Negative Advanced Breast Cancer Research Articles

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.

Frequency of dose reductions of abemaciclib in metastatic and early-stage hormone positive, HER2 negative breast cancer.

e13099 Background: Abemaciclib is a CDK4/6 inhibitor which in combination with endocrine therapy (ET) improves progression-free survival in hormone receptor (HR)-positive, HER2 negative advanced breast cancer, as well as invasive disease free-survival in high-risk early-stage breast cancer. However, abemaciclib is associated with adverse events which may limit treatment adherence. In this single-center study, we describe real-world safety outcomes of early-stage and advanced HR-positive, HER2 negative breast cancer patients prescribed abemaciclib in conjunction with ET. Specifically, we analyze the frequency of adverse events and dose reductions (DR). Methods: We conducted a retrospective study of patients treated at Scripps Clinic between 1/1/2019-1/1/2023 with HR-positive, HER2 negative breast cancer prescribed abemaciclib with ET. Primary analyses were performed to discern clinical characteristic differences between groups. Categorical variables were summarized as frequencies and compared between arms by Chi-Square tests or Fisher’s Exact Tests. All continuous variables were summarized as means and standard deviations and compared between arms by T-Tests if normally distributed or summarized as medians and compared between arms by Mann-Whitney Tests otherwise. Statistical significance was set to 0.05 and all analyses were conducted in R. Results: A total of 77 patients were analyzed including 62% in the adjuvant setting and 38% in the metastatic setting. 51% of patients required DR. Patients requiring DR were older relative to those not requiring DR (59 vs 52 years of age, p=0.019). Those requiring DR remained on abemaciclib longer relative to those without DR (509 vs 350 days, p=0.057). Among those requiring DR, there were higher rates of grades II-IV diarrhea (p<0.001) and Loperamide use (p=0.083). Those requiring DR also had higher rates of neutropenia (54% vs 29%, p=0.027), abdominal cramping (39% vs 8%, p=0.002), nausea (39% vs 13%, p=0.011), and fatigue (51% vs 32%, p=0.079). Among 9 patients who expired on abemaciclib, 7 were in the metastatic setting and 1 was linked to an adverse effect from abemaciclib; none required DR (24% vs 0%, p<0.001). Finally, patients in the adjuvant setting remained on abemaciclib longer relative to those in the metastatic setting (526 vs 281 days, p=0.01). 95% of patients experienced symptom improvement with DR (p<0.001). Conclusions: Our study describes real-world safety outcomes of patients with HR-positive, HER2 negative breast cancer treated with abemaciclib and ET. More than half of patients required DR. Those who reduced their abemaciclib dose had improvement of clinical symptoms and remained on therapy longer. Based on our findings and given the importance of adherence in treatment efficacy, a lower starting dose of abemaciclib may be a more tolerable strategy, especially among older patients who required more DR in our study.

Cisplatin monotherapy as a treatment option for patients with HER-2–negative breast cancer facing hepatic visceral crisis or impending visceral crisis: A single-center cohort study.

e13057 Background: The international consensus guidelines, ESO-ESMO's fifth edition, characterize visceral crisis (VC) in advanced breast cancer (ABC) as a swift rise in bilirubin during disease progression. The guidelines also briefly address the impending VC (IVC) definition. Systemic treatment data for hepatic VC/IVC are scarce and lacking in international guidelines regarding BC treatment. This study explores cisplatin monotherapy's safety and efficacy in HER2-negative BC patients with hepatic IVC/VC. Methods: In this retrospective cohort study conducted at a Reference Cancer Center in Southern Poland, data from HER2 negative ABC patients who underwent cisplatin monotherapy (60-80mg/m2, every 3-4 weeks) between 2016 and 2023 were examined. Hepatic VC followed ABC5 definition of rapid bilirubin elevation >1.5 times the upper limit of normal (ULN) due to diffuse liver metastases, in the absence of biliary tract obstruction or Gilbert's syndrome; IVC was characterized by rapid, symptomatic liver progression, a majority of liver involvement, with ALT or AST >2 x ULN, and significant increases in LDH, alkaline phosphatase, or GGTP. Results: The study included 33 female participants (24 hormonal positive) with a mean age of 53.8 years (range 34-77). Among them, 10 were identified with hepatic VC, and 23 with IVC. Median number of previous palliative systemic treatment lines was 2 (range: 0-5). The median progression-free survival was 1.87 months and the median overall survival was 2.67 months. Patients received median 1 cycle of cisplatin (1-6): 17 patients received only one cycle, 6 patients two cycles and 10 patients ≥three cycles. Using the Conditional Inference Trees algorithm allowed to assess that patients with performance status (PS) 0 or 1 (15 patients) had a 66.67% chance of achieving stable disease (SD) or partial regression (PR) as the best response, while patients with PS ≥2 (18 patients) had a 5.6% chance of achieving SD or PR as per Response Evaluation in Solid Tumors 1.1 Criteria (median time from cisplatin initiation to imaging studies 2.23 months). Eight patients experienced adverse events of grade ≥3, such as fatigue or nephrotoxicity leading to dose reduction in 5 cases and treatment discontinuation in 2. Conclusions: The differentiation between IVC and VC lacks precision. Due to the hepatotoxicity of BC-active drugs, specific recommendations for systemic treatment are lacking. Our study explored cisplatin's potential use, finding it to be a feasible choice in patients with PS ≤1 experiencing hepatic IVC/VC, regardless of liver function parameters. Almost one-third of our patients were administered treatment in the last 30 days of life, potentially adversely affecting their quality of life and causing unwarranted suffering and costs. Academic clinical trials should be organized to address this pressing medical gap.

Clinical characteristics, treatment patterns, and outcomes in adult patients with germline BRCA1/2-mutated, HER2-negative advanced breast cancer: a retrospective medical record review in the United States.

To examine clinical characteristics, real-world treatment patterns, and health outcomes among patients with germline BRCA1/2-mutated, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). A retrospective analysis was conducted using medical records from patients with HER2-negative ABC with BRCA1/2 mutation who received cytotoxic chemotherapy. Data were stratified into groups with triple-negative breast cancer (TNBC) or hormone receptor-positive (HR+)/HER2-negative diagnoses. Time-to-event outcomes (i.e., real-world progression-free survival [rwPFS] and overall survival [OS]) were calculated to summarize health outcomes. When diagnosed with ABC, most patients were younger than 60 years (mean age = 57.3 years), were white (76.4%), and had a family history of BRCA-related cancer (71.5%). A total of 305 patient records were examined; 194 patients (63.6%) had advanced TNBC, and 111 patients (36.4%) had HR+/HER2-negative ABC. Chemotherapy was primarily used as first-line treatment for both subgroups, but the TNBC subgroup received poly (ADP-ribose) polymerase (PARP) inhibitors at triple the rate as a second-line treatment and double the rate as a third-line treatment compared with the HR+/HER2-negative subgroup. Two-year OS rates were similar between the TNBC (73.9%) and the HR+/HER2-negative subgroups (77.0%), and anemia, nausea, and neutropenia were the most commonly reported toxicities across all treatments. Clinicians should consider the use of targeted agents such as PARP inhibitors in earlier lines of therapy for ABC given the growing evidence that PARP inhibitors may improve PFS compared with chemotherapy while potentially offering a more manageable toxicity profile and improved quality of life.

Abstract PO2-20-03: VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader. In the phase 2 portion (VERITAC) of a first-in-human phase 1/2 study (NCT04072952), vepdegestrant 200 mg once daily (QD) was well tolerated and had clinical activity in heavily pretreated patients with ER+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer and was selected as the recommended phase 3 dose (RP3D) for vepdegestrant monotherapy. A phase 1b cohort of the phase 1/2 study is evaluating the safety and clinical activity of vepdegestrant plus palbociclib in patients with ER+/HER2- breast cancer after prior endocrine-based therapy; prior cyclin-dependent kinase (CDK)4/6 inhibitor therapy was permitted. Preliminary results showed encouraging activity for the combination based on clinical benefit rate (CBR; rate of confirmed complete response, partial response, or stable disease ≥24 weeks); an increase in palbociclib exposure was observed relative to historical palbociclib pharmacokinetic data and was accompanied by a higher incidence of grade 3/4 neutropenia compared with prior palbociclib and endocrine therapy combination studies, which was managed by monitoring and standard palbociclib dose modifications. The global, randomized phase 3 VERITAC-3 study (NCT05909397) will compare the efficacy and safety of vepdegestrant plus palbociclib vs letrozole plus palbociclib as first-line treatment for patients with ER+/HER2- advanced breast cancer. An open-label study lead-in (SLI) will evaluate the safety and tolerability of vepdegestrant 200 mg QD plus 2 doses of palbociclib (100 mg QD and 75 mg QD) in patients with ER+/HER2- advanced breast cancer to select the RP3D of palbociclib for this combination. Trial Design: Approximately 50 and 1130 patients will be enrolled in the SLI and the phase 3 parts of the study, respectively. Eligible patients (aged ≥18 years) must have histologically or cytologically confirmed ER+/HER2- locoregionally recurrent or metastatic breast cancer, with no prior treatment in the advanced setting, and no prior treatment in any setting with CDK4/6 inhibitors, vepdegestrant, fulvestrant, elacestrant, or other investigational agents (including novel endocrine therapy, selective ER degraders, selective ER covalent antagonists, and complete ER antagonists). Patients with measurable disease per RECIST v1.1 or nonmeasurable bone-only disease are eligible. Patients with disease recurrence during or ≤12 months after completion of adjuvant endocrine therapy are excluded. For the SLI, patients are randomized 1:1 to receive vepdegestrant 200 mg QD in combination with palbociclib 100 mg QD or 75 mg QD and are treated in 28-day cycles with vepdegestrant given continuously and palbociclib given for 21 days followed by 7 days off treatment. The objective of the SLI is to identify the RP3D of palbociclib in combination with vepdegestrant, which will be determined through the primary outcome measures of incidence of grade 4 neutropenia, study drug dose reduction, and study drug discontinuation within the first 4 cycles of treatment. Secondary outcome measures include safety, antitumor activity (objective response rate, CBR, and duration of response), and plasma concentrations of study drugs. In the planned phase 3 portion of the trial, patients will be randomized to vepdegestrant plus palbociclib or letrozole plus palbociclib. The primary efficacy endpoint of the phase 3 portion is progression-free survival based on blinded independent central review. Enrollment began June 2023 and is ongoing. Citation Format: Seth Wander, Erika Hamilton, Mario Campone, Michael Danso, Sara Hurvitz, Hiroji Iwata, Colombe Chappey, Derek Yang, Julia Perkins Smith, Yuan Liu, Yuanyuan Zhang, Sibyl Anderson, Michelino de Laurentiis. VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced 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 PO2-20-03.

Abstract PO1-04-12: Palbociclib versus ribociclib in first-line treatment of patients with hormone-receptor positive HER2 negative advanced breast cancer – real world outcome data from the German registry platform OPAL

Abstract Introduction CDK4/6 inhibitors (CDKi) plus endocrine therapy (ET) are standard of care in first-line (1L) treatment of hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (ABC). In the pivotal trials the three CDK4/6i (palbociclib, ribociclib and abemaciclib) + ET showed similar progression-free survival (PFS) benefit over ET alone. However, other than ribociclib, palbociclib failed to demonstrate overall survival (OS) benefit. As patient (pts) characteristics differed between the trials, especially in the number of pts with treatment-free interval (TFI) of < 12 months after end of adjuvant ET, head-to-head comparisons of the CDKi are of clinical interest. Here we analyze the outcome of pts treated with palbociclib + ET or ribociclib + ET with real-world data from OPAL. Methods OPAL (NCT03417115) is a prospective observational, open, longitudinal multicenter cohort study (clinical registry) in Germany. Pts with ABC and early breast cancer can be recruited at start of their first systemic treatment. There are no treatment restrictions. Sites from all medical sectors can participate in OPAL (medical and gynecologic oncologists from outpatient centers and hospitals). Details on all (sequential) treatments, patient and tumor characteristics, biomarker testing, clinical and patient-reported outcomes are collected. Follow-Up is until death or up to 5 years. Between 01/2018 and 07/2021 1049 pts with HR+ HER2- ABC were recruited by 143 sites. Database cut was on 31/08/2022. 384 pts received palbociclib + ET and 231 pts received ribociclib + ET as 1L treatment. All endocrine combination partners including switch of ET during first line therapy was allowed, whereas switch of CDK4/6i (n=25) were excluded. PFS in registries can differ from PFS in clinical trials, since the RECIST criteria are usually not applied in routine care. PFS in registries represents the time to clinically relevant progression in routine care. PFS and OS were estimated using the Kaplan-Meier method. To adjust for confounding, inverse probability of treatment weighting (IPTW) by propensity score analysis was used to compare PFS and OS between 1L palbociclib+ET and ribociclib+ET. IPTW was performed for the following variables: age, menopausal status, ECOG, any comorbidity, Charlson comorbidity index, metastatic stage, type of metastasis, number of metastatic sites, estrogen-/progesterone status, IHC status, previous chemo-/endocrine therapy, kind of endocrine combination partner, disease-free interval, and treatment-free interval. Results From 2018 to 2021, the proportion of CDK4/6i increased from 68% to 86% in 1L of HR+HER2- ABC. Overall, palbociclib was used in 44% and ribociclib in 26% of all first-line treatments in OPAL. Median age of pts receiving palbociclib/ribociclib was 66/68 years and for 77/81% of pts at least one comorbidity was documented. 37/35% of pts already had metastasis at diagnosis (M1) and 25/26% of pts had a TFI < 12 months. After IPTW, the two treatment groups were comparable for all tested characteristics. 42/46% of patients had a progression (palbociclib/ribociclib group). IPTW-adjusted median PFS was 25.1 months (95% Confidence interval (CI) 20.1 – 30.1) for the palbociclib and 27.0 months (95%-CI 21.1 – 31.6) for the ribociclib group. Hazard ratio was 0.91 (0.71 – 1.17) for palbociclib versus ribociclib. 26/29% of patients had an OS event (palbociclib/ribociclib group). IPTW-adjusted median OS was 36.7 months (95%-CI 33.0 – NA) for the palbociclib and 36.6 months (95%-CI 33.1 – NA) for the ribociclib group. Hazard ratio was 0.95 (0.69 - 1.30) for palbociclib versus ribociclib. Conclusions This analysis of real word data in the OPAL registry platform showed similar PFS and OS for palbociclib + ET compared to ribociclib + ET, when adjusted for a wide range of potential confounding variables. Further analyses will investigate whether one drug showed favorable results in certain subgroups of pts. Citation Format: Marc Thill, Mark-Oliver Zahn, Anja Welt, Arnd Nusch, Matthias Zaiss, Kathrin Engelken, Gabriele Kaltenecker, Kai Ringwald, Katja Gratzke, Lisa Kruggel, Martina Jänicke, Holger Schulz, Christoph Losem, Volker Hagen, Roland Fricker, Elmar Stickeler, Nadia Harbeck, Achim Wöckel, Thomas Decker. Palbociclib versus ribociclib in first-line treatment of patients with hormone-receptor positive HER2 negative advanced breast cancer – real world outcome data from the German registry platform OPAL [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-12.

Abstract PO3-05-08: Updated results from VERITAC evaluating vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader with activity toward wild-type and mutant ER. The phase 2 expansion (VERITAC) of a phase 1/2 study (NCT04072952) tested 2 vepdegestrant doses (200 mg once daily [QD] and 500 mg QD) in heavily pretreated patients with ER+/HER2- advanced breast cancer. Vepdegestrant 200 mg QD was selected as the phase 3 monotherapy dose based on comparable efficacy and favorable tolerability vs 500 mg QD and robust ER degradation (data cutoff: Jun 6, 2022). We present updated data for the vepdegestrant 200 mg QD cohort after 12 additional months of follow-up. Methods: Vepdegestrant was administered to patients with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 cyclin-dependent kinase (CDK)4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint was clinical benefit rate (CBR; rate of confirmed complete response, partial response, or stable disease ≥24 weeks). Results: As of Jun 6, 2023, 35 patients received vepdegestrant 200 mg QD; 34 (97.1%) were female and median age was 63 y (range: 42–79). Patients had received a median of 4 prior regimens (range: 1–9) in all settings and 3 prior regimens (range: 0–7) in the metastatic setting; 100% had prior CDK4/6 inhibitors, 88.6% had prior aromatase inhibitors, 74.3% had prior fulvestrant, and 74.3% had prior chemotherapy (45.7% in metastatic setting). CBR with vepdegestrant 200 mg QD was 37.1% (95% CI: 21.5–55.1) in all evaluable patients (n=35) and the objective response rate was 8.3% (95% CI: 1.0–27.0) among 24 patients with measurable disease at baseline. Median progression-free survival in all evaluable patients was 3.5 months (95% CI: 1.8–8.2). As of the data cutoff date, 14 patients in the 200 mg QD cohort received treatment for ≥24 weeks (4 for ≥48 weeks) with 1 patient ongoing. No patients required a dose reduction due to a treatment-emergent adverse event (TEAE); 2 (5.7%) patients had a TEAE that led to vepdegestrant discontinuation (grade 3 QT prolongation and grade 3 anemia). The most common treatment-related adverse events (≥10%) were fatigue (43%), hot flush (20%), nausea (17%), arthralgia (11%), increased aspartate aminotransferase (11%), and increased blood alkaline phosphatase (11%); all were grade 1/2. Substantial on-treatment decreases in mutant ESR1 circulating tumor DNA levels were observed with vepdegestrant 200 mg QD and sustained for multiple treatment cycles. Conclusions: With 12 months of additional follow-up from the first data report, durable clinical activity with vepdegestrant 200 mg QD was seen in heavily pretreated patients with ER+/HER2- advanced breast cancer, in addition to sustained reduction in circulating mutant ESR1 tumor DNA levels. Vepdegestrant 200 mg QD continued to show a favorable safety profile. The ongoing global, randomized phase 3 VERITAC-2 study (NCT05654623) is evaluating vepdegestrant 200 mg QD vs intramuscular fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination CDK4/6 inhibitor therapy and endocrine therapy. Citation Format: Sara Hurvitz, Anne Schott, Cynthia Ma, Rita Nanda, George Zahrah, Natasha Hunter, Antoinette Tan, Melinda Telli, Jesus Anampa Mesias, Rinath Jeselsohn, Pamela Munster, Eric Zhi, Elizabeth Duperret, Cecile Mather, Erika Hamilton, Hyo Han. Updated results from VERITAC evaluating vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced 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 PO3-05-08.

Abstract PO3-05-11: Enhancing the interpretation of real-world quality of life (QoL) in patients (pts) with hormone receptor positive human epidermal growth factor 2 negative (HR+/HER2−) advanced breast cancer (ABC) enrolled in the POLARIS trial

Abstract Background POLARIS is a prospective, observational real-world study of pts with HR+/HER2− ABC receiving palbociclib in routine clinical practice. We have previously shown that palbociclib treatment did not have any significant adverse impact on pt QoL when assessed by the EORTC-QLQ-C30 questionnaire,1 consistent with published clinical trial findings. Now, to enhance interpretation, we sought to characterize EORTC scores (using updated POLARIS data) into terms that are meaningful to pts, physicians, and other stakeholders, using a similar approach to established clinical problem threshold methodology.2 Methods EORTC data were collected at baseline (BL), monthly for the first 3 months, and every 3 months thereafter until palbociclib discontinuation. Response options for each EORTC question (ordinal scale from 1=very poor to 7=excellent) were grouped into “favorable” (taking a conservative approach of using only responses 5, 6 or 7) and “less favorable” (response of ≤4) for the two items on global health status/QoL. The proportion of pts with favorable or less favorable response was compared between subgroups (line of therapy, age, race, bone metastases, visceral metastases, and dose modification) at timepoints BL, month 6, 12, and 18 using Fisher’s exact test. Results Between January 2017 and December 2018, 1285 pts were enrolled, of whom 1250 received at least one dose of palbociclib and subsequently analyzed as part of the final data cut of 09 Jan 2023. EORTC Q29 ‒ Overall Health completion rates were 1167/1250 (93.4%) at baseline, 732/1250 (58.6%) at month 6, 484/1250 (38.7%) at month 12, and 353/1250 (28.2%) at month 18 (Table). The proportion of pts with a favorable response for EORTC Q29 was consistently higher than with a not favorable response (BL, 56.1% vs 43.9%; month 6, 69.3% vs 30.7%; month 12, 68.6% vs 31.4%; and month 18, 70.0% vs 30.0%; Table). When analyzed by subgroup, no significant differences were observed in the proportion of pts with a favorable (to less favorable) response for any subgroup covariate, except for age at BL; however, this significance was not observed at month 6, 12 or 18 (Table). Similar results were observed for EORTC Q30 – Overall QoL (data not shown). Conclusions The proportion of pts indicating a favorable response in the EORTC questionnaire Overall Health and Overall QoL questions increased or were maintained in pts with HR+/HER2− ABC treated with palbociclib from BL through to month 18 across overall and all subgroups. It is important to note that these data are conditional on the pts who responded to the questions, whose numbers diminished over time. XX XX Citation Format: Gabrielle Rocque, Joanne Blum, Yan Ji, Timothy Pluard, John Migas, Shailendra Lakhanpal, Erin Jepsen, Eric Gauthier, Yao Wang, Monica Montelongo, Joseph C. Cappelleri, Connie Chen, Meghan Karuturi, Debu Tripathy. Enhancing the interpretation of real-world quality of life (QoL) in patients (pts) with hormone receptor positive human epidermal growth factor 2 negative (HR+/HER2−) advanced breast cancer (ABC) enrolled in the POLARIS trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-11.

Abstract PS15-03: Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: phase 1b cohort

Abstract Background: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader. In a phase 1/2 study (NCT04072952), vepdegestrant monotherapy had a favorable safety profile and encouraging clinical activity, and showed robust ER degradation. The phase 1b cohort of this study is evaluating vepdegestrant in combination with the cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (palbo). In xenograft models, vepdegestrant plus palbo showed substantially greater tumor growth inhibition vs fulvestrant plus palbo, supporting investigation in patients with breast cancer. Methods: Eligible patients for the phase 1b combination cohort had ER+/HER2- locally advanced/metastatic breast cancer and had received ≥1 prior endocrine therapy and ≤2 chemotherapy regimens for advanced disease; prior CDK4/6 inhibitor treatment was permitted. Vepdegestrant was given orally once daily (QD) continuously at doses of 180 mg (n=2), 200 mg (n=21), 400 mg (n=3), or 500 mg (n=20); palbo 125 mg was given orally QD for 21 days followed by 7 days off treatment in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) in the first cycle and safety (adverse events [AEs] and laboratory abnormalities). Enrollment in these 4 dose levels is complete; we report data as of June 6, 2023. Results: Across 46 patients in the phase 1b cohort, 45 (97.8%) patients were female with a median age of 62.0 y (range: 29–78). Patients had received a median of 4 prior therapies (range: 1–11) in any setting, including 87.0% prior CDK4/6 inhibitors (78.3% prior palbo), 80.4% prior fulvestrant, and 76.1% prior chemotherapy (45.7% in the metastatic setting). There were no DLTs. Treatment-emergent AEs (TEAEs) leading to dose reductions or discontinuation of vepdegestrant occurred in 5 and 4 patients, respectively. TEAEs leading to dose reductions or discontinuation of palbo occurred in 34 and 8 patients, respectively. Grade 3/4 treatment-related AEs (TRAEs) to either vepdegestrant or palbo in ≥10% of patients were neutropenia (89.1%), decreased white blood cell count (15.2%), and decreased platelet count (10.9%); there were no grade 5 TRAEs and no patients had febrile neutropenia. The clinical benefit rate (rate of confirmed complete response, partial response, or stable disease ≥24 wks) in patients treated with vepdegestrant plus palbo was 63.0% (95% CI: 47.5–76.8). The objective response rate in evaluable patients with measurable disease at baseline (n=31) was 41.9% (95% CI: 24.5–60.9). Pharmacokinetics (PK) showed dose-dependent exposure for vepdegestrant, consistent with data for vepdegestrant administered as monotherapy; palbo exposure was similar across dose levels of vepdegestrant and modestly higher compared with historical palbo PK data. Circulating tumor DNA levels were evaluated in patients who received vepdegestrant 200 mg QD plus palbo and demonstrated substantial and sustained decreases in ESR1 mutant allele fraction across multiple treatment cycles. Conclusions: The combination of vepdegestrant plus palbo showed promising clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer who had received extensive prior treatment. The safety profile of vepdegestrant plus palbo was generally consistent with the known safety profiles of the 2 agents except for an increased occurrence of grade 3/4 neutropenia, which was readily managed with laboratory monitoring and dose reductions of palbo. There is an ongoing study lead-in to the global VERITAC-3 study (NCT05909397) that is evaluating 2 doses of palbo (100 mg and 75 mg) in combination with vepdegestrant 200 mg QD to determine the recommended phase 3 combination to compare with letrozole plus palbo as first-line treatment for ER+/HER2- advanced breast cancer. Citation Format: Erika Hamilton, Rinath Jeselsohn, Sara Hurvitz, Dejan Juric, Hyo Han, Melinda Telli, George Zahrah, Rita Nanda, Yuanyuan Zhang, Weiwei Tan, Elizabeth Duperret, Eric Zhi, Cecile Mather, Anne Schott. Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: phase 1b cohort [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 PS15-03.

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.

Abstract PO2-05-06: Palbociclib in advanced hormone receptor positive breast cancer: A real world study in South America

Abstract BACKGROUND: First-line combined endocrine therapy is the standard of care for hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). Palbociclib, in combination with aromatase inhibitors or fulvestrant, is a treatment option for HR+/HER2-negative ABC patients. We aimed to analyze the real-world experience of palbociclib in this setting in South America. METHODS: Real-world study collecting sociodemographic and clinical data from women with ABC treated with palbociclib in centers from Chile (n = 40), Perú (n = 61), and Ecuador (n = 10). Treatment efficacy and safety were analyzed. RESULTS: The median age was 54 years (range: 28 – 83), and 81.1% of women had received previous treatment: adjuvant therapy (20.0%), ABC treatment (31.1%), or both (48.9%). The median duration of palbociclib treatment was 14 months (range: 1 – 57), with differences among countries (longer in Perú; p = 0.009). The dose was reduced in 28.2% of women and only 6.5% returned to the previous one. Most women (97.3%) received combined endocrine therapy, letrozole (48.1%) or fulvestrant (44.4%), with differences between countries (p < 0.001). Palbociclib was usually the first-line therapy in Ecuador (60.0%) and Perú (80.3%), and the third line in Chile (37.5%). Considering all women, it was the first- or second-line therapy for 52.3% and 20.7% of them, respectively. The overall response rate was 34.2% and progressive disease was significantly lower in patients receiving first-line palbociclib (25.9 vs. 66.0%, p < 0.001). The disease-free survival was longer than 12 months in 67.2% of patients treated with first-line palbociclib. Regarding safety, 38.7% of women had any relevant adverse event (AE) during the treatment, most frequently neutropenia (39.5%), diarrhea (9.3%), and elevated transaminase levels (4.7%). The number of patients who developed any relevant AE was lower among the first-line treated patients (19.0% vs. 60.4%, p< 0.001). CONCLUSION: The study reflects differences among countries in routine palbociclib use. But considering all data, palbociclib has confirmed its efficacy and safety, supporting its use in HR+/HER2-negative patients, especially as a first-line therapy. Citation Format: Cesar SÁNCHEZ, Suraj Samtani, Henry Gómez, Silvia Falcon-Lizaraso, René Muñoz, Tannia Soria. Palbociclib in advanced hormone receptor positive breast cancer: A real world study in South America [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 PO2-05-06.

Abstract PO1-19-12: VERITAC-2: a phase 3 study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds to and degrades wild-type ER and clinically relevant mutants. Vepdegestrant directly recruits the ubiquitin-proteasome system to degrade ER, whereas selective ER degraders (SERDs) indirectly cause ER degradation. In a first-in-human phase 1/2 study (NCT04072952), vepdegestrant monotherapy was well tolerated and showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The phase 3 monotherapy dose (200 mg once daily [QD]) was chosen due to comparable efficacy and favorable tolerability relative to 500 mg QD and robust ER degradation in paired tumor biopsies. The global, randomized phase 3 VERITAC-2 study (NCT05654623) will compare efficacy and safety of vepdegestrant vs the SERD fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy and endocrine therapy (ET). Trial design: Eligible patients (aged ≥18 years) have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation; 1 prior line of combination CDK4/6 inhibitor therapy and ET; ≤1 additional line of ET; most recent ET given for ≥6 months before disease progression; and radiological disease progression during or after the last line of therapy. Prior chemotherapy in the locally advanced or metastatic setting and prior fulvestrant are not permitted. Patients (N≈560) are randomized 1:1 to receive vepdegestrant 200 mg orally QD continuously or fulvestrant intramuscularly on days 1 and 15 in the first 28-day cycle and on day 1 in subsequent cycles; patients are stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint, progression-free survival, will be assessed by blinded independent central review in the intention-to-treat population and the ESR1 mutation subpopulation. Secondary outcome measures include overall survival, antitumor activity (objective response rate, duration of response, and clinical benefit rate), safety, and quality of life assessments. Citation Format: Mario Campone, Cynthia Ma, Michelino de Laurentiis, Hiroji Iwata, Sara Hurvitz, Seth Wander, Michael Danso, Dongrui Lu, Julia Perkins Smith, Yuan Liu, Lana Tran, Sibyl Anderson, Erika Hamilton. VERITAC-2: a phase 3 study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced 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 PO1-19-12.

Abstract PO4-05-01: Clinical outcomes of breast cancer and its relationship with access to health care in Brazil: prospective study in HER2 negative/hormone receptor positive metastatic disease - BREAST (BRazilian outcomE for metAStatic breasT cancer)

Abstract Background: Cancer survival is one of the key measures of the effectiveness of cancer services and captures whether people have access to effective treatment. The survival rate of breast cancer in low and middle-income countries is notably different from high-income countries; this disparity in survival reflects limited access to first-line systemic therapy for advanced and metastatic tumors. Recent studies have shown benefit of combining cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6) with endocrine therapies in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer. However, in Brazil, the population has limited access to these drugs, mainly in the public health service. The commercialization of CDK 4/6 inhibitors was only released in the national territory in 2018, but until nowadays it is not accessible for most patients. Objective: The aim of this project is to assess whether patients without private health insurance may experience worse outcomes compared to women with private insurance, primarily due to limited access to a specific class of medication during their treatments. The study seeks to gain insights into the clinical outcomes of patients with HR+ HER2- metastatic breast cancer based on their access to health insurance coverage within a real-world setting. Methods: Multicenter, prospective observational study, with patients divided into two groups: one with patients from the public health system and the second with patients treated at the private service. Whereas that the hazard ratio for the primary outcome in the private system compared to the public health system is like that observed in the PALOMA study (0.58), and that event rates after 18 months of follow-up are also similar (approximately 45% and 35%), then a total of 298 patients will provide the study power of 80%, significance level of 5%. This calculation considers a sample size ratio of 1 patient in the private health system for every 2 patients in the public health system. The inclusion criteria specify women with HR+ HER2- metastatic breast cancer who initiated first-line treatment from 2019. Patients will be followed for 24 months and stratified based on the use or non-use of CDK 4/6 inhibitors. The study was approved by the local ethics committee and registered with Clinical Trials (NCT05559528). Results: A total of 300 patients were evaluated, with 199 (66.3%) in the public health system and 101 (33.7%) in the private service. The mean age was 58 years, and 76.2% were postmenopausal. In terms of metastasis site, 84.7% had non-visceral disease, predominantly with bone metastasis (75.7%), which is an expected characteristic of this type of tumor. The use of CDK 4/6 inhibitors at any point in the treatment of metastatic disease was 7.0% in the public health system versus 90.1% in the private service. As a preliminary outcome, with a median time since the diagnosis of metastatic breast cancer of 22.8 months, a mortality rate of 10% was identified in the public health system group compared to 5% in the private service group. Conclusions: The results of our study highlight the disparity in the treatment of metastatic breast cancer among patients in relation to access to healthcare. Patients dependent on the public health system experience higher mortality rates. These findings are crucial for supporting discussions on improving local policies regarding access to medications that have been proven to enhance the prognosis of these patients. Citation Format: Vanessa Sanvido, Lucíola Pontes, Rachel Machado, Marina Nicola, Jackeline Gomes, Letícia Barbante, Nanci Valeis, Alexandre Cavalcanti, Afonso Nazário. Clinical outcomes of breast cancer and its relationship with access to health care in Brazil: prospective study in HER2 negative/hormone receptor positive metastatic disease - BREAST (BRazilian outcomE for 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 PO4-05-01.

Abstract PO4-15-06: Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium analysis

Abstract Background: Limited data are available to determine the best therapeutic strategy for hormone-receptor positive (HR+) HER2 negative (HER2-) advanced breast cancer (ABC) after progression on cyclin dependent kinase 4/6 inhibitors (CDK4/6i). The aim of this study was to characterize the genomic and prognostic profile of patients (pts) that experienced disease progression after first-line therapy with a CDK4/6i. Methods: The study retrospectively analyzed a multi-institutional cohort of 75 patients (pts) with HR+/HER2- ABC after experiencing progression on first-line endocrine therapy (ET) with CDK4/6i and characterized by circulating tumor DNA (ctDNA) next-generation sequencing (Guardant 360). Oncogenic pathways (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, p53, cell cycle, notch, and PI3K) were defined based on previous research (Sanchez-Vega et al. Cell, 2018). Associations across single nucleotide variations (SNVs), copy number variations (CNVs), and pathway classification were tested by uni- and multivariable logistic regression with respect to a CDK4/6i naïve group comprising 247 patients with HR+/HER2- ABC (control). Prognosis was analyzed through Cox regression for overall survival (OS). Result: Our study cohort included 75 ABC pts who experienced progression after first line CDK4/6i plus ET: 43 pts (57.3%) were treated with ET while 31 (41.3%) with a non-ET- second line therapy. The most common histology was invasive ductal carcinoma (70.6%), 37.3% of pts were negative for progesterone expression and 26.7% had de novo metastatic disease. The PI3K (33.3%), p53 (28%) and ER (25.3%) pathways were the most mutated in the CDK4/6i-treated cohort. Comparing our population with a CDK4/6i naïve cohort (N=247), the multivariate analysis showed a higher prevalence in the study cohort of SNVs mutations in: i) ESR1 gene [Odds ratio (OR) 2.93; p=0.005]; ii) cell-cycle pathway (OR 4.24; p=0.033); iii) ER pathway (OR 2.04; p= 0.034). Moreover, in the study cohort a numerical but not significant increase of RB1 SNVs was also observed. Multivariable analyses of the 43 pts that received ET second line therapy showed a negative prognostic impact with TP53 SNVs in both progression-free survival (PFS) [Hazard ratio (HR) = 3.34; 95% CI: 1.15-9.66, p=0.026] and OS (HR = 3.85; 95% CI: 1.52-9.77, p=0.005). The prognostic role of p53 pathway mutations was also confirmed for both PFS (HR = 4.71, 95% CI: 1.64-13.50; p=0.004) and OS (HR = 3.25; 95% CI: 1.27-8.3; p=0.014). The potential interaction between the prognostic oncogenic pathways and the outcome was investigated according to the treatment strategy (ET vs non-ET). A consistent impact was observed across the above prognostic pathways both for PFS and OS. A numerical difference was observed in terms of PFS in pts with p53 pathway mutations that underwent non-ET second line. Conclusions: The genomic landscape of progressive disease after CDK4/6i exposure is significantly different from the genomic alterations detectable in treatment-naïve pts, which could potential impact future treatment strategies for patients with disease progression after adjuvant CDK4/6i exposure. Our data suggest that the choice of second-line treatment could potentially be guided by the identification of actionable mutation by ctDNA, although further prospective studies are needed to validate the clinical utility of this approach. Citation Format: Letizia Pontolillo, Carolina Reduzzi, Andrew Davis, Lorenzo Gerratana, Arielle Medford, Katherine Clifton, Whitney L. Hensing, Marko Velimirovic, Ami N. Shah, Jeannine Donahue, Laura Munoz Arcos, Charles S. Dai, Jennifer Keenan, Amir Behdad, William Gradishar, Emilio Bria, Cynthia Ma, Aditya Bardia, Massimo Cristofanilli. Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium analysis [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 PO4-15-06.

Abstract PO2-20-04: TACTIVE-U: phase 1b/2 umbrella study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER–positive advanced or metastatic breast cancer

Abstract Background: Vepdegestrant (ARV-471), an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in the first-in-human phase 1/2 study in heavily pretreated patients with ER+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer (NCT04072952). The cyclin-dependent kinase (CDK)4/6 inhibitors abemaciclib and ribociclib are approved in combination with an aromatase inhibitor or fulvestrant, or as monotherapy (abemaciclib), for ER+/HER2- advanced or metastatic breast cancer. In preclinical studies, vepdegestrant combined with abemaciclib or ribociclib showed evidence of synergistic interactions in ER+ breast cancer cells and greater tumor growth inhibition in a xenograft breast cancer model compared with fulvestrant in combination with these agents. Inhibitors targeting different CDKs, such as samuraciclib (oral CDK7 inhibitor), are in clinical development for solid tumors. The open-label, phase 1b/2 TACTIVE-U umbrella study will evaluate the safety, efficacy, and pharmacokinetics of vepdegestrant in combination with other anticancer treatments in patients with ER+ advanced or metastatic breast cancer. Vepdegestrant is being evaluated in combination with abemaciclib (sub-study A; NCT05548127), ribociclib (sub-study B; NCT05573555), and samuraciclib (sub-study C). Trial Design: Patients eligible for current sub-studies of TACTIVE-U are aged ≥18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection, and have received prior therapy for advanced or metastatic disease, including any CDK4/6 inhibitor–based regimen in any setting. In each sub-study, patients will receive vepdegestrant orally once daily (QD) continuously in a dose escalation/de-escalation approach. Abemaciclib will be given orally twice daily continuously in sub-study A, ribociclib will be given orally QD for 21 days followed by 7 days off treatment in sub-study B, and samuraciclib will be given orally QD continuously in sub-study C. For all sub-studies, the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of vepdegestrant in combination with the other anticancer treatment. Secondary endpoints of phase 1b are antitumor activity (objective response, clinical benefit rate [CBR], and duration of response [DOR]), progression-free survival (PFS), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drugs. The phase 2 portion of each sub-study will further evaluate the antitumor activity of the combinations; the primary endpoint is objective response and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Future combination sub-studies will be included in TACTIVE-U. Citation Format: Claudine Isaacs, Katarzyna Jerzak, John Hilton, José Luiz Miranda Guimarães, Rachel Layman, Dongrui Lu, Gary Mo, Anna Maria Calella, Olga Valota, Sibyl Anderson, Cynthia Ma. TACTIVE-U: phase 1b/2 umbrella study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER–positive advanced 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 PO2-20-04.

Abstract PO3-19-12: Evaluating the impact of ePRO-based follow-up system (Pink Ribbon Diary) on quality of life and treatment adherence in patients with breast cancer receiving CDK4/6 inhibitors: a single center, randomized controlled study (JPRO-B)

Abstract Background: Treatment-related toxicities (TRT) may decrease patient’s quality of life (QOL) and may result in a decrease of adherence to the therapy. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), such as palbociclib (PAL) and abemaciclib (ABM) improved patients’ outcomes with estrogen receptor-positive (ER+) HER2 negative (HER2-) advanced breast cancer (ABC), however, majority of patients who undergo CDK4/6i therapy experience ≥ Grade 2 TRTs, such as hematological abnormalities, gastrointestinal disorders or general fatigue. While prompt management of those TRTs is mandatory to prevent patients from discontinuing the therapy, real-time monitoring of TRTs has been warranted. Recently, efforts have been made to monitor symptoms using electronic patient-reported outcome (ePRO) to detect side effects as early as possible and to provide timely support. However, the efficacy of ePRO in daily clinical practice for those receiving CDK4/6is is still unclear. In addition, the researches in the field of ePRO to date have only focused on drugs administered intravenously in hospitals, where patients’ adherence has no clinical importance. Study design and eligibility criteria: This randomized, open-label, controlled phase 2 trial is designed to assess the efficacy of a new proprietary ePRO system, the Pink Ribbon Diary (PRD), compared with placebo (usual care without the ePRO system) in breast cancer patients with ER+HER2-ABC receiving oral CDK4/6i-based therapy aged ≥ 20 years. All eligible patients who complete training on how to use ePRO system are randomly allocated to either arm A using ePRO system or arm B receiving usual care (1:1). Participants in the arm A are required to record medication taken and physical condition every day for 3 months, and report adverse events using PRO-CTCAETM once a week. Patients in the arm B are also asked to answer to questions concerning adverse events using PRO-CTCAETM at monthly hospital visit for 3 months. All participants are asked to respond to the EORTC QLQ-C30 at their monthly visit and a questionnaire survey on adherence before the study and after completion of the study. Participants in the arm A and healthcare providers, will answer the questionnaire about the feeling of using the PRD. Primary endpoint is the change in global health status/QOL (EORTC QLQ-C30) at 3 months from baseline. Secondary endpoints are RDI (relative dose intensity), other domains of EORTC QLQ-C30, number of days missed medication, PDC (proportion of days covered), survey of medication compliance awareness using MMAS-8 (Morisky Medication Adherence Scale), questionnaire on use of PRD, and comparison between two groups of occurrence of adverse events and incidence of missed medication. Study objective: To assess the clinical efficacy of PRD in patients with ER+HER2-ABC undergoing CDK4/6i-based therapy. Statistical methods: For analysis of QOL, the primary endpoint, the differences in global health status/QOL (EORTC QLQ-C30) before and after the study will be compared between the two groups using the t-test. Present accrual and target accrual: The study was approved by institutional review board in December 2022, and is open for enrollment. The target sample size is 70. The study is on-going and 22 patients have been accrued to date. Trial registration numbers: Japan Registry of Clinical Trials (jRCT) jRCT1030220626 (https://jrct.niph.go.jp/re/reports/detail/30182). Citation Format: Rie Ozeki, Hideo Shimizu, Kotaro Iijima, Misato Okazaki, Junichiro Watanabe, Mitsue Saito. Evaluating the impact of ePRO-based follow-up system (Pink Ribbon Diary) on quality of life and treatment adherence in patients with breast cancer receiving CDK4/6 inhibitors: a single center, randomized controlled study (JPRO-B) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-12.

Abstract PS17-03: Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant HR positive/HER2-negative advanced breast cancer: exploratory analysis of PFS by AKT pathway gene from the Phase 3 CAPItello-291 trial

Abstract Background: In the Phase 3 randomized, double-blind CAPItello-291 trial, the addition of capivasertib (a potent, selective pan-AKT inhibitor) to fulvestrant in patients with aromatase inhibitor-resistant, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (HER2− defined as immunohistochemistry [IHC] 0, or 1-positive or IHC2-positive/in situ hybridization-negative) advanced breast cancer (ABC) significantly improved progression-free survival (PFS) versus placebo + fulvestrant (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.51–0.71; p< 0.001). PFS benefit was observed in patients with detectable AKT pathway alterations (HR 0.50, 95% CI 0.38–0.65; p< 0.001) and without (0.70; 95% CI; 0.56–0.88). Here, we report PFS by gene within the AKT pathway-altered population. Methods: Patients were randomized 1:1 to receive fulvestrant (500 mg intramuscularly on days 1 and 15 of cycle 1, and day 1 of each subsequent 28-day cycle) with either placebo or capivasertib (400 mg twice daily; 4 days on, 3 days off). AKT pathway-alteration status (at least one qualifying alteration in the genes PIK3CA, AKT1, or PTEN) was determined post-randomization, using next-generation sequencing in tumor tissue. HRs were calculated using Cox proportional hazards models. Data cut-off Aug 15, 2022. Results: Of the 708 patients randomized to treatment, 289 (41%) had AKT pathway-altered tumors (capivasertib-fulvestrant n=155; placebo-fulvestrant n=134). In the AKT pathway-altered population, 43% had liver metastases and 40% primary endocrine therapy resistance. Prior therapy for advanced disease included: 89% of patients with ≥1 line of prior treatment, 71% with a prior cyclin-dependent kinase 4 and 6 inhibitor, and 18% with prior chemotherapy. Baseline characteristics were broadly balanced between treatment groups. Most patients with an AKT pathway-altered tumor had only one detectable alteration (272/289, 94%). Thirteen patients (capivasertib-fulvestrant n=4; placebo-fulvestrant n=9) had co-occurring PIK3CA and PTEN alterations, and four patients (capivasertib-fulvestrant n=2; placebo-fulvestrant n=2) had co-occurring PIK3CA and AKT1 alterations. Consistent PFS benefit of capivasertib-fulvestrant over placebo-fulvestrant was observed across all alterations (Table). The safety profile of capivasertib-fulvestrant in the AKT pathway-altered population was consistent with the overall population. Conclusions: Compared with fulvestrant alone, the addition of capivasertib to fulvestrant provided a consistent PFS benefit across alterations in all three key genes within the AKT pathway in patients with HR-positive/HER2-negative ABC. https://clinicaltrials.gov/: NCT04305496 Funding: CAPItello-291 is sponsored by AstraZeneca. Editorial acknowledgment: AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). Table. Citation Format: Sacha Howell, Hope Rugo, Mafalda Oliveira, Florence Dalenc, Javier Cortés, Henry Gómez, Xichun Hu, Komal Jhaveri, Petr Krivorotko, Sibylle Loibl, Serafin Morales Murillo, Meena Okera, Yeon Park, Joo Hyuk Sohn, Masakazu Toi, Eriko Tokunaga, Lyudmila Zhukova, Andrew Lloyd, Elza de Bruin, Coumaran Egile, Celina D’Cruz, Nicholas Turner. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant HR positive/HER2-negative advanced breast cancer: exploratory analysis of PFS by AKT pathway gene from the Phase 3 CAPItello-291 trial [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 PS17-03.

Abstract PO2-05-07: Which treatment is done in patients with metastatic breast cancer who received a prior treatment with CDK4/6 inhibitors? A real-world experience in a single italian Institution

Abstract Patients with HR positive (HR+) and c-erb-b2 negative (HER2-) advanced breast cancer are treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with hormone therapy (HT). At the time of disease progression with these treatments, no established guidelines are defined for the subsequent therapeutic options.Treatment options after progression can be different, in terms of use of chemotherapy or ET alone, or the combination of the two, or of other biological agents (such as everolimus) or the HT combined with other therapies. We aimed to verify in our Institute (IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy) how HR+ mBC patients are treated after having received a treatment with HT plus CDK4/6 inhibitors (ribociclib, palbociclib, abemaciclib). 105 mBC patients, 32 of whom were treated with CD4/6 inhibitors plus letrozole and 73 treated with CDK4/6 inhibitors and fulvestrant were included in the study. 83 were treated with palbociclib, 16 with ribociclib and 6 with abemaciclib. The median age was 65 years (range 40-86), 58 were younger than 65 years. 90 were in postmenopausal status. On the total 105 patients, 46 (43.8%) were treated with a single chemotherapy regimen while 25 (23.8%) with a combined schedule of chemotherapies (Table 1). Only 9 (8.6%) have been treated with HT alone. 22 (20.95%) patients received combined treatments with ET or chemotherapy+targeted therapy or chemotherapy +immune checkpoint inhibitor. 1 (0.95%) patients was treated with a triplet chemotherapy regimen (cyclophosphamide+capecitabine +vinorelbine), 2 (1.9%) for whom the re-biopsy of the tumor resulted HER2 + were treated with taxol +pertuzumab +trastuzumab. 82/105 (78%) patients performed more lines of therapies after CDK4/6 inhibitors. In conclusion, patients with mBC were treated heterogeneously. The major part of them have been treated with chemotherapy alone or with combination of more chemotherapies. The evaluation of the patient response in relation to the different therapies is still ongoing as well as the effect of all the other therapies beyond the first line of treatment. Table 1. Type of treatments done in mBC patients (Nf105) after treatment with HT+ CDK4/6 inhibitors *1 performed only 1 cycle ** 1 was treated also with a metronomic schedule of therapy Citation Format: Sara Bravaccini, William Balzi, Andrea Roncadori, Alessandra Virga, Paola Ulivi, Giovanni Martinelli, Roberta Maltoni. Which treatment is done in patients with metastatic breast cancer who received a prior treatment with CDK4/6 inhibitors? A real-world experience in a single italian Institution [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 PO2-05-07.

Abstract PO1-16-06: LuciA-15 - A real-world prospective study of PARP inhibitors for the treatment of Latin American patients with HER-2 negative metastatic breast cancer with mutation of BRCA1/2 genes or in the Homologous Recombination Repair genes

Abstract Background PARP inhibitors (PARPi) improves progression free survival among patients with HER2 negative (HER2-ve) advanced breast cancer (ABC) and a BRCA1 or BRCA2 mutation compared to physician choice of chemotherapy (CT). The AIM of this prospective study was to evaluate the clinical benefit of PARPi treatment in terms of response, outcomes and survival by breast cancer type and treatment in a Latin-American population. Methods We analyzed data of patients with HER2-ve ABC with germline and/or somatic mutation of BRCA 1 or BRCA 2 or in the Homologous Recombination Repair genes, treated with olaparib or talazoparib in daily clinical practice by oncologist from Argentina and México. From September 2019 and April 2023, we collected baseline characteristics, previous systemic treatments, type and pattern of use, treatment beyond PARPi progression, and patient predisposition. Objective responses, best response rate, real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were analyzed with R software and RStudio version 14.0. Results After a median follow-up of 18.07 months (CI95% 10.53 - 30.07), 51 patients were treated with PARPi. Mean age at start treatment was 47,08 years. 62.7% had ER+ve/HER2-ve and 35.3% had triple negative breast cancer (TNBC). 62.7% and 37.3% of patients received talalaparib and olaparib, respectively. BRCA 1 and 2 germline mutations were the most common alterations found in 96% of patients. 37.5% of patients received platinum-based CT (PbCT) in the (neo)adjuvant/metastatic setting. 57.5% had visceral metastasis and the median number of metastatic sites were 2 (range 1-4). Median number of lines at the time to start PARPi was 2 (range 0-8), 23.5% and 31.4% received PARPi in the 1st line and 2nd line, respectively. The rwORR was 47.0%, and the median rwPFS1 was 7.77 months (CI95% 5.67-14.7). There was a tendence of better rwPFS1 in patients without previous CT versus previous CT in the advance setting, 14.30 months (CI95% 6.47-NR) versus 6.37 months (CI95% 5.03-8.73), respectively (p 0.084). The median rwOS was 26.97 months (CI95% 13.50-NR) and higher in the subgroup of patients naïve for CT versus previous exposure to CT in the advance setting, the median rwOS was 32.1 months (CI95% 27.0-NR) versus 13.0 (IC95%10.1-NR), respectively (p 0.022). 23.5% of patients progressed on PARPi during the first 6 months of treatment, 32.4% with visceral compromise, 27.8% with visceral crisis, and 26.5% with ≥2 metastatic sites. CT was the treatment of choice in most patients (55.3%). The medium rwPFS2 (next treatment after PARPi failure) was 4.00 months (CI95% 3.43 – 7.13). Treatment was discontinued for adverse events in 4.0 % of patients. Conclusion This is the first Latin-American evidence that replicate the data already published in randomized clinical trials and other scanty real-world evidence studies in this field, positive results in rwORR and rwPFS, encouraging data in rwOS. Notably, high proportion of patients with visceral progression even with visceral crisis and need for CT. Interestingly, similar rwOS results among subgroups (TNBC versus ER+ve/HER2-ve, talazoparib versus Olaparib, etc). <graphic> Citation Format: Fernando E. Petracci, Cynthia Villarreal-Garza, Facundo Argañaraz, Gonzalo Gómez Abuin, José Peñaloza, Marcos A. Flores, Luciano Piazzoni, Cecilia Riggi, Lucía Fabiano, Lucía González, Belén Cieplinski, Sergio Rivero, Ernesto Korbenfeld, Pablo Mandó. LuciA-15 - A real-world prospective study of PARP inhibitors for the treatment of Latin American patients with HER-2 negative metastatic breast cancer with mutation of BRCA1/2 genes or in the Homologous Recombination Repair genes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-06.

Abstract PO5-05-01: ASSESING THE CLINICAL AND SURVIVAL RESULTS OF PATIENTS WITH HR-POSITIVE, HER2 NEGATIVE ADVANCED BREAST CANCER TREATED WITH CDK 4/6 INHIBITORS IN A SPANISH COHORT

Abstract BACKGROUND First line treatment of HR-positive, HER2 negative advanced breast cancer is based on endocrine therapy plus CDK 4/6 inhibitors (CDK 4/6i). Recently, there has been published in ASCO 2023 results from SONIA trial, which explores the use of CDK 4/6i in second-line treatment after monotherapy with endocrine therapy. This trial have shown using a CDK4/6i in the first-line setting did not significantly prolong the time from random assignment to progression on second-line therapy (PFS2) or overall survival (OS) when compared with deferred use until the second-line setting. METHODS We conducted a descriptive, observational and retrospective analyses of patients treated in our centre with CDK4/6i, comparing demographic, clinical and survival results. We also analysed different outcomes between first versus second line CDK4/6i. RESULTS A cohort of 153 patients were included, treated between January 2018 and June 2023, with a median age of 50 years. At diagnosis, 49% were stage I-II and 31% stage IV. 59% had visceral metastases at the start of CDK4/6i treatment. Palbociclib was the most commonly CDK4/6i used (55%), followed by Ribociclib (32%) and Abemaciclib (12.5%). The most widely endocrine therapy used was letrozole (60%), followed by fulvestrant (38%). 58% received CDK4/6i in first-line setting while 9% received them in second-line. The overall median progression-free survival (mPFS) was 18 months. In a subgroup analysis, the mPFS was 19 months with Palbociclib, 26 months with Ribociclib, and 31 months with Abemaciclib. Baseline characteristics were similar between subgroups of CDK4/6i. Better survival data were obtained with letrozole than with fulvestrant (not reached versus 29 months OS respectively). After CDK4/6i disease progression the most common subsequent treatment was chemotherapy (capecitabine, 23%). The median OS with palbociclib and abemaciclib was 37 months, while not reached with ribociclib. We analysed PFS2 using CDK4/6i in the first-line setting compared with deferred use until the second-line. The use of CDK4/6i in second-line showed a PFS2 of 45 months, while first-line PFS2 was 26 months. CONCLUSIONS Our study results are consistent with previous studies assesing the efficacy of cyclin inhibitors in first and second-line setting. Palbociclib seems to have a lower PFS rate. Patients treated with letrozole had a stadistically significant benefit in survival outcomes. Our data continue the trend observed in the SONIA trial in terms of PFS2. Using endocrine therapy as first-line monotherapy may be a valid treatment option. However, larger sample sizes are required to draw definitive conclusions. The identification of potential predictors of treatment response may help in the selection of the most effective treatment for patients with HR-positive HER2 negative advanced breast cancer. Citation Format: Alicia Cano-Jimenez, Rocio Urbano-Cubero, Ruben Garcia-Muñoz, Ana Maria Jaen-Morago, Maria Lomas-Garrido, Pedro Sánchez-Rovira. ASSESING THE CLINICAL AND SURVIVAL RESULTS OF PATIENTS WITH HR-POSITIVE, HER2 NEGATIVE ADVANCED BREAST CANCER TREATED WITH CDK 4/6 INHIBITORS IN A SPANISH COHORT [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 PO5-05-01.