Abstract OT2-06-02: Phase 2 trial with safety-run in of gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive HER2 negative breast cancer

Background: Poly-ADP-ribose polymerase (PARP) inhibition induces synthetic lethality in tumor cells bearing deleterious mutations in the genes BRCA1/2. Talazoparib (BMN 673) is a novel, dual-mechanism PARP inhibitor that potently inhibits the PARP enzyme and effectively traps PARP on DNA. Talazoparib has shown promising single-agent anti-tumor efficacy in several BRCA1/2 mutation-associated advanced cancers. The efficacy of PARP inhibition in BRCA1/2 wild-type TNBC with HR defects and in breast tumors with mutations in other non-BRCA1/2 HR pathway genes is currently unknown. Trial Design & Eligibility: This Phase 2 trial (TBB) explores the activity of single agent talazoparib in BRCA1/2 wild-type BC patients using an optimal Simon two-stage design. Eligible subjects will be assigned to one of two parallel cohorts: 1) Cohort A: Subjects (n=29) with advanced TNBC with underlying HR defects as assessed by the HRD assay and, 2) Cohort B: Subjects (n=29) with advanced HER2-negative BC with a somatic or germline deleterious mutation in a non-BRCA1/2 HR pathway gene. Gene mutations of interest are: PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, Fanconi anemia complementation group of genes (FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL). Other key eligibility criteria include metastatic disease treated with at least one prior line of chemotherapy, no deleterious BRCA1/2 mutation, and no prior platinum exposure. In cohort A, TNBC patients must have a HRD score of ≥ 42. Eligible patients will receive oral talazoparib (1.0 mg/day, 28-day cycles) until disease progression or unacceptable toxicity. Endpoints & Statistical Plan: The primary endpoint is objective response rate (ORR). Secondary endpoints include clinical benefit rate (CBR), progression free survival (PFS), and safety. In this study, we have set a null hypothesis of ≤ 5% objective response rate and alternative response rate of ≥ 20% based on RECIST 1.1. Interim analysis will be performed after accrual of 10 patients in each cohort. If at least one out of the 10 patients responds, then we will accrue 19 additional patients for a total of 29 patients in each cohort. At least four patients have to respond out of the 29 patients in each cohort to declare statistical significance at a one-sided 5% level with 80% power or better. This trial is enrolling patients at Stanford University in California (NCT 02401347). Citation Format: Afghahi A, Chang P-J, Ford JM, Telli ML. The Talazoparib Beyond BRCA (TBB) trial: A phase II clinical trial of talazoparib (BMN 673) in BRCA1 and BRCA2 wild-type patients with (i) advanced triple-negative breast cancer (TNBC) and homologous recombination deficiency (HRD) as assessed by myriad genetics HRD assay, and (ii) advanced HER2-negative breast cancer (BC) with either a germline or somatic mutation in homologous recombination (HR) pathway genes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-05-04.

e13075 Background: Metastatic triple negative breast cancer (TNBC) is a disease subtype with a poor prognosis, though advancements have been made in the use of targeted therapies, such as poly (ADP-ribose) polymerase inhibitors (PARPi) for those with germline BRCA 1/2 mutations. Up to 2/3 of TNBC tumors have acquired defects in homologous recombination (HR) DNA repair, yet PARPi monotherapy has been ineffective in extending survival in these patients. Phosphoinositide-3-kinase (PI3K)/mTOR pathway alterations are also common, and preclinical data supports that PI3K/mTOR inhibition may disrupt normal function of the HR complex and increase dependency on PARP enzymes for HR DNA repair. Thus, combining a PI3K/mTORi with a PARPi may result in a synergistic anti-neoplastic effect. Methods: The safety run-in portion of this study evaluated the safety and preliminary efficacy of the combination of weekly IV gedatolisib (PI3K/mTORi) and continuous daily talazoparib. Germline BRCA mutations were not required. The safety run-in was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). A 3+3 design was utilized for dose escalation, with starting dose at level 1. Dose levels are as shown in the Table. Eligibility criteria included patients ≥ age 18 who had received 1-3 prior lines of therapy for advanced TNBC or advanced HER2-negative BC with a germline BRCA 1/2 mutation. Those with untreated CNS metastasis were excluded as were those type I diabetes or uncontrolled type II diabetes, due to the risk of hyperglycemia with gedatolisib. Results: A total of 14 female patients were enrolled on to the safety run-in phase of the trial. Median age was 53 (range 30-67). Most patients (79%) were Caucasian, 14% were African American, and 7% unknown. The most common adverse events (AEs) of any grade were fatigue, anemia, nausea, and oral mucositis. Grade 1 hyperglycemia was noted in about 1/3 of the cohort, with 1 grade 3 event. There were 3 patients who experienced grade 4 AEs, thrombocytopenia (2) and lymphopenia (1). There was 1 DLT of grade 3 neutropenia which occurred at dose level 1. The MTD of gedatolisib was 180 mg and MTD of talazoparib was 1 mg. In this preliminary cohort, 3 patients achieved PR and 5 patients achieved SD. Median duration of PR was 13.34 months and median duration of SD was 4.11 months. Of the 3 patients with a BRCA 1 or 2 mutation, 2 had a best response of PR and the other SD. Conclusions: The safety run-in indicated that this combination is safe and well tolerated with mostly grade 1-2 AEs. This combination therapy has moved into the phase II trial, with 2 cohorts. Cohort A includes BRCA-wildtype patients with TNBC and cohort 2 includes those with a BRCA mutation and HER2-negative disease. Clinical trial information: NCT03911973. [Table: see text]

Background: Cirmtuzumab is a humanized monoclonal antibody that targets the receptor tyrosine kinase like orphan receptor 1 (ROR1), which is expressed on poor prognosis breast cancer, ovarian cancer, other solid tumors, CLL and mantle cell lymphoma. One clinical study showed increased expression of ROR1 in breast cancers after neoadjuvant chemotherapy and a preclinical PDX breast cancer model showed cirmtuzumab and paclitaxel to have at least additive efficacy1. A recently completed Phase 1 trial of cirmtuzumab in CLL showed the antibody to be both safe and effective in inhibiting tumor cell ROR1 signaling in patients with CLL2. Methods: The primary aim of this trial was to determine the safety of cirmtuzumab and weekly paclitaxel in patients with advanced Her2 negative breast cancer based upon dose limiting toxicities (DLTs) in the first cycle of treatment. Secondary endpoints were clinical activity, pharmacokinetics and correlative biomarkers on tumor specimens. Eligible patients were those with locally advanced, unresectable or metastatic Her2 negative breast cancer who had not received paclitaxel in the metastatic setting, had not developed metastatic disease within 6 months of (neo)adjuvant paclitaxel, had ECOG performance status of 0-2, and had adequate laboratory parameters. Any number of prior lines of therapy were allowed. Study treatment included fixed dose 600 mg cirmtuzumab given days 1 and 15 of cycle 1 and then day 1 of each subsequent 28-day cycle. Paclitaxel was given weekly at a dose of 80mg/m2. Patients were evaluated in dose cohorts of 5 for DLTs with a target of 15 evaluable patients. Results: To date, 6 patients evaluable for safety and 5 patients evaluable for DLTs were treated. Age range was 30 to 59 years. Three of 6 safety-evaluable patients had triple negative breast cancer at study enrollment. Prior lines of chemotherapy in the metastatic setting ranged from 0-3. No discontinuations for toxicity and no DLTs have been observed to date. Adverse events (AEs) have been consistent with the known safety profile of paclitaxel, with 3 episodes of grade 3 neutropenia in 2 patients and 1 episode of grade 3 hyperglycemia. All other AEs were grade 1 or 2. Partial responses have been observed in 2/5 patients with one patient response ongoing with cirmtuzumab alone for at least 17 weeks after stopping paclitaxel. Pharmacokinetic analysis of serial plasma samples for free unbound antibody from two patients provided results similar to those observed in CLL patients treated with cirmtuzumabwith a projected half-life of 30 days2. No decline in antibody concentration over time was observed consistent with the absence of neutralizing antibodies. Conclusions: Preliminary information indicates that the combination of fixed dose cirmtuzumab plus paclitaxel is well-tolerated and safe. Responses to therapy have been observed and preliminary pharmacokinetic results are consistent with sustained potentially therapeutic levels. Updated safety, clinical activity, pharmacokinetics and biomarker analyses will be presented. 1Zhang S et al. Proc Natl Acad Sci USA. 116(4): 1370-1377. PMID 30622177. 2Choi MY et al. Cell Stem Cell 22(6): 951-959. PMID 29859176. Funding sources: CIRM UC San Diego Alpha Stem Cell Clinic and Sanford Stem Cell Clinical Center; Oncternal Therapeutics, Inc.; UC San Diego Moores Cancer Center Padres Pedal the Cause Grant; Gonick Breast Cancer Research Fund Citation Format: Rebecca A Shatsky, Richard B Schwab, Teresa L Helsten, Emily I Pittman, Ruifeng Chen, James B Breitmeyer, Catriona HM Jamieson, Thomas J Kipps, Barbara A Parker. Phase 1b trial of cirmtuzumab and paclitaxel for locally advanced, unresectable and metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-18.

Up to 2/3 of triple negative breast cancers (TNBC) have acquired defects in homologous recombination (HR) DNA repair, yet poly (ADP-ribose) polymerase inhibitor (PARPi) monotherapy has been largely ineffective in the absence of a germline BRCA 1/2 mutation (gBRCA1/2). Phosphoinositide-3-kinase (PI3K)/mTOR pathway alterations are also common in breast cancers. Preclinical data suggest that PI3K/mTOR inhibition may disrupt normal function of the HR complex and increase dependency on PARP enzymes for HR DNA repair. Thus, combining a PI3K/mTOR inhibitor with a PARPi may result in a synergistic anti-neoplastic effect. The run-in portion of this study evaluated the safety of weekly IV gedatolisib (PI3K/mTORi) and continuous daily talazoparib to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). A 3+3 design for dose escalation explored two dose levels. The phase II study began once the MTD and R2PD were confirmed. Eligibility required age ≥ 18, 1-2 prior lines of therapy (protocol later amended to allow up to 3 lines), and advanced TNBC or advanced HER2-negative BC with gBRCA1/2 mutation. The sample size for the phase II study was determined based on a 1-sided binomial test under the null and alternative ORR of 5% vs 20% with a type I error rate of 0.1 and power level of 80%. The primary endpoint was overall response rate (ORR) in TNBC without known gBRCA1/2 with secondary endpoints of progression-free survival (PFS) and overall survival (OS). Patients with a gBRCA1/2 mutation were not included in the primary endpoint analysis. Correlative studies are planned to evaluate HR deficiency mutations, PIK3CA mutations, and other exploratory genomics. A total of 33 patients were enrolled: 14 in the safety run-in phase of the trial and 19 in the phase II study (17 TNBC, 2 with gBRCA2 mutation). In the safety run-in, 6 patients were enrolled at dose level 1 (0.75 mg talazoparib po daily and 180 mg gedatolisib IV weekly) and 8 at dose level 2 (1 mg talazoparib po daily and 180 mg gedatolisib IV weekly). 42% of the cohort developed hyperglycemia, which was mostly grade 1. There was 1 DLT of grade 3 neutropenia at dose level 1. There were 3 patients who experienced grade 4 AEs, thrombocytopenia (2) and lymphopenia (1) which were outside of the DLT window. The MTD was 1 mg of talazoparib daily and 180 mg of gedatolisib weekly, and this was selected as the RP2D. A protocol amendment was made during the phase II portion to allow for a 3 week on/1 week off schedule for gedatolisib due to emerging data showing a more favorable safety profile and enhanced antitumor activity with this dosing schedule. In the 17 patients with TNBC and no gBRCA mutation in the phase II cohort, the ORR was 12%. Best response was partial response (PR) in 2 patients (12%), stable disease (SD) in 7 patients (41%), and progressive disease (PD) in 8 patients (47%). The clinical benefit rate (ORR+SD) at 16 weeks was 23.5%. The most common adverse events (AEs) in all 33 patients were anemia (70%), fatigue (67%), oral mucositis (64%), nausea (60%), neutropenia (45%) and anorexia (45%). Of these, most were grade 1-2 other than anemia (35% grade 3), neutropenia (20% grade 3), fatigue (18% grade 3), and oral mucositis (10% grade 3). There were no grade 4 AEs in the phase II study. Median PFS was approximately 3 months and median OS was approximately 6.4 months. Although this study did not meet its primary endpoint, there were 2 TNBC patients without a gBRCA1/2 mutation who achieved a partial response to this non-chemotherapy regimen. Future biomarker testing may help elucidate these findings and possible predictors of response. Citation Format: Sneha Phadke, Kari Wisinski, Oana Danciu, Ami Shah, Menggang Yu, Yi Chen, Kathy Miller, Mark Burkard. Phase 2 Trial with Safety Run-In of Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast CancersBig Ten Cancer Research Consortium BTCRC-BRE18-337 [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 PO1-06-09.

PurposeMetastatic triple negative breast cancer has a poor prognosis with limited targeted treatment options. In preclinical studies PI3K inhibition led to increased DNA damage and subsequent sensitization to PARP inhibition. This study aimed to investigate the safety and efficacy of the combination of an mTOR/pan-PI3K inhibitor, gedatolisib, with the PARP inhibitor, talazoparib, in patients with advanced triple negative breast cancer or advanced HER2 negative breast cancer and a germline BRCA1/2 mutation.MethodsThe primary objective of the safety run-in was safety and tolerability of the combination and for dose escalation to find the maximum tolerated dose. A 3 + 3 design was utilized for dose escalation. The primary objective of the phase II study was objective response rate (ORR) in the patients with wildtype germline BRCA1/2. The prespecified efficacy threshold was 20%. Secondary objectives included progression-free (PFS) and overall survival (OS) as well as correlative testing, examining homologous recombination deficiency (HRD) status.ResultsThe combination of gedatolisib and talazoparib carried manageable toxicities with a low incidence of grade 3 adverse events. The most common adverse events of all grades were anemia, fatigue, and oral mucositis. The ORR in the phase II study was 12%. There were no new safety signals identified in the phase II study. mPFS was 2.5 months (95% CI 1.71, 9.89), and mOS was 7 months (95% CI 4.3, NA) in the full phase II cohort. HRD status was analyzed by high (≥ 33) or low (< 33) genomic instability score, and there was no difference in response rate between the groups.ConclusionThe combination of gedatolisib and talazoparib is safe but did not meet the prespecified efficacy threshold for objective response rate. Additional preclinical studies of these pathways are warranted prior to future clinical trials of the combination.Trial Registration: ClinicalTrials.gov ID: NCT03911973, Date of registration: 2019-04-11.

Background: In IMpassion 130 trial, programmed death-ligand 1 (PD-L1) expression was seen in about 40% of participated patients with triple negative advanced breast cancer (TN-ABC) [Schmid, 2018, N Engl J Med], however, actual situation of PD-L1 expression in patients HER2-negative ABC patients including with TN-ABC has not been well studied. Furthermore, no biomarker related to chemotherapy for HER2-negative ABC patients except for PD-L1 in TN-ABC has been identified. Recently, several reports regarding the relationship between peripheral immune-related markers; such as absolute lymphocyte count (ALC) or neutrophil-to-lymphocyte ratio (NLR), and efficacy of eribulin therapy [Miyoshi, 2020, Breast Cancer; Watanabe, 2020, Breast Cancer Res Treat] or paclitaxel plus bevacizumab (PB) therapy [Nakamoto, 2021, Sci Rep], however, the relationship between the efficacy of PB therapy and peripheral immune related markers including dynamic change during the therapy or local immune-related markers is unclear. Therefore, we conducted multi-institutional, retrospective study 1) to evaluate the actual situation of PD-L1 expression and other immune-related markers of the primary site by central review, and 2) to explore biomarkers for first-line PB therapy using peripheral and local immune-related markers. Patients and methods: We retrospectively reviewed medical records of HER2-negative ABC patients who received PB therapy as first-line (1L) or second-line chemotherapy for ABC. Clinical data including ALC, NLR and serum albumin (Alb) were extracted from medical records, and the pathology of archived tissues of primary and metastatic site (if available) were centrally reviewed including PD-L1 (VentanaR SP142). Statistical analyses were performed using Kaplan-Meier method, log-rank test, Wilcoxon’s test, and Cox hazard model. Mixed-effects model for repeated measures (MMRM) to evaluate the relationships between dynamic change in immune-related markers and time-to treatment termination (TTT) of PB therapy. Results: We identified 156 HER2-negaive ABC patients who underwent PB therapy, and 114 out of 156 patients were eligible for analyses. Of 114 patients, 63 patients (55.3%) had recurrent disease, and 65 (57.0%) patients had visceral disease. Eighty-seven out of 114 (76.3%) patients received PB therapy as 1L chemotherapy. Eighty-four specimens (73.7%) were diagnosed as estrogen-receptor (ER) positive, and PD-L1 positivity rate were 3.6% (1/84) in ER+ subgroup and 30.0% (6/20) in ER- subgroup, respectively. Paired biopsy specimens were eligible in 14 patients, and significant elevation of Ki67 labeling index was noted. In patients who received 1L PB (n = 87), there was no positive relationship between maintained ALC (&amp;gt;1,500 or &amp;gt;1,000/μL at baseline) or low NLR (&amp;lt; 2.5 or &amp;lt; 3) at the initiation of 1L PB therapy and TTTs. However, low NLR (cut-off at 2.5 and 3) at the initiation of second cycle of PB therapy reduced the risk for treatment-termination as; hazard ratio [HR], 0.427; 95% CI 0.218-0.843; P = 0.0147 and HR, 0.344; 95% CI 0.170-0.731; P = 0.0066, respectively. PD-L1 positive patients (n = 5) showed numerically increased risk of treatment-termination (HR, 2.68; 95% CI, 0.922-6.196; P = 0.0674) for 1L PB therapy, however, there was no significant difference in mortality risk regarding PD-L1 statuses. Multivariate analysis using MMRM disclosed that increase of Alb level was predictive factor for 1L PB therapy (HR, 0.41; 95%CI, 0.18-0.93; P = 0.0338). Conclusion: According to our real-world study, 1) PD-L1 positive rate was lower than that of previous reports, 2) low NLR at the initiation of second cycle of PB therapy and dynamic change in albumin level were identified as predictive factors and 3) PD-L1 overexpression was not a prognostic or a predictive factor for PB therapy in patients with HER2-negative ABC. Funding: Chugai Pharmaceutical CO., LTD. Citation Format: Junichiro Watanabe, Takashi Sugino, Koji Muramatsu, Satoshi Morita, Yu Hidaka, Shogo Nakamoto, Mitsuya Ito, Shoichiro Ohtani, Masahiko Ikeda. Identifying immune-related predictive factors for paclitaxel + bevacizumab therapy in patients with HER2-negative advanced breast cancer- A multicenter retrospective study [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 P5-02-48.

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

Background: The PI3Kα subunit specific inhibitor alpelisib in combination with fulvestrant is approved in advanced breast cancer harbouring PIK3CA mutations, but predictive biomarkers are lacking. We performed a phase II single arm study of alpelisib monotherapy in previously treated advanced hormone receptor-positive HER2-negative (HR+HER2-) and triple negative breast cancer (TNBC) cohorts. Methods: Eligible patients with genomic aberrations in the PI3K pathway determined via tumour sequencing or ctDNA were given alpelisib 350mg oral daily as monotherapy. The primary endpoint was RECIST objective response rate (ORR) by central review. Secondary endpoints were clinical benefit rate (CBR), defined as complete or partial response or stable disease for ≥24 weeks, and progression free survival (PFS). Positron emission tomography (FDG-PET) was performed at baseline and 8 weeks. Efficacy was analysed according to baseline tumour alterations and serial ctDNA assays. Analyses were conducted separately for the HR+HER2- and TNBC cohorts. Stated p values are nominal without multiplicity adjustment. Results: 43 patients were recruited in total (33 in ER+HER2-, 10 in TNBC). Median follow-up was 44.6 months. In the TNBC cohort ORR and CBR were 0%, hence the cohort was stopped early. Data will be presented here for the HR+HER2- cohort. Of 33 ER+HER2- patients recruited, 28 (85%) were evaluable and 26 (79%) were evaluable for ORR after central review. PI3K pathway aberrations at study entry were mutations in PIK3CA (26/28; 93%) and PTEN (2/28; 7%). The median age was 60 (41 - 77yrs) and 27/28 of patients were female. 85.7% of cases had visceral disease, and 57% had &amp;gt;3 metastatic sites. 100% of patients had received prior endocrine therapy and 78.6% prior chemotherapy, with a median of 3 prior lines (range 1 - 9). All patients were endocrine refractory. The ORR was 38% and CBR 43%. Median PFS was 4.6 months (95% CI, 3.7 - 7.3) and median OS 16.0 months (95% CI, 8.5 - 34.4). In patients with PET scans at baseline and 8 weeks, 67% (17/25) achieved a partial metabolic response but this was not associated with clinical benefit. In patients with partial response by RECIST, serial ctDNA levels at week 8 declined from baseline (p = 0.008) compared to patients with stable or progressive disease (p = 0.17), with similar results seen for patients with clinical benefit. Decline in ctDNA at week 8 was also associated with improved PFS (HR 0.24 [95% CI 0.08-0.67], p = 0.0065; 5.6 v 3.6 months). Multiple PIK3CA mutations were detected in plasma in 31% (8/26) of patients but had no impact on ORR/CBR. 39% (11/28) of patients had mutations in ESR1 detected in plasma at baseline, and this was associated with clinical benefit (p = 0.019) and improved PFS (HR=0.22 [95% CI 0.078-0.60], P=0.0032, 8.21 v 4.53 months). ctDNA assays detected 11 cases with ESR1 mutations compared to tumour sequencing which detected 5 cases only. No other baseline alterations were significantly associated with outcomes, although no patients (0/4) with PTEN alterations achieved clinical benefit. End of treatment ctDNA analysis identified multiple new alterations including MAP3K1 in 39% (11/28), TP53 in 32% (9/28) and PTEN in 25% (7/28). Adverse events included 20.9% grade ≥3 hyperglycaemia and 25.6% ≥grade 3 rash consistent with reported data. Permanent discontinuation of alpelisib for toxicity occurred in 15.2% (5/33) of patients. Conclusions: Alpelisib monotherapy in pre-treated ER+HER2- disease showed evidence of clinical efficacy. Decline in the levels of PIK3CA mutations detected with ctDNA on therapy are significantly associated with clinical benefit, as are the presence of ESR1 mutations at baseline. ctDNA improves the yield of ESR1 mutation detection and warrants further study as a biomarker of alpelisib monotherapy benefit in endocrine-refractory populations. Citation Format: Peter Savas, Louisa Lisa Lo, Stephen James Luen, Elizabeth Fay Blackley, Courtney Templeton van Geelen, Yi-An Ko, Kate Moodie, Jason William Callahan, Chen-Fang Weng, Andjelija Zivanovic Bujak, Miriam Manning Yeung, Sarah Ftouni, Prudence Anne Francis, Sarah-Jane Dawson, Sherene Loi. Alpelisib monotherapy for PI3K-altered, pre-treated advanced breast cancer: A phase II study [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 P1-18-14.

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

Background: CDK4/6 inhibitors combined with endocrinotherapy (ET) represent an essential part of the treatment for HR-positive and HER2-negative breast cancer (BC). However, the role of angiogenesis inhibitors, such as bevacizumab, in these patients (pts) is controversial. While it has been demonstrated to improve progression-free survival (PFS), it has failed to show a significant overall survival (OS) benefit in HER2-negative BC. Several preclinical studies have explored the combination of anti-angiogenesis multi-targeted receptor tyrosine kinase inhibitors (TKIs) and CDK4/6 inhibitors in other cancers, suggesting a synergistic effect. Our phase Ib/II trial (NCT05176080, ChiCTR2100053950) aims to evaluate the safety and efficacy of a novel anti-angiogenesis TKI famitinib (F) added to dalpiciclib (D) and ET in advanced HR-positive and HER2-negative BC. Here we report the results of Phase Ib. Methods: A 3+3 de-escalation design was used in this dose-exploring phase (phase Ib). Pts with HR-positive and HER2-negative BC, who had no more than two prior chemotherapies in the advanced setting, were enrolled and administered F (orally, at doses of 15 mg/d, 10 mg/d, or 15 mg qod), D (orally, at doses of 150, 125 or 100 mg/d, 21 days on and 7 days off) and fulvestrant (intramuscularly, at a fixed dose of 500 mg every four weeks) until progression, unaccepted toxicities, or withdrawal. The initial dose level (Level 1) was set as F 15 mg daily and D 150 mg/d. The primary endpoints were recommended phase 2 dose (RP2D) and safety. Results: From December 2021 to June 2022, 18 pts were enrolled, and 3, 6, 3, and 6 pts were assigned to Level 1 (F 15 mg + D 150 mg), Level 2 (F 10 mg + D 125 mg), Level 3 (F 15 mg qod + D 125 mg), and Level 4 (F 10 mg + D 100 mg), respectively. 14 (77.8%) pts had visceral metastasis, and 7 (38.9%) had prior systemic therapies in the advanced setting. 13 (72.2%) pts had received ET, and 11 (61.1%) were resistant to ET before enrolled. A total of 6 dose-limiting toxicities (DLTs) were observed, including 3 Grade 4 thrombopenia (2 in Level 1, 1 in Level 2) and 3 Grade 4 neutropenia (2 in Level 3, 1 in Level 4), 4 of which were serious adverse events (AEs). The most common (≥20%) treatment-related AEs of Grade 3 or above were neutropenia (100.0%), leukopenia (88.9%), thrombocytopenia (33.3%), anemia (27.8%), lymphopenia and hypertension (both 22.2%). No death was reported. Overall 10 pts (55.6%) achieved confirmed partial responses and 16 (88.9%) achieved clinical benefits. Confirmed objective response rates (ORRs), clinical benefit rates (CBRs), and DLTs in different dose levels were shown in Table 1. Considering the efficacy and safety profiles, Level 4 was selected as RP2D. Conclusion: The anti-angiogenesis multi-targeted receptor TKI famitinib combined with CDK4/6i and fulvestrant has shown antitumor effects in advanced HR-positive and HER2-negative BC, and no new safety signals were observed. Citation Format: Min Yan, Mengwei Zhang, Limin Niu, Huimin Lv, Zhenzhen Liu, Huiai Zeng, Shengnan Zhao, Huihui Sun, Jing Wang, Yajing Feng, Huajun Li. Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-01.

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

CCTG IND.236: A Phase 1b trial of combined CFI-402257 and weekly paclitaxel in patients with HER2-negative (HER2-) advanced breast cancer (aBC) Philippe L. Bedard, Mihaela Mates, John Hilton, Nathalie Levasseur, Arif Awan, Amirrtha Srikanthan, David Cescon, Karen Gelmon, Andrew Robinson, Nancy Drummond-Ivars, Irene Li, Laleh Rastgou, Jackie Edwards, Linda Hagerman, Siwei Zhang, Mark Bray, Lesley Seymour, Moira Rushton-Marovac, Pierre-Olivier Gaudreau Background: CFI-402257 is a selective oral inhibitor of TTK protein kinase, a critical regulator of the mitotic spindle assembly checkpoint overexpressed in breast cancer (BC). CFI-402257 monotherapy has anti-proliferative and cytotoxic activity and enhances antitumor activity of paclitaxel in BC xenograft models. Material and methods: Primary objectives were to establish safety and Recommended Phase 2 dose (RP2D) of CFI-402257 combined with weekly paclitaxel (Phase 1b) and Overall Response Rate (ORR) as per RECIST 1.1 (Phase 2). Patients with HER2- aBC with adequate organ function, PS 0-1, previously treated with &amp;gt;1 non-taxane chemotherapy, were eligible. A 3+3 design was used for Phase 1b, with dose limiting toxicities (DLTs) assessed during cycle 1 (28 days). Starting dose CFI-402257 was 84mg (DL1 = 84mg, DL2 = 112mg, DL3 = 168mg, DL4 = 210mg and DL5 = 252mg) on a 2-day on, 5-day off schedule with paclitaxel 80mg/m2 day 1, 8, 15. Safety assessments were performed weekly (CTCAE v5.0) and response every 2 cycles. A Simon 2-stage design was used for Phase 2 (stage 2 required ≥4 responses in 17 evaluable patients from stage 1). Results: 37 patients received a total of 260 cycles including all 5 dose levels. Median age was 59; 92% ER+/HER2-; 49% PS1; 22% 3 prior chemotherapy lines; 41% 4 sites of metastatic disease, and 81% had received prior CDK4/6 inhibitors. Grade 3 hematological adverse events (AEs, all dose levels) were neutropenia (70%), lymphopenia (41%) and anemia (14%). Six DLTs occurred: 5 dose-related grade 4 neutropenia and 1 febrile neutropenia. Three DLTs occurred at DL3, two at DL4, and one at DL5. Three serious AEs (two at DL3, and one at DL4) at least possibly related to treatment were seen: 2 febrile neutropenia and 1 skin infection (all grade 3). Frequent AEs (˃5%; all dose levels) considered at least possibly related to treatment were: diarrhea (38%), nausea (30%), fatigue (27%), vomiting (16%), anorexia (14%), maculo-papular rash (14%), oral mucositis (11%), alopecia (11%) and pruritus (8%). DL3 (168mg) was selected as RP2D. ORR was 3/36=8% and 1/17=5.9% in all vs Phase 2 evaluable patients, respectively. Clinical Benefit Rate (CBR; defined as complete response, partial response or stable disease ˃16 weeks in duration) was 18/33=54.6% and 10/17=58.8% in all vs Phase 2 evaluable patients, respectively. During Phase 2, the 17 evaluable patients from stage 1 did not meet pre-specified threshold for anti-tumor activity to proceed to stage 2. Conclusions: CFI-402257 and paclitaxel was well tolerated, with neutropenia as the main toxicity. DL3 (168mg) was selected as RP2D. Phase 2 ORR and CBR was 5.9% and 58.8%, respectively; during Phase 2, the 17 evaluable patients from stage 1 did not meet the pre-specified threshold for anti-tumor activity to proceed to stage 2 and the trial was closed to accrual on April 7, 2022. Final analysis and correlative analyses are ongoing. Acknowledgements: Coordinated by the CCTG. Funding supported by SU2C Canada - Canadian Cancer Society Breast Cancer Dream Team Research Funding (SU2C-AACR-DT-18-15) and OICR. CFI-402257 provided by Treadwell Therapeutics. Citation Format: Philippe Bedard, Mihaela Mates, John Hilton, Nathalie Levasseur, Arif Awan, Amirrtha Srikanthan, David W. Cescon, Karen Gelmon, Andrew Robinson, Nancy Drummond-Ivars, Irene Li, Laleh Rastgou, Jackie Edwards, Linda Hagerman, Siwei Zhang, Mark Bray, Lesley Seymour, Moira Rushton, Pierre-Olivier Gaudreau. CCTG IND.236: A Phase 1b trial of combined CFI-402257 and weekly paclitaxel in patients with HER2-negative (HER2-) advanced breast cancer (aBC) [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 P3-07-10.

Background: LDE225 is a potent and selective oral inhibitor of Smo, a key component of the hedgehog (Hh) signaling pathway. Up-regulation of the Hh pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer. Here we report an ongoing phase I study exploring the combination of LDE225 with docetaxel in TN ABC patients to identify the Maximum Tolerated Dose (MTD) and the Recommended Phase II Dose (RP2D) (ClinicalTrials.gov Identifier: NCT02027376). Trial Design: Eligibility criteria include patients with TN ABC candidates to receive treatment with docetaxel that have received a maximum of 3 prior chemotherapy regimens. Those patients with CNS involvement are also candidates if treated and clinically stable. Treatment consists of 21-day cycles with docetaxel 75mg/m2 on day 1, every 21 day and LDE225 once daily. We use a standard 3+3 design in sequential cohorts (3 dose levels (DL) of LDE225: 400mg once daily (DL1), 600mg once daily (DL2), 800mg once daily (DL3); and a DL-1: LDE225 400mg once daily and docetaxel 60mg/m2 every three weeks). The primary endpoint is the MTD and RP2D of the combination; secondary endpoints include evaluation of safety and tolerability, in addition to pharmacodynamic (PD) and pharmacokinetic (PK) studies. Patients are treated until radiologic or symptomatic progression or unacceptable toxicity occurs. PK will be performed to evaluate whether LDE225 influences the pharmacology of docetaxel. PD assessments include Hg gene expression signature associated to pathway activation in tumor samples and changes in Smo related biomarkers in skin and blood correlative samples. Efficacy will be measured in terms of time to progression and objective response rate. A minimum of 9 and a maximum of 18 patients will be included in this phase I. The study is approved by ERBs and Competent Authority and already recruiting patients (two patients included in DL1). Citation Format: Miguel Martin, Manuel Ruiz-Borrego, José M Trigo, Silvia Antolin, Jose A Garcia-Saenz, Andres Hernando, Alberto Ocaña, Federico Rojo, Sara Lopez-Tarruella, Jesus Corral, Nuria Ribelles, Lourdes Calvo, Fernando Moreno, Rosalia Caballero, Eva Carrasco. A phase I study of LDE225 in combination with docetaxel in patients with triple negative (TN) advanced breast cancer (ABC): GEICAM/2012-12 (EDALINE study) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-06.

BackgroundPalbociclib, a highly selective inhibitor of CDK4/6, is indicated for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC), in combination with an aromatase inhibitor or with fulvestrant for patients who have progressed with an aromatase inhibitor, and in premenopausal women with a luteinising-hormone-releasing-hormone (LH-RH) agonist. Emerging real world data suggest that the efficacy of a palbociclib-based therapy is highly conserved. We report here the Institut Curie (IC) experience. Patients and methodsWe retrospectively reviewed all patients with HR+ HER2- ABC treated with a palbociclib-based therapy as 1st or 2nd line of therapy for ABC, from November 2016 to December 2018. Clinical, biological and imaging data were retrieved from IC electronic health record system. Data lock was December 31st 2020. Descriptive analyses, univariate and multivariate Cox regression analyses were performed. ResultsWe included 310 consecutive premenopausal (24.5%) and menopausal (75.5%) women. Median age was 61.8 years-old [23.5-92.1]. Among them, Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 59.7%, 1 in 32.1%, and 2 in 8.2% of patients (pts). The ABC diagnosis was de novo for 26.8%. There was at least one visceral lesion in 51.0% of pts, only bone lesions in 30.3%, 28.1% had three metastatic sites or more, and none of them have brain lesions. Previous treatments were chemotherapy (49.4%) and endocrine therapy (60.7%). Among pts pretreated by at least one endocrine therapy, 51.1% had shown prior sensibility, as defined by an absence of recurrence during adjuvant endocrine therapy or during 24 months after its completion, or an absence of progression during 6 months after the beginning of an endocrine therapy for a metastatic disease. Palbociclib was prescribed in the 1st line setting for 72.6% of pts and in the 2nd line setting for 27.4% of pts. The initial dose was 125 mg daily (95.2%). It was associated with an aromatase inhibitor (66.8%) or with fulvestrant (33.2%). LH-RH agonist was prescribed in 19.7% of pts. Denosumab was prescribed in 68.5% of pts with bone lesions. Median follow-up was 20.7 months (m). At 12 m from the initiation of palbociclib, 94.5% of the pts were alive. Median progression free survival was 23.4 m (95%CI: 21.6-NR) for pts without previous endocrine therapy, 22.7 m (95%CI: 14.7-NR) for pts who have shown endocrine sensibility, HR=1.2 (95%CI: 0.81-1.77), p=0.0027 and 13.4 m (95%CI: 10.7-20.8) for pts who have not shown endocrine sensibility, HR=1.88 (95%CI: 1.29-2.73), p=0.003. Although sensibility to previous endocrine therapy was a prognostic factor for progression free survival with the univariate analyse, it was not with the multivariate analysis. Three independent poor prognostic factors for progression free survival were identified: previous chemotherapy, HR=1.6 (95%CI: 1.12-2.29), p&amp;lt;0.001; initial ECOG performance status 2, HR=2.72 (95%CI: 1.55-4.79), p&amp;lt;0.001; and three or more metastatic sites, HR=1.61 (95%CI: 1.152.26), p&amp;lt;0.001. Hematologic grade 3-4 adverse events were neutropenia (72.3%), leukopenia (43.9%), anemia (3.2%) and thrombocytopenia (2.9%). Other adverse events observed (all grades) were infections (16.5%), stomatitis (13.9%) or alopecia (13.9%). At least one dose reduction occurred in 29.4% of pts and permanent discontinuation because of treatment toxicity was observed in 5.7% of pts. ConclusionIn a non-selected population of patients with HR+ HER2- ABC, the efficacy and safety data are strikingly similar to those previously reported. Palbociclib, in combination with hormone therapy, is a cornerstone treatment of HR+ HER2- metastatic breast cancer. Citation Format: Baptiste Porte, Matthieu Carton, Delphine Loirat, François-Clement Bidard, Linda Haroun, Audrey Bellesoeur, Youlia Kirova, Paul Cottu. Real life efficacy of palbociclib and endocrine therapy in HR positive, HER2 negative advanced breast cancer [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 PS10-40.

Background: Metastatic breast cancer remains an incurable disease, and clinical benefit and progression-free survival are the main end points in advanced setting. Targeted therapies have shown promising potentials in HER2-positive breast cancer, but with uncertain effects in HER2-negative breast cancer, especially when the disease is progressing rapidly. The regimen of antiangiogenic therapy in combination with chemotherapy had been studied for years and gained improved efficacy. Apatinib is an oral, highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2. PhaseIIclinical trials of Apatinib single agent had presented objective response and manageable toxicity in heavily pretreated, metastatic breast cancer. Oral vinorelbine represents a good choice for its toxicity and activity in anthracycline and taxane-pretreated breast cancer patients. This all-oral study aims to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in pre-treated metastatic breast cancer. Methods: This study enrolled patients with HER2-negative advanced breast cancer, pretreated with anthracycline/taxanes, and who failed in the metastatic setting at least one prior chemotherapy or endocrine therapy when hormone receptor is positive. Patients were treated with apatinib 500mg/425mg daily plus oral vinorelbine 60mg/m2 day1,8,15 every 3 weeks/cycle. Patients eligible were evaluated by CT or MRI scan at baseline and every 2 cycles (6 weeks) there after until disease progressed. The primary endpoint wasPFS. The secondary endpoints were objective response rate, clinical benefit rate, OS, and safety. Results: 40 patients were enrolled with a median age of 55 (30-70) years. First 17 patients started apatinib at the dose of 500mg/day. Considering safety issues, a lower dose of apatinib 425mg/day was subsequently started as the initial dose after these 17 patients recruited. 26(65.0%) patients experienced treatment delay and 20(50.0%) patients experienced dose modification during treatment. Median follow-up time was 10.3 months. Of all 40 patients, median PFS was 5.4 months (95% CI, 3.4m–7.3m). Median OS was not reached. 32 patients were eligible for efficacy analysis. ORR was 15.6% (5/32). CBR was 46.9% (15/32). Patients with triple-negative breast cancer or who received combined therapy as second line treatment gained better ORR and longer median PFS. The most common adverse events of all grades included gastrointestinal reaction (70.0%), myelosuppression (67.5%), hypertension(62.5%), pain(60.0%), malaise(52.5%), anorexia(50.0%), elevated transaminase(47.5%), hand-foot reaction (47.5%), proteinuria (37.5%), and elevated bilirubin(32.5%). Proteinuria, treatment delay, and ECOG performance status were independent predictive factors for PFS.Conclusions: The all-oral therapy of antiangiogenic tyrosine kinase inhibitor apatinib plus vinorelbine presented objective efficacy in advanced HER2-negative breast cancer who failed from first-line therapy, with acceptable and manageable toxicity. Citation Format: Zhu A, Yuan P, Wang J, Fan Y, Luo Y, Cai R, Zhang P, Li Q, Ma F, Xu B. Phase II study of antiangiogenic tyrosine kinase inhibitor apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-10-01.