Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)

Purpose Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. Patients and Methods Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Results Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31 %), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71 %) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. Conclusion Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.

Purpose Blockade of the programmed death-1 inhibitory cell-surface molecule on immune cells using the fully human immunoglobulin G4 antibody nivolumab mediates tumor regression in a portion of patients with advanced treatment-refractory solid tumors. We report clinical activity, survival, and long-term safety in patients with advanced renal cell carcinoma (RCC) treated with nivolumab in a phase I study with expansion cohorts. Patients and Methods A total of 34 patients with previously treated advanced RCC, enrolled between 2008 and 2012, received intravenous nivolumab (1 or 10 mg/kg) in an outpatient setting once every two weeks for up to 96 weeks and were observed for survival and duration of response after treatment discontinuation. Results Ten patients (29%) achieved objective responses (according to RECIST [version 1.0]), with median response duration of 12.9 months; nine additional patients (27%) demonstrated stable disease lasting > 24 weeks. Three of five patients who stopped treatment while in response continued to respond for ≥ 45 weeks. Median overall survival in all patients (71% with two to five prior systemic therapies) was 22.4 months; 1-, 2-, and 3-year survival rates were 71%, 48%, and 44%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 18% of patients; all were reversible. Conclusion Patients with advanced treatment-refractory RCC treated with nivolumab demonstrated durable responses that in some responders persisted after drug discontinuation. Overall survival is encouraging, and toxicities were generally manageable. Ongoing randomized clinical trials will further assess the impact of nivolumab on overall survival in patients with advanced RCC.

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18 F-FDG PET is often used to monitor tumor response in multicenter oncology clinical trials. This study assessed the repeatability of several semiquantitative standardized uptake values (mean SUV [SUV mean ], maximum SUV [SUV max ], peak SUV [SUV peak ], and the 3-dimensional isocontour at 70% of the maximum pixel value [SUV 70% ]) as measured by repeated baseline 18 F-FDG PET studies in a multicenter phase I oncology trial. Methods: Double-baseline 18 F-FDG PET studies were acquired for 62 sequentially enrolled patients. Tumor metabolic activity was assessed by SUV mean , SUV max , SUV peak , and SUV 70% . The effect on SUV repeatability of compliance with recommended image-acquisition guidelines and quality assurance (QA) standards was assessed. Summary statistics for absolute differences relative to the average of baseline values and repeatability analysis were performed for all patients and for a subgroup that passed QA, in both a multi-and a single-observer setting. Intrasubject precision of baseline measurements was assessed by repeatability coefficients, intrasubject coefficients of variation (CV), and confidence intervals on mean baseline differences for all SUV parameters. Results: The mean differences between the 2 SUV baseline measurements were small, varying from 22.1% to 1.9%, and the 95% confidence intervals for these mean differences had a maximum half-width of about 5.6% across the SUV parameters assessed. For SUV max , the intrasubject CV varied from 10.7% to 12.8% for the QA multiand single-observer datasets and was 16% for the full dataset. The 95% repeatability coefficients ranged from 228.4% to 39.6% for the QA datasets and up to 234.3% to 52.3% for the full dataset. Conclusion: Repeatability results of doublebaseline 18 F-FDG PET scans were similar for all SUV parameters assessed, for both the full and the QA datasets, in both the multi-and the single-observer settings. Centralized quality assurance and analysis of data improved intrasubject CV from 15.9% to 10.7% for averaged SUV max . Thresholds for metabolic response in the multicenter multiobserver non-QA settings were 234% and 52% and in the range of 226% to 39% with centralized QA. These results support the use of 18 F-FDG PET for tumor assessment in multicenter oncology clinical trials. PET,wi th the tracer 18 F-FDG, is used for tumor detection, staging, and follow-up studies for multiple neoplasms (1) and is increasingly becoming an integral part of multicenter clinical trials in oncology for the assessment of treatment effect. Accurate quantitative assessment of response as measured by changes in standardized uptake value (SUV) parameters over the course of treatment serves as an early surrogate for clinical benefit and facilitates drug development in oncology (2).For the accurate assessment of tumor response using 18 F-FDG PET, it is crucial to know the intrasubject variation in the measurement of semiquantitative parameters before the initiation of treatment (3). This study focused on the repeatability of 18 F-FDG PET in a mul...

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BackgroundImmuno-oncology (I-O) therapies target the host immune system, providing the potential to choose a uniform dose and schedule across tumor types. However, dose selection for I-O agents usually occurs early in clinical development and is typically based on tumor response, which may not fully represent the potential for improved overall survival. Here, we describe an integrated approach which incorporates clinical safety and efficacy data with data obtained from analyses of dose-/exposure-response (D-R/E-R) relationships, used to select a monotherapy dose for nivolumab, a programmed death–1 inhibitor, in clinical studies of different tumor types.MethodsDose was selected based on anti-tumor activity and safety data from a large phase 1b, open-label, dose-escalation study of nivolumab at doses ranging from 0.1 to 10 mg/kg administered every 2 weeks (Q2W) in 306 patients with advanced malignancies, and quantitative analyses were performed to characterize D-R/E-R relationships for pharmacodynamic, safety, and efficacy endpoints.ResultsA maximum tolerated dose for nivolumab was not identified, and the safety profile was similar across tumor types and dose levels (0.1–10 mg/kg). Objective response rates (ORRs) were similar across doses in melanoma and renal cell carcinoma (RCC), while higher ORRs were observed in non-small cell lung cancer (NSCLC) at 3 mg/kg and 10 mg/kg versus 1 mg/kg. Peripheral receptor occupancy was saturated at doses ≥ 0.3 mg/kg. In D-R/E-R analyses, a positive dose-dependent objective response trend was observed for each tumor type, but appeared to plateau at nivolumab doses of ≥ 1 mg/kg for melanoma and RCC, and at ≥ 3 mg/kg for NSCLC. Although there was no apparent relationship between tumor shrinkage rate and exposure, tumor progression rate appeared to decrease with increasing exposure up to a dose of 3 mg/kg Q2W for NSCLC.ConclusionsNivolumab monotherapy at 3 mg/kg Q2W provides unified dosing across tumor types. This dose and schedule has been validated in several phase II/III studies in which overall survival was an endpoint. Integrating D-R/E-R relationships with efficacy data and a safety profile that is unique to I-O therapy is a rational approach for dose selection of these agents.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-016-0177-2) contains supplementary material, which is available to authorized users.