Prior Line Of Endocrine Therapy Research Articles

Abstract PO3-18-09: OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy

Abstract Background: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), adding a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to endocrine therapy (ET) has improved outcomes and is the current standard-of-care treatment in the first-line setting. However, resistance to first-line treatment develops in most patients (pts), which is often attributed to acquired mutations in ESR1. Limited data exist for ET-based treatment options after progression on prior ET and CDK4/6 inhibitors, and most pts will transition to chemotherapy for further treatment. Therefore, there is a significant unmet need for more effective ET in pts with ER-positive, HER2-negative MBC to improve outcomes and delay time to chemotherapy. 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 demonstrated better tumor shrinkage in ESR1-wt and ESR1-mut models when compared to fulvestrant; it also showed efficacy in brain metastasis models. In a phase 1/2 monotherapy study in pts with heavily pretreated ER-positive, HER2-negative advanced breast cancer (BC) or MBC (NCT04505826), palazestrant showed a tolerable safety profile, promising antitumor efficacy, and favorable pharmacokinetics (PK) supporting once a day (qd) dosing. The recommended Phase 2 dose of palazestrant is 120 mg qd. Methods: The OPERA-01 trial is an international, multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to standard-of-care ET (fulvestrant, anastrozole, letrozole, or exemestane) in pts with ER-positive, HER2-negative advanced BC or MBC that has relapsed or progressed on 1 or 2 prior lines of ET for MBC, which includes a CDK4/6 inhibitor. Eligible pts are women (pre- or post-menopausal) or men who have a confirmed diagnosis of ER-positive, HER2-negative locally advanced evaluable BC or MBC not amenable to curative therapy. ER and HER2 status are determined according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Patients must have Eastern Cooperative Oncology Group performance status 0 or 1. Prior treatments must include 1 or 2 prior lines of ET as monotherapy or in combination with a CDK4/6 inhibitor for MBC; must have received CDK4/6 inhibitor in combination with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC; most recent ET given for ≥6 months. Prior chemotherapy in the metastatic setting is not permitted. Patients (N∼500) are randomized to palazestrant or standard-of-care ET monotherapy, and are stratified by ESR1 mutation status, prior lines of ET for advanced disease (1 vs 2 lines), and presence or absence of visceral disease. The primary endpoint of progression-free survival will be assessed by blinded independent central review in pts 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 pts with and without ESR1 mutations. The study is planned to be conducted globally. Citation Format: Arlene Chan, Jane Meisel, Komal Jhaveri, Joo Hyuk Sohn, Meritxell Bellet- Ezquerra, Jason Schroeder, Mark Shilkrut, Barbara Pistilli. OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-09.

Abstract RF02-03: Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08)

Abstract Background: Trastuzumab deruxtecan (T-DXd) is approved in over 40 countries for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (a score of 1+ on immunohistochemistry [IHC] analysis or an IHC score of 2+ and negative results on in-situ hybridization) breast cancer who have received prior chemotherapy in the metastatic setting or who developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. DESTINY-Breast08 (DB-08) was designed to establish the safety, tolerability, and preliminary activity of T-DXd in combination with widely used standard of care therapies in HER2-low hormone receptor (HR)+ metastatic breast cancer (mBC). Results reported here are from the dose-expansion stage of the Phase 1b, multicenter, open-label, parallel-assignment DB-08 study arms investigating T-DXd–endocrine therapy (ET) combinations [NCT04556773]. Methods: Eligible patients had centrally confirmed HER2-low advanced/mBC with measurable disease per RECIST 1.1 and were documented as HR+. Among patients with mBC, ≤1 prior line of ET ± a targeted therapy was allowed, and prior chemotherapy in the mBC setting was exclusionary. Patients received T-DXd 5.4 mg/kg intravenously (IV) every three weeks (Q3W) + anastrozole 1 mg orally daily (T-DXd + ANA) or T-DXd 5.4 mg/kg IV Q3W + fulvestrant 500 mg intramuscularly Q4W, with a 500 mg loading dose on Cycle 1 Day 15 (T-DXd + FUL). Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival, duration of response (all evaluated by investigator per RECIST 1.1), and overall survival (OS). Data cutoff (DCO) was ~24 weeks after the last patient in each arm had received study treatment. Results: As of February 20, 2023, 21 patients in the T-DXd + ANA arm and 20 patients in the T-DXd + FUL arm had received study treatment. Median age was 55 and 66 years, 67% and 75% of patients received a prior line of ET ± a targeted therapy for mBC, 33% and 25% had no prior line of treatment for mBC, and median follow up in censored patients was 12.1 months (range 4.0, 17.3) and 8.5 months (range 1.3, 15.1) in the T-DXd + ANA and T-DXd + FUL arms, respectively. Adverse events (AEs) occurred in 95.2% (20/21) of patients in the T-DXd + ANA arm and 100% (20/20) of patients in the T-DXd + FUL arm, with AEs ≥Grade 3 occurring in 47.6% (10/21) and 55.0% (11/20) of patients in each arm, respectively. The most common any-grade AEs, occurring in ≥30% of patients in either arm, are reported in the Table. Three (15%) adjudicated drug-related interstitial lung disease/pneumonitis events were reported in the T-DXd + FUL arm (all Grade 2; at DCO, one case had resolved, one was resolving, and one was not resolved); none were reported in the T-DXd + ANA arm. AEs were manageable by drug interruption and dose reduction. Confirmed ORR was 71.4% (15/21; 95% confidence interval [CI] 47.8, 88.7) in the T-DXd + ANA arm, and 40.0% (8/20; 95% CI 19.1, 64.0) in the T-DXd + FUL arm (Table). OS data were not mature at this DCO. Conclusions: Safety profiles for T-DXd-ET combinations were generally comparable to T-DXd monotherapy and manageable with dose modification and routine clinical practice. T-DXd in combination with anastrozole or fulvestrant was active in first- or second-line treatment of patients with HER2-low HR+ mBC. Citation Format: Komal Jhaveri, Fabrice André, Erika Hamilton, Peter Schmid, Carey Anders, Laura Testa, Inna Ganshina, Yen-Shen Lu, Seock-Ah Im, Robyn Young, Magdalena Wrona, Caron Lloyd, Yiwen Zhang, Sherene Loi. Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08) [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 RF02-03.

Abstract PS17-08: A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies

Abstract Background The combination of an aromatase inhibitor with a CDK4/6 inhibitor is the mainstay of first-line endocrine therapy (ET) for locally advanced or metastatic HR+/HER2− breast cancer (LA/mBC). Management of recurrent disease in the post-CDK4/6 inhibitor setting includes additional lines of ET single agent or in combination with a targeted agent. For patients with HR+/HER2− LA/mBC tumors, fulvestrant monotherapy as the second- or third-line therapy has limited activity with a median PFS of 1.9-3.6 months. Effective targeted treatments for these patients are needed to maintain quality of life, improve survival, and delay the initiation of cytotoxic chemotherapy. Methods This ongoing single arm, open-label global study (NCT04851613) is to evaluate the efficacy and safety of the combination therapy of afuresertib (a pan-AKT inhibitor) plus fulvestrant in patients with HR+/HER2− LA/mBC. Eligible patients must have received 1-2 prior lines of ET. Patients may have prior treatment of CDK4/6 inhibitors (up to 1 therapy), and/or up to 1 line of chemotherapy. Patients received afuresertib (125 mg PO, QD) in combination with fulvestrant (500 mg IM; Day 1 and 15 in Cycle 1, and Day 1 in subsequent 28-day cycles). The safety of the initial treatment doses of the combination therapy was evaluated in the first 6 patients during the Cycle 1 safety run-in period. Radiographic assessment per RECIST 1.1 was performed every 8 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included safety and tolerability of the combination therapy and pharmacokinetic characterization. Results Twenty patients (1 male and 19 females, 3 in the US and 17 in China) were enrolled between May 2022 and April 2023. As of the data cut-off date of May 26th, 2023, 10 patients had discontinued the study treatment (9 due to disease progression, 1 due to patient’s withdrawal of consent) and 10 patients were still in treatment. Of the 19 patients who had at least one post-baseline tumor assessment, 4 patients observed confirmed Partial Response (cPR), 12 had best overall response of Stable Disease, and 3 had Progressive Disease (PD). The Disease Control Rate is 84%. Of the 15 patients who had at least 2 tumor assessments or who discontinued treatment early due to PD, the confirmed ORR is 26.7% (4 cPR). No dose modification was required during the safety run-in. The most common treatment-emergent adverse events (TEAEs, > 20% of patients) of all grades were hyperglycemia (50%), diarrhea (45%), ALT/AST increase (40%), nausea (35%), rash (35%), hypercholesterolemia (35%), and anemia (30%), the majority of which were Grade 1. Grade 3 AEs were reported in 4 patients, including diarrhea (1 patient), WBC increase (1 patient), creatine phosphokinase increase (1 patient), and ALT/AST increase and rash (1 patient). No SAE or TEAE >= Grade 4 were reported. No patient discontinued treatment due to TEAE. Conclusions The preliminary data from the combination therapy of afuresertib plus fulvestrant has shown promising efficacy with a well-tolerated safety profile in patients with HR+/HER2− LA/mBC who progressed on 1-2 prior lines of standard of care therapies. These results support further evaluation of this combination therapy in this patient population in an upcoming phase III study. Citation Format: Binghe Xu, Pin Zhang, Tao Sun, Ying Wang, Zhongsheng Tong, Sneha Phadke, Trevor Feinstein, Pengfei Guo, Jing Qu, Xiaoyu Wang. A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-08.

Preventing alpelisib-related hyperglycaemia in HR+/HER2−/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial

Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC). Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100mg/dL [<5.6mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140mg/dL [5.6-7.8mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n=48) and B (n=20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P<0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P=0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Novartis Pharmaceuticals.

A phase II, multicenter, open-label study of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancer: ALEPRO trial

BackgroundLow-grade serous and endometrioid ovarian cancers and adult-type granulosa cell tumors are rare ovarian malignancies that show high estrogen receptor positivity. Recurrences of these subtypes of ovarian cancer are often...

The real-world modeling of benefits demonstrated in major clinical trials on 2 HR+/HER2− metastatic breast cancer treatment with CDK4/6 inhibitor in the US: PALOMA-2 and MONALEESA-3.

e13070 Background: This retrospective study addresses the question of whether real-world treatment with CDK4/6 inhibitors in combination with Endocrine Therapy (ET) for advanced hormone receptor positive (ER+) HER2 negative breast cancer yields similar benefits as reported by the major clinical trials: PALOMA-2 and MONALEESA-3. Methods: This study used the nationwide electronic health record-derived-Flatiron Health de-identified database to test the benefits demonstrated in major clinical trials on MBC patients under treatment with CDK4/6 + Letrozole (PALOMA-2) or CDK4/6 + Fulvestrant (MONALEESA-3). Regarding PALMOMA-2, a total of 1,774 patients with ≥ 3 months of follow-up received either CDK4/6 + Letrozole (n=1,277) or Letrozole alone (n=497) as the first line of treatment between February 3, 2015, and November 02, 2021. To test the benefits reported in MONALEESA-3, 1,187 patients are selected who were treated with either CDK4/6 + Fulvestrant (n=786) who received no or up to 1 line of prior ET or Fulvestrant alone (n=401). We conducted inverse probability weighting to balance the baseline demographic and clinical characteristics between patients in all subgroups. Kaplan-Meier method and Cox proportional hazards were used to test for the association of CDK4/6 treatment on rwPFS as the primary outcome and rwOS as the secondary outcome while adjusting for patient characteristics (e.g., age, race, ECOG PS value, health insurance, etc). Results: The real-world analysis of PALOMA-2 showed similar results as demonstrated in the clinical trials. The findings showed receiving CDK4/6 + Letrozole as the first-line treatment was associated with significantly longer median PFS compared to receiving Letrozole alone (28.3 vs 18 months; hazard ratio [HR], 0.57; 95% CI, 0.46–0.69; P &lt; 0.0001). Median OS was 56.5 months for the group with first line CDK4/6 + Letrozole and 50.4 months for the group with Letrozole alone (HR=0.76, 95% CI, 0.61–0.93, P-value = 0.01). Analysis of real-world practices of MONALEESA-3 also endorsed the results reported from the trial. Median PFS was 17.5 months for the group treated with CDK4/6 + Fulvestrant who received no or up to 1 line of prior ET, while it was about 14.3 months for patients treated with only Fulvestrant (HR=0.64, 95% CI, 0.52–0.80, P-value &lt; 0.0001). Consistent OS benefit was observed in patients treated with CDK4/6 + Fulvestrant compared to those treated with only Fulvestrant (44.72 vs 35.83 months; hazard ratio [HR], 0.70; 95% CI, 0.52–0.94; P &lt; 0.0001). Conclusions: Consistent with what was reported in major clinical trials: PALOMA-2 and MONALEESA-3, receiving CDK4/6 inhibitor plus endocrine therapy (Letrozole or Fulvestrant) was associated with improved progression free survival compared with patients treated with ET alone in this “real-world” population of patients with HR+/HER2− MBC.

Treatment patterns and clinical outcomes following endocrine resistance among with HER2-low metastatic breast cancer: Retrospective observational study.

e13069 Background: Endocrine therapy (ET) ± CDK 4/6 inhibitors is a common initial treatment for HR+/HER2-low (IHC 1+ or IHC2+/ISH-) metastatic breast cancer (mBC). However, many patients eventually progress on ET-based regimen and receive subsequent chemotherapy (CT). This study aimed to describe treatment patterns and outcomes following endocrine resistance among HR+/HER2-low mBC patients in U.S community oncology practices. Methods: Participating oncologists from Cardinal Health’s Oncology Provider Extended Network (OPEN) provided data from the medical charts of adult patients with HR+/HER2-low mBC who received at least two lines (2L) of systemic therapy, with first line (1L) initiated between Feb 19, 2016, and Dec 31, 2018. Analysis was performed among patients who received a subsequent chemotherapy (CT) after progression on their last observed line of ET-based regimen. Patient characteristics and treatment history were summarized descriptively. Kaplan-Meier analyses of treatment outcomes, including physician-reported real-world progression free survival (rwPFS), time to treatment response (TTR) and time to treatment discontinuation (TTD) were performed. Results: 150 HR+/HER2-low mBC patients who received subsequent chemotherapy after ET resistance were included [mean age: 61±11 years, 57.3% were white and 32.7% were black]. The proportion of patients who stopped ET after 1L, 2L and ≥3L of ET were 23.3% (n=35), 70.7% (n=106) and 6.0% (n=9), respectively. The mean duration of ET-based regimens was 29.7 (SD: 13.12) months. Among patients who stopped ET after 1L (n=35), most patients received fulvestrant + palbociclib (48.6%) in 1L prior to switching to CT. Among those who stopped ET after 2 or more lines (n=115), most patients received letrozole + palbociclib (57.4%) in 1L and fulvestrant (46.1%) in 2L. The most common CT regimen utilized was capecitabine (47.0%) followed by paclitaxel (28.0%). The median rwPFS on CT was 8.12 months (95% CI 7.36-9.24), with slightly shorter median rwPFS among those who stopped ET after 1L (7.82 months, 95% CI 7.07-9.53) vs. 2L+ (8.19 months, 95% CI 6.97-9.99). The median TTD of CT was 7.82 months (95% CI 7.07-8.61) and TTR was 4.96 months (95% CI 4.24-5.72), with similar estimates observed between patients who stopped ET after 1L and 2L+. Conclusions: In this small sample of HR+/HER2-low mBC patients, most patients switched to CT after receiving two lines of ET based regimens. Following ET resistance, durability of response with subsequent CT was short and similar irrespective of number of prior lines of ET based regimens. This preliminary chart review study highlights the unmet need for a more effective therapeutic alternative to CT after ET for HR+/HER2-low mBC patients. Further research using larger sample and more robust clinical data is warranted to confirm the study findings.

Randomized trial of fixed dose capecitabine compared to standard dose capecitabine in metastatic breast cancer: The X-7/7 trial.

1007 Background: In metastatic breast cancer (MBC), oral capecitabine prescribed at the FDA approved dose of 1250 mg/m2 twice daily, 14 days on followed by 7 days off, is associated with poor tolerance and high discontinuation rates. Mathematical models suggest a fixed dose, dose dense (7 days on, 7 days off) schedule may be optimal for capecitabine efficacy. We conducted a randomized trial to compare the efficacy and tolerability of fixed-dose capecitabine, 1500 mg twice daily, 7 days on, 7 days off (FD) to the FDA approved dose and schedule (SD). Methods: Females with MBC and any prior lines of endocrine therapy or chemotherapy were included. HER-2 positive patients were allowed with concurrent trastuzumab. Patients were stratified by line of chemotherapy (first or subsequent), measurable disease, and ER status, and randomized 1:1 to either FD or SD. The primary endpoint was 3-month progression free survival (PFS). Additional endpoints included PFS and overall survival (OS). Capecitabine related toxicities were solicited and graded at each visit. Results: Between October 2015 and April 2021, 153 patients were enrolled (N=80 FD, N=73 SD) . 78% were hormone receptor positive/HER-2 negative, 11% each were HER-2 positive and triple negative. The 3-month PFS was 76% in the FD arm and 76% in the SD arm (HR=1.01; 95% CI, 0.52 to 1.94; p=0.99). Landmark analysis of PFS at 12, 24 and 36 months is reported. Non-proportional hazards were detected, so restricted mean survival time (RMST) was used to report estimates of effect. PFS (restricted mean) at 36 months was 13.9 months in the FD arm versus 14.6 months in the SD arm (hazard ratio for progression or death, 1.31; 95% CI, 0.56 to 1.15; p=0.24). OS (restricted mean) at 36 months was 21.2 months in the FD arm versus 19.6 months in the SD arm (hazard ratio for death, 0.80; 95% CI, 0.55 to 1.81; p=0.27). Toxicity related treatment discontinuation occurred in 21 patients (28.8%) in the SD arm compared to 6 patients (7.5%) in the FD arm (p&lt;0.0006). Grade 2-4 toxicities (Table) occurred more frequently in patients receiving SD capecitabine (49.3%) as compared to FD capecitabine (25.0%) (p=0.0018). Conclusions: Fixed dose capecitabine (1500 mg twice daily) on a 7/7 schedule has less toxicity and similar survival when compared to standard BSA-based dosing on a 14/7 schedule in MBC. Clinical trial information: NCT02595320 . [Table: see text]

Abstract P3-07-04: A multicenter, single-arm, open-label Phase I study of AN1004 (Pelareorep) oncolytic virus plus paclitaxel in Chinese patients with Hormone receptor-positive and HER2-negative advanced/metastatic breast cancer (REO 026-1)

Abstract A multicenter, single-arm, open-label Phase I study of AN1004 (Pelareorep) oncolytic virus plus paclitaxel in Chinese patients with Hormone receptor-positive and HER2-negative advanced/metastatic breast cancer (REO 026-1) Background: AN1004, also known as Pelareorep is an intravenously delivered immuno-oncolytic unmodified reovirus being evaluated to treat multiple malignancies. AN1004 was shown to be safe and well-tolerated in both monotherapy and combination therapy in multiple clinical trials in North American and European populations, including two completed and two ongoing breast cancer studies. The completed phase 2 study (NCT01656538) in advanced/metastatic breast cancer demonstrated improved median overall survival (OS) in Canadian patients treated with AN1004 plus paclitaxel (PTX) versus PTX alone, and the greatest benefit in OS was observed in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) subtype. Since there has been no clinical trial assessing AN1004 in Chinese population, a bridging study (REO 026-1) was initiated to evaluate its safety and tolerability in combination with PTX in Chinese patients with HR+/HER2- advanced/metastatic breast cancer. Methods: Eligible Chinese patients must be female with good performance status (ECOG PS: 0 or 1), have had histopathological diagnosis with HR+/HER2- advanced/metastatic breast cancer, and were previously treated with at least one endocrine therapy with no more than one line of chemotherapy regimen for recurrent/metastatic disease. Patients are intravenously infused with AN1004 at escalating dose levels of 1.5 × 10^10 (Dose Level 1, DL1 group), 3 × 10^10 (DL2 group) and 4.5 × 10^10 TCID50 (DL3 group) on days 1, 2, 8, 9, 15, and 16 every 28 days plus PTX 80 mg/m^2 intravenously on days 1, 8, and 15 every 28 days. Three to six patients will be enrolled in the DL1 group, and 6 patients will be enrolled in each of the DL2 and DL3 groups. The primary objective is to assess the safety and tolerability of AN1004 in combination with PTX. A secondary objective is to evaluate the preliminary activity of AN1004 and PTX combination therapy. Results: By the data cutoff date of June 2nd, 2022, a total of 10 female patients were enrolled, with a median age of 58 years (range 36-67). Two (20%) patients had failed more than one prior line of endocrine therapy for advanced/metastatic disease, and 3 (30%) patients were previously treated with a CDK4/6 inhibitor. Three patients were treated with AN1004 and PTX in DL1 group; six patients were treated in DL2 group; one patient was treated in DL3 group. The most common (&amp;gt;50%, and/or liver function related) treatment emergent adverse events (TEAEs) included neutrophil count decreased and white blood cell count decreased (90% each), hypertriglyceridemia (70%), pyrexia, ALT increased and anemia (60% each), and AST increased (40%). Three (30%) patients had Grade 3 or above TEAEs, including neutrophil count decreased (30%), white blood cell count decreased (20%), hypertriglyceridemia, ALT increased and GGT increased (10% each). No serious AE or AE leading to treatment discontinuation was reported to date. One patient was not evaluable for dose-limiting toxicity (DLT) due to early withdrawal, and there were no DLTs observed in the 9 evaluable patients. Among the 10 treated patients, 2 (20%) patients achieved confirmed partial response (PR), 2 (20%) patients achieved unconfirmed PR, and 5 (50%) patients showed stable disease (SD). One patient in DL1 group achieved a confirmed PR and later progressed, and the other 8 patients who had PR or SD continue to receive treatment as of the data cut. Conclusion: To date, intravenous administration of AN1004 plus PTX is safe and well-tolerated in Chinese patients with advanced/metastatic breast cancer, and demonstrates anti-tumor activity. Citation Format: Wei Li, Yongmei Yin, Jiuwei Cui, Wenna Wang, Yan Liang, Hongming Liang, Binghe Xu. A multicenter, single-arm, open-label Phase I study of AN1004 (Pelareorep) oncolytic virus plus paclitaxel in Chinese patients with Hormone receptor-positive and HER2-negative advanced/metastatic breast cancer (REO 026-1) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-04.

Abstract P3-07-15: Preliminary data from a Phase 1b dose escalation study of OP-1250, an oral CERAN, in combination with palbociclib in patients with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer

Abstract Background: OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) that binds the ligand binding domain of the ER and completely blocks ER-driven transcriptional activity. CDK4/6 inhibitors in combination with endocrine therapy have improved progression free survival and overall survival for patients (pts) with metastatic breast cancer (MBC) in the first- and second-line settings. However, most patients will progress and newer combinations such as with OP-1250 may provide improved clinical outcome. OP-1250 potently inactivates both wild-type ER and mutant forms of ER. The latter confers ligand independent activity and is a mechanism of resistance to standard of care endocrine therapies. In preclinical studies, OP-1250 in combination with palbociclib demonstrated synergistic activity in models of wild-type ER and those containing ESR1 activating mutations, and in models of brain metastasis. A Phase 1/2 monotherapy study of OP-1250 is ongoing in MBC subjects who have received 1 or more prior endocrine therapies (NCT04505826). Monotherapy is well tolerated and the recommended phase 2 dose is 120 mg QD. The aim of this combination trial is to define the maximum tolerated dose (MTD), safety, tolerability, and pharmacokinetics (PK) of OP-1250 in combination with palbociclib. Methods: Eligibility criteria include pts with MBC or locally advanced breast cancer who have received no more than 1 prior line of endocrine therapy (prior CDK4/6 inhibitors and one line of chemotherapy are permitted) and measurable or non-measurable disease. Using a 3+3 design, cohorts are sequentially enrolled, and pts receive escalating doses of OP-1250 orally QD continuously in combination with 125 mg of palbociclib orally for 21 of 28 days. Pts are evaluable for dose limiting toxicities (DLTs) if &amp;gt;75% of both treatments were administered within the first 28-day treatment cycle. Blood is collected for PK on cycle 1 days 1, 2 and cycle 2 days 15, 16 for OP-1250 and cycle 1 day 15 for palbociclib. PK profiles, exposure parameters, and drug-drug interactions (DDIs) are assessed. Pts are monitored for adverse events (AE) and tumor assessments (RECIST 1.1) are conducted every two cycles. Results: As of July 7, 2022, 9 pts were evaluable for DLTs after 28 days of treatment in dose levels 30 mg, 60 mg, and 90 mg of OP-1250 in combination with palbociclib. No DLTs occurred at any of the dose levels. As of May 13, 2022, of the 7 pt safety data set, the most common Grade 1/2 treatment emergent adverse events (TEAE), which occurred in 2 patients, were nausea, gastroesophageal reflux, vomiting, and fatigue. Grade 3 neutropenia occurred in 4 pts and all were attributed to palbociclib by the investigator. No Grade 4 events were observed. OP-1250 was highly bioavailable and showed dose proportional exposure in combination with palbociclib. The single and multiple dose exposure of OP-1250 was consistent with that observed in the monotherapy study, indicating an absence of effect of palbociclib on OP-1250 PK. 90 mg steady-state evaluation is ongoing. Palbociclib concentrations at steady state did not demonstrate a meaningful difference from published exposure parameters for the three dose levels evaluated, indicating an absence of DDI. Conclusions: In the first three cohorts of OP-1250 and palbociclib, the combination was well tolerated and no DLTs occurred. There were no clinically significant DDIs observed between OP-1250 and palbociclib at the doses evaluated and exposure of each drug was consistent with observed monotherapy exposure levels. Dose escalation of OP-1250 continues to 120 mg, to be followed by dose expansion. Updated data will be presented. (NCT05266105) Citation Format: Arlene Chan, Daphne Day, Rina Hui, Nicole McCarthy, Rosalind Wilson, Demiana Faltaos, Morena Shaw, Caitlin Murphy. Preliminary data from a Phase 1b dose escalation study of OP-1250, an oral CERAN, in combination with palbociclib in patients with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-15.

271P Eribulin (E) plus endocrine therapy (ET) in patients (pts) with HR[+]/HER2[-] metastatic breast cancer (mBC) after progression on previous ET: The REVERT study

Most pts with luminal mBC progress to ET +/- targeted therapy. E treatment promotes intrinsic subtype changes in the neoadjuvant setting, shifting luminal B to luminal A tumors. REVERT (NCT03795012) explores if E increases hormonal sensitivity in aromatase inhibitor (AI)-pretreated luminal mBC pts. REVERT is a multicenter, randomized, non-comparative phase II trial in which pts with AI-resistant, HR[+]/HER2[-], mBC were randomized (1:1) to receive E (1.23 mg/m2 on days 1 and 8 of every 21-day cycle) or E plus AI. Pts were stratified by previous CDK4/6 inhibitors. Pts must have received at least one anthracycline- and/or taxane-based regimen in the (neo)adjuvant setting and up to 3 prior lines of ET in the metastatic setting. Previous chemotherapy for mBC was not allowed. The primary endpoint was the overall response rate (ORR) as per RECIST v. 1.1 in E+AI arm. Secondary endpoints included ORR in E pts and progression-free survival (PFS) and safety as per the NCI-CTCAE v.4.0.3 in both arms. The target sample size was 60 pts. An interim analysis was planned with 22 recruited pts based on two-stage Simon design. Between June, 2019 and January, 2021, a total of 22 pts from 7 centers in Spain were enrolled. Median age was 63.0 (range 50-77) years, 21 (95.5%) pts had visceral disease and 8 (36.4%) pts presented ≥3 metastatic sites. The trial was terminated early on March 31, 2021 with 8 pts (36.4%) remained on treatment. ORR was achieved in 4 (26.7%; 95% CI: 7.8 to 55.1) of 15 pts in E+AI arm and 2 (28.6%; 95% CI: 3.7 to 71.0) of 7 pts in E arm (p=1). Median PFS was 6.3 months(mo) with E+AI and 6 mo with E alone (HR: 1.1; 95% CI, 0.3 to 3.9; p=0.932). A significant interaction (p=0.1) between treatment arm and pts with previous CDK4/6 inhibitor (HR= 0.3 favors E+AI) or without previous CDK4/6 inhibitor (HR = 3.2 favors E) was observed. All grade and grade ≥3 adverse events were similar in both arms, being neutropenia and fatigue the most frequent. Although superiority of E+AI over E single therapy seems unlikely in this scenario, E+AI combination deserves further investigation in pts with ET-resistant, HR[+]/HER2[-] mBC, after progression to CDK4/6 inhibitors.

Abstract 5247: Using real-world data to evaluate the performance of endocrine therapies in ER+/Her2- metastatic breast cancer patients

Abstract Background Real-world data (RWD) has been increasingly used in drug development. A reliable evaluation of efficacy for current treatments is challenging with very limited publication data of clinical trials available. The RWD provides a unique value and an alternative way to achieve such goal. Use data from metastatic Breast Cancer (mBC) patients in the real world clinical practice, we examine the treatment patterns and durations of different endocrine monotherapies in various clinical settings. Methods We obtained Flatiron Health subject-level mBC data set which consists a group of 20645 mBC patients. The analysis set consisted of subjects who were ER+/Her2-/(PgR+ or PgR-), received at least one prior line of CDK4/6 inhibitor (mono or combo) and one prior line of endocrine therapy (mono or combo) in the mBC settings, and had an ECOG performance score&amp;lt;=2. Time to treatment discontinuation (TTD) was used as real world endpoint. We assessed the median TTD of endocrine monotherapies in various mBC ER+/Her2- patient subgroups using Kaplan-Meier estimates. Result Out of all subjects in the mBC RWD database, 263 subjects met the inclusion criteria and were included in the analysis set. Among all 263 ER+/Her2- subjects, the median TTD of endocrine monotherapies was 3.0 months (95% CI: 2.8-3.7 months, N=263) in all subjects, 3.7 months (95% CI: 3.0-4.3 months, N=186) in PgR+ group and 2.1 months (95% CI: 1.9-2.9 months, N=77) in PgR- group. Among 186 ER+/PgR+/Her2- subjects, 1) the median TTD of endocrine monotherapies was 3.3 months (95% CI: 2.8-4.6 months, N=153) in ECOG&amp;lt;=1 group and 3.7 months (95% CI: 3.2-6.0 months, N=33) in ECOG=2 group; 2) the median TTD of endocrine monotherapies was 3.4 months (95% CI: 2.3-5.4 months, N=47) in Aromatase inhibitors group, 3.7 months (95% CI: 2.8-5.6 months, N=110) in Fulvestrant group, and 3.1 months (95% CI: 2.3-6.0 months, N=29) in Tamoxifen group; 3) the median TTD of endocrine monotherapies was 3.6 months (95% CI: 2.8-5.9 months, N=74) in one prior treatment line group, 3.7 months (95% CI: 2.0-6.0 months, N=57) in two prior treatment lines group, and 3.7 months (95% CI: 2.3-5.4 months, N=55) in &amp;gt;=3 prior treatment lines group. Conclusion By investigating the RWD, we observed that the PgR status is prognostic in post CDK setting: endocrine monotherapies in PgR+ group has longer TTD compared to PgR- group in ER+/Her2- mBC subjects. By further looking into ER+/PgR+/Her2- subjects, we observed different treatment durations of endocrine therapies in various clinical scenarios, which may provide a helpful understanding of the mBC monotherapy treatments. Citation Format: Tenghui Chen, Zhaojie Zhang, Lei Gao, Catherine Scholz, Antonio Gualberto, Lihua Yu, Kun Yu. Using real-world data to evaluate the performance of endocrine therapies in ER+/Her2- metastatic breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5247.

DOLAF: An international multicenter phase II trial of durvalumab (MEDI4736) plus olaparib plus fulvestrant in patients with metastatic or locally advanced ER-positive, HER2-negative breast cancer selected using criteria that predict sensitivity to olaparib.

TPS1116 Background: PARP inhibitors have documented clinical activity in patients with HER2 negative breast cancer (BC) and a germline pathogenic variant (PV) in BRCA1 or BRCA2. Defects in other genes involved in homologous recombination DNA repair (HRR) or mismatch repair pathway (microsatellite instability MSI) have been associated with preclinical cellular sensitivity to PARP inhibitors. Several preclinical and clinical studies have suggested synergy between immune checkpoint blockade and PARP inhibitors. Indeed, tumors with deficiency in HRR have higher mutagenic potential and produce a larger number of neoantigens. Around 60% of BC with a germline PV in BRCA1/ 2 are ER+/HER2- tumors, and the ER-pathway remains a key target of their therapy. The combination of PARP inhibitors with endocrine therapy has shown to be superior to monotherapy. Methods: DOLAF is an open-label, international, multicentric, phase II trial assessing the combination of olaparib, fulvestrant, and durvalumab in ER+/HER2- metastatic or locally advanced BC with somatic or germline PV in BRCA1, BRCA2 or other genes implicated in the HRR pathway (ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status or other actionable genes ( AKT1, ESR1, FGFR1, FGFR2, FGFR3, and PIK3CA) all based on central tumor NGS. Further an amendment in May 2021, patients with only alterations in these other actionable genes can no longer be included. Patients must have received 1 prior line of endocrine therapy for their metastatic BC, including CDK4/6 inhibitor and maximum of 1 line of chemotherapy in the metastatic setting. Patients receive olaparib (twice daily at 300 mg), fulvestrant (2 intramuscular injections of 250 mg every 28 days) and durvalumab (1500 mg intravenous every 4 weeks). The primary objective is to evaluate the progression-free survival rate at 24 weeks. Secondary endpoints include safety, overall survival, objective response rate, in the overall population and in the germline BRCA mutated population. With an optimum two-stage Simon design, α = 2.5%, β = 5%, p0 (probability of inefficiency maximum) = 50%, p1 (probability of minimum efficiency) = 65%, it is necessary to include 158 patients. The strategy could be considered sufficiently effective if there are at least 87 patients without progression at 24 weeks. Given the lack of safety data from this association, a safety run-in phase including 6 patients has been completed without DLT. As of December 31, 2021, 266 patients have been screened of whom 102 have been treated. The first interim analysis occured in November 2021 after the inclusion of 64 evaluable patients. IDMC suggested that the trial continue as planned. Clinical trial information: NCT04053322.

Abstract OT1-14-02: Phase 3 study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09

Abstract Background: A combination of a taxane, trastuzumab, and pertuzumab (THP) is the standard-of-care (SOC) 1L treatment for patients (pts) with HER2+ mBC; THP demonstrated median progression-free survival (mPFS) of 18.7 mo and overall survival (OS) of 56.5 mo (Swain et al. N Engl J Med. 2015;372:724-734). However, pts eventually develop resistance to treatment. Novel treatment options are necessary in order to delay the emergence of resistance and provide better clinical outcomes, improve quality of life (QOL), and prolong survival in the 1L setting. T-DXd has demonstrated efficacy in pts with heavily pretreated HER2+ mBC, with an objective response rate (ORR) of 61.4%, duration of response (DOR) of 20.8 mo, and mPFS of 19.4 mo (Modi et al. Cancer Res. 2021. Abstract PD3-06). Data from DESTINY-Breast01 supported global approvals of T-DXd in HER2+ mBC. Here we describe a phase 3 trial evaluating the efficacy and safety of T-DXd ± pertuzumab compared with THP in the 1L treatment of HER2+ mBC. Trial design: DESTINY-Breast09 (NCT04784715) is a global, multicenter, randomized, phase 3 trial assessing the efficacy and safety of T-DXd with or without pertuzumab compared with SOC THP as 1L treatment in pts with HER2+ (IHC 3+ or ISH+ assessed locally per ASCO-CAP guidelines and centrally confirmed) advanced or mBC. This study consists of 3 treatment arms: arm A (T-DXd + placebo), arm B (T-DXd + pertuzumab), and arm C (THP). Randomization is 1:1:1 and pts will be stratified by prior treatment status (de novo vs recurrent), hormone receptor status (positive vs negative), and PIK3CA mutation status (detected vs not detected). Pts (N≈1134) must have had no prior chemotherapy or HER2-targeted therapy for advanced or mBC (1 prior line of endocrine therapy is allowed for mBC). The primary endpoint is PFS by blinded independent central review. Secondary endpoints include PFS by investigator assessment, OS, ORR, DOR, PFS2, health-related quality of life (QOL), pharmacokinetics, immunogenicity, and safety. Citation Format: Sara M Tolaney, Romualdo Barroso-Sousa, Zefei Jiang, Yeon Hee Park, Mothaffar Rimawi, Cristina Saura, Andreas Schneeweiss, Masakazu Toi, Tinghui Yu, Jagdish Shetty, Pia Herbolsheimer, Sibylle Loibl. Phase 3 study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-14-02.

Abstract OT2-23-01: A Phase 1b/2a, open-label platform study to evaluate mirdametinib in combination with fulvestrant in ER+ metastatic breast cancers harboring MAPK-activating mutations

Abstract Background: Approximately 70% of all metastatic breast cancers (MBCs) express estrogen receptor (ER). Hormonal therapies targeting ER are highly active against these cancers and have been remarkably successful in improving outcomes. Unfortunately, resistance to hormonal therapy is nearly universal and over 90% of patients develop resistance to various drugs targeting ER. We have identified mutations in three non-overlapping gene sets that are associated with the hormone-resistant phenotype: (1) ESR1, (2) MAPK pathway, and (3) transcription factors. The finding of mutations that might activate MAPK signaling was particularly striking given the known oncogenic function of this pathway in other cancers and the potential to target this pathway with selective inhibitors. Indeed, in preclinical models, the combination of an allosteric MEK inhibitor with an ER antagonist induced tumor regression in NF1-null, ER+ xenografts that were resistant to antiestrogen monotherapy. These data suggest that MAPK pathway alterations promote resistance to ER-targeted therapies in MBC and lead us to hypothesize that MAPK-targeted therapies will prove highly effective in such patients. However, NF1 (prevalence 6%) is only one of several RAS modulators that are associated with hormone resistance, and KRAS and HRAS mutations were also present in this dataset. Further, receptor tyrosine kinase (RTK) alterations (EGFR amplification and ERBB2 somatic mutations) and mutations in the RAF/MEK kinase cascade (BRAF and MEK1) are present and may comparably confer resistance to hormonal therapy and sensitivity to MAPK pathway inhibition. We hypothesize that MAPK pathway-activated MBCs can be effectively treated using MAPK targeted therapies in combination with hormonal therapy. Patient Accrual:The workflow to enroll patients to clinical trials at MSKCC is automated such that genomic alterations that are deposited on the cBioPortal are matched with appropriate clinical trials using database queries. A recent query of cBioPortal data from ER+ MBC patients treated at MSKCC showed 216 patients harboring actionable alterations in the MAPK pathway. Clinical Trial Design: This investigator-initiated trial being performed in collaboration with SpringWorks Therapeutics is IRB-approved and anticipated to open at MSKCC in August 2021. This is a Phase IB/IIA clinical trial of the allosteric MEK1/2 inhibitor mirdametinib (oral, daily) with the ER antagonist fulvestrant (500mg IM monthly). Inclusion criteria for the study will include ER+ tumor (ASCO-CAP guidelines), MAPK-activating genomic alteration documented by a CLIA-certified NGS assay at any time before the start of treatment, measurable disease, and at least one line of prior endocrine therapy. The feasibility of the combination will be established in a brief safety run-in of full-dose fulvestrant together with mirdametinib with dose de-escalation planned if two Dose Limiting Toxicities (DLT) are observed in the first six patients. This drug combination will then be expanded in three cohorts of patients defined by tumor genotype: (1) RAS activating: NF1 loss, KRAS or HRAS activating mutation, (2) RTK: EGFR amplification or ERBB2 hotspot mutation, (3) RAF/MEK: activating mutation in BRAF, CRAF, or MEK1/2. The primary endpoint for the study will be safety and tolerability of mirdametinib in combination with fulvestrant, and secondary endpoints include Overall Response Rate (ORR), Progression Free Survival (PFS), Clinical Benefit Rate (CBR), and Duration of Response (DOR) for the drug combination in each cohort and for the total study population. Overall survival is not an endpoint of this protocol. Citation Format: Ezra Y. Rosen, Payal Patel, Nenad Sarapa, Badreddin Edris, Alexia Iasonos, Komal Jhaveri, Pedram Razavi, Mark Robson, Alexander Drilon, Michael F. Berger, David B. Solit, Sarat Chandarlapaty. A Phase 1b/2a, open-label platform study to evaluate mirdametinib in combination with fulvestrant in ER+ metastatic breast cancers harboring MAPK-activating mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-23-01.

A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer

AimsFulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. Materials and methodsMedical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. ResultsData from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21–95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0–1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0–5) prior lines of endocrine therapy and median 0 (range 0–6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1–88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0–88). ConclusionsThis is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

Cost Effectiveness of Ribociclib in Combination with Fulvestrant for the Treatment of Postmenopausal Women with HR+/HER2- Advanced Breast Cancer Who Have Received No or Only One Prior Line of Endocrine Therapy: A Canadian Healthcare Perspective.

The MONALEESA-3 trial demonstrated the efficacy and safety of ribociclib plus fulvestrant versus placebo plus fulvestrant for patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). This analysis evaluated the cost effectiveness of ribociclib plus fulvestrant versus fulvestrant in patients with HR+/HER2- ABC from a Canadian healthcare payer perspective. The incremental cost-effectiveness ratio (ICER), expressed as incremental costs per quality-adjusted life-year (QALY) gained for ribociclib plus fulvestrant versus fulvestrant, was estimated using a semi-Markov cohort model developed in Microsoft Excel, with states for progression-free, post-progression, and dead. A 15-year time horizon was used. Survival distributions for progression-free survival (PFS), post-progression survival (PPS), and time to discontinuation (TTD) were based on parametric survival distributions fit to data from MONALEESA-3. Health-state utilities were estimated using EQ-5D index values collected in MONALEESA-3. Direct costs of ABC treatment (medication and administration costs, follow-up and monitoring, adverse events, subsequent treatments) were based on Canadian-specific values from published sources. Costs (2019 CAN$) and QALYs were discounted at 1.5% annually. In the base case, ribociclib plus fulvestrant was estimated to result in gains of 1.19 life-years and 0.96 QALYs versus fulvestrant, at an incremental cost of $151,371. The ICER of ribociclib plus fulvestrant versus fulvestrant was $157,343 per QALY gained based on the mean of probabilistic analyses. Results were sensitive to parametric distributions used for projecting long-term TTD, PFS, and PPS. For patients with HR+/HER2- ABC, ribociclib plus fulvestrant is projected to result in substantial gains in QALYs compared with fulvestrant. At its current list price, ribociclib used in combination with fulvestrant is likely to be cost effective in these patients at a threshold ICER of $157,343. These results may be useful in deliberations regarding reimbursement and access to this treatment.

Results from VERONICA: A randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC).

1004 Background: For patients (pts) with ER-positive, HER2-negative MBC, CDK4/6 inhibitors + endocrine therapy (ET) is standard first-line treatment, with single-agent ET considered for second-line. Nevertheless, most pts progress. A novel therapeutic target is the antiapoptotic protein BCL2, which is overexpressed in ̃85% of primary ER-positive breast cancers. VEN is a potent, selective BCL2 inhibitor that has shown promising clinical activity in pts with ER-positive and BCL2-positive MBC who have received prior ET. We report the prespecified primary and updated (for overall survival [OS]) analysis of VERONICA (NCT03584009), a phase II study of VEN + F vs F in ER-positive, HER2-negative LA/MBC. Methods: Pts were ≥18-year-old women with ER-positive, HER2-negative LA/MBC, who received ≤2 prior lines of ET and no prior chemotherapy in the LA/MBC setting and experienced disease recurrence/progression during/after CDK4/6 inhibitor therapy (received ≥8 weeks prior). Pts were randomized 1:1 to VEN (oral; 800 mg daily) + F (intramuscular; 500 mg day 1 and 15 of cycle 1; day 1 of subsequent 28-day cycles) or F, and were treated until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end. Pts were stratified by prior lines of therapy in the LA/MBC setting (1 vs 2) and BCL2 status (high vs low). Primary endpoint was clinical benefit rate (CBR; complete response, partial response, and stable disease ≥24 weeks). Secondary endpoints included progression-free survival (PFS) and OS; safety and exploratory subgroup analyses were also conducted. Results: At primary analysis (cutoff: Aug 5, 2020), 103 pts had been randomized (intention-to-treat [ITT] population). Median age was 58.0 and 59.5 years in the VEN + F and F arms, respectively. CBR was similar between arms (VEN + F: 11.8% [n = 6/51; 95% confidence interval (CI) 4.44–23.87]; F: 13.7% [7/51; 5.70–26.26]; risk difference: -1.96% [95% CI -16.86–12.94]). Median PFS was 2.69 months (95% CI 1.94–3.71) in the VEN + F vs 1.94 months (1.84–3.55) in the F arm (stratified hazard ratio: 0.94 [95% CI 0.61–1.45]). Results for CBR and PFS were similar in the BCL2-high and -low subgroups vs the ITT population. More grade 3–4 adverse events (AEs) were observed in the VEN + F vs F arm (n = 13/50 [26%] vs 6/51 [11.8%]). AEs observed with VEN + F were consistent with their individual safety profiles. At updated analysis (cutoff: Oct 22, 2020), OS data were not mature (35.0% event/pt ratio); median OS was 16.99 months in the VEN + F vs not reached in the F arm (stratified hazard ratio: 2.06 [1.04–4.09]). Conclusions: From the primary analysis, VERONICA did not show an improved CBR or PFS with VEN + F, vs F alone, in pts with endocrine- and CDK4/6 inhibitor-refractory LA/MBC. Biomarker analysis is ongoing. Clinical trial information: NCT03584009 .

Abstract PS5-05: Serum thymidine kinase activity in patients with luminal metastatic breast cancer treated with palbociclib and fulvestrant within the PYTHIA trial

Abstract Background: The CDK4/6 inhibitor palbociclib (P) plus fulvestrant (F) is approved for the treatment of patients (pts) with luminal metastatic breast cancer (MBC) progressed on prior endocrine therapy (ET). Despite clinical activity, a significant proportion of pts in this setting show primary resistance to P+F, with treatment failure within 3-6 months of initiation. To date there is no validated biomarker to identify such pts. Thymidine kinase 1 is a cancer proliferation marker downstream of the CDK4/6 pathway, whose activity can be measured in serum as a readout of tumour proliferation. Circulating thymidine kinase activity (TKa) is a potential prognostic and monitoring marker in pts treated with ET alone or in combination with P for MBC. However, the prognostic value of early changes in TKa during P+F treatment and its role in identifying pts with primary resistance are not yet defined. Here we prospectively investigated the role of serum TKa measured at different timepoints in pts treated with P+F within the PYTHIA trial (IBCSG 53-14/BIG 14-04; NCT02536742), a downstream trial of the AURORA platform (BIG 14-01; NCT02102165). Methods: PYTHIA is a biomarker discovery phase II trial including pts (Aug ‘16 to Jun ’19) with ET-resistant luminal MBC who received P+F at standard schedule and dose with 3-monthly imaging. Serum samples were collected at baseline (D0; n=122), on-treatment at day 11-16 of cycle 1 (D15; n=108), and during the one week off P before initiating cycle 2 (D28: Day 24-37 of Cycle 1; n=108). TKa was measured with DiviTum®, a refined ELISA-based assay. Complete TKa response (CTR) was defined as TKa below the limit of detection (LOD; 20 Du/L) at D15. Cox models evaluated association of log-transformed TKa measurements with progression-free survival (PFS; from initiation of therapy until progression by RECIST criteria or death). Kaplan-Meier method estimated median, 3 and 6 months (95% CI) PFS in groups of patients defined by dichotomizing TKa as “high” or “low” at the median or by CTR. A sample size of 120 provided 80% power to detect a hazard ratio of 2.0 for biomarker with 30-50% prevalence (two-sided α=0.05) after ≥80 events. Results: A total of 122 pts were enrolled. About half had received one prior line of ET for MBC, and 18% had received one prior line of chemotherapy. 48% had visceral metastases and 31% had bone-only disease. TKa at D0 was not associated with clinical characteristics. Median TKa (mTKa) at D0 was 87 Du/L. Overall, 82 pts experienced progression, with a median PFS (mPFS) of 11 months (95% CI: 8.6 - 16). P+F dramatically suppressed mTKa levels at D15, with 90/108 (83%) pts achieving CTR. At D28, TKa showed some rebound in most pts. At each timepoint, higher TKa was significantly and consistently associated with shorter PFS (each p&amp;lt;0.001). The effect of TKa on PFS remained statistically significant after adjusting for clinical variables. At 6 months, the largest difference between PFS probabilities was observed between patients with CTR versus no CTR at D15. Conclusions: TKa is an independent prognostic biomarker in pts treated with P+F. High baseline TKa and incomplete suppression of TKa during treatment may identify pts with poor prognosis and primary resistance to P+F. TKa may represent a novel biomarker to select pts for alternative treatment modalities. These results warrant further investigation in prospective comparative trials. TimepointBaseline (D0)D151D28TK median value (Du/L) (range)87 (&amp;lt;20 - 14,510)&amp;lt;20 (&amp;lt;20 - 7,060)52 (&amp;lt;20 - 3,533)Sample sizeHigh TKa611854Low TKa619054mPFS (months) (95% CI)High TKa7.4 m (5.5 - 8.7)4.9 m (2.8 - 5.9)8.3 m (5.6 - 11)Low TKa17.0 m (14 - NR2)16.0 m (11 - 30)19.0 m (17 - NR2)PFS at 3 months(95% CI)High Tka79% (43% - 68%)61% (42% - 88%)78% (67% - 90%)Low TKa93% (87% - 100%)92% (87% - 98%)96% (91% - 100%)PFS at 6 months(95% CI)High TKa54% (43% - 68%)17% (6% - 47%)56% (44% - 71%)Low TKa88% (81% - 97%)85% (78% - 93%)92% (86% - 100%)1For D15 High/Low TKa correspond to no CTR/CTR; 2 NR = not reached Citation Format: Luca Malorni, Svitlana Tyekucheva, Florentine S Hilbers, Michail Ignatiadis, Patrick Neven, Marco Colleoni, Stéphanie Henry, Alberto Ballestrero, Andrea Bonetti, Guy Jerusalem, Konstantinos Papadimitriou, Antonio Bernardo, Francois Duhoux, Iain MacPherson, Alastair Thomson, David Mark Davies, Mattias Bergqvist, Matteo Benelli, Amelia McCartney, Heidi De Swert, Barbara Ruepp, Manuela Rabaglio, Rudolf Maibach, Martine Piccart, Meredith M Regan. Serum thymidine kinase activity in patients with luminal metastatic breast cancer treated with palbociclib and fulvestrant within the PYTHIA trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-05.

Abstract PS12-04: Rintodestrant (G1T48), an oral selective estrogen receptor degrader in ER+/HER2- locally advanced or metastatic breast cancer: Updated phase 1 results and dose selection

Abstract Background: Rintodestrant (G1T48) is a potent oral selective estrogen receptor degrader (SERD) that competitively binds to the estrogen receptor (ER) and blocks ER signaling in tumors resistant to other endocrine therapies. Preliminary results from Part 1 dose escalation showed robust target engagement on 18F-fluoroestradiol positron emission tomography (FES-PET), a favorable safety profile, and encouraging antitumor activity in patients with heavily pretreated ER+/HER2- advanced breast cancer (ABC), including those with ESR1 mutations (Dees et al., ESMO 2019 [abstract #3587]). Here, we present updated results from dose escalation and expansion (Parts 1 and 2). Methods: This Phase 1, first-in-human, open-label study evaluated rintodestrant monotherapy in women with ER+/HER2- ABC after progression on endocrine therapy. Part 1 was a 3+3 dose escalation (200-1000 mg once daily [QD]); Part 2 expanded 600 and 1000 mg QD; and Part 3 was added to assess rintodestrant with palbociclib in patients in earlier lines in the advanced setting. Primary objectives included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and recommended Phase 2 dose. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included pharmacodynamic inhibition of ER target engagement (FES-PET), mutation profiling (cell-free DNA [cfDNA]), and change in ER expression from baseline to on-treatment tumor biopsies. Results: As of May 13, 2020, 67 patients (Part 1: n = 26; Part 2: n = 41) were treated, with a median age of 61 years (range 34-83) and ECOG PS of 0 (49%) or 1 (51%). Median number of prior lines in the advanced setting was 2 (range 0-9), including prior fulvestrant (64%), CDK4/6 inhibitor (69%), mTOR inhibitor (22%), and/or chemotherapy (46%). Median number of prior lines of endocrine therapy in the advanced setting was 2 (range 0-5), with 61% of patients having received ≥2 lines. Treatment-related adverse events (TRAEs) were reported in 70% of patients. The most common TRAEs in ≥10% of patients included hot flush (24%), fatigue (21%), nausea (19%), diarrhea (18%), and vomiting (10%), mostly grade 1 or 2. No DLTs were reported and MTD was not reached. Dose reduction due to TRAEs occurred in 1 patient (1%), with elevated transaminases (grade 3 ALT and grade 2 AST) at 600 mg. Serious TRAEs occurred in 2 patients at 1000 mg (grade 5 cerebral hemorrhage in the setting of low molecular weight heparin and grade 2 upper abdominal pain). Two patients (3%) discontinued treatment due to TRAEs. Overall, the frequency of patients with TRAEs at 800 mg was comparable with that at 600 mg (57% vs 63%) and less than that at 1000 mg (81%). Of 67 patients, 16 were on study treatment for ≥24 weeks and 3 (n = 1 at 600 mg; n = 2 at 1000 mg, including 1 with ESR1 mutation) had a confirmed partial response (clinical benefit rate [CBR]: 28%). FES-PET standard uptake values decreased at week 4 with a mean reduction of 87% (±8%) at doses ≥ 600 mg. Of 59 patients tested for baseline cfDNA, 41% harbored ≥1 ESR1 mutation, with a similar CBR in both groups (33% in ESR1 mutant and 29% in ESR1 wild-type). Seven of 9 patients had a decrease in ER immunohistochemistry H-score at both 600 and 1000 mg (median [range]: -27.8% [-33.8%, -3.4%]), irrespective of ESR1 mutation status. Based on safety, efficacy, and ER degradation, 800 mg was selected as the optimal dose for further study. Conclusions: Rintodestrant continues to demonstrate an excellent safety/tolerability profile across all doses, with promising antitumor activity in patients with heavily pretreated ER+/HER2- ABC, including those with tumors harboring ESR1 mutations. Part 3 of this study, evaluating rintodestrant 800 mg QD with palbociclib in a more endocrine-sensitive population, is ongoing (NCT03455270). Citation Format: Philippe Aftimos, Patrick Neven, Mark Pegram, Catharina Willemien Menke-van der Houven van Oordt, E. Claire Dees, Carolien Schröder, Agnes Jager, Iurie Bulat, Linnea Chap, Marina Maglakelidze, Erika Hamilton, Massimo Cristofanilli, Susanna Ulahannan, Jorianne Boers, Ramsha Iqbal, Adrian Crijanovschi, Curt D Wolfgang, Wenli Tao, Christina Sipes, Rajesh Malik, Sarika Jain. Rintodestrant (G1T48), an oral selective estrogen receptor degrader in ER+/HER2- locally advanced or metastatic breast cancer: Updated phase 1 results and dose selection [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-04.