Abstract Background: Patients (pts) with advanced breast cancer (ABC) who present with visceral metastases (mets) have a poorer prognosis vs pts with non-visceral disease. In the Phase III MONALEESA (ML) trials, ribociclib (RIB) + endocrine therapy (ET) prolonged progression-free survival (PFS) vs placebo (PBO) + ET in hormone receptor-positive (HR+), HER2-negative (HER2–) ABC. Here we show data for pts with and without visceral mets from the ML-2, -3, and -7 trials. Methods: Data were collated from 3 trials in HR+, HER2– ABC: in ML-2 (NCT01958021; data cutoff [DCO] Jan 2/4, 2017), postmenopausal pts (no prior ET for ABC) received RIB or PBO + letrozole; in ML-3 (NCT02422615; DCO Nov 3, 2017), postmenopausal pts (no prior ET for ABC subgroup only) received RIB or PBO + fulvestrant; in ML-7 (NCT02278120; DCO Aug 20, 2017), premenopausal pts (no prior ET and ≤1 chemotherapy for ABC) received RIB or PBO + goserelin + anastrozole/letrozole. Endpoints; primary: local PFS; secondary: overall response rate (ORR), clinical benefit rate (CBR), safety. Results: Of all 820 pts treated with RIB + ET, 484 (59%) had visceral mets (ML-2 197/334; ML-3 137/238; ML-7 150/248); of all 710 pts treated with PBO + ET, 416 (59%) had visceral mets (ML-2 196/334; ML-3 77/129; ML-7 143/247). Median PFS was prolonged for RIB vs PBO in pts with and without visceral mets (Table). ORR and CBR were also higher for RIB vs PBO in pts with and without visceral mets. The most common (≥10% of pts in any arm) Grade [G] 3 and 4 adverse events (AEs) for each trial are shown in the table; no G4 AEs occurred in ≥10% of pts in ML-3. Visceral metsNo visceral metsML-2 Median PFS (RIB/PBO), months (95% CI)24.9 (22.2–30.9)/13.4 (12.7–16.5)25.3 (22.2–NR)/18.2 (15.0–24.6)Hazard ratio (95% CI)0.538 (0.408–0.709)0.634 (0.448–0.897) ORR (RIB/PBO),* %48/3735/17 CBR (RIB/PBO),† %79/7282/75 Most common (≥10% in any arm) G3 AEs (RIB/PBO), %Neutropenia56/147/1Leukopenia19/121/<1Hypertension11/1115/15 Most common (≥10% in any arm) G4 AEs (RIB/PBO), %Neutropenia10/09/0 ML-3 Median PFS (RIB/PBO), months (95% CI)NR (19.1–NR)/16.5 (9.0–NR)NR (NR–NR)/21.9 (14.8–NR)Hazard ratio (95% CI)0.610 (0.403–0.926)0.521 (0.295–0.921) ORR (RIB/PBO),* %46/2931/21 CBR (RIB/PBO),† %74/6075/81 Most common (≥10% in any arm) G3 AEs (RIB/PBO), %Neutropenia50/045/0Leukopenia12/010/0Increased ALT6/012/0 ML-7 Median PFS (RIB/PBO), months (95% CI)23.8 (14.8–NR)/10.4 (7.2–12.9)27.5 (NR–NR)/19.3 (16.5–NR)Hazard ratio (95% CI)0.507 (0.367–0.700)0.609 (0.377–0.984) ORR (RIB/PBO),* %45/3630/19 CBR (RIB/PBO),† %79/5783/81 Most common (≥10% in any arm) G3 AEs (RIB/PBO), %Neutropenia54/356/4Leukopenia14/116/1 Most common (≥10% in any arm) G4 AEs (RIB/PBO), %Neutropenia11/<19/0CI, confidence interval; NR, not reached. *ORR = complete response + partial response; †CBR = complete response + partial response + (stable disease + non-complete response/non-progressive disease ≥24 weeks). Conclusions: Although the presence of visceral mets is associated with a poorer prognosis, RIB + ET is an effective and well-tolerated treatment option for pts with HR+, HER2– ABC irrespective of the presence of visceral mets. Citation Format: Yardley DA, Chan A, Nusch A, Sonke GS, Yap Y-S, Bachelot T, Esteva FJ, Slamon DJ, Burris HA, Gaur A, Kong O, Diaz-Padilla I, Rodriguez Lorenc K, Wheatley-Price P. Ribociclib + endocrine therapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer presenting with visceral metastases: Subgroup analysis of phase III MONALEESA trials [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 P6-18-07.

Abstract Background: In Phase III trials, ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + various endocrine therapy (ET) partners has demonstrated significantly prolonged progression-free survival vs placebo (PBO) + ET in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC). Here we further evaluate the safety of RIB-based regimens of interest for the proposed indication (i.e. with a non-steroidal aromatase inhibitor [NSAI] or fulvestrant [FUL]) using pooled data from three Phase III trials (MONALEESA [ML]-2 [NCT01958021], -3 [NCT02422615], and -7 [NCT02278120]). Methods: Postmenopausal pts with HR+, HER2– ABC received RIB (600 mg/day; 3-weeks-on/1-week-off) or PBO + letrozole (LET; 2.5 mg/day; ML-2 [no prior ET for ABC]) or FUL (500 mg, Days 1 and 15 of Cycle 1, then Day 1 of every cycle thereafter; ML-3; no or ≤1 prior line of ET for ABC]). Premenopausal pts (ML-7; no prior ET and ≤1 chemotherapy for ABC]) received RIB or PBO + anastrozole (1 mg/day)/LET (2.5 mg/day) + goserelin (3.6 mg every 28 days). Adverse events (AEs) were characterized per Common Terminology Criteria for Adverse Events v4.03; safety analyses included time to first event, duration of event, and rate of associated RIB/PBO discontinuations. Results: Data for 1883 pts were pooled; 1065 pts received RIB + ET and 818 pts received PBO + ET (median exposure to study treatment: 17 and 13 months, respectively). Exposure-adjusted incidence rates for AEs of special interest were 561 and 131 per 100 pt-years in the RIB and PBO arms, respectively. The most common all-causality Grade 3/4 AEs (≥10% in any arm; RIB vs PBO) were neutropenia (59% vs 2%), leukopenia (18% vs 1%), and hypertension (13% vs 13%). A new Fridericia's corrected QT interval (QTcF) >480 ms occurred in (n/N) 52/1054 (5%) vs 11/814 (1%) pts in the RIB vs PBO arms; a new QTcF >500 ms occurred in 14/1054 (1%) vs 1/814 (<1%) pts. Median time to first event for Grade ≥2 neutropenia, elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), and QTc prolongation in the RIB arm was 2, 12, and 2 weeks, respectively; median duration of first Grade ≥2 event was 4, 4, and 2 weeks. In the RIB arm vs PBO arms, 7% vs 3% of pts discontinued study treatment due to AEs; common all-grade AEs leading to RIB/PBO discontinuation (≥2% in any arm) were elevated ALT (4% vs <1%) and elevated AST (2% vs 1%). Discontinuation due to QT prolongation occurred in 4 pts in the RIB arm and 2 in the PBO arm (both <1%). All-grade serious AEs occurred in 25% of pts in the RIB arm vs 15% of pts in the PBO arm. Conclusions: RIB in combination with various ET partners continues to demonstrate a predictable and manageable tolerability profile across a broad population of pts with HR+, HER2– ABC. Citation Format: Burris HA, Chan A, Im S-A, Chia S, Tripathy D, Esteva FJ, Campone M, Bardia A, Kong O, Bao W, Diaz-Padilla I, Rodriguez Lorenc K, Yardley DA. Ribociclib + endocrine therapy in hormone receptor-positive, HER2-negative advanced breast cancer: A pooled safety analysis [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 P6-18-15.

Abstract Background gpNMB is an internalizable transmembrane protein overexpressed in ˜40% of TNBC, and associated with a worse prognosis. Preclinical data implicates gpNMB in tumor invasion and metastasis. GV is a novel ADC designed to deliver monomethyl auristatin E (MMAE) to gpNMB-overexpressing cells. Prior phase 1/2 studies suggested promising activity of GV in gpNMB-overexpressing TNBC. Methods In the METRIC trial (NCT#01997333), patients (pts) with mTNBC were randomized 2:1 to GV (1.88 mg/kg IV q21 days) or capecitabine (2,500 mg/m2 PO daily d1-14 q21 days) until disease progression or intolerance. Key eligibility criteria included: gpNMB over-expression (>25% tumor cells positive by central immunohistochemistry of archival tissue); estrogen and progesterone receptor expression <10% and HER2 negative; ECOG 0-1; prior taxane; prior anthracycline exposure (if indicated); <2 chemotherapy regimens for advanced BC. The primary endpoint was progression-free survival (PFS) per independent, blinded central review using RECIST 1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), safety, and pharmacokinetics. The trial had 85% power to detect a PFS hazard ratio of 0.64 with two-sided α = 0.05. Results From Feb 2014 to Aug 2017, 327 women were randomized at 120 institutions to GV (n=218) or capecitabine (n=109). Pretreatment characteristics were well balanced between arms: median age of 55 years; 77% visceral disease; 2.4 years median duration of disease at study entry; 1 median prior anticancer regimen for metastatic disease. At the cut-off for final data analysis (Nov 30, 2017), 21 pts remained on treatment and 98 pts were alive. For GV vs. capecitabine based on independent central review, median PFS was 2.9 (95% CI: 2.8, 3.5) vs. 2.8 (95% CI: 1.6, 3.2) months (HR=0.95; p=0.76); median OS was 8.9 (95% CI: 7.9, 10.5) vs. 8.7 (95% CI: 6.9, 10.8) months (HR=1.06; p=0.73); ORR was 16% (95% CI: 11.1, 22.4) vs. 15% (95% CI: 8.6, 23.5); and median DOR was 5.6 (95% CI: 3.0, 7.8) vs. 4.2 (95% CI: 3.0, 12.2) months. A post-hoc subgroup analysis suggested the greatest benefit from GV was in potentially taxane-sensitive disease (i.e., not previously rechallenged or >6 months progression-free interval following last taxane). The incidence of grade ≥ 3 treatment-related adverse events (TRAEs) was 58% in the GV arm and 37% in the capecitabine arm. The most common grade ≥ 3 TRAEs were neutropenia (27%), rash (15%), and leukopenia (9%) in the GV arm, and diarrhea (14%) and palmar-plantar erythryodysesthesia (8%) in the capecitabine arm. There was 1 fatal TRAE of neutropenic sepsis in the GV arm and none in the capecitabine arm. Conclusion The METRIC study evaluating GV in mTNBC did not meet the primary efficacy endpoint of improved PFS over capecitabine. While anticancer activity was seen with GV, it was comparable to capecitabine with no therapeutic advantage of GV in terms of ORR, PFS, or OS. The safety profile of GV was consistent with prior experience with no new safety signals identified. Citation Format: Vahdat LT, Forero-Torres A, Schmid P, Blackwell K, Telli ML, Melisko M, Holgado E, Moebus V, Cortes J, Fehrenbacher L, Montero AJ, Ma C, Nanda R, Wright GS, He Y, Bagley RG, Halim A, Turner CD, Yardley DA. METRIC: A randomized international phase 2b study of the antibody-drug conjugate (ADC) glembatumumab vedotin (GV) in gpNMB-overexpressing, metastatic, triple-negative breast cancer (mTNBC) [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 P6-20-01.

Abstract Treatment (tx) choices for HER2+ early stage breast cancer (EBC) have become increasingly complex. Clinicians and patients must decide 1) which chemotherapy and HER2-targeted agents to use, 2) the sequence of surgery and chemotherapy: either neoadjuvant (neoadj) or adjuvant (adj) tx, and 3) whether to shorten or extend maintenance HER2-targeted tx. As tx options expand, so does the need for online decision aids. One online decision support tool was developed in 2015 to provide specific tx recommendations for pts with EBC and showed that community healthcare providers (HCPs) did not consistently align with experts for neoadj or adj tx of many pts with EBC (SABCS 2015 Abs P5-09-04). This study includes analysis of neoadj and adj tx practice patterns of 5 breast cancer experts based on their tx recommendations for 270 unique HER2+ EBC case scenarios made for development of a 2018 online decision tool. We aim to compare these recommendations with the intended treatment of clinicians using the tool. Results Experts agree on neoadj tx approaches: initial surgery, no neoadj tx for pts with cT1a/b N0 tumors; neoadj tx before surgery for pts with ≥cT2 or N+ tumors. There was disparity among experts for pts with cT1c N0 disease: 3 experts recommend neoadj TCH±P and 2 recommend proceeding directly to surgery. Experts generally recommend adj TCHP for pts with stage II N+ or higher HER2+ EBC who did not receive neoadj tx. In addition, 5/5 experts would consider extended adj tx with neratinib for these pts if HR+ and 2/5 experts would also consider neratinib if HR–. In pts who received neoadj chemo+HER2 tx, post-surgery management depends on response to neoadj tx. For pts with pCR, 5/5 experts generally agree on continuing H+P if both were given as neoadj tx or H alone if only H given as neoadj tx for a total of 1 yr of anti-HER2 Ab tx and 2/5 experts would consider extended adj tx with neratinib for HR+ disease. For pts with residual disease, experts would recommend continuing H+P if both were given as neoadj tx and most would add P for subsequent adj tx if H alone was given to complete a total of 1 yr of anti-HER2 Ab tx (Table1). All experts would consider extended adj tx with neratinib for HR+ disease and 3/5 experts would also consider neratinib for HR– disease. None of the experts recommended less than 12 mos of adj HER2-targeted tx. We will present analyses of cases entered into our online tool and detailed comparisons of expert and the intended treatment of clinicians using the tool. Conclusions Practice patterns are changing rapidly and are more complex in response to the evolving treatment landscape for HER2+ EBC. This analysis highlights several areas of expert consensus; however, disparities remain for select cases. The current tool addresses an unmet medical need for expert-led evaluation of HER2+ EBC tx choices and warrants further investigation. Expert Recommendations: Initial Adj HER2 Ab Tx After Neodj Tx With H Alone ExpertsResponse12345pCR (HR-)HHHHHpCR (HR+)HHHHHypT1a-c N0 (HR-)H + PHH + PH + PH + PypT1a-c N0 (HR+)H + PHHH + PHypT2 N0 (HR-)H + PH + PH + PH + PH + PypT2 N0 (HR+)H + PH + PHH + PH + PypTany N+ (HR+ or HR-)H + PH + PH + PH + PH + P Citation Format: Holmes FA, Rosenthal KM, Hurvitz S, Pegram MD, Yardley DA, Obholz KL, O'Shaughnessy J. Consensus and disagreement among experts for treatment of patients with HER2+ early-stage breast cancer suggests unmet need for online decision support tool [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 P6-17-36.

Abstract Background: Adjuvant ET with or without chemotherapy reduces the risk for recurrence of HR+, HER2– EBC. However, recurrence is still common, especially in patients with adverse clinical and pathologic features. In the phase 3 MONALEESA-2 trial, the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011), in combination with letrozole, prolonged progression-free survival versus letrozole plus placebo in postmenopausal women with HR+, HER2– advanced breast cancer and no prior therapy for advanced disease (HR = 0.56, 95% CI, 0.43-0.72; P = 3.29×10−6; Hortobagyi et al. N Engl J Med. 2016). EarLEE-2 is investigating the efficacy and safety of ribociclib with ET versus placebo with ET as adjuvant treatment in patients with intermediate-risk EBC. Trial design: In this double-blind, placebo-controlled, phase 3 adjuvant trial, ˜4,000 women and men with fully resected, intermediate-risk, HR+, HER2– EBC (defined as AJCC 8th ed. Prognostic Stage Group II) are being randomized 1:1 to oral ribociclib (600 mg/day, 3 weeks on/1 week off for ˜24 months) plus ET or to placebo plus ET. Adjuvant ET may include tamoxifen, letrozole, anastrozole, or exemestane for ≥ 60 months with ovarian suppression for premenopausal women at the discretion of the investigator. Adjuvant ET in men will be tamoxifen only. Neoadjuvant therapy is not permitted. Randomization is stratified by menopausal status (men and premenopausal women vs postmenopausal women), prior adjuvant chemotherapy (yes vs no), Prognostic Stage Group (IIA vs IIB), and geographic region (North America/Europe/Australia vs rest of the world). Eligible patients must have tumor tissue from the surgical specimen, adequate bone marrow and organ functions, normal serum electrolytes, QTc interval < 450 msec, and completed and recovered from acute toxicities of adjuvant radiotherapy and/or chemotherapy. The primary endpoint is invasive disease-free survival (per STEEP system; Hudis et al. J Clin Oncol. 2007). Secondary endpoints include recurrence-free survival, distant disease-free survival, overall survival, quality of life, and safety. Global recruitment to EarLEE-2 is ongoing. NCT03081234 Citation Format: O'Shaughnessy J, Alba E, Bardia A, Dent S, Dieras V, Hortobagyi G, Im S-A, Montemurro F, Untch M, Yardley DA, Chakravartty A, Germa C, Miller M, Slamon D. EarLEE-2: A phase 3 study of ribociclib + endocrine therapy (ET) for adjuvant treatment of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–), intermediate-risk, early breast cancer (EBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-06.

Abstract This abstract was not presented at the symposium.

Background: The addition of first-line ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) to letrozole (LET) significantly improved progression-free survival (PFS) compared with placebo (PBO) + LET in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in the Phase III MONALEESA-2 study. Identifying biomarkers that predict response to treatment remains a key challenge in pts with HR+ ABC. Here we analyze results from MONALEESA-2 by molecular alterations detected in circulating tumor DNA (ctDNA) at baseline, including PIK3CA mutations and other alterations considered to be important in HR+ ABC. Methods: Postmenopausal women (N=668) with HR+, HER2– ABC who had not received any prior therapy for ABC were randomized 1:1 to RIB (600 mg/day; 3-weeks-on/1-week-off) + LET (2.5 mg/day; continuous) or PBO + LET. The primary endpoint was PFS. Biomarker analysis of the ctDNA mutation profile was an exploratory endpoint. Plasma samples for ctDNA analysis were collected at baseline and end of treatment. ctDNA was analyzed using next-generation sequencing with a targeted panel of ˜550 genes. Results: Baseline ctDNA was successfully sequenced in 494 pts (RIB + LET: n=212; PBO + LET: n=215); 67 (14%) of 494 pts were removed from the analysis due to limited tumor DNA in circulation. 427 (86%) pts had ≥1 alteration, including 1,573 mutations, 513 short insertions/deletions, 166 amplifications, and 8 translocations. Alterations (frequency) were commonly observed in the following genes: PIK3CA (33%), TP53 (12%), ZNF703/FGFR1 (5%), and ESR1 (4%), and in genes involved in receptor tyrosine kinase (RTK) signaling (12%). RIB + LET treatment benefit was consistent in pts with wild-type (WT) and altered PIK3CA, and in pts with WT and altered TP53 (Table). RIB + LET improved PFS regardless of RTK or ZNF703/FGFR1 alterations. However, there was a weak trend for increased benefit in pts with WT vs altered RTK genes and in pts with WT vs altered ZNF703/FGFR1 genes. These results should be interpreted with caution due to the small number of pts with these alterations. There were too few ESR1 alterations for firm conclusions to be drawn. Conclusions: Consistent RIB + LET treatment benefit was observed compared with PBO + LET, irrespective of the status of baseline ctDNA biomarkers. Citation Format: Hortobagyi GN, Stemmer S, Campone M, Sonke GS, Arteaga CL, Paluch-Shimon S, Petrakova K, Villanueva C, Nusch A, Grischke E-M, Chan A, Jakobsen E, Marschner N, Hart LL, Alba E, Ohnstand HO, Blau S, Yardley DA, Solovieff N, Su F, Germa C, Yap Y-S. First-line ribociclib + letrozole in hormone receptor-positive, HER2-negative advanced breast cancer: Efficacy by baseline circulating tumor DNA alterations in MONALEESA-2 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-06.

Abstract Background: The androgen receptor (AR) is expressed in >75% of hormone receptor (HR)+ tumors. AR signaling has been associated with resistance to endocrine therapy (ET). Aromatase inhibitors (AIs) divert estrogen precursors to androgens; in preclinical models enzalutamide (ENZA) blocked both estrogen- and androgen-mediated growth of HR+ cells. In a phase 1 study of ET+ENZA in breast cancer, doubling the dose of exemestane (EXE) to 50 mg was necessary to restore exposure observed with 25 mg.1 Methods: This placebo (PBO)–controlled phase 2 trial randomized patients (pts) with HR+/HER2-normal advanced/metastatic breast cancer (MBC) to either 25 mg EXE+PBO or 50 mg EXE+160 mg ENZA daily (NCT02007512). Two parallel cohorts enrolled pts who had no prior ET (C1) or who had received 1 prior ET for MBC (C2). Randomization was stratified on resistance to prior ET and prior exposure to AI. Tissue samples for biomarker development were mandatory. Brain metastases or a history of seizure was exclusionary. One prior chemotherapy regimen for MBC was permitted. Response was assessed every 8 weeks for 48 weeks, then every 12 weeks. Crossover to ENZA+EXE was allowed at disease progression. A gene signature–based biomarker (Bmkr) indicating AR signaling predictive of response to ENZA was developed using a training set of RNAseq data from 2/3 of randomized pts and validated using a test set of data from the remaining 1/3 of pts. Progression-free survival (PFS) according to RECIST v1.1 was the primary endpoint in the intent-to-treat (ITT) population and in the Bmkr+ subgroup of each cohort. Secondary endpoints included clinical benefit rate at 24 weeks (CBR24), best overall response, and safety. Results: A total of 247 pts were randomized (C1, n=127; C2, n=120). In C1, 50 pts (39.4%) were Bmkr+; in C2, 35 pts (29.2%) were Bmkr+. Statistically significant improvements in median PFS and CBR24 were observed only in the Bmkr+ population with no prior ET (Table). The most common adverse events (AEs) reported in the ENZA+EXE arms were nausea (39%) in C1 and fatigue (37%) in C2. In C1, 9 pts (15%) and 10 pts (16%) discontinued the study due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. In C2, 11 pts (18%) and 5 pts (8%) discontinued due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. Conclusions: In the first reported randomized trial of ENZA in HR+ MBC, ENZA+EXE was well tolerated with no new safety signals. The study met its primary endpoint in pts with Bmkr+ MBC with no prior ET. 1. Schwartzberg et al. Clin Cancer Res. 2017 Mar 9 [Epub ahead of print]. C1: No Prior ETC2: 1 Prior ET ITTBmkr+ITTBmkr+EXE+ENZA | PBOENZA | PBOENZA | PBOENZA | PBO n=63 | n=64n=24 | n=26n=60 | n=60n=15 | n=20Primary endpointPFS, median, months11.8 | 5.816.5 | 4.33.6 | 3.96.0 | 5.3(95% CI)(7.3, 15.9) | (3.5, 10.9)(11.0, NR) | (1.9, 10.9)(1.9, 5.5) | (2.6, 5.4)(2.3, 26.7) | (1.8, 6.7)Hazard ratio0.820.441.020.55(95% CI)(0.54, 1.26)(0.21, 0.96)(0.66, 1.59)(0.23, 1.36)P value0.36310.03350.92120.1936Secondary endpointCBR24, n (%)39 (62) | 29 (45)20 (83) | 10 (38)12 (20) | 19 (32)6 (40) | 6 (30)(95% CI)(49, 74) | (33, 58)(63, 95) | (20, 59)(11, 32) | (20, 45)(16, 68) | (12, 54)P value0.06090.00120.14430.5374 Citation Format: Krop I, Abramson V, Colleoni M, Traina T, Holmes F, Estevez L, Hart L, Awada A, Zamagni C, Morris P, Schwartzberg L, Chan S, Wheatley D, Gucalp A, Biganzoli L, Steinberg J, Gianni L, Trudeau M, Tudor IC, Markova D, Barry E, Tarazi J, Stewart R, Winer E, Yardley DA. Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-07.

Background: Endocrine-based therapy is the standard of care for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), in whom delaying disease progression is the primary goal. In the randomized Phase 3 MONALEESA-2 study (ClinicalTrials.gov identifier, NCT01958021), first-line ribociclib (a selective inhibitor of cyclin-dependent kinases 4 and 6) + letrozole significantly prolonged progression-free survival (PFS) compared with placebo + letrozole in postmenopausal women with HR+, HER2− ABC (hazard ratio, 0.556; 95% confidence interval [CI], 0.429–0.720) at the interim analysis cutoff date. Here, we present safety and efficacy data from US patients who were enrolled in the MONALEESA-2 study. Methods: Postmenopausal women (N=668) with HR+, HER2− ABC who did not receive prior systemic treatment for ABC and had an Eastern Cooperative Oncology Group performance status score of ≤1, adequate bone marrow and organ function, and no history of active cardiac dysfunction were randomized 1:1 to receive either ribociclib (600 mg/d, 3 weeks on/1 week off) + letrozole (2.5 mg/d, continuous) or placebo + letrozole. The primary end point was locally assessed PFS. The data cutoff for this analysis was January 29, 2016. Results: Baseline demographics, patient disposition, and prior therapy were well balanced across treatment groups in the US subset (N=213; ribociclib group, n=100; placebo group, n=113). Median treatment duration was 16.3 months. In US patients, median PFS was significantly prolonged in the ribociclib group (median PFS, not reached [NR]; 95% CI, 17.1 months to NR) versus the placebo group (median PFS, 14.4 months [95% CI, 11.1–18.4 months]; hazard ratio, 0.451 [95% CI, 0.281–0.724]; P=0.000363), with a median follow-up of 11.0 months. In a subsequent preplanned analysis of overall survival, median PFS was 27.6 months in the ribociclib group versus 15.0 months in the placebo group (hazard ratio, 0.527; 95% CI, 0.351–0.793). The overall response rate (ORR) was significantly greater in the ribociclib group (ORR, 38.0%; 95% CI, 28.5–47.5%) versus the placebo group (ORR, 26.5%; 95% CI, 18.4–34.7%; P=0.040). A trend toward benefit was observed with ribociclib in all subgroups (including age, disease burden, prior therapy, and biomarker status), which was consistent with the overall population. No on-treatment deaths occurred. The most common all-grade adverse events, irrespective of causality, were neutropenia (ribociclib, 69.0%; placebo, 3.7%), nausea (ribociclib, 65.0%; placebo, 39.4%), fatigue (ribociclib, 56.0%; placebo, 46.8%), and diarrhea (ribociclib, 41.0%; placebo, 32.1%). The most common grade 3 (≥25% in either group) and grade 4 (≥10% in either group) AE was neutropenia (grade 3: ribociclib, 39.0%; placebo, 0%; grade 4: ribociclib, 14.0%; placebo, 0%). Two patients (2.0%) in the ribociclib group and none in the placebo group experienced febrile neutropenia. Conclusions: The US patients in the MONALEESA-2 study derived significant PFS benefit from ribociclib + letrozole compared with placebo + letrozole, with a 55% reduction in the relative risk of disease progression. The safety profile was consistent with and comparable to the global study population. Citation Format: Yardley DA, Hart L, Favret A, Blau S, Diab S, Richards D, Sparano J, Beck JT, Richards P, Ward P, Ramaswamy B, Tsai M, Pluard T, Tolaney S, Esteva F, Small T, Purkayastha D, Miller M, Hortobagyi G. Efficacy and safety of ribociclib plus letrozole in US patients enrolled in the MONALEESA-2 study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-27.

Abstract Introduction HR+ metastatic breast cancer (MBC) generally has a more indolent course than HR– MBC. Less is known about differences in BL characteristics and disease outcomes by HR status in HER2+ MBC in the modern tx setting where patients (pts) may recur after adjuvant therapy. SystHERs is an ongoing, prospective, observational cohort study of HER2+ MBC pts. Here we describe BL characteristics, tx patterns, and outcomes by HR status and MBC diagnosis type. Methods SystHERs enrolled pts aged ≥18 years and within 6 months of MBC diagnosis. Locally-determined HR status was captured at initial diagnosis and/or disease recurrence; HR+ was defined as ER+ and/or PR+ disease in primary (early BC) or MBC. Tx data are shown for pts ≥9 months from MBC diagnosis to capture the completion of chemotherapy and the addition of hormonal therapy during maintenance tx. Median overall survival (OS; Kaplan-Meier) and the hazard ratio (Cox regression) were estimated. Results As of Feb 2016, data were available for 872 eligible pts with known HR status; 70% had HR+ disease and 50% had de novo MBC. Median follow-up from MBC diagnosis was 16.5 months (range, 0.4–49.4 months). Clinically important BL demographics and disease characteristics with noticeable differences are presented in Table 1. More black (vs white) pts were observed to be HR–. More recurrent (vs de novo) pts were observed to be HR+. MBC tx choices may be influenced by adjuvant tx. Table 2 shows the most common first-line tx regimens in de novo vs recurrent pts with HR+ HER2+ disease and ≥9 months from MBC diagnosis. Among these pts, 60% de novo and 56% recurrent pts received any hormonal therapy. The most common first-line tx regimen for pts with HR– disease was chemotherapy + HER2-targeted therapy (92%). There were 88 (15%) and 55 (21%) deaths in the HR+ and HR– groups, respectively. Median OS was not reached for either group, but the hazard ratio favored pts with HR+ disease (log-rank P=0.026; hazard ratio 0.683; 95% CI 0.488–0.957). Table 1. BL characteristics HR+ HER2+ (n=608)HR– HER2+ (n=264)Race, % White8272Black1321MBC diagnosis type, % De novo4758Recurrent*5342Visceral disease, %6375No significant differences in other characteristics by HR status (eg, sex, ethnicity, education, menopausal status, performance status, number of metastatic sites at diagnosis). *Pts with prior adjuvant therapy: HR+, 89%; HR–, 83%. Table 2. Most common first-line tx regimens in pts with HR+ HER2+ disease and ≥9 months from MBC diagnosis De novo (n=227)Recurrent (n=235)Chemotherapy + HER2-targeted therapy + hormonal therapy, %4938Chemotherapy + HER2-targeted therapy only, %3741HER2-targeted + hormonal therapy only, %1014 Conclusions In SystHERs, 70% of pts with HER2+ MBC had HR+ disease. A higher percentage of recurrent pts had HR+ disease vs de novo pts, perhaps suggesting selective elimination of HR– clones during adjuvant tx. While black pts are known to be more likely to develop HR– HER2– BC, our results show that HR– HER2+ disease is also more common in black pts, suggesting a proclivity for this population to develop HR– MBC regardless of HER2 status. In these early results, survival was higher in pts with HR+ HER2+ MBC. Citation Format: Cobleigh M, Yardley DA, Brufsky A, Rugo H, Swain S, Kaufman PA, Tripathy D, Mayer M, Hurvitz S, O'Shaughnessy J, Mason G, Chu L, Antao V, Beattie M, Yoo B, Jahanzeb M. Baseline (BL) characteristics, treatment (tx) patterns, and outcomes in patients with hormone receptor (HR)+ vs HR– HER2+ disease from the SystHERs registry [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-08.

Abstract BACKGROUND: Lucitanib is a potent, oral antiangiogenic tyrosine kinase inhibitor of Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3), Platelet-Derived Growth Factor Receptors alpha and beta (PDGFRα/β), and Fibroblast Growth Factor Receptors 1-3 (FGFR1-3). FGF aberrancies (amplification of FGFR1,or 11q[amplicon containing FGF ligands 3, 4, and 19]), are genomic alterations observed in over 20% of breast cancer pts and promote cancer proliferation and survival. METHODS: MBC pts who had received at least 1 metastatic line of therapy were randomized 1:1 to 10 or 15 mg QD of lucitanib. Stratification was based on local assessment of FGF aberrancy; pts with both FGFR1 and 11q-amplified tumors were stratified as FGFR1 amplified. Central confirmation of FGFR1 or 11q amplification was done using Abbott FISH probes (FGFR1 or 11q copy number ≥ 6 and a ratio of FGFR1 or 11q to centromere ≥ 2). Investigator-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints included objective response rate (ORR) per RECIST 1.1, disease control rate (DCR), duration of response (DR), and incidence of treatment-emergent adverse events (TEAE). RESULTS: Enrollment completed in 3/2016; 178 pts that received at least 1 dose of lucitanib are included in this analysis (baseline characteristics in Table 1). Due to grade 3 hypertension in the 15 mg group (46% vs 37% in 10 mg group), enrollment to the 15 mg group was halted. Overall, most pts (97%) experienced at least 1 TEAE, with the most frequently (≥ 30%) occurring events being hypertension (73%), fatigue (48%), nausea (43%), hypothyroidism (40%), and headache (33%). Grade ≥ 3 TEAEs occurred in 66% of pts, with hypertension as the most frequent event (40%) followed by proteinuria and hyponatremia (both 6%). AEs were manageable with dose interruption or reduction, with approximately 8% of pts ending treatment due to an AE. Current median PFS is 3.5 mos (95% CI 2.8-4.6; range 0.62-12.95) and 2.6 mos (95% CI 1.8-2.9; range 0.82-18.87) respectively for the 10 mg and 15 mg treatment groups. No differences in clinical activity were observed by treatment group, FGF aberrancy, hormone receptor or HER2 status. Of the 168 evaluable pts, confirmed ORR was 3%; overall DCR was 27% (32% for pts in the 10 mg group compared to 20% for the 15 mg group); overall mean (standard deviation) DR of 3.3 (1.8) mos. Baseline Characteristics 10 mg QD15 mg QD N=109N=69Age (years)Median5653Range27-8227-80SexFemale109 (100%)67 (97%)Male02 (3%)ECOG PSmissing5 (5%)2 (3%)051 (47%)30 (43%)153 (49%)37 (54%)Number of prior anticancer therapies in the metastatic setting> 332 (29%)21 (30%)3-648 (44%)32 (46%)> 629 (27%)16 (23%)Endocrine/HER2 statusmissing7 (6%)1 (1%)ER+ or PR+74 (68%)50 (73%)HER2+12 (11%)7 (10%)TNBC16 (15%)11 (16%)FGFR aberrancyFGFR1 amplified54 (49%)29 (42%)11q amplified31 (28%)24 (35%)FGFR1 and 11q amplified13 (12%)9 (13%)FGFR1 and 11q non-amplified11 (10%)7 (10%) CONCLUSION: At 10 mg QD, lucitanib has modest activity with manageable toxicity in this heavily pretreated pt population. Future clinical development for lucitanib may focus on alternative biomarkers to identify sensitive tumors and rational combinations with other anti-cancer drugs. Citation Format: Mayer IA, Arteaga CL, Nanda R, Miller KD, Jhaveri K, Brufsky AM, Rugo H, Yardley DA, Vahdat LT, Sadeghi S, Audeh MW, Rolfe L, Litten J, Knox A, Raponi M, Tankersley C, Isaacson J, Wride K, Morganstern DE, Vogel C, Connolly RM, Gradishar WJ, Patel R, Pusztai L, Abu-Khalaf M. A phase 2 open-label study of lucitanib in patients (pts) with FGF aberrant metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-03.

Abstract This abstract was withdrawn by the authors.

Abstract Background: Systemic inflammation is associated with poor prognosis in pts with ABC. The JAK/STAT pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. We evaluated the efficacy and safety of RUX, a JAK1/JAK2 inhibitor, plus CAPE in pts with HER2-negative ABC and high systemic inflammation defined by the modified Glasgow Prognostic Score (mGPS). Methods: In this double-blind phase 2 trial, pts were randomized 1:1 to 21 day cycles of RUX+CAPE or PBO+CAPE: RUX 15 mg or PBO PO BID for 21 d; CAPE 1000 mg/m2 PO BID for 14 d. Key inclusion criteria were systemic inflammation by mGPS of 1 or 2 (ie, CRP >10 mg/L), ECOG performance status ≤2, ≤2 prior chemotherapy regimens, and no prior CAPE. The primary endpoint was overall survival (OS); key secondary endpoints were progression-free survival (PFS), objective response rate (ORR; complete [CR] + partial response [PR]) per RECIST v1.1, clinical benefit rate (CBR; CR + PR + stable disease for ≥6 mo), duration of response, and safety. Treatment differences in OS and PFS were analyzed by the log-rank test; HRs and CIs were analyzed by the Cox proportional hazards model. Results: Baseline characteristics were similar between pts randomized to RUX+CAPE (n=76) vs PBO+CAPE (n=73): mGPS status (1, 82.9% vs 83.6%), hormone receptor (HR) status (positive, 67.1% vs 63.0%), and number of prior chemotherapy regimens for ABC (0, 50.0% vs 50.7%; 1, 38.2% vs 34.2%; 2, 9.2% vs 13.7%). Median treatment durations were 85 d with RUX in the RUX+CAPE group and 65 d with PBO in the PBO+CAPE group. Median OS was 11.2 mo with RUX+CAPE vs 10.9 mo with PBO+CAPE (HR, 0.932; 95% CI, 0.59–1.46; P=0.762). Median OS was 6.1 mo with RUX+CAPE vs 5.5 mo with PBO+CAPE in HR-negative pts and 11.7 mo and 12.2 mo in HR-positive pts. Median PFS was 4.5 mo with RUX+CAPE and 2.5 mo with PBO+CAPE (HR, 0.737; 95% CI, 0.49–1.12; P=0.151). Median PFS was 2.1 mo with RUX+CAPE vs 2.2 mo with PBO+CAPE in HR-negative pts and 6.1 mo and 4.1 mo in HR-positive pts. ORRs were 28.9% and 13.7% (P=0.024) in the RUX+CAPE and PBO+CAPE arms, respectively. The CBRs were 13.2% and 6.8%, respectively (P=0.278). Worsening of hematologic toxicity was higher and rates of grade 3/4 palmar-plantar erythrodysethesia (PPE) were lower (1.4% vs 12.7%, respectively) with RUX+CAPE (Table). Safety RUX+CAPE (n=71)PBO+CAPE (n=71)%All-GradeGrade 3/4All-GradeGrade 3/4Nonhematologic Adverse Event*Fatigue56.35.643.74.2Nausea54.98.549.35.6Diarrhea47.98.526.82.8PPE46.51.438.012.7Vomiting38.05.629.64.2Hypokalemia15.58.57.02.8Worsening of Hematologic Toxicity†Anemia80.323.956.37.0Lymphopenia40.815.545.112.7Neutropenia39.411.322.52.8Thrombocytopenia39.411.315.51.4*Most common all-grade (≥35%) or grade 3/4 (≥5%) events in the RUX+CAPE arm (safety group). †Laboratory abnormalities. Conclusion: These data support the prognostic capabilities of the mGPS. The addition of RUX to CAPE for pts with ABC and high systemic inflammation was associated with an improved ORR compared with PBO+CAPE, but did not improve OS or PFS. Citation Format: O'Shaughnessy J, DeMichele A, Ma C, Richards P, Yardley DA, Wright G, Kalinsky K, Steis R, Diab S, Kennealey G, Geschwindt R, Jiang W, Rugo H. A randomized, double-blind, phase 2 study of ruxolitinib (RUX) or placebo (PBO) in combination with capecitabine (CAPE) in patients (pts) with advanced HER2-negative breast cancer (ABC) and elevated C-reactive protein (CRP), a marker of systemic inflammation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-04.

Abstract Introduction In 2010, the cutoff for HR positivity in breast cancer was established as ≥1% of cells staining HR+, previously having varied from 1% to 10%. The impact of this change on treatment patterns and outcomes is poorly understood. SystHERs is a prospective, observational cohort registry of patients (pts) with HER2+ metastatic breast cancer (MBC) that commenced enrollment in 2012. To our knowledge, SystHERs is the largest registry to collect and analyze data for the HER2+ subgroup. We report baseline characteristics, treatment patterns, and early outcomes by %HR+ (1–9% vs 10–100%). Methods SystHERs enrolled pts aged ≥18 years and within 6 months of HER2+ MBC diagnosis. For pts with locally-determined HR+ disease, defined as HR+ in primary or metastatic tissue, %HR+ is the highest percentage of ER+ or PR+ tissue in early breast cancer or MBC. The percentage of ER+ or PR+ cells was not reported for pts considered HR– by the investigator. Median overall survival (OS; Kaplan–Meier) and hazard ratios (Cox regression) were estimated. Results As of Feb 1, 2016, data were available for 872 eligible pts with known HR status, of whom 608 (70%) had HR+ disease. Of the 608 pts, 53 (9%) had 1–9%HR+ and 496 (82%) had 10–100%HR+; %HR+ was not reported for 59 pts. Baseline characteristics were similar between %HR+ subgroups (Table 1). As shown in Table 2, the 1–9%HR+ subgroup was less likely to receive first-line hormonal therapy (26%) than the 10–100%HR+ subgroup (56%). 87% and 79% of pts received chemotherapy, respectively. Median time from MBC diagnosis was 16.5 months (range, 0.4–49.4 months). Median OS was not reached at the data cutoff. The number of deaths was 13 (25%) in the 1–9%HR+ subgroup, and 68 (14%) in the 10–100%HR+ subgroup (log-rank P=0.025). The OS hazard ratio (0.514, 95% CI 0.283–0.931) favored the 10–100%HR+ subgroup. OS did not differ significantly between pts with 1–9%HR+ vs HR– disease (log-rank P=0.582, hazard ratio 1.185, 95% CI 0.647–2.169). Table 1. Baseline characteristics 1-9%HR+ (n=53)10-100%HR+ (n=496)HR– (n=264)Age at MBC diagnosis, median yrs (range)54 (30–86)57 (21–86)55 (28–88)Race, % White838372Black151320Premenopausal, %282522ECOG performance status, % 04654441463942≥2878MBC diagnosis type, % De novo404958Recurrent605142Visceral, %*686275*Non-hepatic abdominal, ascites, CNS, liver, lung, or pleural effusion sites of metastasis Table 2. First-line treatment 1-9%HR+ (n=53)10-100%HR+ (n=496)HR– (n=264)HER2-targeted therapy, %969391Chemotherapy, %877989Hormonal therapy, %26564 Conclusions These preliminary observational data suggest potential differences in treatment patterns and survival outcomes in low vs moderate/high HR+ expressers, with the former being less likely to receive hormonal therapy (26% vs 56%). Furthermore, low HR positivity was associated with poorer OS and was similar to OS observed in pts with HR– disease. Citation Format: Jahanzeb M, Tripathy D, Rugo H, Swain S, Kaufman PA, Mayer M, Hurvitz S, O'Shaughnessy J, Mason G, Yardley DA, Brufsky A, Chu L, Antao V, Beattie M, Yoo B, Cobleigh M. Treatment patterns and clinical outcomes in patients with hormone receptor (HR)+ HER2+ metastatic breast cancer and low vs high levels of HR positivity from the SystHERs Registry [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-27.

Abstract Background: Therapies targeting estrogen receptor (ER) signaling are standard for patients (pts) with hormone receptor positive (HR+) (ER and/or progesterone receptor [PR] positive) metastatic breast cancer (MBC). Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been associated with endocrine therapy (ET) resistance. BOLERO-2 demonstrated that the addition of the mTOR inhibitor, everolimus (EVE), to exemestane doubled the PFS in HR+ HER2- MBC pts who previously progressed on nonsteroidal aromatase inhibitor therapy.The premise of this phase 2 trial in HR+ MBC is that the addition of EVE to the last ET on which the disease progressed may restore sensitivity to ET and extend the benefit of the anti-estrogen therapy. Methods: Pts ≥18 yrs with HR+, HER2- unresectable, locally recurrent, or MBC refractory to ET in either the adjuvant or advanced/metastatic setting. 0-1 chemotherapy (chemo) regimens for MBC were permitted. Post-/ pre-/peri-menopausal women were eligible with ovarian function suppression permitted. Additional eligibility requirements include: no prior mTOR inhibitor therapy, measurable or evaluable disease, ECOG ≤2, adequate bone marrow and organ function. EVE (10 mg PO daily) was administered on a 4-wk cycle in combination with the same dose and schedule of the last ET to which their disease became resistant. Disease assessments were performed every 2 cycles and treatment continued until disease progression or unacceptable toxicity. Blood samples and archival tumor were collected respectively for the VeriStrat Assay and for the Foundation One molecular profiling platform. Results: 48 pts were enrolled; data from 26 pts is presented. Median age 63.5 yrs (range, 36-81) with 46% ≥ 65 yrs. 14 (54%) pts had received chemo in the adjuvant setting, 9 pts (35%) received chemo for MBC, and 4 pts (15%) received chemo in both settings. All pts had at least 1 prior hormonal therapy; 9 pts received ≥ 3 hormonal agents. EVE was combined with tamoxifen (27%), AIs (61%), and fulvestrant (12%). Median time on treatment was 18.6 wks (range 1-48.9 weeks). 5 pts (19%) remain on treatment and 21 (81%) have discontinued therapy due to: disease progression - 17, toxicity -2, and other causes - 2. 23 pts were evaluable for response. 1 pt on fulvestrant plus EVE had a PR and 18 pts (78%) had SD as best response, with SD > 6 mos in 7 pts, for a clinical benefit rate (CR+PR+ SD ≥ 6 months) of 35%. With a median follow up of 11 mos (range 2-16 mos), the median PFS was 6.6 months (range 3.6-9.4); the median OS has not been reached. Treatment-related adverse events consisted mostly of stomatitis, rash and fatigue with few G3 events: stomatitis 3 pts, rash 2 pts, and 1 each of fatigue, edema, and neutropenia. G1 pneumonitis was present in 2 pts. There were no G4 events or treatment related deaths. Conclusions: In HR+ HER2- advanced/MBC patients who progressed on prior ET, the addition of EVE to the ET to which their disease became resistant, resulted in 1 PR and 7 pts with SD > 6 mos. The results of the full study population will be presented. Modulation of the mTOR/AKT/PI3K pathway with EVE may extend the benefit of ET, even after tumor progression on ET alone. Citation Format: Yardley DA, Blakely L, Hemphill B, Joseph M, Liggett W, Daniel B, Castrellon A, Shastry M, Finney L, DeBusk L, Hainsworth JD, Burris III HA. A phase 2 open label study of everolimus in combination with endocrine therapy in resistant hormone receptor-positive HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-09.

Abstract Background: There is extensive crosstalk between the cyclin D–CDK4/6–inhibitor of CDK4–retinoblastoma and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways at the G1/S cell-cycle checkpoint. Both pathways are frequently dysregulated in hormone receptor-positive (HR+) breast cancer and have been associated with endocrine therapy (ET) resistance. CDK4/6 and PI3K/mTOR inhibitors have demonstrated clinical activity in combination with ET. Although CDK4/6 inhibitors combined with ET significantly improve progression-free survival (PFS) in ABC, disease progression eventually occurs, highlighting the need for effective treatment options following doublet therapy. Ribociclib (LEE011; CDK4/6 inhibitor; 3-weeks-on/1-week-off) + EVE (mTOR inhibitor) + EXE triplet therapy has shown preliminary clinical activity in heavily pretreated HR+, human epidermal growth factor receptor 2-negative (HER2–) ABC including patients (pts) with prior exposure to CDK4/6 inhibitors, suggesting this combination may restore sensitivity to CDK4/6 inhibitor-based therapy. Trial design and objectives: TRINITI-1 (NCT02732119) is a US-based, phase I/II, single arm, open-label study of ribociclib (continuous daily dosing) + EVE (2.5 mg/day) + EXE (25 mg/day) in men and postmenopausal women with HR+, HER2– ABC refractory to ≥1 line of ET. Phase I dose escalation consists of 2 ribociclib dose-level cohorts (250 and 300 mg/day), followed by a Simon Two-Stage phase II trial in pts with disease progression on prior CDK4/6 inhibitor-based therapy. No more than 3 lines of therapy for ABC, including ≤1 prior chemotherapy regimen, are permitted. Previous EXE treatment of >28 days for metastatic disease, prior mTOR inhibitors, and progression on >1 CDK4/6 inhibitor are prohibited. All pts in phase II must have progressed on a CDK4/6 inhibitor as the last regimen before study entry. Additional eligibility criteria include measurable disease or lytic/mixed bone lesions and Eastern Cooperative Oncology Group performance status of ≤1. Exclusion criteria include visceral crisis, unstable CNS metastases, and clinically significant heart disease. Phase I primary objective: maximum tolerated dose and/or recommended phase II dose of the triplet combination. Phase II primary objective: clinical benefit rate (CBR) at 24 weeks (0.1 significance level, 80% power to test CBR ≤15% against CBR ≥30%) with centrally-assessed PFS as a key secondary objective. Other secondary objectives include preliminary antitumor activity (phase I), safety and pharmacokinetics (phase I/II), and overall response rate, overall survival, and duration of overall response (phase II). Tumor assessments (RECIST v1.1) will be performed every 8 weeks for the first 12 months, and every 12 weeks thereafter until disease progression. Exploratory analyses include biomarkers potentially predictive of response and mechanisms of resistance. Target accrual: Approximately 52 pts at ∼30 sites; 3–6 pts per cohort in phase I, an initial 19 in phase II with another 20 enrolled upon demonstration of clinical benefit in ≥4 pts. Citation Format: Bardia A, Hurvitz S, Yardley DA, Zelnak A, DeMichele A, Clark AS, Warsi G, Small T, Tucci C, Moulder S. TRINITI-1: Ribociclib + everolimus (EVE) + exemestane (EXE) triplet combination in men or postmenopausal women with HR+, HER2– advanced breast cancer (ABC) following progression on a cyclin-dependent kinase (CDK) 4/6 inhibitor [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-05.

Background: There is extensive crosstalk between the cyclin D–CDK4/6–inhibitor of CDK4–retinoblastoma and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways at the G1/S cell-cycle checkpoint. Both pathways are frequently dysregulated in hormone receptor-positive (HR+) breast cancer and have been associated with endocrine therapy (ET) resistance. CDK4/6 and PI3K/mTOR inhibitors have demonstrated clinical activity in combination with ET. Although CDK4/6 inhibitors combined with ET significantly improve progression-free survival (PFS) in ABC, disease progression eventually occurs, highlighting the need for effective treatment options following doublet therapy. Ribociclib (LEE011; CDK4/6 inhibitor; 3-weeks-on/1-week-off) + EVE (mTOR inhibitor) + EXE triplet therapy has shown preliminary clinical activity in heavily pretreated HR+, human epidermal growth factor receptor 2-negative (HER2–) ABC including patients (pts) with prior exposure to CDK4/6 inhibitors, suggesting this combination may restore sensitivity to CDK4/6 inhibitor-based therapy. Trial design and objectives: TRINITI-1 (NCT02732119) is a US-based, phase I/II, single arm, open-label study of ribociclib (continuous daily dosing) + EVE (2.5 mg/day) + EXE (25 mg/day) in men and postmenopausal women with HR+, HER2– ABC refractory to ≥1 line of ET. Phase I dose escalation consists of 2 ribociclib dose-level cohorts (250 and 300 mg/day), followed by a Simon Two-Stage phase II trial in pts with disease progression on prior CDK4/6 inhibitor-based therapy. No more than 3 lines of therapy for ABC, including ≤1 prior chemotherapy regimen, are permitted. Previous EXE treatment of u003e28 days for metastatic disease, prior mTOR inhibitors, and progression on u003e1 CDK4/6 inhibitor are prohibited. All pts in phase II must have progressed on a CDK4/6 inhibitor as the last regimen before study entry. Additional eligibility criteria include measurable disease or lytic/mixed bone lesions and Eastern Cooperative Oncology Group performance status of ≤1. Exclusion criteria include visceral crisis, unstable CNS metastases, and clinically significant heart disease. Phase I primary objective: maximum tolerated dose and/or recommended phase II dose of the triplet combination. Phase II primary objective: clinical benefit rate (CBR) at 24 weeks (0.1 significance level, 80% power to test CBR ≤15% against CBR ≥30%) with centrally-assessed PFS as a key secondary objective. Other secondary objectives include preliminary antitumor activity (phase I), safety and pharmacokinetics (phase I/II), and overall response rate, overall survival, and duration of overall response (phase II). Tumor assessments (RECIST v1.1) will be performed every 8 weeks for the first 12 months, and every 12 weeks thereafter until disease progression. Exploratory analyses include biomarkers potentially predictive of response and mechanisms of resistance. Target accrual: Approximately 52 pts at ∼30 sites; 3–6 pts per cohort in phase I, an initial 19 in phase II with another 20 enrolled upon demonstration of clinical benefit in ≥4 pts. Citation Format: Bardia A, Hurvitz S, Yardley DA, Zelnak A, DeMichele A, Clark AS, Warsi G, Small T, Tucci C, Moulder S. TRINITI-1: Ribociclib + everolimus (EVE) + exemestane (EXE) triplet combination in men or postmenopausal women with HR+, HER2– advanced breast cancer (ABC) following progression on a cyclin-dependent kinase (CDK) 4/6 inhibitor [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-05.

Abstract Background: Residual breast cancer after NAC is associated with a high risk of recurrence. Little evidence supports the use of further chemotherapy in this setting. Eribulin, an inhibitor of microtubule dynamics, demonstrated a survival advantage in patients with metastatic breast cancer who had progressed after previous anthracycline and taxane therapy. This phase 2 trial assessed the efficacy of eribulin (2-yr disease-free survival) administered postoperatively to breast cancer pts not achieving a pCR following standard NAC. Methods: Women with invasive breast cancer (stage T1-4b, N0-2, M0 at diagnosis) and evidence of residual cancer (>5 mm) in the breast or axillary lymph nodes (LN) following ≥4 cycles of standard anthracycline and/or taxane-containing NAC were eligible. Additional eligibility criteria: age ≥18 yrs, peripheral neuropathy < 1, adequate hematologic, hepatic, and renal function. 3 groups were studied: Cohort A-triple negative (TN), Cohort B-HR+/HER2-, Cohort C-HER2+. After recovery from definitive surgery, all pts received eribulin mesylate 1.4mg/m2 IV on days 1 and 8 every 21 days for 6 cycles. Cohort C pts also received trastuzumab 6mg/kg IV day 1 every 21 days for a total of 1 yr from start of NAC. Adjuvant hormonal therapy and loco-regional radiotherapy were administered per institutional guidelines. We hypothesized post-operative eribulin would result in a 40% increase over the reported 40% 2 yr DFS for TN, and a 15% increase over the reported 80% 2 yr DFS for HR+/HER2- pts who did not achieve pCR following standard NAC. Results: 127 pts were enrolled (54, Cohort A; 42, Cohort B; 31, Cohort C). Pts on Cohort C continue with study treatment. Here, we present the results of 95 pts treated on Cohorts A and B. Median age-52 yrs (range, 27-74). 87 pts (92%) had invasive ductal adenocarcinoma, 6 (6%) invasive lobular, 1 (1%) mucinous, and 1 (1 %) unknown; 34 pts (36%) had T3 or T4 tumors and 65 (68%) had N1-2 disease at diagnosis. NAC with anthracyclines was administered to 74 pts (78%), taxanes to 88 (93%), and 72 (76%) received both. 71 pts (75%) had mastectomies, 24 (25%) had breast conserving surgery. Median residual tumor was 17.5 mm (range 0.1 to 80); 60 pts (63%) were LN+. 78 pts (81%) completed the planned 6 cycles of eribulin. Adjuvant radiation was administered in 28 pts (30%). 3 pts discontinued treatment due to toxicity (1 each with G3 neutropenia, G3 nausea, and unknown grade neuropathy). The most common treatment-related G3/4 adverse events were neutropenia [29 pts (31%)] and leukopenia [10 pts (11%)]. 3 pts (3%) had G3/4 febrile neutropenia and 2 pts (2%) had G3/4 neuropathy. Growth factors were administered to 22 pts (24%). There were no treatment-related deaths. With a median follow up of 19.2 and 14.9 months for Cohorts A and B respectively, the 2 yr DFS probabilities calculated from date of surgery were 61.1 % (95% CI-41.2-76.0) for Cohort A; 82.2% (95% CI-60.2-92.7) for Cohort B. Conclusions: The addition of eribulin is safe and feasible in pts who do not achieve pCR following anthracycline and/or taxane based NAC. At a median follow up of 19.2 months, a statistically significant improvement in the estimated 2 yr DFS was evident in the TN (Cohort A) pts. Citation Format: Yardley DA, Peacock N, Shroff S, Molthrop, Jr DC, Anz B, Daniel BR, Young RR, Weaver R, Harwin W, Webb CD, Ward P, Shastry M, DeBusk LM, Midha R, Hainsworth JD, Burris III HA. A phase 2 study of eribulin in breast cancer not achieving a pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC). [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 P1-12-04.

Background: The frequency of AR expression varies in the different breast cancer subtypes with 88%, 59%, and 32% expression reported in ER+, HER2+, and triple negative tumors, respectively. AR expression is associated with resistance to endocrine therapy in ER+ breast cancer. Androgen levels frequently increase following treatment with aromatase inhibitors suggesting a role for androgen synthesis inhibitors in ER+ breast cancer. AR signaling and expression are seen in triple negative breast cancer (TNBC), and a distinct AR TNBC subtype can be identified by gene expression profiling. AR expression in TNBC offers a potential therapeutic target. Preclinical and clinical studies demonstrated anti-androgen agent activity in breast cancer cell lines; preliminary clinical data suggests activity in TNBC. Orteronel is a novel, oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis that is being evaluated as endocrine therapy in various hormone-sensitive cancers. In this phase 2 study we are evaluating single agent orteronel in AR+ MBC. Methods: Pts with AR expressing MBC (≥10% staining by central immunohistochemistry) were eligible. Pts were grouped into 2 cohorts for analysis: Cohort 1-TNBC and Cohort 2-ER+ (HER2 could be +/- in this cohort). Pts must have been previously treated with standard therapy for MBC (1-3 chemotherapy regimens for TNBC, 1-3 hormonal therapies + 1 chemotherapy for ER+ patients, ≥2 HER2-targeted regimens for HER2+ patients). A 6 pt lead-in for safety and tolerability of orteronel in AR+ female MBC pts was followed by open enrollment to either cohort. All pts received 300 mg orteronel PO BID over a 4 week cycle and underwent response assessment every 2 cycles. Treatment was continued until disease progression or unacceptable toxicity. The hypothesized response rate for Cohort 1 was 10% and 13% for Cohort 2. We present the results of a protocol-specified interim analysis of the ER+ MBC pts (Cohort 2). Results: From 3/2014 to 4/2015, a total of 29 pts were enrolled on cohort 2. Median age was 65 years (range, 39-79); 90% ECOG ≤1; 90% HER2-/10% HER2+; median of 7 prior therapies (range 3-11). 93% had prior chemotherapy. Pts received a median of 2 cycles of orteronel treatment (range 1-4) and 3 pts (10%) are still on treatment. Of the 26 pts (90%) pts that have discontinued, 19 (66%) discontinued due to disease progression, 4 (14%) due to pt decision, 2 (7%) due to adverse event (AE), and 1 (3%) due to non-compliance. The most common treatment-related G 3/4 AEs were increased lipase [3 pts (10%)] and hypertension [2 pts (7%)]. There were no treatment-related SAEs or deaths on study. Three pts (10%) had stable disease as their best response. Further response evaluation is underway. Conclusions: Orteronel monotherapy was well tolerated but appears to have limited single-agent activity in this heavily pre-treated ER+ MBC pt population. The full results from this interim analysis will be presented. Citation Format: Yardley DA, Peacock N, Young RR, Silber A, Chung G, Webb CD, Jones SF, Shastry M, Midha R, DeBusk LM, Hainsworth JD, Burris HA. A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic breast cancer: Interim analysis. [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 P5-14-04.