Receptor 2-negative Metastatic Breast Cancer Research Articles

Double-Faced Immunological Effects of CDK4/6 Inhibitors on Cancer Treatment: Challenges and Perspectives

Cyclin-dependent kinases (CDKs) are generally involved in the progression of cell cycle and cell division in normal cells, while abnormal activations of CDKs are deemed to be a driving force for accelerating cell proliferation and tumorigenesis. Therefore, CDKs have become ideal therapeutic targets for cancer treatment. The U.S FDA has approved three CDK4/6 inhibitors (CDK4/6is) for the treatment of patients with hormone receptor-positive (HR+) or human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer, and these drugs showed impressive results in clinics. Besides cell-cycle arrest, there is growing evidence that CDK4/6is exert paradoxical roles on cancer treatment by altering the immune system. Indeed, clinical data showed that CDK4/6is could change the immune system to exert antitumor effects, while these changes also caused tumor resistance to CDK4/6i. However, the molecular mechanism for the regulation of the immune system by CDK4/6is is unclear. In this review, we comprehensively discuss the paradoxical immunological effects of CDK4/6is in cancer treatment, elucidating their anticancer mechanisms through immunomodulatory activity and induction of acquired drug resistance by dysregulating the immune microenvironment. More importantly, we suggest a few strategies including combining CDK4/6is with immunotherapy to overcome drug resistance.

Palbociclib plus aromatase inhibitors in patients with metastatic breast cancer and cardiovascular diseases: real-world effectiveness.

Patients with cardiovascular disease (CVD) comorbidities are often excluded from participating in breast cancer clinical trials. Consequently, data to inform treatment decisions for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and CVD are limited. We compared the effectiveness of first-line palbociclib plus an aromatase inhibitor (AI) vs an AI alone and evaluated palbociclib treatment patterns in patients with HR+/HER2- mBC and CVD in routine clinical practice. Data from the Flatiron Health Analytic Database were captured for patients with HR+/HER2- mBC and CVD who initiated first-line treatment with palbociclib plus an AI or an AI alone between February 2015 and March 2020 (data cutoff: September 30, 2020). Overall survival (OS), real-world progression-free survival (PFS), and treatment patterns were evaluated. Of the 469 patients with identifiable CVD, 160 received palbociclib plus an AI, and 309 received an AI alone. After stabilized inverse probability treatment weighting, both median OS (40.7 vs 26.5 months; hazard ratio [HR], 0.732 [95% CI, 0.537-0.997]; P = .048) and median real-world PFS (20.0 vs 12.5 months; HR, 0.679 [95% CI, 0.512-0.900]; P = .007) were significantly prolonged in patients treated with palbociclib plus an AI vs an AI alone. Among patients with a documented palbociclib starting dose, 78.5% started palbociclib at 125mg/day, and 38.6% experienced dose adjustment. In this real-world analysis, first-line palbociclib plus an AI was associated with improved effectiveness compared with an AI alone in patients with HR+/HER2- mBC and CVD. NCT05361655 (ClinicalTrials.gov).

Sacituzumab govitecan in HR+HER2- metastatic breast cancer: the randomized phase 3 EVER-132-002 trial.

Sacituzumab govitecan (SG) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2-) metastatic breast cancer (mBC) in the global TROPiCS-02 study. TROPiCS-02 enrolled few Asian patients. Here we report results of SG in Asian patients with HR+HER2- mBC from the EVER-132-002 study. Patients were randomized to SG (n = 166) or chemotherapy (n = 165). The primary endpoint was met: PFS was improved with SG versus chemotherapy (hazard ratio of 0.67, 95% confidence interval 0.52-0.87; P = 0.0028; median 4.3 versus 4.2 months). OS also improved with SG versus chemotherapy (hazard ratio of 0.64, 95% confidence interval 0.47-0.88; P = 0.0061; median 21.0 versus 15.3 months). The most common grade ≥3 treatment-emergent adverse events were neutropenia, leukopenia and anemia. SG demonstrated significant and clinically meaningful improvement in PFS and OS versus chemotherapy, with a manageable safety profile consistent with prior studies. SG represents a promising treatment option for Asian patients with HR+HER2- mBC (ClinicalTrials.gov identifier no. NCT04639986 ).

The different sequences of CDK4/6 inhibitor and mTOR inhibitor in HR+/HER2-advanced breast cancer: A multicenter real-world study

BackgroundCyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and everolimus (EVE) are effective for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, the efficacy of different sequences of CDK4/6i and EVE are largely unknown. The study aimed to explore the efficacy of different sequences in China. Methods146 patients with HR+/HER2- MBC who received both CDK4/6i and EVE in salvage setting were collected. Objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS) were investigated. Results56 patients received CDK4/6i prior to EVE (Group A), 90 patients received CDK4/6i subsequent to EVE (Group B). The median PFS of CDK4/6i and EVE in Group A vs Group B were 8.4m and 2.5m vs 4.6m and 6.1m respectively. The total PFS of first-line and second-line endocrine therapy were not different between Group A and Group B [13.1m vs 17.7m (P = 0.330, HR = 0.738, 95%CI: 0.399–1.365)]. The 5y OS of patients in Group A or Group B were 62.0 % vs 57.4 %, P = 0.569. ConclusionsWe found that no matter CDK4/6i or EVE was used first, the survival were not significantly different between Group A and Group B. Both can be clinical options.

374P Real-world (Rw) outcomes in patients (pts) with hormone receptor-positive and human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (mBC) treated with chemotherapy (CT) in France and Germany

374P Real-world (Rw) outcomes in patients (pts) with hormone receptor-positive and human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (mBC) treated with chemotherapy (CT) in France and Germany

Current and Novel Treatment Options in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer.

Metastatic breast cancer (mBC) remains an incurable disease, and most patients will experience disease progression during their treatment course. Although endocrine therapy remains the mainstay of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative mBC, significant progress has been and continues to be made in the treatment of this BC subtype. The discovery of molecular markers, mutations in key cellular pathways, and genomic signatures have led to the development of novel and targeted agents, such as antibody-drug conjugates, oral selective estrogen receptor downregulators, and inhibitors of the PI3K/AKT/mTOR pathway. This has resulted in significant improvements in the survival and quality of life of patients. With the increasing number of treatment options for patients, appropriate drug sequencing remains a challenge. Treatment discussions should involve patient-physician shared decision making, with consideration of genomic data, previous lines of therapy, side effect profiles, and clinical trial enrollment.

OPERA-01: A randomized, open-label, phase 3 study of palazestrant (OP-1250) vs standard-of-care for patients with ER+, HER2- advanced or metastatic breast cancer after endocrine therapy and CDK4/6 inhibitors.

TPS22 Background: In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC), endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard-of-care (SOC) treatment in the first-line setting. However, patients develop resistance, most commonly due to acquired mutations in ESR1. Efficacy of available ET post CDK4/6i treatment is limited. Therefore, a significant unmet need exists for patients with ET-CDKi-resistant ER+, HER2– MBC to improve outcomes and delay time to chemotherapy. Palazestrant is an oral small molecule complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds ER and completely blocks ER-driven transcriptional activity, irrespective of ESR1 mutation status. In a phase 1/2 monotherapy study in heavily pretreated patients with ER+, HER2– advanced or MBC (NCT04505826), palazestrant showed a tolerable safety profile, favorable pharmacokinetics and encouraging antitumor efficacy in patients with and without ESR1 mutation at the recommended Phase 2 dose of 120 mg once a day (qd) (Lin et al. ESMO 2023 MO382). Methods: OPERA-01 (NCT06016738) is a multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET (fulvestrant, anastrozole, letrozole, or exemestane) in patietns with ER+, HER2– MBC that relapsed or progressed on 1-2 prior lines of ET, including a CDK4/6i. Eligible patients are adults who have a confirmed diagnosis of evaluable ER+, HER2– inoperable locally advanced or MBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior treatments must include 1-2 prior lines of ET, last ET duration for ≥6 months; must have received CDK4/6i with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC. No prior chemotherapy in the metastatic setting is permitted. In the dose selection part of the study, 120 patients are randomized to 90 mg qd or 120 mg qd palazestrant or SOC monotherapy. The dose selection will be conducted when 80 patients in both palazestrant arms have had an opportunity to be on treatment for 16 weeks. Overall, 510 patients, including patients from the dose selection part, will be randomized to palazestrant or SOC ET. The primary endpoint of progression-free survival will be assessed by blinded independent central review in patients with and without ESR1 mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in patients with and without ESR1 mutations. The study started recruitment in November 2023. Clinical trial information: NCT06016738 .

The role of everolimus in metastatic breast cancer and possibilities of moving forward-a narrative review.

In hormone-receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer endocrine-based therapies are preferred over chemotherapy. One of the treatment options is the combination of everolimus with exemestane or other endocrine drug in later lines mainly based on progression-free survival (PFS) results of the phase 3 BOLERO-2 trial. Altogether, clinical trials did not prove an overall survival (OS) benefit and considerable side effects hampered its application in the day-by-day practice. In recent years CDK4/6-inhibitors became a first-choice combination partner to the endocrine treatment, everolimus still has a place within the treatment armamentarium. Although everolimus is a targeted drug, there is no accepted predictive biomarker and further patient selection is not possible. However, several directions can be defined how to optimally use everolimus. For update information on everolimus treatment in breast cancer I have performed a literature search. I used the keywords "breast cancer" and "everolimus" and extended the search in PubMed from 01/01/2014 to 10/02/2023. I considered all phase 3 trials, the phase 1-2 trials with not repetitive information, studies with biomarker results and I also checked review articles to identify potential relevant other clinical trial reports. I also have made a search in clinicaltrials.gov for recently completed and ongoing trials. I summarized the search results in this concise and brief report focusing on main trial results and ongoing research with everolimus. The most promising research directions seem to be further investigations for useable predictive biomarkers, for combinations with other targeted drugs (even in a triple combination) and for the feasibility of pharmacologically guided dosing method.

Social Determinants of Health and Other Predictors in Initiation of Treatment with CDK4/6 Inhibitors for HR+/HER2- Metastatic Breast Cancer.

In hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC), cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) have replaced endocrine therapy alone as the standard of care; however, several barriers to treatment initiation still exist. We assessed social determinants of health (SDOH) and other factors associated with the initiation of CDK4/6i for HR+/HER2- MBC in the Medicare population. Using a retrospective cohort design, patients aged ≥65 years and diagnosed during 2015-2017 were selected from the SEER-Medicare database. Time from MBC diagnosis to first CDK4/6i initiation was the study outcome. The effect of SDOH measures and other predictors on the outcome was assessed using the multivariable Fine and Gray hazard modeling. Of 752 eligible women, 352 (46.8%) initiated CDK4/6i after MBC diagnosis (median time to initiation: 27.9 months). In adjusted analysis, SDOH factors significantly associated with CDK4/6i initiation included high versus low median household income (HHI) (hazard ratio [HR] = 1.70; 95% CI = 1.03-2.81) and the percentage of population with high versus low Medicare-only coverage (HR = 1.54; 95% CI = 1.04-2.27). In summary, older Medicare patients with HR+/HER2- MBC residing in areas with high median HHI and a high proportion of Medicare-only coverage had higher rates of initiating CDK4/6i, suggesting inequitable access to these novel, effective treatments and a need for policy intervention.

Retrospective registry of patients with locally advanced/metastatic HR+/HER2- breast cancer treated in clinical practice in Andalusia.

Limited data are available regarding the real-world effectiveness and safety of Cyclin Dependent Kinase 4/6 inhibitor (CDK4/6i) (palbociclib/ribociclib) just as a first-line treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2‒) metastatic breast cancer (MBC). To assess whether clinical or demographic characteristics limit access to first-line CDK4/6i treatment in clinical practice in the Autonomous Community of Andalusia (Spain) between November 2017 and April 2020. In addition, effectiveness will be described in an exploratory analysis. Physicians from 12 centers participated in selecting demographic and clinical characteristics, treatment, and outcome data from women with HR + /HER2- MBC treated with or without CDK4/6i in addition to hormonal in the first-line setting, in a 3:1 proportion. Kaplan-Meier analysis estimated progression-free rates (PFRs) and survival rates (SRs). A total of 212 patients were included, of whom 175 (82.5%) were in the CDK4/6i treatment group and 37 (17.5%) were in the non-CDK4/6i treatment group (control group). Patients in the CDK 4/6i treatment group were younger (p = 0.0011), the biopsies of the metastatic site at the moment of the relapse were most commonly performed (p = 0.0454), and had multiple metastatic sites (p = 0.0025). The clinical benefit rate (CBR) was 82.3% in the CDK4/6i group and 67.8% in the control group. Median time to a progression event or death (PFS) was 20.4months (95%CI 15.6-28) in the CDK4/6i group and 12.1months (95%CI 7.9-not reached) in the control group. Younger patients, biopsies of metastatic disease and with multiple metastatic sites were more frequently treated with CDK4/6i in our daily clinical practice.

A case of biopsy proven acute tubular injury from cyclin dependent kinase 4/6 inhibitor

Cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with endocrine therapy, stand as one of the preferred first-line treatment regimens for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. However, data regarding renal toxicities from CDK 4/6 inhibitors is conflicting. Some literature suggests a link to pseudo-acute kidney injury (AKI), while others indicate a potential intrinsic injury. These conflicting findings are compounded by the novelty of the treatment. We report a case of a 66-year-old woman with metastatic breast cancer who developed a true AKI on ribociclib, a CDK4/6 inhibitor. Upon evaluation, her urinalysis demonstrated proteinuria, and her serologic workup (including complements and free light chains) was within normal limits. Her Cystatin C-based eGFR was also found to be decreased. She ultimately underwent a kidney biopsy that demonstrated acute tubular injury (ATI). The etiology of her ATI was thought to be secondary to her CDK 4/6 inhibitor, as other factors causing ATI were ruled out. This case highlights that although much attention is put on CDK 4/6 inhibitors causing pseudo-AKI, it is imperative to ensure that patients are not experiencing true AKIs by assessing kidney function with alternative methods outside of creatinine, such as Cystatin C and exogenous filtration markers such as radionuclides, along with pursuing a renal biopsy when appropriate.

Efficacy of subsequent treatments after disease progression on CDK4/6 inhibitors therapy in patients with hormone receptor-positive metastatic breast cancer: A Kaplan-Meier derived individual-patient data meta-analysis.

1065 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are standard-of-care for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/ HER2-) metastatic breast cancer (mBC). Yet, disease progression is common in these patients. In the absence of established guidelines for optimal sequencing post-progression, we conducted a pooled analysis of patient data to assess the efficacy of subsequent treatment options following disease progression on CDK4/6i therapy. Methods: We conducted a systematic review and meta-analysis, searching PubMed, Embase, Cochrane, and conference proceedings for randomized controlled trials (RCTs) and observational cohort studies reporting subsequent treatment post-CDK4/6i progression in patients with HR+HER2-mBC from 2016 to December 2023. We performed a pooled analysis of Kaplan-Meier-derived individual patient data for progression-free survival (PFS) and overall survival (OS). Subgroups analysis according to drug type, and a sensitivity analysis including only RCTs were also conducted. Statistical analysis was performed with R Statistical Software. Results: Of 12,895 identified records, 18 studies (7 RCTs and 11 cohort studies) comprising 4,868 patients with HR+HER2-mBC were included. Maintaining treatment with a CDK4/6i post-CDK4/6i progression was associated with longer PFS (HR: 0.64; 95% CI: 0.54-0.76; p<0.01; n=1,397) and prolonged OS (HR: 0.70; 95% CI: 0.61-0.79; p<0.01; n=2,369) compared with ET monotherapy. The PFS benefit was seen in both continuing the prior CDK4/6i (HR 0.62; 95%CI: 0.54-0.72; p<0.01; n=1,178) or switching to a different CDK4/6i (HR 0.49; 95%CI: 0.30-0.82; p<0.01; n=638). Subsequent therapy with PI3K/AKT/mTOR inhibitors plus ET also achieved longer PFS (HR: 0.74; 95% CI: 0.61-0.90; p<0.01; n=744), but significantly shorter OS (HR 1.36; 95%CI: 1.09-1.71; p<0.01; n=1,564) compared with ET monotherapy. PFS with chemotherapy was not different from ET monotherapy (HR 0.93; 95%CI: 0.76-1.13; p=0.45; n=879) but exhibited shorter OS (HR 1.55; 95%CI: 1.38-1.72; p < 0.01; n=2,476). Sensitivity analyses including only RCTs, confirmed the greater PFS of maintaining CDK4/6i plus ET compared with ET monotherapy (HR: 0.69 95% CI: 0.57-0.83; p<0.01; n=751). Conclusions: This extensive data pool of RCTs and cohort studies suggests the potential clinical benefit of continued CDK4/6i after disease progression compared to ET monotherapy. Data from phase III trials will further aid in understanding this question. Our data also supports current guideline recommendations of ET-based therapies over chemotherapy as the preferred treatment sequencing in HR+ HER2- mBC.

Overall survival with palbociclib (PAL) plus an aromatase inhibitor (AI) versus AI alone in older patients (pts) with de novo, HR+/HER2− metastatic breast cancer: A SEER-Medicare analysis.

1111 Background: Cyclin-dependent kinase 4/6 inhibitor in combination with endocrine therapy (CDK4/6i) is the current standard of care in first line (1L) treatment for hormone receptor–positive and human epidermal growth factor receptor 2-negative (HR+/HER2–) metastatic breast cancer (mBC). Comparative effectiveness evidence assessing overall survival (OS) outcomes are limited, particularly in older pts. Our primary objective was to compare OS in Medicare pts treated with 1L PAL + AI versus AI alone in the current SEER dataset. Methods: We conducted a retrospective analysis of HR+/HER2–mBC pts using the SEER-Medicare database. Medicare-enrolled pts aged ≥65 years diagnosed with de novo HR+/HER2– mBC between February 1, 2015, and December 31, 2019 were included. Pts were followed from the start of 1L therapy line until death, Medicare disenrollment, enrollment in a health maintenance organization plan, or the end of available study follow-up (December 31, 2020), whichever came first. Stabilized inverse probability of treatment weighting (sIPTW) was the primary method used to balance patient characteristics at baseline, with propensity score matching (PSM) and multivariable CPH regression as sensitivity analyses. Median OS and the hazard ratio (HR) were estimated using the weighted Kaplan-Meier (KM) method and the weighted Cox proportional hazard (CPH) regression model, respectively. Results: Of 779 included pts, 296 received PAL+AI and 483 received AI alone. Median follow-up was 23.9 months for the PAL+AI arm and 18.2 months for the AI alone arm. After sIPTW adjustment, median OS was 37.6 months (95% CI=34.8-42.0) for PAL+AI vs 25.5 months (95% CI=22.0-28.9) for AI alone (HR=0.73, 95% CI=0.59-0.91). Results from the PSM and CPH regression analyses were consistent with the primary analysis. Key patient characteristics are presented (Table). Conclusions: This comparative effectiveness study showed that PAL+AI was associated with significantly prolonged OS vs AI alone in the 1L treatment of older pts with de novo HR+/HER2- mBC treated in US clinical practice using the SEER-Medicare database. Our results add to the body of evidence on the survival benefit of PAL+AI in this population. [Table: see text]

The effects of anlotinib combined with chemotherapy following progression on cyclin-dependent kinase 4/6 inhibitor in hormone receptor-positive metastatic breast cancer.

e13052 Background: Endocrine therapy combined with cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) is the preferred treatment for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC). However, there are currently no recommendations for therapeutic strategies after progression on CDK4/6i-based treatment. This study aimed to examine the efficacy and safety of anlotinib plus chemotherapy in HR+/HER2-MBC after progression on CDK4/6 inhibitors. Methods: We collected data from 32 patients with HR+/HER2– MBC treated with anlotinib plus chemotherapy after progressing on CDK4/6i at Jiangsu Cancer Hospital from March 2020 to October 2023. The median follow-up was 9.1 months (range, 2.0-19.7 months) as of the data cutoff date in October 2023. The primary endpoint was median progression-free survival (PFS), secondary endpoints included objective response rate (ORR), disease control rate (DCR), and adverse events. Results: The median PFS (mPFS) of all patients was 7.6 months [95% confidence interval (CI), 5.75-9.45]. There was no significant difference in mPFS between patients who responded to prior CDK4/6i treatment and those who did not. (8.3 months versus 6.8 months, p = 0.580). Besides, the ORR was 34.4% and DCR was 93.8%. The most frequently observed adverse events were anemia (50.0%), neutropenia (40.6%), thrombocytopenia (34.4%), and epistaxis (34.4%). Dose interruption or reductions due to adverse events occurred in 2(6.3%) and 5 (15.6%) patients, respectively. Conclusions: The study preliminarily demonstrates that anlotinib combined with chemotherapy may be an optional recommendation for patients with HR+/HER2- metastatic breast cancer who have progressed after CDK4/6i.

OPERA-01: A randomized, open-label, phase 3 study of palazestrant (OP-1250) vs standard-of-care for ER+, HER2- advanced or metastatic breast cancer patients after endocrine therapy and CDK4/6 inhibitors.

TPS1135 Background: In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC), endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard-of-care (SOC) treatment in the first-line setting. However, patients develop resistance, most commonly due to acquired mutations in ESR1. Efficacy of available ET post CDK4/6i treatment is limited. Therefore, a significant unmet need exists for patients with ET-CDKi-resistant ER+, HER2– MBC to improve outcomes and delay time to chemotherapy. Palazestrant is an oral small molecule complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds ER and completely blocks ER-driven transcriptional activity, irrespective of ESR1 mutation status. In a phase 1/2 monotherapy study in heavily pretreated patients with ER+, HER2– advanced or MBC (NCT04505826), palazestrant showed a tolerable safety profile, favorable pharmacokinetics and encouraging antitumor efficacy in patients with and without ESR1 mutation at the recommended Phase 2 dose of 120 mg once a day (qd) (1). Methods: OPERA-01 (NCT06016738) is a multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET (fulvestrant, anastrozole, letrozole, or exemestane) in patients with ER+, HER2– MBC that relapsed or progressed on 1-2 prior lines of ET, including a CDK4/6i. Eligible patients are adults who have a confirmed diagnosis of evaluable ER+, HER2– inoperable locally advanced or MBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior treatments must include 1-2 prior lines of ET, last ET duration for ≥6 months; must have received CDK4/6i with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC. No prior chemotherapy in the metastatic setting is permitted. In the dose selection part of the study, 120 patients are randomized to 90 mg qd or 120 mg qd palazestrant or SOC monotherapy. The dose selection will be conducted when 80 patients in both palazestrant arms have had an opportunity to be on treatment for16 weeks. Overall, 510 patients, including patients from the dose selection part, will be randomized to palazestrant or SOC ET. The primary endpoint of progression-free survival will be assessed by blinded independent central review in patients with and without ESR1mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in patients with and without ESR1mutations. The study started recruitment in November 2023. 1. Lin et al. ESMO 2023 MO382. Clinical trial information: NCT06016738 .

Prognostic and Predictive Significance of HER2-low Expression in Metastatic Hormone Receptor Positive Breast Cancer Patients Receiving CDK4-6 Inhibitor Therapy

Objective: This study aimed to analyze the predictive and prognostic value of HER2-low expression in hormone receptor (HR) positive human epidermal growth factor receptor-2 (HER2) negative metastatic breast cancer patients receiving cyclin-dependent kinase-4/6 inhibitor (CDK4/6i) therapy. Methods: This retrospective study included patients who received CDK4/6i plus endocrine therapy (ET). The pathological and clinical characteristics and survival times of the patients were compared and analyzed. Results: Our study included 122 patients. There were HER2-zero 88(72%) and HER2-low 34 (28%) patients. The median progression free survival (mPFS) of all patients who received CDK4/6i+ET was 21 (95% confidence interval (CI),18.5–23.5) months, while mPFS was not reached in the HER2-zero group, and mPFS in the HER2-low group was 12 (95%CI, 6.8–17.1) months (p=0.001). The mPFS was shorter in patients with primary endocrine resistance (6 vs. 21 months, p=0.001). There was a change in the HER2-low status of 26(45%) patients with recurrence compared to the first biopsy. In the HER2-zero and HER2-low groups, 22(25%) and 24(71%) patients, respectively, progressed with CDK4/6i+ET (p=0.001). Estrogen receptor (ER) levels less than and greater than 50% resulted different mPFS (6 and 21 months, respectively) (p=0.025). Median PFS differed based on CDK4/6i+ET combination, treatment line, and best treatment response (all p=0.001). In multivariate analysis, HER2 status(p=0.018), chemotherapy status(p=0.006), best response status with CDK4/6i (p=0.001) for PFS, and best response status with CDK4/6i therapy (p=0.007) for OS were significant. Conclusions: In patients with HR+HER- metastatic breast cancer receiving CDK4/6i therapy, the duration of mPFS was lower in the HER2-low group than that in the HER2-zero group. HER2-low expression is a predictive biomarker of response to CDK4/6 inhibitor therapy.

Abstract PO2-05-03: Costs associated with adverse events in patients receiving treatment for hormone receptor positive/human epidermal growth factor receptor-2 negative metastatic breast cancer

Abstract Background:Adverse event (AE)-related health care resource utilization (HCRU) and costs are an important component in understanding the economic burden associated with managing patients (pts) with cancer and can inform treatment decision-making and access for pts, providers, and payers. At present, there are little data on AE-related HCRU and costs among pts receiving late-line treatment for hormone receptor positive (HR+)/human epidermal growth factor receptor-2 negative (HER2–) metastatic breast cancer (mBC). As such, the objective of this analysis was to describe the AE-related HCRU and costs among pts with HR+/HER2– mBC receiving chemotherapy (CT) who have received prior CT and endocrine-based therapies (ET). Methods: This retrospective study included pts who had at least 1 prior ET, had completed at least 2 CTs, had initiated their third (or greater) CT (post-ET) in the metastatic setting between Jan 2016 and Mar 2022, and were included in the Optum Research Database. The start date for the current line of CT was the index date. Pts were followed until disenrollment from health plan, study end date (Jun 2022), or death. AEs included in this study were based on clinical impact; these AEs were then organized into categories. AE-related HCRU and costs were reported as per pt per month (PPPM) and included outpatient visits, office visits, emergency room visits, inpatient stays, other medical costs (eg, laboratory/ancillary costs), and pharmacy costs. Costs were adjusted to 2021 US dollars using the Consumer Price Index. Results: A total of 769 pts were included with a mean age of 64 y (standard deviation: 13 y) and baseline National Cancer Institute comorbidity score of 0 (44%) or 1–2 (39%). 51% were commercially insured. A total of 715 (93%) pts had ≥1 AE during the follow-up period; the mean total PPPM cost associated with AEs was $7421 (Table 1) and the majority of costs were driven by ambulatory visits (office and outpatient visits: $3846 PPPM; Table 1) and inpatient stays ($3042 PPPM; Table 1). Among pts who experienced AEs, AEs that were associated with the highest mean total PPPM costs included infections, hepatoxicity, gastrointestinal toxicity and renal failure events. The costs associated with infections and renal failures were predominantly driven by inpatient stay costs ($5540 and $3298 PPPM, respectively; Table 1). Conclusions: This real-world analysis suggests that there is high prevalence of AEs associated with CTs in late-line (≥3 CTs) HR+/HER2– mBC, which may lead to a substantial economic burden and suboptimal treatment outcomes. Newer, effective therapies with manageable AE profiles may offer a better benefit-to-risk profile and improve outcomes compared with chemotherapies. Citation Format: Anju Shah, Amy Sainski-Nguyen, Kristin Moore, MK Rehnquist, Rita Nanda. Costs associated with adverse events in patients receiving treatment for hormone receptor positive/human epidermal growth factor receptor-2 negative 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 PO2-05-03.

Abstract PO2-05-02: Real-world experience of patients receiving treatment for hormone receptor-positive/human epidermal growth factor receptor-2 negative metastatic breast cancer: A global analysis of symptoms and side effects

Abstract Background: Advances in treatment for patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor-2 negative (HER2–) metastatic breast cancer (mBC) have improved overall survival, but treatment resistance is common and median survival remains only a few years. These pts usually need chronic therapy and often experience symptoms and side effects. There is limited knowledge on pts’ experiences outside the clinical trial setting, largely because this information is not routinely reported. This analysis leverages a unique database of physician- and pt-reported data to describe symptoms and side effects among a real-world, geographically diverse population of pts receiving treatment for HR+/HER2– mBC. Methods: This retrospective cohort study used Adelphi Disease Specific Programme Real World Data, comprising validated, linked pt and physician questionnaire data from the US, France, Germany, Italy, Spain, and UK. Eligible pts were ≥18 y, currently receiving treatment for advanced BC and not enrolled in a clinical trial. Data were collected between August 2022 and February 2023. Physician surveys provided data on individual pt demographics and disease characteristics, comorbidities, treatment history, and treatment (including adherence). Physicians also reported presence or absence of symptoms and side effects after treatment initiation for each pt they considered. A subset of pts completed one-time validated quality of life (QOL) instruments, including the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and EORTC QLQ-breast (BR23). Results: Data from 1578 pts receiving treatment for HR+/HER2– mBC were analyzed. Mean age was 65-y, 91% were white, 71% had de novo mBC, and 82% had ECOG performance status 0-1 at the start of current treatment. Across all lines of therapy, 71% of pts were receiving endocrine-based therapy, 16% were receiving chemotherapy only, and 13% were receiving other therapies; 40% of all pts were receiving second or later lines of any systemic therapy (2L+). Among all pts, the most common physician-reported symptoms and side effects (in ≥10% of pts) were bone pain (30%), change in appetite (13%), weight loss (12%), neutropenia (11%), and joint/muscle pain (11%). Pts on 2L+ therapy experienced a greater frequency of symptoms and side effects than those on first-line therapy (Table). Of 220 pts who completed QOL questionnaires, the most commonly reported symptoms and side effects (in ≥70% of pts) were feeling tired (87%), worry about future health (80%), general worrying (79%), needing to rest during the day (74%), feeling weak (74%), having trouble doing strenuous activity (71%), and trouble taking a long walk (71%). These were common irrespective of pt age, disease state (recurrent vs de novo), current treatment regimen, and line of therapy. Conclusions: This real-world analysis shows that both physicians and pts identified substantial symptoms and side effects during treatment. These were pervasive across the population and more common in those receiving 2L+ therapy, although it remains unclear which were due to treatment or disease. Thus, it is important to continue to develop treatments and supportive care to improve both clinical outcomes and pt QOL. Citation Format: MK Rehnquist, Ann Partridge, Annabel Lambert, Allison Kurian, Natalia Sadetsky, Emily Freeman, Lisa Carey. Real-world experience of patients receiving treatment for hormone receptor-positive/human epidermal growth factor receptor-2 negative metastatic breast cancer: A global analysis of symptoms and side effects [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 PO2-05-02.

Abstract PO1-04-10: Body Mass Index and Treatment Efficacy in advanced Luminal Breast Cancer: Insights from the GEICAM/2013-02 (PEARL) trial

Abstract Background: Endocrine therapy (ET) and treatment directed against molecular targets (CDK 4/6, PI3K, mTOR) constitute the basis of initial treatments for patients with advanced luminal breast cancer. Most of these treatments are oral and have been developed at a fixed dose, without weight adjusted dosing. There is little evidence on the influence that patients’ weight might have on clinical outcomes of these oral drugs in the context of a randomized clinical trial. The present study analyzes the potential impact of the weight of patients treated in the two cohorts of the PEARL trial (NCT02028507) on Progression-Free Survival (PFS), Overall Survival (OS) and the incidence of side effects in each treatment arm. Methods: GEICAM/2013-02 (PEARL) is a multicenter, phase III randomized clinical trial that enrolled patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) who progressed to a prior aromatase inhibitor. Patients were randomized 1:1 to receive ET + palbociclib or capecitabine. Patient weight was assessed based on baseline body mass index (BMI) categories: normal (BMI ≤25 Kg/m2), overweight (BMI 25-29.9 Kg/m2) and obesity (BMI ≥30 Kg/m2). Cox's stratified proportional hazard model was used for survival analysis. Adverse events were assessed and graded according to National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 4.0. Results: A total of 600 patients were included in the study and all were evaluable for the weight-based analysis, including 301 in the ET +palbociclib arm and 299 in the capecitabine arm. The distribution of patient’s weights is shown in Table 1. For the Intention-to-treat (ITT) population, no significant difference in the median OS was found between the different weight categories (Normal: 32.8 months vs overweight: 31.9 months, [p=0.467]; obese: 32 months [p=0.407]). Specifically, for patients with normal weight, the median PFS was 9.3 months in the ET + palbociclib group compared to 9.0 months in the capecitabine group (hazard ratio (HR) 0.83, 95% confidence interval [CI]: 0.61-1.13; p=0.23). In the overweight group, the PFS was 7.5 months in the ET+palbociclib group and 11.1 months in the capecitabine group (HR 1.17, 95% CI: 0.87-1.58; p=0.30) while for the obese group, the PFS was 5.7 months vs 11.7 months (HR 1.14, 95% CI: 0.82-1.59; p=0.43), respectively. No substantial differences in the incidence of grade ≥ 3 events were observed when considering weight categories in the different treatment groups (capecitabine arm (Normal: 60%, Overweight: 70.4%, Obese: 61.6%) and ET+palbociclib arm (Normal: 74.5%, Overweight: 76.1%, Obese: 51.6%). Conclusions: Our findings, despite not finding statistically significant differences, suggest a potentially clinically relevant trend towards improved PFS with capecitabine in overweight and obese patients compared to those receiving palbociclib plus ET. The impact of weight on the outcomes with fixed-dose oral drugs warrants further investigation in future studies. Table 1. Citation Format: Manuel Alva, Sara López-Tarruella, Christoph Zielinski, Manuel Ruíz - Borrego, Nicholas Turner, Eva Ciruelos, Montserrat Muñoz, Begoña Bermejo, Mireia Margelí, Antonio Antón, Zsuzsanna Kahan, Tibor Csöszi, Maribel Casas, Laura Murillo, Serafin Morales Murillo, Emilio Alba, Einav Nili-Gal Yam, Angel Guerrero, Lourdes Calvo, Juan de la Haba-Rodríguez, Manuel Ramos, Isabel Álvarez, Andrés García-Palomo, María Koehler, José Ángel García-Sáenz, J. Ignacio Chacón, Claire Swift, Christiane Thallinger, Miguel Gil-Gil, Miguel Martín. Body Mass Index and Treatment Efficacy in advanced Luminal Breast Cancer: Insights from the GEICAM/2013-02 (PEARL) 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 PO1-04-10.

Abstract PS15-04: A Phase 1b/2 study of palazestrant (OP-1250), an oral complete estrogen receptor antagonist (CERAN) and selective ER degrader (SERD), with palbociclib in ER-positive, HER2-negative, advanced or metastatic breast cancer patients

Abstract Background: Palazestrant (OP-1250) is a small molecule oral complete estrogen receptor (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 demonstrated improved tumor growth inhibition and shrinkage when combined with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. In a Phase 1/2 monotherapy clinical study in patients with ER-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, palazestrant was well tolerated with demonstrated antitumor efficacy and favorable pharmacokinetics (PK) supporting once a day (qd) dosing at the recommended Phase 2 dose of 120 mg. In this study, pts received palazestrant at escalating doses of 30, 60, 90, and 120 mg qd in combination with palbociclib (125 mg qd) and no dose-limiting toxicities were observed. Palazestrant did not affect palbociclib PK and no drug–drug interactions (DDIs) occurred. Here we report updates on safety, efficacy, and PK from the ongoing study of palazestrant in combination with palbociclib. Methods: Patients with advanced or metastatic breast cancer with progression on or after ≤1 line of endocrine therapy (prior CDK4/6 inhibitor therapy and ≤1 chemotherapy allowed) were enrolled to receive oral palazestrant 120 mg qd with oral palbociclib 125 mg qd for 21 of 28 days (NCT0526610). Results: As of May 12, 2023, 33 patients have been treated with palazestrant in combination with palbociclib; 12 pts were dosed in the dose-escalation phase and 21 patients were dosed in the dose-expansion phase of the study. Twenty-two patients (67%) received prior CDK4/6 inhibitor therapy; 15 patients received prior palbociclib. Thirteen of 25 patients (52%) with available baseline ctDNA had an ESR1 mutation. The most common (≥20%) treatment-emergent adverse events (TEAEs) were neutropenia, nausea, vomiting, constipation, and diarrhea. Most of these events were grade 1 or 2. The most common grade 3 or 4 related AE was neutropenia (18/33 [55%] were grade 3; 3/33 [9%] were grade 4). The steady-state exposure of palazestrant when dosed with 125 mg palbociclib was consistent with the monotherapy study. Palbociclib exposure at steady-state was comparable to published monotherapy data when combined with palazestrant at all dose levels tested. As of the data cut-off, there were 4 partial responses (2 confirmed) out of 19 response-evaluable patients, with a clinical benefit rate (CBR) of 42% (8/19) across all patients and 67% (6/9) in patients with ESR1 mutations. Conclusions: Palazestrant and palbociclib dosed in combination were well tolerated with a safety profile consistent with the individual profiles of each drug as monotherapy, and there were no DDIs. Tumor responses and clinical benefit were observed in this population of patients, including those who received prior CDK4/6 inhibitors. Expanding on our previous report, these data provide the rationale to continue advancing the clinical development of palazestrant with the approved dose of palbociclib. Updated data will be presented. Citation Format: Arlene Chan, Daphne Day, Phuong Dinh, Michael Slancar, Janine Lombard, Vinod Ganju, Nicole McCarthy, Rosalind Wilson, Demiana Faltaos, Gurpreet Mathauda-Sahota, Caitlin Murphy. A Phase 1b/2 study of palazestrant (OP-1250), an oral complete estrogen receptor antagonist (CERAN) and selective ER degrader (SERD), with palbociclib in ER-positive, HER2-negative, advanced or metastatic breast cancer patients [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 PS15-04.