HER2-negative Advanced Breast Cancer Research Articles

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.

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]

Real-world treatment outcomes in patients with HR+ HER2- advanced breast cancer treated with CDK4/6 inhibitors and endocrine therapy.

1067 Background: The addition of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) to endocrine therapy (ET) improves progression-free (PFS) and overall survival (OS) in hormone receptor-positive, HER2-negative advanced breast cancer (HR+/HER2- ABC) in 1st and 2nd line setting. The international guidelines advise using 1st line CDK4/6i; however, its superiority over 2nd line use is debatable. Methods: We retrospectively analyzed clinical data of HR+/HER2- ABC pts administered palbociclib (PAL), ribociclib (RIB) or abemaciclib (ABM) added to either 1st or 2nd line ET. Results: A total of 1511 pts (PAL=507; RIB=724; ABM=280) from 11 cancer Polish centers treated between Sep 2017 and Dec 2023. Median follow-up was 29.6 (95%CI 28.2 to 30.9) months (m). Mean age was 62.6±11.9, 58.9±12.2 and 61.4±10.8 years in PAL, RIB and ABM, respectively. 815 patients (53.9%) had visceral and 1109 (73.4%) bone metastases. 1254 pts (83%) received 1st line CDK4/6i, in 841 (67%) combined with aromatase inhibitor (AI) and in 413 (33%) with fulvestrant (FUL). Second-line CDK4/6i was used in 257 pts (17%); 59 (23%) and 198 (67%) with AI and FUL, respectively. There was no difference in PFS, PFS2, and OS between three CDK4/6i in combination with AIs in 1st and 2nd line setting. Median PFS (95%CI) for 1st line AI with PAL, RIB, ABM were 29.0 (21.6-37.0), 32.0 (24.5-36.9), not reached (N/R) (21.9-N/R) m; PFS2: 37.0 (28.8-N/R), 33.0 (29.5-40.2), N/R (28.9-N/R); OS: 48.9 (42.9-N/R), 48.6 (41.9-N/R), N/R (36.7-N/R). Median PFS (95%CI) for 2nd line AI with PAL, RIB, ABM were 11.9 (9.49-N/R), 10.8 (8.27-N/R), 11.0 (6.43-N/R); PFS2: 22.7 (16.8-N/R), 32.3 (24.9-N/R), 31.0 (13.2-N/R); OS: 27.4 (24.4-N/R), 36.7 (30.1-N/R), 45.5 (29.0-N/R) (no statistical significance). In contrast, RIB+FUL was superior to PAL+FUL and ABM+FUL in both lines (Table). The safety profile was concordant with the reported data for ET + CDK4/6i. Conclusions: Identifying predictive factors of response is essential for the rational use of CDK4/6i and ET in HR+/HER2- ABC. [Table: see text]

Real-world (RW) elacestrant use patterns and therapeutic outcomes in patients (pts) with hormone receptor-positive (HR+)/HER2-negative advanced breast cancer (aBC).

1071 Background: Elacestrant was the first novel endocrine therapy (ET) to receive FDA approval in over two decades. In the EMERALD study, pts with ESR1-mutant ( ESR1m) HR+/HER2-negative aBC had a median progression free survival (PFS) of 3.8 months (mos). Here, we use a large clinical-genomic database to assess the RW use of elacestrant and examine the impact of line of therapy (LOT) and number of ERS1m on pt outcomes. Methods: Pts with HR+/HER2- aBC were identified via the GuardantINFORM database; all pts with ESR1m detected on circulating tumor DNA (ctDNA) testing done in routine clinical care and treated with elacestrant after the FDA approval date were included. Real-world time to treatment discontinuation (TTD) and time to next treatment (TTNT) were used as proxies for PFS (measured in mos). For TTD/TTNT, Kaplan-Meier curves and median time-to-event with 95% confidence intervals (CI) were used. For outcomes specific to single versus >1 ESR1m, only pts with an ESR1m detected within the 6 months prior to elacestrant start were included. Results: 418 aBC pts were treated with elacestrant, with a median age of 62 years. Elacestrant was used across metastatic LOT (2nd: 12%, 3rd: 18%, 4tH: 17%, 5th+: 53%). Considering all prior therapies, pts commonly received prior aromatase inhibitors (AI) (89%), CDK4/6i (73%), fulvestrant (63%), and chemotherapy (49%). Of 312 pts with testing within 6 months of elacestrant start, 56% harbored a single ESR1m, with a maximum of 11 ESR1m detected in a single patient. TTD was 5.4 mos (95% CI: 4.2 - not reached [NR]) and TTNT was 6.2 mos (95% CI: 5.7 - NR); most pts were censored at the time of analysis (65% for TTD, 71% for TTNT). There were no significant differences in TTD or TTNT based on number of prior LOT or number of ESR1m mutations (Table 1). Data was not yet mature to assess differences in outcomes based on prior ET use, duration of prior CDK4/6i exposure, specific ESR1m, or co-occurring alterations. Conclusions: Using a clinical-genomic database, we present early RW insights of aBC pts treated with elacestrant. Initial outcomes, as assessed via TTD and TTNT, exceed the PFS reported in the EMERALD trial, perhaps due to multiple factors impacting patient selection and restaging protocols, which can differ in prospective trials versus routine clinical care. Factors such as prior LOT and number of ESR1m did not impact patient outcomes; additional factors such as prior ET use, duration of CDK4/6i treatment, specific ESR1m, and co-occurring mutations will be assessed as data matures. [Table: see text]

Safety and patient-reported outcomes in patients with hormone receptor-positive, HER2-negative advanced breast cancer treated with CDK4/6 inhibitors in China: A cross-sectional study.

1054 Background: It is reported that the adverse event (AE) profile may vary with different CDK4/6 inhibitors. With the prolongation of survival, AEs occurred during the treatment period may affect quality of life (QoL) for patients with advanced disease. Currently, there has been no study focusing on the safety and patient-reported outcomes in Chinese patients treated with different CDK4/6 inhibitors. Methods: This was a large cross-sectional study conducted at 10 sites in China. Randomly selected patients with hormone receptor-positive, HER2-negative advanced breast cancer and their physicians were asked to fill the self-designed questionnaires. Disease characteristics and AEs were collected from the perspectives of both patients and physicians, while the patient questionnaire additionally included feedback on the AE management and the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-breast cancer module (QLQ-BR23). Results: Between Jan 30, 2023 and Sep 15, 2023, a total of 1254 patients (median age, 55 years) were included; 212 (16.9%) patients were treated with palbociclib, 483 (38.5%) with abemaciclib, 550 (43.9%) with dalpiciclib, and 9 (0.7%) with ribociclib. Of them, 197 (15.7%) had switching history or dose adjustment of CDK4/6 inhibitor, with the main reason being AEs (51.8%). From the perspective of physicians, the most common AEs for patients were decreased white blood cell (63.3%), decreased neutrophil count (58.7%), and diarrhea (36.3%). The incidence of increased alanine aminotransaminase (ALT) and increased aspartate aminotransaminase (AST) was 9.3% (grade ≥3, 6.0%) and 8.4% (grade ≥3, 6.7%), respectively. Dalpiciclib showed the lowest incidence of increased ALT (3.5%; grade ≥3, none), increased AST (4.2%; grade ≥3, none), and diarrhea (10.5%) compared with other CDK4/6 inhibitors (P<0.001). From the perspective of patients, dalpiciclib showed the lowest incidence of fatigue, alopecia, hot flashes, insomnia, arthralgia, nausea, vomiting, diarrhea, and anorexia (P<0.05). Regarding QoL, the mean scores of upset by hair loss for different CDK4/6 inhibitors were higher than other symptom subscale scores. Dalpiciclib showed the lowest mean score of upset by hair loss compared with abemaciclib and palbociclib, whether in total (19.74 vs 27.23 vs 21.47, P=0.006) or in patients with >6 months of treatment (12.59 vs 27.78 vs 17.95, P<0.001). Conclusions: AEs are different among various CDK4/6 inhibitors. Dalpiciclib has the lowest risk of diarrhea and hepatotoxicity based on physicians' reports, and shows the best patient-perceived safety. Regarding QoL, CDK4/6 inhibitors can result in upset by hair loss, while patients have the least concern about this issue when using dalpiciclib, especially for those with long treatment duration (>6 months).

Neoadjuvant dalpiciclib, exemestane, and goserelin in premenopausal women with HR-positive, HER2-negative breast cancer: A prospective, multicenter, randomized two-group, non-controlled phase 2 clinical trial.

TPS625 Background: The combination of CDK4/6 inhibitors (CDK4/6i) with endocrine therapy has significantly improved progression-free survival and overall survival in patients with HR-positive, HER2-negative advanced breast cancer (BC), revolutionizing the treatment landscape. However, previous CDK4/6i neoadjuvant studies have predominantly focused on postmenopausal populations, leaving a gap in preoperative treatment for early HR-positive, HER2-negative premenopausal BC patients. Therefore, the present trial is conducted to investigate the efficacy of dalpiciclib, exemestane and goserelin as neoadjuvant therapy in premenopausal women with HR-positive, HER2-negative BC. Methods: This is a multicenter, randomized two-group, non-controlled phase 2 clinical trial. Key eligibility criteria include: Patients aged 18 years or older with no prior treatment, an ECOG performance status of 0-1, at least 1 measurable lesion, and clinical stage II-III HR-positive, HER2-negative premenopausal invasive BC. Initially, all enrolled patients will receive two cycles of treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC). Subsequently, patients with complete response (CR) or partial response (PR) will receive an additional four cycles of TAC, whereas patients with progressive disease (PD) will undergo surgery or treatment options decided upon by the investigators. Those with stable disease (SD) will be randomly assigned 1:1 to either an experimental group receiving 16 weeks of dalpiciclib, exemestane, and goserelin (dalpiciclib: 125 mg daily for 21 days followed by 7 days off, exemestane: 25 mg daily for 28 days, goserelin: 3.6 mg every 28 days) or a standard chemotherapy group receiving four more cycles of TAC. Treatment response is assessed according to RECIST 1.1 criteria. Surgery will be performed after completion of the planned neoadjuvant treatment, followed by radiation therapy and systemic treatment according to local guidelines or the investigators' choices. The study's primary endpoint is the objective response rate (ORR) of the experimental group. Secondary endpoints include the ORR, residual cancer burden, preoperative endocrine prognostic index, event-free survival, and safety of both. Using Simon's two-stage optimal design and assuming a 40% response rate as desirable in the experimental group, at least 13 responses among a total of 43 patients were required to meet the primary endpoint. The trial will be terminated if fewer than 3 patients respond in the first stage. Considering an 80% SD rate post two neoadjuvant TAC cycles and a 10% attrition, the sample size was ultimately set at 119. The trial is actively recruiting. Clinical trial information: NCT06009627 .

Efficacy and Safety of Chidamide in Combination with PD-1 Inhibitor and Radiotherapy for HER2-Negative Advanced Breast Cancer: Study Protocol of a Single Arm Prospective Study.

As one of the most important breakthroughs in cancer therapy, immune checkpoint inhibitors have greatly prolonged survival of patients with breast cancer. However, their application and efficacy are limited, especially for advanced HER2-negative breast cancer. It has been reported that epigenetic modulation of the histone deacetylase (HDAC) inhibitor chidamide, as well as immune microenvironment modulation of radiotherapy are potentially synergistic with immunotherapy. Thus, the combination of chidamide, radiotherapy and immunotherapy is expected to improve prognosis of patients with advanced HER2-negative breast cancer. This is a single-arm, open, prospective clinical trial investigating the efficacy and safety of the combination of HDAC inhibitor chidamide, anti-PD-1 antibody sintilimab, and the novel immuno-radiotherapy, which aims to enhance efficacy of immunotherapy, in subsequent lines of therapy of HER2-negative breast cancer. Our study will include 35 patients with advanced breast cancer that has failed endocrine therapy and first-line chemotherapy. Participants will receive 30 mg of chidamide twice a week, 200 mg of sintilimab once every 3 weeks, combined with immuno-radiotherapy. Radiotherapy will be centrally 8 Gy for at least one lesion, and at least 1 Gy for the other lesions. We will complete three fractions of radiotherapy in one cycle. The primary endpoint is progression-free survival, and secondary endpoints are objective response rate, disease control rate and safety. Moreover, biomarkers including cytokines and lymphocyte subgroups will be explored. As a single-arm clinical trial, the analysis of the influence of each single treatment is limited. Besides, our study is an open study, which involves neither randomization nor blinding. In spite of the abovementioned limitations, this prospective clinical trial will give an insight into subsequent lines of therapy of HER2-negative advanced breast cancer, prolong the survival or achieve long remission for these participants, and identify potential responders.

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.

Clinical outcomes with alpelisib (ALP) plus fulvestrant (FUL) in patients with HR-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (ABC) with PIK3CA mutations (m) in routine practice at several Russian centers.

e13053 Background: The data of ALP efficacy after FUL, chemotherapy (CT) and in later lines is limited. Only a small percentage of pts in BYLieve trial in cohort C received FUL (32%), CT (37%) and received ALP in later lines (only 4 pts received ALP in 4/4L+ lines). Therefore, we reported the real-world data of ALP+FUL efficacy in pts with HR+/HER2−ABC with PIK3CAm from initial year access in Russian Federation. Methods: Pts with HR+/HER2- ABC with PIK3CAm were treated with ALP 300mg QD orally and FUL 500mg IM until disease progression or intolerance. The primary endpoints were progression free survival (PFS) and clinical benefit (CB) defined per RECIST 1.1. Here we present the results of treatment pts with ALP+FUL in routine practice after prior FUL, chemotherapy and outcomes depend on the line of therapy in which pts received ALP+FUL. Results: 139 pts with HR+/HER2-ABC with PIK3CAm were included in our retrospective analysis from 2020 to 2023. Median lines of previous treatment in ABC was three (1-9), the most pts have received CDK 4/6, n=123 (86%), fulvestrant-containing regimens, n=83 (79%) and CT, n=77 (55%). The median of PFS (mPFS) on ALP+FUL was 7.0 months (CI 95%: 5.0-8.9); CB was achieved in 58% of pts, including partial response in 18% and stable disease ≥6 months in 40% pts. The mPFS was statistically longer in pts who didn’t receive CT and FUL compared with pts who had prior CT and FUL-containing regimens (Table). Pts received AlP+FUL in the 2L (n=45, 32%), 3L (n=35, 25%), 4L and 4L+ (n=59, 42%). The mPFS was statistically longer in pts treated with ALP+FUL in earlier lines (Table 1). The pts received metformin for hyperglycemia (HG) prevention according to their metabolic status; any grade of hyperglycemia (HG) was reported in 86 out of 138 pts (62%). HG grade (G) 1 was detected in 43 (31%) pts, G2 – in 27 (20%) pts, G3 – in 16 (12%) pts and no cases HG G4 were detected. 14 patient required ALP dose reductions to 250 mg due to HG G3; 3 pts discontinued ALP due to HG. Other most common AEs included rash and creatinine increase. The pts received cetirizine 10 mg orally during 4 weeks for rash prevention; rash any G occurred in 53 (39%) pts (G1 - 7%, G2 -10% G3 -19%, G4 - 0,7%), 20 pts required ALP dose reductions to 250 mg due to rash G3 and 11 pts discontinued ALP due to AEs. Blood creatinine increase was detected in 21/139 – all G 1-2. Conclusions: ALP+FUL demonstrated high efficacy in heavily pretreated pts with HR+/HER2- ABC with PIK3CAm in routine practice. ALP+FUL should be used in earlier lines of treatment in metastatic setting before chemotherapy and/or fulvestrant-containing regimens. [Table: see text]

LEONARDA-2: Lerociclib plus letrozole versus placebo plus letrozole in HR+/HER2- advanced or metastatic breast cancer.

1052 Background: Following promising outcomes in hormone receptor (HR)-positive, HER2-negative endocrine-resistant advanced breast cancer (BC) with lerociclib plus fulvestrant, this study assesses the efficacy and safety of lerociclib and letrozole in HR+/HER2- advanced or metastatic BC. Methods: This randomized, double-blind, placebo-controlled phase III study involved HR+/HER2- advanced or metastatic BC patients without prior systemic therapy for advanced disease. Participants were allocated 1:1 to either lerociclib (150mg twice daily) with letrozole or placebo with letrozole. The primary endpoint was progression-free survival (PFS) as assessed by investigators. Secondary endpoints included PFS (assessed by Blinded Independent Central Review (BICR)), response rates, overall survival (OS), and safety. The interim analysis was planned approximately 80 PFS events. Results: By September 20, 2023, 279 patients were randomized (137 to lerociclib + letrozole, 142 to placebo + letrozole), with a median follow-up of 12.91 months. Baseline characteristics were comparable across groups. At the data cutoff, 83 PFS events were reported. The lerociclib significantly improved PFS versus placebo (median: not reached (NR) versus 16.56 months; hazard ratio: 0.464; 95% CI: 0.293-0.733; p=0.0004). BICR analysis confirmed these results (median: NR versus NR; hazard ratio: 0.457; 95% CI: 0.274-0.761; p=0.0011). Subgroup benefits were consistent, including in patients with visceral metastases, extensive metastatic sites and previous (neo)adjuvant endocrine therapy, etc. For patients with measurable disease, lerociclib plus letrozole showed a higher objective response rate (62.3%) compared to placebo group (48.5%). OS data were immature at the cutoff. Adverse events were primarily hematological toxicity, with higher incidences of grade 3/4 neutropenia (grade 3: 41.6% vs. 0.7%; grade 4: 5.1% vs. 0%) and leucopenia (grade 3: 27.0% vs. 0%; grade 4: 1.5% vs. 0%) in the lerociclib group. All of neutropenia and leukopenia were considered to be treatment related. Grade 3 diarrhea was infrequent, only 1 case (0.7%) was reported in lerociclib group. QTc prolongation was reported comparable between lerociclib group (4.4%, Grade 3:1.5%) and placebo group (3.5%, Grade 3:0.7%). No venous thromboembolism was reported. Serious AEs were slightly higher in the lerociclib group (13.1% vs. 7.7%). Treatment discontinuation due to AEs was rare (1 patient [0.7%]) with lerociclib. Conclusions: Lerociclib with letrozole had an excellent safety profile and significantly prolonged PFS in HR+/HER2- advanced or metastatic BC patients. This benefit was consistent across all clinically relevant subgroups, suggesting lerociclib as a viable first-line therapeutic option with a favorable benefit-risk balance. Clinical trial information: CTR20212139; NCT05851014.

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.

Disease landscape of advanced HER2-breast cancer patients by treatment line in three EU countries and USA.

Aim: To report treatment patterns and quality of life (QoL) in HER2-negative advanced breast cancer patients.Methods: Data were drawn from a cross-sectional survey in Europe and USA.Results: Hormone plus targeted therapy was the most frequent first-line (1L, 62%) and second-line (2L, 45%) treatment for HR+/HER2-patients. Chemotherapy was most frequent at third-line or greater (3L+, 39%) for HR+/HER2- patients, 2L (51%) and 3L+ (48%) for triple negative breast cancer (TNBC) patients. Time to progression was 13.8 (2L) and 11.0 (3L+) months for HR+/HER2- patients. No comparisons were observed for TNBC patients. EQ-5D-5L scores were highest in patients at 1L and lowest at 3L+.Conclusion: Reduced QoL and treatment response were reported in patients at later lines of therapy.

A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results

SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in pre- and post-menopausal women with ER+, HER2- advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. Patients and Methods Women aged 18 years or older with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, anti-tumor efficacy, pharmacokinetics, and impact on ESR1m circulating tumor (ct)DNA levels were assessed. By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events (TRSAEs) at doses ≤150 mg. Median tmax was achieved ∼2-4 hours post-dose at all doses investigated, with an estimated half-life of 20-23 hours. Efficacy was observed at all doses investigated, including in patients with prior CDK4/6 inhibitor and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. Camizestrant is a next-generation oral SERD and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75, 150 and 300 mg QD doses for Phase 2 testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

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 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.

Abstract PO2-05-01: Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative breast cancer

Abstract Background: CDK4/6 inhibitors combined with endocrinotherapy (ET) represent an essential part of the treatment for HR-positive and HER2-negative breast cancer (BC). However, the role of angiogenesis inhibitors, such as bevacizumab, in these patients (pts) is controversial. While it has been demonstrated to improve progression-free survival (PFS), it has failed to show a significant overall survival (OS) benefit in HER2-negative BC. Several preclinical studies have explored the combination of anti-angiogenesis multi-targeted receptor tyrosine kinase inhibitors (TKIs) and CDK4/6 inhibitors in other cancers, suggesting a synergistic effect. Our phase Ib/II trial (NCT05176080, ChiCTR2100053950) aims to evaluate the safety and efficacy of a novel anti-angiogenesis TKI famitinib (F) added to dalpiciclib (D) and ET in advanced HR-positive and HER2-negative BC. Here we report the results of Phase Ib. Methods: A 3+3 de-escalation design was used in this dose-exploring phase (phase Ib). Pts with HR-positive and HER2-negative BC, who had no more than two prior chemotherapies in the advanced setting, were enrolled and administered F (orally, at doses of 15 mg/d, 10 mg/d, or 15 mg qod), D (orally, at doses of 150, 125 or 100 mg/d, 21 days on and 7 days off) and fulvestrant (intramuscularly, at a fixed dose of 500 mg every four weeks) until progression, unaccepted toxicities, or withdrawal. The initial dose level (Level 1) was set as F 15 mg daily and D 150 mg/d. The primary endpoints were recommended phase 2 dose (RP2D) and safety. Results: From December 2021 to June 2022, 18 pts were enrolled, and 3, 6, 3, and 6 pts were assigned to Level 1 (F 15 mg + D 150 mg), Level 2 (F 10 mg + D 125 mg), Level 3 (F 15 mg qod + D 125 mg), and Level 4 (F 10 mg + D 100 mg), respectively. 14 (77.8%) pts had visceral metastasis, and 7 (38.9%) had prior systemic therapies in the advanced setting. 13 (72.2%) pts had received ET, and 11 (61.1%) were resistant to ET before enrolled. A total of 6 dose-limiting toxicities (DLTs) were observed, including 3 Grade 4 thrombopenia (2 in Level 1, 1 in Level 2) and 3 Grade 4 neutropenia (2 in Level 3, 1 in Level 4), 4 of which were serious adverse events (AEs). The most common (≥20%) treatment-related AEs of Grade 3 or above were neutropenia (100.0%), leukopenia (88.9%), thrombocytopenia (33.3%), anemia (27.8%), lymphopenia and hypertension (both 22.2%). No death was reported. Overall 10 pts (55.6%) achieved confirmed partial responses and 16 (88.9%) achieved clinical benefits. Confirmed objective response rates (ORRs), clinical benefit rates (CBRs), and DLTs in different dose levels were shown in Table 1. Considering the efficacy and safety profiles, Level 4 was selected as RP2D. Conclusion: The anti-angiogenesis multi-targeted receptor TKI famitinib combined with CDK4/6i and fulvestrant has shown antitumor effects in advanced HR-positive and HER2-negative BC, and no new safety signals were observed. Citation Format: Min Yan, Mengwei Zhang, Limin Niu, Huimin Lv, Zhenzhen Liu, Huiai Zeng, Shengnan Zhao, Huihui Sun, Jing Wang, Yajing Feng, Huajun Li. Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative 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 PO2-05-01.

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 PO2-15-06: ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial

Abstract ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial Background: DNADX, a novel machine learning-based approach, utilizes DNA from tumor tissue or plasma ctDNA to identify clinically relevant phenotypic tumor features and classify breast cancer into 4 subtypes (Nat Comm 2023). Here, we evaluated DNADX's ability to predict prognosis and treatment benefit in HR+/HER2- advanced breast cancer following endocrine therapy and a CDK4/6 inhibitor. Methods: DNADX was evaluated centrally in available baseline plasma ctDNA samples from PARSIFAL trial (NCT02491983) which randomized 486 patients (pts) with HR+/HER2- advanced breast cancer to receive (1:1 ratio) first line palbociclib with either fulvestrant or letrozole. Shallow whole genome sequencing was performed on ctDNA, and the 4 DNA-based subtypes (Clusters-1, -2, -3, and -4) were identified if the ctDNA tumor fraction (TF)≥3%. The main objective was to evaluate the association of DNADX subtypes with progression-free survival (PFS) and overall survival (OS). Secondary objective was to identify the subgroup of pts who benefit more from each endocrine treatment. Uni- and multi-variable Cox regression models were used after adjusting for TF, menopausal status, ECOG status, de novo metastasis (vs. recurrence), visceral disease and number of metastatic sites. Results: DNADX was evaluated in plasma ctDNA samples from 122 pts (25.1%). Clinical variables and median PFS (27.6 months) were similar as the overall PARSIFAL population. DNADX identified 56.6% pts with TF of < 3%, 14.8% with Cluster-1, 19.7% with Cluster-2, 5.7% with Cluster-3 and 3.3% with Cluster-4. In terms of PFS, pts classified with TF< 3% had a lower risk of progression compared to Cluster-1, Cluster-2, Cluster-3, Cluster-4 subtypes (pairwise PFS hazard ratios [HRs] of 1.88, 2.02, 3.15, and 5.62, respectively, with a global log-rank test of p=0.010). Similar results were obtained after adjusting for other clinical-pathologic variables. A numerical benefit of fulvestrant in comparison with letrozole was observed in pts classified in Cluster-1 and Cluster-4 (HR=0.42, 95% CI 0.14-1.24) in contrast to the other groups (HR=1.21, 95% CI 0.68-2.18), and the interaction test was statistically significant after adjusting for clinical-pathologic variables (anova p-value=0.037). In terms of OS, pts classified with TF< 3% had a lower risk of death compared to Cluster-1, Cluster-2, Cluster-3, and Cluster-4 subtypes (pairwise OS HRs of 1.90, 4.23, 11.13, and 6.80, respectively, with a global log-rank test of p=0.003). In the multivariable analysis, results were consistent after adjusting for clinical-pathologic variables and TF. Conclusions: Liquid biopsy-based DNADX subtypes predict outcomes in pts with HR+/HER2- advanced breast cancer on endocrine therapy and CDK4/6 inhibitors, potentially identifying the most optimal endocrine treatment for each pt. Citation Format: Fara Brasó-Maristany, Javier Cortés, José Manuel Pérez-García, Rosario Vega-León, Laia Paré, Guillermo Villacampa, Judit Matito, Francisco Pardo, Marina Gomez-Rey, Mario Mancino, Elena Martínez-García, Carmen Mora Gallardo, Leonardo Mina, Florence Dalenc, Meritxell Bellet- Ezquerra, Manuel Ruíz - Borrego, Miguel Gil-Gil, Peter Schmid, Charles M. Perou, Joel S. Parker, Patricia Villagrasa, Ana Vivancos, Aleix Prat, Antonio Llombart-Cussac. ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL 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 PO2-15-06.