.035, TNBC HR: 1.96 P<0.001, ERlow HR: 2.32 P<0.001). Conclusions: This study highlights several clinical and molecular similarities between TNBC and ERlow MBC, while suggesting specific endocrine resistance mechanisms in PRneg that are less reliant on ESR1 and more exposed to alternative mechanisms such as FGFR1 amplification. These findings underscore the importance of more precise disease subtyping to inform future drug development trials. 1. Sanchez-Vega F et al, Cell. 2018.

Real-world tumor BRCA testing patterns and PARP inhibitor use in HER2-negative metastatic breast cancer.

1113 Background: Testing for BRCA1/BRCA2 mutations (BRCAm) aids systemic treatment decisions for patients (pts) with metastatic breast cancer (mBC). This retrospective study explored real-world germline/tumor (g/t) BRCA testing patterns and PARP inhibitor (PARPi) use in US pts with mBC. Methods: Data from pts ≥18 years old diagnosed with HER2-negative mBC from 2014–2022 were captured in the nationwide Flatiron Health electronic health record-derived deidentified database. Patterns and timing of prospective or incidental BRCA testing were compared across mBC subtypes (hormone receptor-positive [HR+ mBC]/triple-negative mBC [mTNBC]) and disease stage (recurrent/ de novo). BRCAm prevalence was compared by testing modality and mBC subtype. PARPi initiation was assessed in pts with mBC diagnosed from 2018 onwards and a positive BRCAm test result. Clinical characteristics were compared by receipt of a BRCA test, testing modality, and PARPi initiation. Real-world overall survival (OS) by PARPi use was estimated using the Kaplan-Meier method. Results: Of 15,006 pts (including 12,349 with HR+ mBC; 1998 with mTNBC), 8178 (54.5%) did not receive any type of BRCA test, 4654 (31.0%) received a gBRCA test, 3075 (20.5%) received a tumor tissue DNA (ttDNA) test, and 1418 (9.4%) received a circulating tumor DNA (ctDNA) test. BRCA testing prevalence was numerically higher in pts with mTNBC (n=1164; 58.3%) than in pts with HR+ mBC (n=5323; 43.1%). As expected, testing prevalence was higher with ttDNA than with ctDNA (mTNBC: n=569 [28.5%] vs n=137 [6.9%]; HR+ mBC: n=2339 [18.9%] vs n=1224 [9.9%]). Over 93% of pts (recurrent and de novo) who received a tBRCA test were tested after an mBC diagnosis, and >1/3 were tested after first-line therapy, with median times from diagnosis to a ttDNA and ctDNA test of 127 and 431 days, respectively. Both gBRCA and tBRCA testing rates increased from 2014–2022, and testing occurred earlier in pts with recurrent than de novo disease. Among pts with tBRCAm, 66.0% had HR+ mBC, and 25.6% had mTNBC. BRCA1 mutations were more common in mTNBC (59.0%) than in HR+ mBC (22.9%) tumors. Of 219 pts with tBRCAm tumors who were diagnosed with mBC from 2018 onwards, PARPi was initiated in 39/74 (52.7%) pts with gBRCAm, 15/71 (21.1%) pts who were gBRCAm-negative, and 19/74 (25.7%) pts with gBRCAm status unknown. Among pts with g or tBRCAm and available OS data, median OS was numerically longer in pts who received PARPi (32.3 months [95% CI: 24.2, 47.4], n=128) versus pts who did not (29.0 months [95% CI: 21.9, 31.9], n=204; median follow-up time 23.2 months). Conclusions: While NCCN guidelines recommend gBRCA testing for all pts with mBC, more than half of pts with HER2-negative mBC (56.9% of pts with HR+ mBC) did not receive any BRCA test. Among pts with tBRCAm, ~2/3 had HR+ disease. Despite the potential benefits of PARPi for pts with BRCAm mBC, utilization remained low from 2018–2022.

Results and exploratory biomarker analyses of a phase II study CHANGEABLE: Combination of HX008 and niraparib in germ-line-mutated metastatic breast cancer.

1084 Background: The combination of poly (ADP-ribose) polymerase inhibitors and immune-checkpoint inhibitors demonstrated synergistic antitumor activity in preclinical studies. Here we report the efficacy, safety, and biomarker analyses of the combination of niraparib and PD-1 inhibitor HX008 in metastatic breast cancer (MBC) patients with germline DDR gene mutations in a phase II trial (CHANGEABLE). Methods: Eligible patients had histologically confirmed MBC with at least one measurable disease and germline pathogenic/suspected pathogenic mutations in DDR genes. Patients were enrolled into two cohorts: the main cohort (HER2-negative MBC patients with gBRCA1/2, gPALB2, gCHEK2) and the exploration cohort (MBC patients with gDDR gene mutations and brain metastases). Simon's Two-Stage design was used for recruiting patients in the main cohort. Patients with HER2-negative MBC received niraparib 200 mg qd combined with HX008 200 mg q3w, while HER2-positive patients received additional anti-HER2 TKI pyrotinib 400mg qd if having brain metastases, until disease progression. The primary endpoint was ORR. NGS of tissue and ctDNA were performed for exploratory biomarker analyses. Results: As of January 12, 2024, 37 patients were enrolled. In the main cohort with gBRCA1/2 mutations (n = 28), ORR was 78.6% (22/28), with 3 patients having complete response. DCR was 96.4% (27/28). Median PFS was 7.3 months (95%CI 4.2 to 10.4). According to Simon's Two-Stage design, since two patients with gCHEK2 mutations in the first stage had only stable disease, the recruitment was terminated. One patient with gPALB2 mutation had stable disease and the remaining one is in the screening process. In the patients having brain metastases (exploration cohort), ORR was 40% (2/5) and DCR was 80% (4/5). The most common treatment-related adverse events of grade 3 or higher were anemia (13 [35.1%]), thrombocytopenia (4 [10.8%]), and neutropenia (3 [8.1%]). No treatment-related deaths were reported. In the biomarker analysis, NGS of 700 genes was performed on 24 patients with gBRCA1/2 mutations in the main cohort. No significant difference was found in ORR or PFS between gBRCA1 and gBRCA2 mutations. Somatic mutations in XPO1 (16 patients (73%), 15/18 PR+CR, 1/4 SD+PD) showed significant correlation with response. Somatic TP53 mutations are significantly correlated with shorter PFS, while ASXL1 mutations are significantly correlated with longer PFS. Four somatic mutations (AR_c.1418_1420del, AR_c.231_239dup, 2 DUSP22 mutations) showed a consistent trend of decreasing in PD samples, while NF1_c.3198-4dup showed a consistent trend of increasing in PD samples. Conclusions: The combination of niraparib and HX008 demonstrated promising clinical benefits with a tolerable safety profile in MBC patients with germline BRCA1/2 mutations, even in patients with brain metastases. Clinical trial information: NCT04508803 .

Prognostic Factors for Long-Term Eribulin Response in a Cohort of Patients With HER2-Negative Metastatic Breast Cancer

Context and AimsEribulin is used in taxane and anthracycline refractory HER2-negative metastatic breast cancers (MBC). Patients treated in pivotal clinical trials achieved low survival rates, therefore, the identification of prognostic criteria for long progression-free survival (PFS) is still an unmet medical need. In this study, we sought to determine potential prognostic criteria for long-term eribulin response in HER2-negative MBC. MethodsOur retrospective cohort includes female patients with HER2-negative MBC treated with eribulin in Franche-Comté, France. We defined a long-term response as at least 6 months of eribulin treatment. The primary endpoint was the analysis of criteria that differ according to the progression-free survival. Secondary outcomes concerned overall survival and response rate. ResultsFrom January 2011 to April 2020, 431 patients treated with eribulin were screened. Of them, 374 patients were included. Median PFS was 3.2 months (2.8-3.7). Eighty-eight patients (23.5%) had a long-term response to eribulin. Four discriminant criteria allowed to separate PFS in 2 arms (PFS < 3 months or > 6 months) with a 78% positive predictive value: histological grade, absence of meningeal metastasis, response to prior chemotherapy, and OMS status. We have developed a nomogram combining these 4 criteria. Median overall survival was 8.5 months (7.0-9.5). ConclusionEribulin response in MBC can be driven by clinical and biological factors. Application of our nomogram could assist in the prescription of eribulin.

The impact of vitamin D levels on the progression-free survival of women with hormone receptor-positive, HER2-negative metastatic breast cancer treated with CDK4/6 inhibitors.

e13075 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) halt the transition from the G1 to the S phase, a process governed by the hyperphosphorylation of the retinoblastoma (Rb) protein. Similarly, vitamin D3 has been demonstrated to induce cell cycle arrest through the inhibition of various cyclin-dependent kinases, including those responsible for phosphorylating the Rb protein. Therefore, we hypothesized that suboptimal vitamin D levels may compromise the efficacy of CDK4/6i used to treat hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). Methods: We conducted a retrospective single-center study of women diagnosed with HR-positive, HER2-negative MBC and treated with any CDK4/6i between 2020 and 2023. Eligible patients were those who received at least one cycle of CDK4/6i, had a baseline 25-OH vitamin D measurement, and had a follow-up period of more than three months. Independent samples T-test, X2, and Fisher’s exact tests were used to evaluate associations between variables. Progression-free survival (PFS) was calculated using the Kaplan-Meier method and compared according to vitamin D levels using the log-rank test. Results: Among 31 patients, the mean age at diagnosis was 53 years (SD 14), 24 (77%) received CDK4/6i in the first-line setting, and 9 (29%) had suboptimal vitamin D levels (&lt;20 ng/ml). Clinicopathological features based on vitamin D levels are shown (Table). The type of iCDK was different according to vitamin D levels (p = 0.036), with no other observed differences between groups. With a median follow-up of 26 months (95% CI 17-35) since iCDK initiation, median PFS was not reached for the entire cohort. A univariate analysis revealed that patients with suboptimal vitamin D levels had an inferior median PFS compared to patients with optimal levels (14 months [95%CI 4-24] vs. not reached [p=0.016]). Notably, no other parameter was associated with PFS in univariate analyses. Conclusions: In this cohort of Mexican patients with HR-positive, HER2-negativeMBC, suboptimal vitamin D levels adversely impacted PFS. Given the retrospective nature of this study and the limited number of patients, we emphasize the importance of studying these findings prospectively. [Table: see text]

Serial analysis of ESR1 and PIK3CA mutations in cell-free DNA from metastatic breast cancer during 1st line endocrine therapy.

e13060 Background: Activating mutations ofESR1 and PIK3CA genes are known mechanisms of endocrine resistance. Recent analysis supported benefit of early intervention at presence of ESR1 mutation in blood (bESR1) before clinical progression. We aimed to investigate ESR1 and PIK3CA mutations detected in cell-free DNA (cfDNA) from patients with hormone receptor-positive, HER2-negative metastatic breast cancer (MBC) and its impact on progression-free survival (PFS). Methods: Thirty patients undergoing 1st line endocrine therapy (ETx) were identified from a prospective cohort. Seven ESR1 hotspot mutations in the ligand binding domain were tested in cfDNA with droplet digital polymerase chain reaction (ddPCR) assay (Genopeaks Co., Ltd). Eleven PIK3CA hotspot mutations were tested using amplicon-targeted sequencing method (Genopeaks Co., Ltd) in both tumor and cfDNA. PFS analyses were performed using Kaplan-Meier methods and compared with the log-rank test. Results: We examined serial cfDNA samples from 26 patients collected every 3-6 months. ESR1 mutations were found in 61.5% (16/26) patients at any timepoint during 1st line endocrine therapy, with D538G being the most common followed by Y537C and 68.8% (11/16) being polyclonal. Among the 50.0% (8/16) bESR1 positive patients with clinical progression, 4 had bESR1 detected before clinical progression while 4 were diagnosed clinical progression concurrently, suggesting the necessity of closer intervals of cfDNA analyses. While presence of bESR1 did not affect PFS overall, 18.8% of patients with bESR1 detected within 6 months after 1st line ETx, displayed worse outcome (median PFS 5 vs 52 months). Also, patients with clearance of bESR1 mutation in subsequent cfDNA (81.3%, 13/16) were shown to have a better outcome (median PFS 52 vs 41 months). Among 14 patients with clinical progression, 8 had bESR1 mutation. Median PFS between patients with bESR1 positive vs negative was 14 vs 9 months. PIK3CA mutations were detected in 69.5% (16/23) of cfDNA at diagnosis of distant metastasis, among them 53.3% (8/15) had co-occurrence with bESR1 mutations. While presence of PIK3CA mutation in primary tumor tissue did not affect disease-free survival nor PFS, patients with blood PIK3CA mutation at diagnosis of metastasis displayed significantly worse outcome (p = 0.041). Conclusions: Substantial number of hormone receptor-positive, HER2-negative MBC patients were detected with ESR1 and PIK3CA mutation in plasma. Though it was a small-sized analysis to accurately assess statistical significance, we observed worse outcome in patients with 1) early detection (&lt;6 months) of bESR1 and with 2) sustained bESR1 during palliative ETx. Patients with clinical progression without bESR1 mutation displayed shorter PFS than patients with bESR1. PIK3CA mutations in cfDNA were prognostic supporting the benefit of combined targeted therapy.

A phase II trial of anlotinib combined chemotherapy as second-line and above therapy in HER2-negative advanced breast cancer.

e13140 Background: The group of HER2-negative accounts for about 75% of breast cancer and has limited response to chemotherapy. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. In this study, we assessed the efficacy and safety of anlotinib plus chemotherapy in second-line and above treatment of HER-2 negative advanced breast cancer. Methods: This open-label, single-arm, phase II study enrolled women aged 18-75 years with HER2-negative breast cancer who underwent at least one-line chemotherapy. All patients were treated with anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle) in combination with investigator-selected chemotherapy. The primary endpoint evaluated in this study was the median progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and safety. Results: From August 2022 to August 2023, 33 patients were enrolled in this study including 22(66.7%) HR+/HER2- patients and 11(33.3%) TNBC patients. After a median follow-up time of 11 months (95% CI, 5.8-16.2), the median PFS (mPFS) of the all patients was 8.6 months (95% CI 7.3-NA). In the HR+ and HR- populations, mPFS was 7.6 months versus 9.5 months (HR,0.376 [95%CI 0.12-1.13], p=0.072), respectively. All the patients had the confirmed best overall response assessments, no patient achieved complete response (CR); 11(33.3%) patients got partial response (PR) and 19(57.6%) patients achieved stable disease (SD). ORR was 33.3% (95% CI 18.0-51.8), DCR was 90.9% (95% CI 75.7-98.1) and CBR was 60.6% (95% CI 42.1-77.1). The most frequently observed adverse events were elevated triglycerides (78.8%), elevated blood sugar (63.6%), anemia (60.6%), elevated cholesterol (51.5%), elevated alanine aminotransferase (48.5%), and leukopenia (48.5%). Dose reductions due to adverse events occurred in 7 (21.2%) patients. Conclusions: Anlotinib combined with chemotherapy showed a promising efficacy with an acceptable safety profile for second-line and above patients with HER2-negative metastatic breast cancer. Further studies enrolling more patients are still needed.

Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer (MBC): A multicenter, open-label, single-arm, phase II study.

e13139 Background: The combination of eribulin and gemcitabine has demonstrated a similar progression-free survival (PFS) benefit as paclitaxel plus gemcitabine, with less neurotoxicity, for patients with MBC who have not received prior cytotoxic chemotherapy. However, the effect of eribulin plus gemcitabine on PFS in second line or beyond remains unclear. Methods: This open-label, single-arm, phase II study (NCT05263882) was conducted at 14 institutions in China. Eligible patients had histologically confirmed HER2-negative MBC and had received at least one prior taxane-containing chemotherapy regimen for advanced disease, and anthracycline-containing regimens in the adjuvant setting. Patients received intravenous infusions of eribulin (1.4 mg/m2) and gemcitabine (1.0 g/m2) on days 1 and 8 of a 21-day cycle. Efficacy outcomes, including PFS, objective response rate (ORR), and disease control rate (DCR), were assessed using RECIST v1.1. Adverse events (AEs) were graded according to NCI-CTC version 5.0. Results: A total of 70 patients were enrolled from November 2021 to October 2023; 47 (71.4%) had HR+HER2- and 18 (28.6%) had triple-negative MBC. The median patient age was 50 years (range: 31-68), and the sites of metastasis were the bone (68.6%), liver (52.9%), lymph nodes (48.6%), lung (44.3%) and brain (10.0%). Patients had received a median of 3 prior lines of systemic treatment, 2 lines of chemotherapy, and 1 line of endocrine treatment. Among all patients, the ORR was 48.6%, the DCR was 92.9% and the median PFS was 7.2 months. For the HR-positive subgroup, the median PFS was 8.4 months, while for the triple-negative subgroup, it was 6.3 months. Among HR+ patients who had received prior CDK4/6 inhibitor treatment, the median PFS was 7.2 months. In the subgroup of HR+ patients who had not received CDK4/6 inhibitor treatment, the median PFS had not been reached. For the HR+ HER2-low subgroup, the median PFS was 8.4 months. The most common grade 3-4 AEs were hematological, including neutropenia (38.6%), leukopenia (31.4%), anemia (24.3%), and thrombocytopenia (15.7%). Grade ≥3 perceived AEs were relatively low. Conclusions: Eribulin plus gemcitabine was effective in heavily pretreated patients with HER2- MBC, while maintaining a predictable and manageable safety profile. Clinical trial information: NCT05263882 . [Table: see text]

A deep learning–enabled workflow to estimate real world progression-free survival in patients with metastatic breast cancer.

11176 Background: Progression-free survival (PFS) is frequently measured in oncology clinical trials. In analyses outside of the trial setting, various strategies have been utilized to assess real-world PFS (rwPFS), including manual abstraction of clinical records, natural language processing (NLP) of oncology notes and radiology reports, and longitudinal analyses of radiologic images. Here we develop and validate a new semi-automated workflow that combines NLP of clinical notes with structured electronic health record data to facilitate the evaluation of rwPFS in patients with metastatic breast cancer (mBC). Methods: This study analyzes de-identified EHR data using nference nSights. The data is extracted following privacy-preserving protocols and is HIPAA compliant. The overall cohort included 316 patients with HR-positive, HER2-negative mBC who initiated Palbociclib and Letrozole combination therapy between January 1, 2015 and December 31, 2021. We developed and implemented an ensemble of deep-learning NLP frameworks to capture progression events from unstructured clinical notes and radiology reports. A change in the line of therapy, as determined by structured drug order/administration records, was also considered a progression event. We used manually curated “ground-truth” datasets to evaluate the performance of the progression-event capture workflow at the levels of both sentences (N = 1000) and patients (N = 100) by calculating sensitivity, specificity, precision, accuracy, and F1 scores. Progression events and censoring events (death, loss to follow-up, end of study period) were considered to compute rwPFS. Results: At the sentence level, progression events were captured from clinical notes and radiology reports with a sensitivity of 99.8%, specificity of 96.7%, and accuracy of 98.2% (Table). At the patient level, initial progression was correctly captured within a window of +/-30 days with a sensitivity of 92.5%, specificity of 83.0%, and accuracy of 88.0% (Table). In a sample of 100 patients, the median rwPFS was determined to be 25 months (95% CI; 15-35 months) by manual curation and 22 months (95% CI; 15-35 months) by the semi-automated workflow. In the overall cohort, median rwPFS was 20 months (95% CI; 18-25 months). Conclusions: An ensemble of NLP algorithms extracted progression events from clinical notes and radiology reports with high accuracy. A semi-automated workflow enabled rapid and accurate determination of rwPFS in mBC patients receiving a combination chemotherapy regimen. Further evaluation of this workflow to estimate rwPFS in other cancers and therapeutic settings is warranted. [Table: see text]

Toxicity differences in CDK 4/6 inhibitors seen in Asian and Pacific Islanders.

e13086 Background: Cyclin-dependent kinases (CDK) 4/6 inhibitors are the standard of care, first line treatment for hormone receptor positive metastatic breast cancer and adjuvant high-risk hormone receptor positive early stage breast cancer along with endocrine therapy. There have been multiple clinical trials validating the effectiveness, along with toxicities of these agents; however, the majority of these trials lack ethnic diversity. This shortcoming limits the ability to apply these findings in diverse patient populations, especially among Asian and Pacific Islanders in Hawaii. Objective: To determine if the toxicity profile of CDK 4/6 inhibitors in women with breast cancer is different among patients at a community oncology practice in Hawaii, in which the majority of patients are Asian, Pacific Islander or a combination of both when compared to three landmark trials. Methods: A retrospective analysis of thirty-two patients with hormone receptor positive, HER2 negative metastatic or high risk breast cancer who started endocrine therapy and CDK 4/6 inhibitor therapy (abemaciclib, ribociclib, or palbociclib) between 2018-2023. Graded toxicities of each individual patient based on CTCAE criteria V. 5, along with demographic data was reviewed and compared to three main registration trials for these agents (MONARCH-3, MONALEESA-2, PALOMA-2). Results: Combined results from the three large randomized trials reported an average of 75% of participants were Caucasian, as compared to 15% in the Hawaii data. While 19% percent of participants from the combined large randomized trials reported being of Asian descent, none of these trials reported a breakdown of Asians versus Pacific Islanders. In the Hawaii sample, 41% were reported as Pacific Islander and 41% reported as Asian, 15% Caucasian, with the final 3% reported as Hispanic. Collective analysis of the FDA registration trials contained 0% Pacific Islander, 19.8% Asian, 74.3% White, 1.5% Black, and 4.4% Other. The majority of all toxicities of all grades were higher in the Hawaii population as compared to the three national trials, except for neutropenia with ribociclib and diarrhea with palbociclib (Table). Conclusions: The Hawaii analysis that was primarily comprised of Asians and Pacific Islanders revealed an increased incidence of toxicities, despite starting at lower doses rates for all CDK 4/6 inhibitors. This data analysis begins to highlight the importance of representative populations in clinical trials for the most effective and safest care of diverse populations. [Table: see text]

Racial differences in genomic profiles and targeted treatment use in ER+ HER2- metastatic breast cancer.

1017 Background: Despite well-documented disparities in survival between patients (pts) with Black and White racial backgrounds, there are limited data on racial equity of targeted treatment use for pts with estrogen receptor positive, HER2 negative (ER+/HER2-) metastatic breast cancer (MBC). We evaluated differences in circulating tumor DNA (ctDNA) genomic alterations in Black and White pts with ER+/HER2- MBC. Methods: This retrospective cohort study analyzed a database of 1327 pts with MBC who were treated at Washington University in St. Louis, Massachusetts General Hospital, and Northwestern University and had ctDNA testing through the commercially available Guardant360 assay. Progesterone receptor (PR) status of the ER+/HER2- pts was identified to categorize pts as ER+/PR+/HER2- (N=60 Black, N=435 White) and ER+/PR-/HER2- (N=24 Black, N=237 White). Pts were evaluated by self-reported race and use of PIK3CA, CDK4/6, and mTOR inhibitors, either through clinical trial enrollment or after FDA approval. A multivariate logistic analysis was performed to determine genomic and prognostic differences by race. Overall survival (OS) from time of first ctDNA testing was determined by subgroup. Results: Black pts with PIK3CA single nucleotide variants (SNVs) were significantly less likely to receive targeted therapy than White pts (5.9%, 1/17 pts vs. 28.8%, 45/156 pts, Fisher’s exact test p=0.045), while there was no difference in use of CDK4/6 or mTOR inhibitors. None of the Black pts with PIK3CA mutations were enrolled in clinical trials vs. 11.5% of White pts. Black pts with ER+/PR+/HER2- tumors were more likely to have CCND1 copy number variation (cnv) (odds ratio (OR) 2.4, 95% confidence interval (CI) 1.1-5.4, p=0.030) when compared with White pts. Black pts with PR- tumors were more likely to have de novo metastatic disease (OR 3.4, 95% CI 1.1-10.8, p=0.034) and GATA3SNV (OR 3.5, 95% CI 1.04-11.6, p=0.044). KRAS cnv was more common in White PR- pts (HR 2.9, CI 1.02-8.3, p=0.045). There were significant differences in OS between Black and White pts with ER+/PR+/HER2- tumors (median OS of 25 vs. 32 months, respectively) and for Black and White pts with ER+/PR-/HER2- MBC, (median OS of 9.1 vs. 21 months, respectively, log-rank test p=0.00093). Conclusions: To our knowledge, this is the largest clinicogenomic dataset comparing genomic alterations and targeted treatment use by race in MBC. We identified significant disparities in the use of PI3K inhibitors for Black pts while other drugs that do not require genomic profiling were similarly utilized. OS and clinical trial enrollment disparities are consistent with prior findings and must continue to be addressed. Further research is needed to validate these findings, elucidate the factors contributing to these disparities, and explore interventions to improve racial disparities in use of precision medicine therapies and enrollment in clinical trials.

(CDK) 4/6 inhibitors: An effective treatment for homologous recombination deficient (HRD) luminal breast cancers (BC)?

e13100 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) still represents the best 1st-line choice for hormone receptor (HR) positive(+)/HER2 negative(-) metastatic breast cancer (MBC) patients (pts). Approximately 8% of pts with HR+ BC harbors germline BRCA mutation (g BRCAmt). The interaction between Cyclin/CDK pathway, endocrine receptor (ER) and Breast Cancer gene 1/2 (BRCA1/2) is complex and evidence reported so far, await confirmation in the context of future randomized clinical trials. So far, limited data exist about treatment effectiveness of CDK4/6i in homologous recombination deficiency (HRD) Luminal BC. A current frequent question in clinical practice is which additional adjuvant therapy to prioritize for luminal BRCA tumors (tu), considering the approval of both CDK4/6i andpoly ADP ribose polymerase (PARP) inhibitors in this scenario. Considering potential impacts of genetic instability in tu biology, such as potential loss of Rb protein related to Loss of Heterozygosity (LOH) of BRCA2 as a primary resistance mechanism in CDK4/6i, we sought to analyze the clinical results of that drug in tu with genetic instability. Methods: We retrospectively analyzed real-world outcomes of CDK4/6i performance in HR+/HER2- MBC treated in a single institution, with focus in clinical outcomes of HRD BC. germline HR genes status and somatic phosphatidylinositol 3-kinase (PIK3CA) status were also analyzed. Results: A total of 384 consecutive MBC pts treated with CDK4/6i were included in this study. The most used CDK4/6i was palbociclib (40,6%), followed by ribociclib (29,8%) and abemaciclib (29,2%). Considering the whole cohort PFSm 30months (95%IC 26-34) and OSm were 56 months (95%IC 52-60) No differences in PFS or OS was observed among the 3 CDK4/6i. Median age of the cohort was 60 years old. 38.5% were premenopause Pts and 59.9% were postmenopause. A total of 149 (39%) pts performed germline screening. Between 19 pts with gHR mt, 12 were BRCA1/2 mt (just one BRCA1). The other were: 2 PALB2, 2 CHEK2, 1 ATM, 1 RAD51D, 1 RAD51C mt. So far, no differences in PFS ou OS was observed in the presence of BRCA 1/2 or other gHR mt. Nevertheless, PIK3CA mt was tested in 142 pts, 51 were positives. That mt was a predictor of worse OS (55m; 95%IC 45-65) x 63m (95%IC 56-69), p 0,019. Conclusions: The results of this real-world study suggest that treatment outcomes with CDK4/6i may be worse in pts with HRD tu due to potential differences in tu biology. Future exploration in larger samples of patients who have had biomarker testing is ongoing. Patients with Pik3CA mt treated with CDK4/6i presented worse clinical outcomes.

A phase 1 study of liposomal irinotecan in patients with advanced breast cancer.

1080 Background: Liposomal irinotecan (HE072) is a liposomal formulation that encapsulates irinotecan in a lipid bilayer vesicle, and as a generic drug, had been approved in China, recently, in patients with pancreatic cancer after gemcitabine treatment. Advanced triple negative breast cancer (TNBC) has very poor prognosis and limited treatment choices. Here we present results of breast cancer treated with HE072 in patients with highly pre-treated metastatic TNBC and HER2 negative breast cancer brain metastasis (BCBM). Methods: HE072-CSP-002 was a phase 1 study, consisting of two parts, dose escalation and expansion part (part 1) and expansion cohort part (part 2). In part 1, standard 3+3 design was used to investigate up to three dose levels of HE072 (50 mg/m2, 70 mg/m2 and 90 mg/m2), up to 6-9 additional subjects may be enrolled for dose expansion. In part 2, patients were enrolled in two cohorts (TNBC cohort and BCBM cohort), and received HE072 70 mg/m2 every two weeks (Q2W). The primary endpoints were the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and the incidence and severity of treatment emergent adverse events (TEAEs). Secondary endpoints included progression free survival (PFS), objective response rate (ORR), overall survival (OS). Results: As of June 5th, 2023, 119 patients were enrolled, including 101 patients with TNBC and 18 patients with HER2 negative BCBM (part 1: n=27; part 2: n=92). In the part 1, one dose-limiting toxicity (grade 3 nausea and grade 3 vomiting) was observed at 70 mg/m2 dose level, and MTD was not reached. A total of 115 patients (96.6%) had at least one TEAEs of any grade, and 55 patients (46.2%) had ≥grade 3 TEAEs. The most common ≥grade 3 TEAEs related to HE072 included neutropenia (21.0%), leukopenia (18.5%), diarrhea (10.1%), anemia (9.2%) and hypokalemia (8.4%). Eighty-three (82.2%) of the 101 patients with TNBC were evaluable for response. After a median follow-up of 10.1 months (range 8.8-10.8), 22 patients (26.5%, 95%CI 17.4-37.3) achieved overall response, which were all partial response and 58 patients (69.9%, 95%CI 58.8-79.5) achieved disease control. The median PFS and OS were 4.8 months (95%CI 3.9-5.8) and 14.1 months (95%CI 11.2-not reached), respectively. 12(66.7%) of the 18 patients with HER2 negative BCBM were evaluable for response. 1 patient (8.3%, 95%CI 0.2, 38.5) achieved overall response, which is partial response and 8 patients (66.7%, 95%CI 34.9, 90.1) achieved disease control. The median PFS was 5.6 months (95%CI 1.4~ not reached), 12-month OS rate was 55.5%. Conclusions: HE072 exhibited excellent antitumor activity in heavily pre-treated patients with TNBC and HER2 negative BCBM with acceptable safety profiles. 70 mg/m2 Q2W was determined as the RP2D. Further clinical trials are under plan. Clinical trial information: NCT04728035 .

Innovation of the first-line strategy optimized as abemaciclib with endocrine therapy based on the ESR1mutation of ctDNA for patients with HR-positive HER2-negative advanced metastatic breast cancer (JBCRG-M08; AMBER study).

TPS1134 Background: Aromatase inhibitor (AI) + CDK4/6 inhibitor (CDK4/6i) has been established as a standard of care of 1st line treatment for hormone receptor (HR)-positive/HER2-negative advanced metastatic breast cancer (AMBC). ESR1 mutations are considered to be one of the causes of acquiring resistance against the AI +CDK4/6i. PADA-1 trial showed that replacing AI with fulvestrant (FUL) as a partner of palbociclib (PAL) at occurrence of some ESR1 mutations improved progression-free survival (PFS) and PFS2, suggesting PAL should be used based on the strategy of selecting endocrine agents according to ESR1 mutation status by ctDNA analysis. On the other hand, we don’t know if this strategy is effective in the case of abemaciclib (ABM), another CDK4/6i established as the standard of care for AMBC. We are conducting a study to make evidence on this clinical question. Methods: This multicenter, single-arm phase II study is designed to evaluate the efficacy and safety of the strategy to replace AI with FUL for detectable ESR1 mutations in combination with ABM. Key eligibility criteria include patients receiving AI+ABM for at least 6 months as first-line treatment for HR-positive/ HER2-negative AMBC without progressive disease (PD). While continuing AI+ABM, ctDNA analysis will be performed at approximately 3, 9, 15 months from enrollment. If ESR1 mutation is identified at any point and non-PD is confirmed by CT, FUL+ABM will be initiated instead of AI+ABM. In patients with ESR1 mutations completely cleared by ctDNA analysis 6 months after the start of FUL+ABM, AI+ABM will be resumed (Re-AI+ABM arm); the Re-AI+ABM arm is intended to investigate whether the discontinuation of FUL will allow clones with ESR1 mutations to proliferate again. Primary endpoint is 2-year PFS rate in full analysis set. Key secondary endpoints include 2-year PFS rate by treatment sequences, and rate of disappearance of ESR1mutations in ctDNA with FUL+ABM. Plasma-SeqSensei Breast Cancer IVD Kit, which can simultaneously detect mutations in a wide range of six genes including ESR1, as well as PIK3CA, AKT1, ERBB2, KRAS, and TP53, is used for ctDNA analysis in this study. Based on PFS data in MONARCH3 study, the threshold and expected value of the 2-year PFS rate were estimated to be 45% and 55%, respectively, and target sample size was calculated as 160 patients. Patient enrollment started in December 2022 and run through December 2024; as of December 2023, 54 patients have been enrolled. Clinical trial information: 051220133.

Results of a retrospective study on the efficacy and safety of alpelisib in patients with HR+/HER2- metastatic breast cancer in real-world clinical practice.

e13058 Background: The combination of alpelisib and fulvestrant is an optimal therapy option for patients with hormone receptor-positive (HR+), HER2-negative (HER2–) metastatic breast cancer with PIK3CA gene mutations. The aim of this work to retrospectively analyze the efficacy and safety of alpelisib in real-world clinical practice in patients with pre-treated luminal HER2– negative metastatic breast cancer. Methods: The study included an analysis of 33 patients with widespread luminal HER2- negative breast cancer with detected PIK3CA gene mutation. The median age was 57 ± 13 months (95% CI 52-62). In 12 (36.4%) patients, the PIK3CA gene mutation was detected in exon 9, and in 21 (63.6%) – in exon 20. Alpelisib was prescribed to pre-treated patients in different lines. Most women (32/33; 97%) had received ET combined regimens with CDK4/6 inhibitors before starting alpelisib therapy: 14 (42.4%) patients underwent palbociclib therapy in combination with fulvestrant; 4 (12.1%) – palbociclib with aromatase inhibitors; 13 (39.5%) – ribociclib in combination with fulvestrant; 1 (3.0%) – ribociclib with aromatase inhibitors. It is important to note that 63.6% of patients had previous progression on fulvestrant monotherapy and 72.7% on aromatase inhibitor therapy. Patients with luminal B-subtype of breast cancer dominated - 72.7% (24/33). Results: The median overall survival (OS) in this study was 14 ± 2.5 months (95% CI: 9-18.9), and the median progression-free survival (PFS) was 6 ± 2.7 months (95% CI: 0.7-11.3). The rate of objective response was 30.3%, and prolonged disease stabilization was observed in 24.2% of cases. Prognostic factors were brain metastases (increasing the risk of death by 18 times) and discontinuation of the drug for any reason (increasing the risk of death by 8 times). It should be noted that the main reason for discontinuation or disruption of the drug's timing was unmanageable toxicity. All patients registered adverse events of varying degrees, with 21 (63.6%) patients experiencing hyperglycemia (grade 3-4 – 30.3%) and 14 (42.4%) patients experiencing skin toxicity (grade 3-4 – 15.2%). In the SOLAR-1 study, the frequency of hyperglycemia was comparable (64.8%), and rash was noted in a third of all patients, which is comparable to our data. Conclusions: The results of using alpelisib with fulvestrant confirm its effectiveness in real-world clinical practice in patients with pre-treated HR+HER2- negative widespread breast cancer with the presence of somatic PIK3CA gene mutation. Brain involvement is an unfavorable prognostic factor in patients with PIK3CA mutation and increases the risk of death by 18 times, requiring the need to optimize the therapeutic algorithm, including through radiation methods. Discontinuation of the drug, which increases the risk of death by 8 times.

Utidelone plus bevacizumab for the treatment of HER2-negative breast cancer brain metastases (U-BOMB): A multicenter, single-arm phase II study.

1081 Background: The primary treatment for brain metastases in patients with HER2-negative advanced breast cancer is predominantly local therapies like radiotherapy, owing to the limited efficacy of systemic therapies. Prior research has demonstrated utidelone's significant permeability across the blood-brain barrier and the preliminary effectiveness of bevacizumab for breast cancer brain metastases. Consequently, this study investigated the efficacy and safety of utidelone combined with bevacizumab in the treatment of advanced breast cancer brain metastases. Methods: This study was a single-arm, multi-center phase II clinical trial (NCT05357417). Eligible patients were aged 18 years or older with either radiotherapy-naive or progressive brain metastases post-radiotherapy, presented with asymptomatic or symptomatic brain metastases associated with HER2-negative breast cancer.Patients received intravenous bevacizumab (15 mg/kg on day 1 of each 3-week cycle) and utidelone (30 mg/m2 on days 1 to 5 of each cycle) until intolerance or disease progression. The primary endpoint was central nervous system objective response rate (CNS-ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. Results: Between May 5, 2022, and October 25, 2023, a total of 46 patients were recruited, with a median age of 52.5 years (range, 33 to 69). Among them, 35 patients had untreated CNS lesions, while 11 had progressive brain metastases after local radiotherapy. The CNS-ORR was 43.5% (95% confidence interval [CI], 28.9%-58.9%). As of January 8, 2024, the median duration of follow-up was 14.6 months, and the median progression-free survival (PFS) was 7.7 months (95% CI: 5.5-10.8) as shown in Table. The 12-month overall survival (OS) rate reached 74.4% (95% CI: 60.0%-92.3%). The most common grade 1-2 adverse events (AEs) were peripheral neuropathy (87.5%), decreased neutrophil count (62.5%), anemia (47.5%), diarrhea (37.5%), and increased alanine aminotransferase (25%). No grade 3 or higher treatment-related AEs occurred. Conclusions: This study preliminarily shows promising efficacy and manageable safety of the combination of utidelone and bevacizumab in the treatment of HER2-negative metastatic breast cancer patients with brain metastases. Clinical trial information: NCT05357417 . [Table: see text]

Advancing HER2-low breast cancer management: enhancing diagnosis and treatment strategies.

Recent evidence brought by novel anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates is leading to significant changes in HER2-negative breast cancer (BC) best practices. A new targetable category termed 'HER2-low' has been identified in tumors previously classified as 'HER2-negative'. Daily practice in pathology and medical oncology is expected to align to current recommendations, but patient access to novel anticancer drugs across geographies might be impeded due to local challenges. An expert meeting involving ten regional pathology and oncology opinion leaders experienced in BC management in four Central and Eastern Europe (CEE) countries (Bulgaria, Croatia, Serbia, Slovenia) was held. Herein we summarized the current situation of HER2-low metastatic BC (mBC), local challenges, and action plans to prevent delays in patient access to testing and treatment based on expert opinion. Gaps and differences at multiple levels were identified across the four countries. These included variability in the local HER2-low epidemiology data, certification of pathology laboratories and quality control, and reimbursement conditions of testing and anticancer drugs for HER2-negative mBC. While clinical decisions were aligned to international guidelines in use, optimal access to testing and innovative treatment was restricted due to significant delays in reimbursement or limitative reimbursement conditions. Preventing delays in HER2-low mBC patient access to diagnosis and novel treatments is crucial to optimize outcomes. Multidisciplinary joint efforts and pro-active discussions between clinicians and decision makers are needed to improve care of HER2-low mBC patients in CEE countries.

Effectiveness of cyclin-dependent kinase 4 and 6 inhibitors for the treatment of hormonesensitive HER2-negative metastatic breast cancer in first-line therapy: A systematic literature review

At present, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors such as palbociclib, ribociclib, and abemaciclib are widely used for the first-line treatment of locally advanced or metastatic breast cancer. However, direct comparisons of these treatment options in randomized studies have not been conducted.Aim of the work is to gather and analyze published data on the comparative effectiveness of CDK4/6 inhibitors in combination with aromatase inhibitors in postmenopausal patients with HR+/HER2– locally advanced or metastatic breast cancer. A systematic review of publications presenting results from original studies on the impact of CDK4/6 inhibitor therapy in combination with aromatase inhibitors on the survival of patients was performed. Nineteen studies with original data on progression-free survival and overall survival were identified. None of the studies found significant differences between different CDK4/6 inhibitors and aromatase inhibitors in terms of progression-free survival. A statistically significant superiority of ribociclib over palbociclib in terms of overall survival was observed in a single matching-adjusted indirect comparison, while seven other studies of various types (real-world data studies, matching-adjusted indirect comparisons, and meta-analyses) did not find significant differences between the investigated drugs in terms of overall survival.Currently, there is no compelling evidence of the superiority of one CDK4/6 inhibitor over others. The decision on the preference for a specific drug within the class can only be made after conducting direct randomized comparison trials, or accumulating sufficient real-world data on the use of palbociclib, ribociclib, and abemaciclib.

Abstract PO4-04-12: A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/or metastatic breast cancer

Abstract Background: Endocrine therapy (ET) when administered with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has improved outcomes in patients (pts) with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (BC) or metastatic breast cancer (MBC) and is the current standard of care for first-line treatment. Addition of the PIK3 inhibitor alpelisib to ET significantly improved progression-free survival in pts with PIK3CA-mutated, ER-positive, HER2-negative MBC, and alpelisib + fulvestrant is the standard of care for second or later-line treatment. Most pts will acquire resistance to ET, with mutations in ESR1 constituting the most common mechanism of resistance. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant in combination with ribociclib demonstrated activity in both ESR1-wt and ESR1-mut xenograft models and showed efficacy in brain metastasis xenograft models. In a Phase 1/2 monotherapy study in pts with ER-positive, HER2-negative MBC, palazestrant was well tolerated with demonstrated antitumor efficacy and favorable pharmacokinetics (PK) supporting once a day (qd) dosing at the recommended Phase 2 dose (RP2D) of 120 mg. The aim of this study is to evaluate the safety, PK, and antitumor activity of palazestrant + ribociclib or alpelisib in pts with ER-positive, HER2-negative advanced BC or MBC. Methods: Eligible pts have evaluable ER-positive, HER2-negative advanced BC or MBC; ≤2 prior ETs (prior CDK4/6 inhibitors allowed); and ≤1 prior line of chemotherapy. In the alpelisib arm, pts must have a PIK3CA mutation in the tumor or ctDNA. Patients are administered oral palazestrant at escalating doses of 30, 60, and 120 mg qd in combination with the approved dose of oral ribociclib (600 mg qd; days 1–21 of 28-day cycle) or approved dose of oral alpelisib (300 mg qd) in a 3+3 design to identify the RP2D. The dose-expansion part will assess additional safety and PK parameters and the antitumor activity of palazestrant in combination with ribociclib or alpelisib (NCT05508906). Results: As of June 15, 2023, 10 pts have received 30 mg and 60 mg doses of palazestrant in combination with ribociclib (n=6) or alpelisib (n=4). No dose-limiting toxicities have been observed. After administration in the first two combination dose levels of 30 and 60 mg, palazestrant exposure was consistent with monotherapy administration; exposure data show no drug–drug interactions (DDI) when compared to published exposure parameters. Most reported treatment-emergent adverse events (TEAEs) were grade 1 or 2 and consistent with the known safety profiles of all 3 drugs. In the ribociclib arm, the TEAEs occurring in ≥2 pts included grade 1 nausea (n=4), grade 1 constipation (n=2), and neutropenia (grade 2, n=1; grade 3, n=3). For the 3 pts in the 30 mg palazestrant + alpelisib cohort, the only TEAE occurring in ≥2 pts was grade 1 diarrhea. One pt had grade 1 hyperglycemia. Conclusions: In this ongoing study, palazestrant in combination with ribociclib or alpelisib was well tolerated, and enrollment to the palazestrant 120 mg dose with ribociclib or alpelisib is ongoing. No new safety signals were observed for the 3 drugs, and no clinically significant DDIs were observed between palazestrant and ribociclib or alpelisib at the doses evaluated. Exposure of each drug was consistent with observed monotherapy exposure levels. Updated data will be presented. Citation Format: Virginia Borges, Carlos Alemany, Nancy Lin, Sara Nunnery, Cynthia Ma, Margaret Tonda, Morena Shaw, Arlene Chan. A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/or 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 PO4-04-12.