John F. Kurland

Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma

Purpose: Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating prospective mRCC trial. Experimental Design: Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs. <5% tumor membrane staining), tumor gene expression (Affymetrix U219), serum chemokines, and safety were assessed. Results: In 91 treated patients, median overall survival [95% confidence interval (CI)] was 16.4 months [10.1 to not reached (NR)] for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0 to NR) for 10 mg/kg, and NR for treatment-naïve patients. Median percent change from baseline in tumor-associated lymphocytes was 69% (CD3+), 180% (CD4+), and 117% (CD8+). Of 56 baseline biopsies, 32% had ≥5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included upregulation of IFNγ-stimulated genes (e.g., CXCL9). Median increases in chemokine levels from baseline to C2D8 were 101% (CXCL9) and 37% (CXCL10) in peripheral blood. No new safety signals were identified. Conclusions: Immunomodulatory effects of PD-1 inhibition were demonstrated through multiple lines of evidence across nivolumab doses. Biomarker changes from baseline reflect nivolumab pharmacodynamics in the tumor microenvironment. These data may inform potential combinations. Clin Cancer Res; 22(22); 5461–71. ©2016 AACR.

1050OPHASE I STUDY OF NIVOLUMAB IN COMBINATION WITH IPILIMUMAB IN METASTATIC RENAL CELL CARCINOMA (MRCC)

ABSTRACT 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.

Phase I–IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours

PURPOSE BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514. PATIENTS AND METHODS In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD. RESULTS In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (≥4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways. CONCLUSION This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.

1052PDNIVOLUMAB (N) (ANTI-PD-1; BMS-936558, ONO-4538) IN COMBINATION WITH SUNITINIB (S) OR PAZOPANIB (P) IN PATIENTS (PTS) WITH METASTATIC RENAL CELL CARCINOMA (MRCC)

ABSTRACT 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.

1051PDIMMUNOMODULATORY ACTIVITY OF NIVOLUMAB IN PREVIOUSLY TREATED AND UNTREATED METASTATIC RENAL CELL CARCINOMA (MRCC): BIOMARKER-BASED RESULTS FROM A RANDOMIZED CLINICAL TRIAL

ABSTRACT Aim: Nivolumab, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has shown encouraging activity in mRCC. This trial assessed immunomodulatory activity, antitumor response, and safety of nivolumab in patients (pts) with mRCC. Methods: 91 pts received nivolumab IV Q3W: previously treated pts (1-3 prior therapies; ≥1 anti-angiogenic agent) received 0.3 (n = 22), 2 (n = 22), or 10 mg/kg (n = 23); untreated pts received 10 mg/kg (n = 24). Fresh biopsies and serum were obtained at baseline (BL) and at nivolumab cycle 2 day 8 (C2D8; biopsy) and cycle 4 day 1 (C4D1; serum). The primary objective assessed immunomodulatory activity of nivolumab on serum chemokines (CXCL9, CXCL10) and tumor T cell infiltrates from BL to posttreatment. Secondary/exploratory objectives included safety, antitumor activity (ORR, RECIST 1.1; PFS), BL and treatment-induced changes in PD-1 ligand (PD-L1) expression (Dako immunohistochemistry assay; PD-L1 positivity: >5% tumor membrane staining at any intensity) and association of clinical activity with BL PD-L1 expression. Results: T cell infiltrates increased by a median of 70% (CD3 + ; range 53-220%) and 88% (CD8 + ; 61-257%) from BL to C2D8. Mean increase from BL to C4D1 was 180% for CXCL9 and 79% for CXCL10. In evaluable pts ORR was 17% (15/90); 18% previously treated, 13% untreated pts. Median duration of response was 64 weeks; 6 (43%) responses are ongoing. PFS rate at 48 wks was 18% (16/90). Grade 3-4 AEs occurred in 15% (14/91): colitis and elevated AST (n = 2 each), diarrhea, elevated ALT and pneumonitis (n = 1 each). Of 56 evaluable pretreatment biopsies, 18 (32%) were PD-L1+. ORR was 22% (4/18) for PD-L1+ pts vs 8% (3/38) for PD-L1–. In 5/27 (19%) matched biopsy pairs PD-L1 expression increased >5% by C2D8. Conclusions: In this prospective study, changes in biomarkers were consistent with PD-1 inhibition, evidence of nivolumabs immunomodulatory effects in serum and the tumor microenvironment. Nivolumab demonstrated antitumor activity and manageable safety in pts with previously treated or untreated mRCC. Responses were numerically higher in PD-L1+ pts, but also present in PD-L1– pts. Disclosure: T. Choueiri: Ad Board: Pfizer, Novartis, GSK, Bayer, Aveo Research: Pfizer; M.N. Fishman: I have received funding for research trials from Bristol Myers Squibb; B. Escudier: I have received compensation for consultation/ advisory position to the following: Bayer, Pfizer, Novartis I have received honoraria from the following: Bayer, Roche, Pfizer, Genentech, Novartis, AVEO, GSK; W.M. Stadler: University of Chicago/I has received funding for research from Bristol Myers-Squibb; J.L. Perez-Garcia: I have received funding for research from Bristol Myers Squibb; M.R. Harrison: I have consulted/worked in advisory role to: Novartis, AVEO, Exelixis, Bayer; I have received honoraria from: Novartis, Prometheus; I have received funding for research from: BMS, Argos, Exelixis, Pfizer, Exelixis; E.R. Plimack: Has received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; L. Appleman: I have received funding from Bristol Myers-Squibb; L. Fong: I have received funding for research from Bristol Myers-Squibb; C.G. Drake: Sponsored Research: Aduro Biotech, BMS, Janssen, I have consulted to: BMS, Compugen, Dendreon, Pfizer, Roche/ Genentech, NexImmune; L. Cohen: I am an employee of Bristol Myers Squibb; S. Srivastava: I am an employee of Bristol Myers Squibb; M. Jure-Kunkel: I am an employee of and have stock or other ownership interest in BMS; Q. Hong: I am an employee of and have stock or other ownership interest in BMS; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; M. Sznol: I have received personal Fees from BMS, Amgen, Medimmune, Genentech, Symphogen, Nektar, Anaeropharma, Immune Design, Merus, Lion Biotechnologies, Kyowa-Kirin, Astra-Zeneca-Medimmune. All other authors have declared no conflicts of interest.