Background: ABBV-368 is a novel humanized IgG1 agonist monoclonal antibody specific for human OX40, a TNF receptor superfamily member expressed on activated and memory T-cell subsets, as well as T regulatory cells. The proposed ABBV-368 therapeutic mechanism of action includes activation of T effector cells and inhibition of the suppressive capacity of T regulatory cells. This ongoing first-in-human, phase 1, two-part study (NCT03071757) is investigating the safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary antitumor activity of ABBV-368 in patients (pts) with advanced solid tumors. Methods: Eligible pts include adults (≥18 years) with advanced or metastatic solid tumors. ABBV-368 was administered intravenously in a 3 + 3 dose-escalation design at doses ranging from 0.01 to 3.0 mg/kg every 2 weeks (4 cohorts). PK was assessed in cycle 1 and cycle 3. OX40 receptor saturation, Ki67 proliferation marker expression in peripheral blood immune cell subsets, and additional PD biomarkers were evaluated. Results: As of Feb 12, 2018, 38 pts with advanced or metastatic tumors were enrolled in dose-escalation cohorts. Median age was 65 years (range, 38–78). No dose-limiting toxicities were reported during dose escalation. Overall, 15 (39.5%) pts reported grade (Gr) ≥3 treatment-emergent adverse events (TEAEs). Three (7.9%) pts reported Gr ≥ 3 TEAEs related to ABBV-368. Two investigator-reported immune-related AEs were documented, including hypothyroidism; neither were serious. ABBV-368 PK was approximately dose-proportional from 0.1- to 3-mg/kg doses during cycle 1, with dose-dependent target saturation. Initial antitumor activity has been observed. Updated safety, PK, PD, and efficacy data will be reported. Conclusions: ABBV-368 was well tolerated; a maximum tolerated dose was not reached. Antitumor activity was observed at doses predicted to be biologically active. Further evaluation of ABBV-368 is ongoing in pts with advanced solid tumors. Clinical trial identification: NCT03071757. Editorial acknowledgement: Medical writing support was provided by Mary L. Smith, PhD, CMPP, from TRM Oncology, Atlanta, GA, and funded by AbbVie. Legal entity responsible for the study: AbbVie Inc. Funding: AbbVie Inc. Disclosure: A. Spira: Consultant and Institutional research support: AbbVie. A. Patnaik: Research grants to institution: Merck & Co., Inc. LG; Advisory board member: Merck & Co., Inc., AstraZeneca, AbbVie, Pfizer, Genentech/Roche; Research grant: Bristol-Myers Squibb. A.W. Tolcher: Consultant: AbbVie. M.E. Blaney, A. Parikh, A. Reddy, W. Henner, M. McDevitt, D. Afar: Employee and may own stock: AbbVie. J. Powderly: Employee and leadership role: Carolina BioOncology Institute PLLC; Stock/ownership: Iovance, Juno, Bluebird Bio, Kite Pharma, ZioPharm; Speaker bureau: Genentech, Bristol-Myers Squibb, Merck; Research funding: AstraZeneca, Genentech, Clovis, Corvus, Incyte, AbbVie, Bristol-Myers Squibb, MacroGenics; Patent or intellectual property: Founder of BioCytics, developing T-cell immunotherapies. All other authors have declared no conflicts of interest.

Background: AR expression occurs in a subset of TNBC and may identify patients (pts) who benefit from AR inhibition. ENZA, a potent oral AR inhibitor, improves OS in men with metastatic castration-resistant prostate cancer and is being evaluated in pts with advanced AR+ TNBC. Methods: MDV3100-11 is an open-label, Simon 2-stage study evaluating ENZA in pts with AR expressing (>0% by IHC) TNBC; AR prescreening was allowed (NCT01889238). Bone-only disease was permitted with no limit on prior therapies. Pts with CNS metastases or seizure history were excluded. The primary endpoint is clinical benefit rate (CBR) at 16 wks (CBR16) in ‘evaluable’ pts, defined as having both AR IHC ≥10% (centrally) and a response assessment. CBR16 is complete or partial response (CR or PR) or stable disease ≥16 wks per RECIST 1.1. Secondary endpoints are CBR24, overall response rates and safety. Stage 2 enrolled if CBR16 was ≥3 of 26 ‘evaluable’ pts in Stage 1; the null hypothesis is rejected if CBR16 is ≥9 in 62 ‘evaluable’ pts. Results: Over 400 tissue samples were received; 79% had some AR expression and 55% had AR ≥10%. Among the 42 pts enrolled into Stage 1, 16 pts were not ‘evaluable’ (10 had AR <10%; 6 had AR ≥10% but no response assessment). Of the 26 ‘evaluable’ pts, 77% had measurable disease, 62% had visceral involvement, 69% had ≥3 metastatic sites, and 35% received ≥3 prior regimens. CBR16 was 42% (11/26) and CBR24 was 35% (9/26), with 1 PR and 1 CR. Related adverse events (AEs) in ≥15% of all 42 pts were fatigue (36%), nausea (33%), diarrhea (21%) and decreased appetite (19%). Fatigue (7%) was the only AE ≥ Grade 3 in ≥5%. Go to Stage 2 criteria were met; enrollment is now complete at 118. As of Nov 2014, 27 pts reached CBR16 (including 4 PRs and 2 CRs); data continue to mature. Conclusions: The 42% CBR16 observed in Stage 1 was sufficiently high to reject the null hypothesis for the whole study and a majority of pts with CBR16 also had CBR24. AEs were generally mild and consistent with other ENZA studies. These results suggest that ENZA may provide meaningful benefit to pts with metastatic AR+ TNBC. Genomic analyses on tumor tissues are underway and may better identify TNBC pts most likely to benefit from ENZA. Clinical trial identification: NCT01889238 Disclosure: J. Cortes Castan: Consultant/Advisor: Celgene, Roche Honoraria: Novartis, Celgene, Roche, Eisai. A. Awada: Board Membership: Nektar, Roche, Bayer. H. Uppal, I.C. Tudor and M.E. Blaney: Employee: Medivation, Inc. J.L. Steinberg: Employee: Astellas Pharma. T.A. Traina: Consultant/Advisor: Genentech, Eisai, Halozyme Honoraria: Genentech, Celgene, Eisai, Prostrakan Research Funding: Medivation, AstraZeneca, Eisai, Ziopharm, Janssen, Genentech, Novartis. All other authors have declared no conflicts of interest.

Background: Enzalutamide (ENZA) is a potent novel oral inhibitor of the androgen receptor (AR) which is expressed in a majority of breast cancers (BC). ENZA demonstrated preclinical activity in all BC subtypes that express the AR and thus could be effective in AR+ BC. This is the first trial of ENZA in women with advanced BC (aBC). Methods: Stage 1 (S1) of this Phase 1 study in patients (pts) with aBC evaluated single agent ENZA at daily doses of either 80 or 160 mg; blood was collected for PK analysis and dose-limiting toxicities (DLTs) were recorded through Day 35. Stage 2 (S2) evaluated daily ENZA (160 mg) added to patients receiving either anastrozole 1 mg (ANA) or exemestane 25 mg (EXE). In S2, blood for PK and hormones was collected pre (D1) and post (D29) ENZA treatment. Tumor assessments were performed approximately every 3 months in both stages. Results: S1 (n = 15) confirmed 160 mg of ENZA as the daily dose in women with aBC. A single DLT (adrenal insufficiency) occurred at the 80 mg dose. As of 8 Oct 2013, 20 pts were enrolled to ANA and 16 to EXE. Median age, ECOG, and prior therapies for aBC were 57, 1, and 5 in S1, and the values were 59, 0, and 4 in S2, respectively. In S1, common (>15%) treatment-related adverse events (TAEs) of any grade included: AST elevation, nausea, and nasal congestion, and in S2: fatigue, anorexia, nausea, hot flush, and vomiting. Grade ≥3 AEs in ≥2 pts were anemia (n = 2) in S1 and fatigue (n = 2) in S2. The geometric mean ratio (GMR) of D29:D1 AUC for ANA was 0.12 (90% CI: 0.07, 0.20) and for EXE was 0.60 (90% CI: 0.40, 0.81). Preliminary hormone data showed increased estradiol on D29 over D1 in 7 of 14 pts in ANA vs. 1 of 12 in EXE. Conclusions: The PK and tolerability of single-agent ENZA in women is similar to that reported in men. ENZA reduced exposure to ANA by 88% and to EXE by 40%. Estradiol remained low in combination with EXE but possibly not with ANA. EXE with or without ENZA is being evaluated in a randomized Phase 2 study. Disclosure: T.A. Traina: Advisory board membership for Genentech, Eisai and Prostrakan. Received honoraria from Genentech, Celgene, Merck, Eisai and Prostrakan. Received research funding from Medivation, AstraZeneca, Eisai, Ziopharm, Janssen, Genentech and Novartis. D.A. Yardley: Consultancy and advisory board membership for Medivation. M.R. Patel: Honoraria for speakers bureau for Medivation. M.E. Blaney: Employee of Medivation. J. Gibbons: Employee of Medivation. P. LoRusso: Research grant form Astellas. Consultancy for Astellas. All other authors have declared no conflicts of interest.