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Aim: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has shown durable responses and encouraging overall survival (OS) data in mRCC. IPI, a fully human monoclonal antibody to CTLA-4, improved OS in melanoma and has antitumor activity in mRCC. The combination of these agents showed encouraging antitumor activity and an acceptable safety profile in advanced melanoma. We report preliminary results of this combination in mRCC. Methods: Patients (pts) with mRCC were randomized to nivolumab 3 mg/kg + IPI 1 mg/kg (arm N3 + I1) or nivolumab 1 mg/kg + IPI 3 mg/kg (N1 + I3) IV every 3 wk for 4 doses then nivolumab 3 mg/kg IV every 2 wk until progression/toxicity (protocol-defined post-progression treatment allowed). The primary objective was to assess safety; secondary objective was to assess efficacy (RECIST 1.1). Results: 21 and 23 pts were randomized to the N3 + I1 and N1 + I3 arms, respectively. Most pts (n = 35; 80%) had prior systemic therapy (N3 + I1: 17; N1 + I3: 18). Treatment-related adverse events (AEs) were seen in 39 pts (89%); 8 pts (18%; N3 + I1: 2; N1 + I3: 6) discontinued due to related AEs. Grade 3-4-related AEs occurred in 20 pts (46%; N3 + I1: 6; N1 + I3: 14), most commonly ↑ lipase (21%, n = 9), ↑ ALT (14%, n = 6), diarrhea (9%, n = 4), and ↑ AST (7%, n = 3). No grade 3-4 pneumonitis was seen. Objective response rate (ORR) was 43% (N3 + I1) and 48% (N1 + I3); median duration of response (DOR) was 31.1 wk (7 ongoing) in N3 + I1 and not reached (9 ongoing) in N1 + I3 (Table). Responses occurred by first tumor assessment (wk 6) in 44% of pts in the N3 + I1 arm and 55% of pts in the N1 + I3 arm. Stable disease (SD) as best overall response was seen in 5 (24%) (N3 + I1) and 8 (35%) (N1 + I3) pts. Arm N3 + I1 n = 21 Arm N1 + I3 n = 23 ORR, n (%) 9 (43) 11 (48) SD, n (%) 5 (24) 8 (35) DOR, range (wk) 4.1+ - 42.1+ 12.1+ - 35.1 + Median progression-free survival, wk (95% CI) 36.6 (6.0, ) 38.3 (18.3, ) CI, confidence interval Conclusions: Nivolumab + IPI showed acceptable safety and encouraging antitumor activity in mRCC, with most responses ongoing. Studies are ongoing to explore this combination in a Phase III trial. Disclosure: H. Hammers: Has received Honoraria from Ono Pharma USA; E.R. Plimack: Has received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; M. Ernstoff: I have received funding for research from Bristol Myers Squibb, and hold stocks in BMS; B.I. Rini: I have consulted for the following companies: Pfizer, BMS, Merck, GSK; received funding for research from: Pfizer, BMS, Immatics, GSK, Roche, Acceleron; D.F. McDermott: I have received honoraria from and worked as a consultant/ in an advisory capacity to Bristol-Myers Squibb; M. Voss: Dr. Voss reports grants from BMS, outside the submitted work; P. Sharma: I have served as a consultant for: MedImmune, GSK, BMS, Jounce, Janssen, Pfizer, and Helsinn Therapeutics. I also own stock in Jounce; D. Heng: I have worked as a consultant for the following: BMS, Bayer, Pfizer, Novartis; Y. Shen: I am an employee of Bristol-Myers Squibb, and immediate family member employed at BM.; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; P. Gagnier: I am an employee of and have stock or other ownership interest in BMS; A. Amin: I have worked as a consultant/ in an advisory capacity to: Bristol Myers Squibb. I have received Honoraria from: Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Aim: Antiangiogenic agents S and P are standard of care in mRCC, but effects are not durable. N, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has clinical activity in mRCC. VEGF TKIs have been shown to suppress Tregs and MDSCs making the immune environment more conducive for T cell-mediated antitumor activity. Combining VEGF TKIs with positive immune modulation may result in greater and more durable therapeutic benefit. We report preliminary results of a phase I trial of N in combination with S or P in mRCC. Methods: mRCC pts received N in combination with S (50 mg, 4 wk on/2 wk off; arm S) or P (800 mg daily; arm P) until progression/unacceptable toxicity. Starting dose of N was 2 mg/kg IV every 3 wk (N2), with planned escalation to 5 mg/kg IV every 3 wk (N5). Based on tolerability, arm S N5 was expanded to treatment-naive pts. Primary objectives were safety/tolerability and determination of maximum tolerated dose (MTD) for the combinations; secondary objective was antitumor activity. Results: 7 pts each were treated on arms S N2 and N5. No dose-limiting toxicities (DLTs) were observed and MTD was not reached; thus N5 was expanded by 19 pts (total n = 33). Arm P had 20 pts at N2; 4 DLTs (elevated ALT/AST [n = 3], fatigue [n = 1]) were observed, leading to closure of the arm. Grade 3-4-related adverse events (AEs) were observed in 27/33 pts (82%) in arm S and 14/20 pts (70%) in arm P. Most common related grade 3-4 AEs were elevated ALT and hypertension (18% each), hyponatremia and lymphocyte count decreased (15% each) in arm S, and elevated ALT and AST, and diarrhea (20% each) and fatigue (15%) in arm P. Grade 3 pneumonitis occurred in 1 pt (arm S, N5). Grade 3-4-related AEs led to discontinuation in 10/33 pts (30%; 2 N2, 8 N5) in arm S and 4/20 pts (20%) in arm P. Objective response rate was 52% (17/33) in arm S and 45% (9/20) in arm P. Responses occurred by first assessment (6 wk) in 41% (arm S) and 56% (arm P) of pts. Duration of response (wk) was 18.1-80+ in arm S and 12.1-90.1+ in arm P. Progression-free survival rate at 24 wk was 79% for arm S and 55% for arm P. Conclusions: N plus S showed encouraging antitumor activity and a manageable safety profile in pts with mRCC. Arm P was closed due to DLTs. Disclosure: A. Amin: I have worked as a consultant/ in an advisory capacity to: Bristol Myers Squibb I have received Honoraria from: Bristol Myers Squibb; E.R. Plimack: I have received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; M. Ernstoff: I have received funding for research from Bristol Myers Squibb, and hold stocks in BMS; B.I. Rini: I have consulted for the following companies: Pfizer, BMS, Merck, GSK; received funding for research from: Pfizer, BMS, Immatics, GSK, Roche, Acceleron; D.F. McDermott: I have received honoraria from and worked as a consultant/ in an advisory capacity to Bristol-Myers Squibb; M. Voss: Dr. Voss reports grants from BMS, outside the submitted work; P. Sharma: I have served as a consultant for: MedImmune, GSK, BMS, Jounce, Janssen, Pfizer, and Helsinn Therapeutics. I also own stock in Jounce; D. Heng: Has worked as a consultant for the following: BMS, Bayer, Pfizer, Novartis; Y. Shen: I am an employee of Bristol-Myers Squibb, and immediate family member employed at BMS; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; P. Gagnier: I am an employee of and have stock or other ownership interest in BMS; H. Hammers: Has received Honoraria from Ono Pharma USA. All other authors have declared no conflicts of interest.

Aim: Carboplatin and paclitaxel are mainstays of treatment for metastatic solid tumors, and the PI3K/mTOR pathway is one of the most commonly dysregulated in cancers. The combination of PI3K inhibition and platinum-based chemotherapy may enhance anti-cancer effect. Methods: Patients with metastatic solid tumors were treated with two regimens: Group 1 received carboplatin AUC 5 and paclitaxel 175mg/m2, on day 1 of a 21 day cycle with pegfilgrastim support; Group 2 received carboplatin AUC 5 (day 1) and paclitaxel 80mg/m2 (days 1, 8 and 15) on a 28-day cycle without growth factor support. In both groups, the pan-PI3K inhibitor buparlisib (BKM120) was administered daily with dose escalation of 50, 80 or 100mg/day, with optional continuation of BKM120 until progression, after cessation of chemotherapy following Cycle 6. The primary endpoint was Recommended Phase II Dose (RP2D). Results: Between 5 Apr 2011 and 28 Jan 2013, 30 subjects were enrolled. Median age was 53 (range 23-71). The most common tumor types were non-small cell lung cancer (N = 5) and ovarian cancer (N = 5). 16 patients were treated in Group 1 and 14 in Group 2. The median number of cycles was 4.5 (Group 1) or 6 (Group 2). Dose reductions and treatment delays during all cycles were more common in Group 2. The most common adverse events (AE) of any grade in Group 1 were fatigue, hyperglycemia, alopecia, arthralgias, alkaline phosphatase elevation and thrombocytopenia. In Group 2, the most common AEs were hyperglycemia, leucopenia, neutropenia, thrombocytopenia, fatigue and alopecia. The DLTs were elevated alkaline phosphatase (N = 1) and uncomplicated neutropenia (N = 2). The MTD for BKM120 was 100mg/d in Group 1 and 80mg/day in Group 2. Among 25 patients with measurable disease, the objective response rate was 28% (1CR, 4 PR, 2uPR). 5 patients with evaluable disease (not measurable by RECIST) experienced clinical benefit (clinical stability with no new radiographic lesions) for ≥ 10 cycles. Correlative studies in process include analysis of PIK3CA mutation status and PTEN expression status in pre-treatment tumor samples, and pharmacokinetic analysis of BKM120. Conclusions: BKM120 at 100 mg/d + carboplatin AUC 5 + paclitaxel 175mg/m2, both on day 1 of a 21 day cycle with growth factor support, is a well-tolerated regimen with promising activity in advanced solid tumors. Disclosure: M. Fury: MGF has served on an advisory board for Novartis within the last 12 months. All other authors have declared no conflicts of interest.