F. Graf Finckenstein

BACKGROUND: Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity. METHODS: In this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non-small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS: Overall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab versus 39% (95% CI, 33 to 45) with docetaxel. With additional follow-up, the overall survival rate at 18 months was 39% (95% CI, 34 to 45) with nivolumab versus 23% (95% CI, 19 to 28) with docetaxel. The response rate was 19% with nivolumab versus 12% with docetaxel (P=0.02). Although progression-free survival did not favor nivolumab over docetaxel (median, 2.3 months and 4.2 months, respectively), the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel (19% and 8%, respectively). Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (≥1%, ≥5%, and ≥10%) of the PD-1 ligand. Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group. CONCLUSIONS: Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy, overall survival was longer with nivolumab than with docetaxel. (Funded by Bristol-Myers Squibb; CheckMate 057 ClinicalTrials.gov number, NCT01673867.).

3104 Background: BMS-754807 is a potent reversible inhibitor of IGF-1R and IR family kinases (IGF-1R, IR; Ki <2nM). Methods: CA191002 is an ascending dose study of once daily BMS-754807 in subjects with solid tumors. Study objectives include determination of maximum tolerated dose, assessment of safety, effects on metabolic parameters, pharmacokinetics, and pharmacodynamics. Antitumor activity is assessed by radiological responses and FDG- and FLT-PET imaging. Results: To date 19 subjects (12 M, 7 F, median age 59 yr) have been treated at daily doses of 4, 10, 20, 30, 50 or 70 mg. Dosing duration was 17 - 233 d. Fatigue (G1, n=3) and hyperglycemia (≤ G3, n=3) were the most frequent related adverse events (AEs). One related AE (reversible asymptomatic postprandial hyperglycemia) was G3; all other related AEs were ≤ G2. Metabolic AEs were managed by diet and/or comedication. No dose limiting toxicities have been observed and further dose escalation continues. BMS- 754807 exposure increased in relation to dose; mean accumulation index was 1.2 - 1.5. Minimum effective exposures (MEE) for Rh41 xenograft (IGF-1R dependent) tumor growth inhibition were achieved in all subjects. 15/16 subjects dosed with ≥ 10 mg achieved MEE for GEO xenografts (less IGF-1R dependent). Dose related increases of plasma glucose, insulin and C-peptide were observed at 2h post-dose and demonstrate pharmacological activity. Partial metabolic response and stable metabolic disease on FDG-PET by D56 was achieved by 1/12 and 11/12 evaluable subjects respectively. Reduction of FLT uptake by > 25% by D10 was observed in 4/16 evaluable subjects. To date stable disease (SD) > 100 d by radiological assessment was achieved in 7 subjects, including subjects with SCLC (168 d) and osteosarcoma (≥ 2 prior chemotherapy regimens, 225 d). Conclusions: Daily dosing of BMS-754807 resulting in exposures exceeding preclinical MEE is feasible and safe. Effects on blood glucose were manageable and did not lead to discontinuation of dosing. PD effects of IR inhibition were observed and differentiate BMS-754807 from IGF-1R specific agents. PET results and prolonged SD suggest anti-tumor activity. MTD has not been reached and accrual is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb

TPS111 Background: Resistance to endocrine therapy in breast cancer is a major clinical problem. Evidence shows that insulin-like growth factor (IGF) pathway signaling contributes to tamoxifen resistance. Thus, blockade of IGF signaling may enhance the activity and reverse resistance to endocrine therapy. Preclinical evaluation with the oral IGF-1R/insulin receptor (IR) kinase inhibitor BMS-754807 showed synergistic in vitro anti-proliferative activity in combination with tamoxifen, letrozole or fulvestrant in the aromatase expressing breast cancer model, MCF-7/AC-1. In treatment-naïve tumors and in tamoxifen- or letrozole-resistant tumors, the combination of letrozole with BMS-754807 induced significant tumor regression in vivo, which was not observed with an anti-IGF-1R monoclonal antibody. The lack of activity of the IGF-1R specific antibody and IR isoform expression analyses suggested that IR-isoform A blockade was important for this synergy. Methods: These preclinical data led us to start a phase II non-comparative clinical trial investigating the combination of BMS-754807 and 2.5 mg letrozole or single agent BMS-754807 in patients with locally advanced/metastatic, estrogen receptor-positive, non-steroidal aromatase inhibitor resistant breast cancer. The primary objective is 6-month progression free survival for the combination. Secondary endpoints include response rate, safety profile, and the 6-month treatment failure rate for BMS-754807 and for the combination. The Study will accrue through sites in the US, including the Translational Breast Cancer Research Consortium. Tumor biopsy and serum assessments will be made prior to and during (Day 28) treatment to determine the effects of BMS-754807 ± letrozole on IR isoforms expression and activity of IGF pathway components in tumor tissue and circulating tumor cells (CTCs), serum levels of receptor ligands and IGF binding proteins, and numbers of total and IGF-1R positive CTCs. Pre-study and Day 14 FLT-PET will assess anti-proliferative effects of single agent and combination treatment. Clinical Trials.gov #: NCT01225172. Funded by Bristol-Myers Squibb and NIH (CA116201 and CA090628).