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Purpose:In advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC), there is a need to identify biomarkers of response to therapies, such as immune checkpoint inhibitors.Patients and Methods:In post hoc exploratory analyses from CheckMate 032 (GC/GEJC cohort), we evaluated associations between nivolumab ± ipilimumab (NIVO ± IPI) efficacy and programmed death ligand 1 (PD-L1) expression, defined by tumor cells (% TC) or combined positive score (CPS; sum of PD-L1–staining TCs + immune cells, divided by total viable TCs, × 100) using the Dako PD-L1 IHC 28-8 pharmDx assay, or inflammatory gene expression.Results:There was a trend toward increased efficacy (objective response and overall survival) when PD-L1 expression was determined by CPS compared with % TC at higher cutoffs of ≥5 and ≥10 in the pooled analysis of all treatment regimens. In this analysis, 19% and 26% of patients with PD-L1–positive tumors at a CPS cutoff of ≥5 and ≥10, respectively, had an objective response compared with 8% and 9% of patients at the equivalent % TC cutoffs. Longer survival was demonstrated in patients with PD-L1–positive (defined by CPS cutoffs of ≥5 and ≥10) versus PD-L1–negative status. Similar results were observed in the NIVO 1 mg/kg + IPI 3 mg/kg subgroup. Multiple inflammatory gene signatures/transcripts, including a signature consisting of four genes (CD274, CD8A, LAG3, and STAT1), showed associations with response to NIVO ± IPI.Conclusions:This study suggests a greater association of PD-L1 expression by CPS with NIVO ± IPI efficacy compared with % TC PD-L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO ± IPI response, warranting further investigation.See related commentary by Moutafi and Rimm, p. 3812

Purpose Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers. Patients and Methods Patients with locally advanced or metastatic chemotherapy–refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated. Results Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively. Conclusion Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway.

Background Immunotherapies have demonstrated efficacy across a diverse set of tumors supporting further evaluation in glioblastoma. The objective of this study was to evaluate the safety/tolerability and describe immune-mediated effects of nivolumab ± ipilimumab in patients with recurrent glioblastoma. Exploratory efficacy outcomes are also reported. Methods Patients were randomized to receive nivolumab 3 mg/kg every 2 weeks (Q2W; NIVO3) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO1+IPI3). An alternative regimen of nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO3+IPI1) was investigated in a nonrandomized arm. Results Forty patients were enrolled (NIVO3, n = 10; NIVO1+IPI3, n = 10; NIVO3+IPI1, n = 20). The most common treatment-related adverse events (AEs) were fatigue (NIVO3, 30%; NIVO1+IPI3, 80%; NIVO3+IPI1, 55%) and diarrhea (10%, 70%, 30%, respectively). AEs leading to discontinuation occurred in 10% (NIVO3), 30% (NIVO1+IPI3), and 20% (NIVO3+IPI1) of patients. Three patients achieved a partial response (NIVO3, n = 1; NIVO3+IPI1, n = 2) and 8 had stable disease for ≥12 weeks (NIVO3, n = 2; NIVO1+IPI3, n = 2; NIVO3+IPI1, n = 4 [Response Assessment in Neuro-Oncology criteria]). Most patients (68%) had tumor-cell programmed death ligand-1 expression ≥1%. Immune-mediated effects mimicking radiographic progression occurred in 2 patients. Conclusions Nivolumab monotherapy was better tolerated than nivolumab + ipilimumab; the tolerability of the combination was influenced by ipilimumab dose. These safety and exploratory findings merit further investigation of immunotherapies in glioblastoma.

Purpose Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non–small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC). Patients and Methods Patients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression. Results No dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed death ligand-1 expression. Conclusion The safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.

Summary Background Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. Methods The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394. Findings Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0–464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0–470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0–288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. Interpretation Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. Funding Bristol-Myers Squibb.

The anti-EGF receptor monoclonal antibody cetuximab provides a case study for the development of predictive biomarkers in oncology. The identification and validation of KRAS mutation status as a predictor of lack of benefit from cetuximab in metastatic colorectal cancer provides an important first step. However, KRAS mutation status does not appear to be predictive of cetuximab benefit in advanced non-small-cell lung cancer, illustrating the necessity for separate biomarker validation to occur across tumor types. Numerous candidate biomarkers have been suggested based on noncontrolled exploratory analyses, but they require validation in sufficiently sized controlled studies. Key pending issues include distinguishing markers predictive of treatment benefit from those prognostic of disease outcome, selecting the best specimen for analysis (determining the tissue type and collection site, as well as the sample matrix type); and optimizing and standardizing assay technology and scoring systems, particularly for markers expressed over a continuous dynamic range.

Summary Background Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Methods We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Findings Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Interpretation Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Funding Bristol-Myers Squibb.

BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS We randomly assigned 272 patients 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 The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P

BackgroundImmune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells.MethodsWe obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients.ResultsMalignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.ConclusionsThese findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti-CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund and others.).

Importance Nivolumab, a monoclonal antibody that inhibits programmed cell death 1, is approved by the US Food and Drug Administration for treating advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies. Data on long-term survival among patients receiving nivolumab are limited. Objectives To analyze long-term overall survival (OS) among patients receiving nivolumab and identify clinical and laboratory measures associated with tumor regression and OS. Design, Setting, and Participants This was a secondary analysis of the phase 1 CA209-003 trial (with expansion cohorts), which was conducted at 13 US medical centers and included 270 patients with advanced melanoma, RCC, or NSCLC who received nivolumab and were enrolled between October 30, 2008, and December 28, 2011. The analyses were either specified in the original protocol or included in subsequent protocol amendments that were implemented between 2008 and 2012. Statistical analysis was performed from October 30, 2008, to November 11, 2016. Intervention In the CA209-003 trial, patients received nivolumab (0.1-10.0 mg/kg) every 2 weeks in 8-week cycles for up to 96 weeks, unless they developed progressive disease, achieved a complete response, experienced unacceptable toxic effects, or withdrew consent. Main Outcomes and Measures Safety and activity of nivolumab; OS was a post hoc end point with a minimum follow-up of 58.3 months. Results Of 270 patients included in this analysis, 107 (39.6%) had melanoma (72 [67.3%] male; median age, 61 [range, 29-85] years), 34 (12.6%) had RCC (26 [76.5%] male; median age, 58 [range, 35-74] years), and 129 (47.8%) had NSCLC (79 [61.2%] male; median age, 65 [range, 38-85] years). Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC. In a multivariable analysis, the presence of liver (odds ratio [OR], 0.31; 95% CI, 0.12-0.83;P = .02) or bone metastases (OR, 0.31; 95% CI, 0.10-0.93;P = .04) was independently associated with reduced likelihood of survival at 5 years, whereas an Eastern Cooperative Oncology Group performance status of 0 (OR, 2.74; 95% CI, 1.43-5.27;P = .003) was independently associated with an increased likelihood of 5-year survival. Overall survival was significantly longer among patients with treatment-related AEs of any grade (median, 19.8 months; 95% CI, 13.8-26.9 months) or grade 3 or more (median, 20.3 months; 95% CI, 12.5-44.9 months) compared with those without treatment-related AEs (median, 5.8 months; 95% CI, 4.6-7.8 months) (P Conclusions and Relevance Nivolumab treatment was associated with long-term survival in a subset of heavily pretreated patients with advanced melanoma, RCC, or NSCLC. Characterizing factors associated with long-term survival may inform treatment approaches and strategies for future clinical trial development. Trial Registration ClinicalTrials.gov identifier:NCT00730639

Background: In the CheckMate 032 phase 1/2 study, NIVO ± IPI demonstrated clinically meaningful antitumor activity in patients with chemotherapy-refractory mGEC. Archival or fresh tumor biopsies were analyzed to determine whether expression of PD-L1 and selected immune gene signatures were predictive of response to NIVO ± IPI. Methods: Pooled analyses included all treatment regimens (NIVO 3 mg/kg, NIVO 1 mg/kg + IPI 3 mg/kg, NIVO 3 mg/kg + IPI 1 mg/kg, and patients treated with NIVO 1 mg/kg + IPI 1 mg/kg in the dose-escalation phase). PD-L1 immunohistochemistry (IHC; Dako PD-L1 IHC 28-8 pharmDx assay) was used to evaluate tumor PD-L1 expression, referred to as tumor proportion score (TPS). Combined positive score (CPS) was determined by evaluating PD-L1 expression on previously stained IHC slides using the CPS algorithm. Gene expression profiling (GEP) by RNA sequencing was used to evaluate immune cell activation and infiltration signatures, a Bristol-Myers Squibb (BMS) inflammatory signature, and PD-L1 gene expression. Results: The pooled CPS (N = 104), TPS (N = 130), and GEP (N = 40) cohorts were mostly representative of the overall CheckMate 032 mGEC cohort (N =163). At a median (range) follow-up of 23.4 (17.0-35.4) months, CPS at higher cutoffs correlated better with efficacy and had higher prevalence than TPS in all analyses (Table). For all immune gene signatures examined, responders had higher signature scores in aggregate. For the BMS inflammatory signature, the association between signature score and response was significant (P = 0.004; false discovery rate = 0.037). Conclusions: CPS demonstrated stronger association with efficacy of NIVO ± IPI than TPS in mGEC. Prevalence of CPS was higher than that of TPS. Among immune gene signatures examined, the BMS inflammatory signature achieved the best association with efficacy and warrants further investigation. All treatments combinedMethodNCutoffResponse rate, %Prevalence, %All patients163NA9.8100CPS1041026.533519.250114.168TPS130109.1857.710117.531NIVO 1 mg/kg + IPI 3 mg/kgMethodNCutoffResponse rate, %Prevalence, %All patients49NA20.4100CPS331054.533541.252128.076TPS421002502140.024CPS = combined positive score (number of PD-L1-staining tumor cells, lymphocytes, and macrophages relative to all viable tumor cells x 100); IPI = ipilimumab; NA, not applicable; NIVO = nivolumab; TPS = tumor proportion score Citation Format: Ming Lei, Nathan Siemers, Dimple Pandya, Han Chang, Teresa Sanchez, Cecile Dorange, Christopher Harbison, Peter M. Szabo, Yelena Janjigian, Patrick A. Ott, Padmanee Sharma, Johanna Bendell, Jeffry Evans, Filippo de Braud, Ian Chau, Zachary Boyd. Association of PD-L1 combined positive score and immune gene signatures with efficacy of nivolumab (NIVO) ± ipilimumab (IPI) in patients with metastatic gastroesophageal cancer (mGEC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2673.

The therascreen KRAS RGQ polymerase chain reaction kit is being developed as a companion diagnostic to aid clinicians, through detection of KRAS mutations, in the identification of patients with metastatic colorectal cancer (mCRC) who are more likely to benefit from cetuximab.To assess whether KRAS mutation status, determined by using the therascreen KRAS kit, is a predictive marker of cetuximab efficacy.Tissue samples were obtained from patients with mCRC treated on the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) CO.17 phase 3 study of cetuximab plus best supportive care (BSC) versus BSC alone. Tumor DNA samples were assessed for the presence of KRAS mutations by using the therascreen KRAS kit. Efficacy and safety were assessed to determine whether mutation status was predictive of outcomes. Results.-Evaluable samples were available from 453 patients (79.2%) enrolled in the NCIC CTG CO.17 trial. The KRAS wild-type subset represented 54.1% (245 of 453) of the evaluated population. Median overall survival of patients with KRAS wild-type tumors was 8.6 months among those who received cetuximab plus BSC and 5.0 months among patients who received BSC alone (hazard ratio [HR], 0.63; P = .002). Among patients with KRAS mutant mCRC, no meaningful difference in overall survival was observed between arms (HR, 0.91; P = .55). These results are consistent with a previous report that analyzed patient tumor samples by using bidirectional sequencing.These data support the utility of the therascreen KRAS kit as a means of selecting patients who may benefit from cetuximab therapy.

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-naive (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.

The role of tumor PD-L1 expression was investigated across the nivolumab clinical development program. Phase III nivolumab trials have shown that patients with tumors not expressing PD-L1 may benefit; therefore, testing is not required to select patients for therapy. The Dako PD-L1 IHC 28-8 pharmDx assay may be used to determine tumor PD-L1 expression as a complementary and informative test.

Purpose Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved survival over docetaxel in previously treated advanced non–small-cell lung cancer (NSCLC). First-line monotherapy with nivolumab for advanced NSCLC was evaluated in the phase I, multicohort, Checkmate 012 trial. Methods Fifty-two patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity; postprogression treatment was permitted per protocol. The primary objective was to assess safety; secondary objectives included objective response rate (ORR) and 24-week progression-free survival (PFS) rate; overall survival (OS) was an exploratory end point. Results Any-grade treatment-related adverse events (AEs) occurred in 71% of patients, most commonly: fatigue (29%), rash (19%), nausea (14%), diarrhea (12%), pruritus (12%), and arthralgia (10%). Ten patients (19%) reported grade 3 to 4 treatment-related AEs; grade 3 rash was the only grade 3 to 4 event occurring in more than one patient (n = 2; 4%). Six patients (12%) discontinued because of a treatment-related AE. The confirmed ORR was 23% (12 of 52), including four ongoing complete responses. Nine of 12 responses (75%) occurred by first tumor assessment (week 11); eight (67%) were ongoing (range, 5.3+ to 25.8+ months) at the time of data lock. ORR was 28% (nine of 32) in patients with any degree of tumor PD–ligand 1 expression and 14% (two of 14) in patients with no PD–ligand 1 expression. Median PFS was 3.6 months, and the 24-week PFS rate was 41% (95% CI, 27 to 54). Median OS was 19.4 months, and the 1-year and 18-month OS rates were 73% (95% CI, 59 to 83) and 57% (95% CI, 42 to 70), respectively. Conclusion First-line nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC.

Background: Although it is accepted that metastatic colorectal cancers (mCRCs) that carry activating mutations in KRAS are unresponsive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, a significant fraction of KRAS wild-type (wt) mCRCs are also unresponsive to anti-EGFR therapy. Genes encoding EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are promising gene expression-based markers but have not been incorporated into a test to dichotomise KRAS wt mCRC patients with respect to sensitivity to anti-EGFR treatment. Methods: We used RT–PCR to test 110 candidate gene expression markers in primary tumours from 144 KRAS wt mCRC patients who received monotherapy with the anti-EGFR antibody cetuximab. Results were correlated with multiple clinical endpoints: disease control, objective response, and progression-free survival (PFS). Results: Expression of many of the tested candidate genes, including EREG and AREG, strongly associate with all clinical endpoints. Using multivariate analysis with two-layer five-fold cross-validation, we constructed a four-gene predictive classifier. Strikingly, patients below the classifier cutpoint had PFS and disease control rates similar to those of patients with KRAS mutant mCRC. Conclusion: Gene expression appears to identify KRAS wt mCRC patients who receive little benefit from cetuximab. It will be important to test this model in an independent validation study.

Purpose The anti–epidermal growth factor receptor (EGFR) antibody cetuximab is efficacious in multiple tumor types. Patient selection with markers predictive of benefit may enhance its therapeutic index. This retrospective, correlative analysis of the phase III trial BMS099 of cetuximab in advanced non–small-cell lung cancer (NSCLC) was conducted to identify molecular markers for the selection of patients most likely to benefit from cetuximab. Methods In BMS099, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC of any histology or EGFR expression status were randomly assigned to taxane/carboplatin (T/C) with or without cetuximab. Biomarkers analyzed included K-Ras and EGFR mutations by direct sequencing, EGFR protein expression by immunohistochemistry (IHC), and EGFR gene copy number by fluorescent in situ hybridization (FISH). Relationships between biomarker status and progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) were assessed by log-rank tests per treatment arm for treatment-specific effects and across the total evaluable population. Results Tumor samples were available from 225 randomly assigned patients. K-Ras mutations were found in 17% of evaluable patients (35 of 202 patients), EGFR mutations were found in 10% (17 of 166 patients), EGFR positivity by IHC was found in 89% (131 of 148 patients), and FISH positivity was found in 52% (54 of 104 patients). No significant associations were found between biomarker status and PFS, OS, and ORR in the treatment-specific analyses. Conclusion In contrast with colorectal cancer, and within the limitations of the data set, efficacy parameters did not appear to correlate with K-Ras mutation status or with any of the EGFR-related biomarkers evaluated. Additional exploratory analyses are essential to identify predictive markers and to optimize patient selection for cetuximab therapy in NSCLC.

Purpose To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. Patients and Methods This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m2) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m2/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. Results Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m2 weekly plus irinotecan 16 mg/m2/d (pediatric) or 20 mg/m2/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). Conclusion The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.

Cetuximab is a chimeric monoclonal antibody directed against the epidermal growth factor receptor (EGFR) that has proven clinical efficacy in metastatic colorectal cancer (mCRC) and other solid tumor types. Several candidate predictive markers of cetuximab efficacy in mCRC emerged recently from clinical studies, most notably the KRAS mutation status of the tumor. Retrospective data strongly suggest that the benefit/risk ratio for cetuximab treatment in patients with wild-type KRAS mCRC tumors is greater than for patients with mutant KRAS tumors. In addition, high expression of genes encoding the EGFR ligands epiregulin and amphiregulin may also identify patients who are likely to benefit from cetuximab. In contrast, EGFR expression by immunohistochemistry and EGFR gene copy number appear to be less reliable in predicting response to cetuximab. Prospective validation of wild-type KRAS and high gene expression of epiregulin and amphiregulin as predictive markers of cetuximab activity in mCRC is still required.

Specialized gene expression programs are induced by signaling pathways that act on transcription factors. Whether these transcription factors can function in multiple developmental programs through a global switch in promoter selection is not known. We have used genome-wide location analysis to show that the yeast Ste12 transcription factor, which regulates mating and filamentous growth, is bound to distinct program-specific target genes dependent on the developmental condition. This condition-dependent distribution of Ste12 requires concurrent binding of the transcription factor Tec1 during filamentation and is differentially regulated by the MAP kinases Fus3 and Kss1. Program-specific distribution across the genome may be a general mechanism by which transcription factors regulate distinct gene expression programs in response to signaling.

4014 Background: In the phase 3 ONO-12 study, 3rd- or later-line nivolumab (N) monotherapy prolonged OS vs placebo in Asian pts with adv G/GEJ cancer (median OS, 5.3 vs 4.1 mo; HR, 0.63; P < 0.0001; ASCO-GI 2017, Kang YK et al. J Clin Oncol. 2017;35 (suppl 4S) [abstract 2]). The phase 1/2 CheckMate 032 study showed favorable clinical activity of N ± ipilimumab (I) in Western pts with adv CTx-R G/E/GEJ cancer (NCT01928394). We report updated long-term follow-up data of G/E/GEJ pts in CheckMate 032. Methods: Pts received N 3 mg/kg Q2W (N3), N 1 mg/kg + I 3 mg/kg Q3W (N1+I3), or N 3 mg/kg + I 1 mg/kg Q3W (N3+I1). Primary endpoint was ORR. Secondary endpoints included DOR, OS, PFS, and safety. Efficacy in pts by PD-L1 status was assessed. Results: 160 heavily pretreated pts (79% had ≥ 2 prior Tx) were enrolled (N3, n = 59; N1+I3, n = 49; N3+I1, n = 52); 24% had PD-L1+ (≥ 1%) tumors. ORR was 12% in N3, 24% in N1+I3, and 8% in N3+I1. In pts with PD-L1 ≥ 1%, ORR was 19% (3/16) in N3, 40% (4/10) in N1+I3, and 23% (3/13) in N3+I1; in pts with PD-L1 < 1%, ORR was 12% (3/26), 22% (7/32), and 0% (0/30), respectively. Median DOR was 7.1 mo in N3, 7.9 mo in N1+I3, and NA in N3+I1. OS in all pts and in pts with PD-L1 ≥ 1% is in the Table. Grade 3–4 treatment-related AEs reported in ≥ 10% of pts in any treatment arm were diarrhea (N3, 2%; N1+I3, 14%; N3+I1, 2%), ALT increased (N3, 3%; N1+I3, 14%; N3+I1, 4%), and AST increased (N3, 5%; N1+I3, 10%; N3+I1, 2%). Conclusions: N ± I led to durable responses and long-term OS in heavily pretreated Western pts with adv G/E/GEJ cancer, which is consistent with the clinical activity observed in Asian pts in the ONO-12 study. Safety was consistent with prior reports. These data support ongoing investigation of N ± I in pts with adv G/E/GEJ cancer. Clinical trial information: NCT01928394. [Table: see text]

We used genome-wide expression analysis to explore how gene expression in Saccharomyces cerevisiae is remodeled in response to various changes in extracellular environment, including changes in temperature, oxidation, nutrients, pH, and osmolarity. The results demonstrate that more than half of the genome is involved in various responses to environmental change and identify the global set of genes induced and repressed by each condition. These data implicate a substantial number of previously uncharacterized genes in these responses and reveal a signature common to environmental responses that involves ∼10% of yeast genes. The results of expression analysis with MSN2/MSN4 mutants support the model that the Msn2/Msn4 activators induce the common response to environmental change. These results provide a global description of the transcriptional response to environmental change and extend our understanding of the role of activators in effecting this response.

Background: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy–refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit. Methods: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment–biomarker interaction. Results: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status (‘co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P

Background: Nivo, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, is approved in the United States and European Union for the treatment of pts with advanced SQ NSCLC refractory to prior chemotherapy, based on results of phase 2 (CheckMate 063) and phase 3 (CheckMate 017) trials. In these studies, PD-1 ligand (PD-L1) expression was neither predictive nor prognostic of survival benefit. Here we present results of exploratory analyses from these studies evaluating the potential correlation of baseline serum cytokines with overall survival (OS) in pts with SQ NSCLC. Methods: Baseline serum cytokine concentrations in evaluable pts from CheckMate 063 and CheckMate 017 treated with nivo (n = 222) or doc (n = 118) were analyzed using a custom HumanMAP quantitative multiplexed immunoassay (Myriad RBM, Austin, TX). Multivariate analyses using a stepwise variable selection were performed in a Cox model using a 6:4 training:test validation in nivo-treated subjects. The performance of the association with OS of the identified cytokine set in nivo-treated subjects was tested using time-varying receiver-operating characteristic (ROC) analysis. SQ-cytoscore, generated to quantify the effect of the identified cytokine set on OS, was computed as follows: 1) calculation of the tertile bin distribution of each cytokine in the set in all pts and assignment of a point score (0, 1, or 2) for each tertile expression of each cytokine; 2) calculation of SQ-cytoscore for each pt as the sum of points; 3) categorization of pts as SQ-cytoscore “high” or “low” based on the median cutoff. OS was analyzed in pts with high vs low SQ-cytoscore treated with nivo and doc using the Kaplan-Meier method and 18-mo data cutoffs for CheckMate 063 (June 2015) and CheckMate 017 (August 2015). Results: Of 26 evaluable baseline cytokines, a set of 14 was identified to be associated with OS. Median OS was longer in pts with high vs low SQ-cytoscore in both nivo- and doc-treated cohorts (nivo [n = 102 vs 120]: 15.6 vs 5.3 months, HR:0.48, 95%CI:0.36-0.64, P Conclusion: In pts with advanced SQ NSCLC pooled from 2 clinical trials, a set of serum cytokines (details to be presented) potentially associated with OS benefit was identified. The benefit of a high SQ-cytoscore appeared more profound in pts treated with nivo vs doc. These preliminary findings require prospective validation in future studies. Citation Format: Benedetto Farsaci, William J. Geese, Kaushal D. Desai, Chelsea Jin, Scott J. Antonia, Hervé Lena, Leora Horn, David Planchard, Karen L. Reckamp, Thomas E. Stinchcombe, Scott Gettinger, Hossein Borghaei, Matthew D. Hellmann, Christopher Harbison, Dong Xu, M. Anne Blackwood-Chirchir, Naiyer Rizvi. Impact of baseline serum cytokines on survival in patients (pts) with advanced squamous (SQ) non-small cell lung cancer (NSCLC) treated with nivolumab (nivo) or docetaxel (doc): Exploratory analyses from CheckMate 063 and CheckMate 017. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-072.

2014Background: Patients (pts) with recurrent/progressive GBM have a poor prognosis and limited therapeutic options. The phase 1 CheckMate-143 study evaluates safety and tolerability of the anti-PD-1 monoclonal antibody nivo, alone or in combination with the anti-CTLA-4 antibody ipi, in pts with recurrent GBM. Preliminary results from a phase 1 safety cohort (Cohort 1, Methods) were presented previously. Herein, we present updated safety, overall survival (OS) data, and PD-L1 biomarker status for the completed phase 1 Cohorts 1 and 1b. Methods: Eligible pts had a first recurrence of GBM after radiation and temozolomide. In Cohort 1, 20 pts were randomized 1:1 to receive nivo 3 mg/kg (N3) every 2 weeks (Q2W) or nivo 1 mg/kg + ipi 3 mg/kg every 3 weeks (Q3W; N1+I3) for 4 doses followed by N3 Q2W. Pts in Cohort 1b (n = 20) received nivo 3 mg/kg + ipi 1 mg/kg Q3W (N3+I1) for 4 doses followed by N3 Q2W. Treatment continued until disease progression or unacceptable toxicity. PD-L1 status was determined by immun...

100Background: Patients (pts) with advanced (adv) SCLC after first-line platinum-based chemotherapy have limited options. Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, is approved for previously treated metastatic NSCLC in the US and for squamous NSCLC in the EU. Nivolumab + ipilimumab, a cytotoxic T-lymphocyte antigen-4 immune checkpoint inhibitor, has shown durable responses in multiple tumor types. CheckMate 032 was designed to evaluate nivolumab +/- ipilimumab in adv tumors including SCLC. Methods: AdvSCLC pts with progressive disease (PD) after ≥1 platinum-based chemotherapy, regardless of platinum sensitivity or tumor PD-1 ligand 1 (PD-L1) expression, were eligible. Pts received nivolumab ([mg/kg] N3 Q2W) or nivolumab + ipilimumab combination (N1 + I3 or N3 + I1 Q3W for 4 cycles then N3 Q2W). Primary endpoint was objective response rate (ORR). Additional endpoints were safety, overall survival (OS), progression-free survival (PFS), and biomarkers. Results: 180 pts were enrolled...

4501Background: Minimal antitumor activity of existing therapies and the observation of immune dysfunction in bladder cancer have prompted evaluation of immunotherapy in this malignancy. Nivolumab (fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody) monotherapy has shown survival benefit in patients (pts) with melanoma, lung cancer, and renal cell carcinoma. Here, we report efficacy and safety of nivolumab monotherapy in pts with mUC after ≥1 prior line of platinum-based therapy in an open-label, multicenter phase I/II study (NCT01928394). Methods: Pts (unselected by PD-L1 expression status) with mUC received nivolumab 3 mg/kg intravenously every 2 weeks until progression or discontinuation. Primary endpoint was objective response rate (ORR; RECIST 1.1). Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of 78 treated pts (median age 65.5 years; range, 31–85), 65.4% had received ≥2 prior therapies. At a me...

6 Background: Patients (pts) with GC/GEC often present with A/M disease, which has a poor prognosis, with 1-year survival < 30%, and few treatment options. Nivolumab is a fully human anti-PD-1 IgG4 monoclonal antibody with a favorable safety profile and efficacy in melanoma, non–small-cell lung cancer, and renal cell carcinoma. The phase I/II, open-label CheckMate-032 study evaluated nivolumab ± ipilimumab in pts with solid tumors. Here, we report initial results for pts with GEC/GC receiving nivolumab monotherapy. Methods: Pts with A/M histologically confirmed GC/GEC, irrespective of PD-L1 status, were assigned to receive nivolumab alone (3 mg/kg IV Q2W) and treated until disease progression (PD) or intolerable toxicity. The primary endpoint was objective response rate (ORR); other endpoints included safety, progression-free survival, overall survival (OS), and biomarker status. Results: 59 pts were enrolled and treated with single-agent nivolumab. Median age was 60 y (range 29–80), and 83% of pts received ≥ 2 prior regimens. At database lock, 10 pts were on active treatment; 49 pts discontinued (PD, n = 40; unrelated adverse events, n = 4; treatment-related adverse events [TRAEs], n = 2; other, n = 3). Pts received a median of 4 doses (range 1–25). ORR was 12% (n = 7/58; 1 complete response, 6 partial responses); 12 pts (21%) had stable disease. Among responders, median duration of response was 7.1 mo (95% CI, 3.0–13.2). Median OS was 6.8 mo (95% CI, 3.3–12.4); 12-mo OS rate was 38% (95% CI, 23.2–52.7). 39% of tumor samples were PD-L1 positive ( ≥ 1% cutoff). ORRs in pts with PD-L1-positive and -negative tumors were 18% and 12%, respectively. TRAEs occurred in 66% of pts; most were Grade 1/2. Grade 3/4 TRAEs occurred in 14% of pts and included pneumonitis, fatigue, diarrhea, vomiting, hypothyroidism, and increased aspartate and alanine aminotransferase and alkaline phosphatase levels. No treatment-related deaths occurred. Conclusions: Nivolumab monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated pts with GC/GEC. Objective responses occurred in pts with PD-L1-positive and -negative tumors. Clinical trial information: NCT01928394.

an AESI reported in 2% of pts in the N single-agent treatment to progression phase were rash (Any Gr: 25.5%; Gr 3: 4.0%, hypomagnesemia (Any Gr: 16.0%; Gr 3: 2.5%), conjunctivitis (Any Gr: 4.7%; Gr 3: 0.7%), venous thromboembolic events (Any Gr: 2.5%; Gr 3 1.8%), and arterial thromboembolic events (Any Gr: 2.2%; Gr 3: 1.8%). Conclusions: OS and PFS were statistically significantly improved when N was added to GC. Pts who continued on N single-agent to progression had substantially better outcomes than the general population, and long-term use of N did not result in any unexpected increases in AESIs. Author Disclosure: M.A. Socinski: None. N. Thatcher: F. Honoraria; Eli Lilly and others. H. Speakers Bureau; Eli Lilly and others. K. Advisory Board; Eli Lilly and others. A.V. Luft: None. A. Szczesna: None. T. Ciuleanu: None. W. Szafra nski: None. R. Ramlau: None. B. Balint: None. A. Kazarnowicz: None. O. Molinier: G. Consultant; Eli Lilly. K. Advisory Board; Roche. H. Depenbrock: A. Employee; Eli Lilly. M. Stock; Eli Lilly. S. Nanda: A. Employee; Eli Lilly. M. Stock; Eli Lilly. C. Obasaju: A. Employee; Eli Lilly. M. Stock; Eli Lilly. N. Stock Options; Eli Lilly. L. Paz-Ares: F. Honoraria; Eli Lilly.

Other; Novartis, Roche, Boehringer-Ingelheim. M. Thomas: F. Honoraria; Lilly, Bristol Meyers Squibb, Roche. G. Consultant; Lilly, Bristol Meyers Squibb, Roche, Novartis. M. Schuler: E. Research Grant; Boehringer Ingelheim, Novartis. F. Honoraria; Boehringer Ingelheim, Celgene, GlaxoSmithKline, Lilly, Novartis, Pfizer. G. Consultant; AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer. G. Liu: G. Consultant; Astra Zeneca, Pfizer, Novartis. A. Santoro: None. M. Geraldes: A. Employee; Novartis Pharmaceuticals. M. Stock; Novartis Pharmaceuticals. A.L. Boral: A. Employee; Novartis Pharmaceuticals. A. Yovine: A. Employee; Novartis Pharma AG. A.T. Shaw: G. Consultant; Ignyta. K. Advisory Board; Novartis, Pfizer, Ariad, Chugai, Genentech.

(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non-small-cell lung cancer and metastatic breast cancer. The disposition of [(14)C]BMS-690514 was investigated in nine healthy male subjects (group 1, n = 6; group 2, n = 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose. In group 2 subjects, bile was collected from 3 to 8 h postdose. Across groups, approximately 50 and 34% of administered radioactivity was recovered in the feces and urine, respectively. An additional 16% was recovered in the bile of group 2 subjects. Less than 28% of the dose was recovered as parent drug in the combined excreta, suggesting that BMS-690514 was highly metabolized. BMS-690514 was rapidly absorbed (median time of maximum observed concentration 0.5 h) with the absorbed fraction estimated to be approximately 50 to 68%. BMS-690514 represented ≤7.9% of the area under the concentration-time curve from time 0 extrapolated to infinite time of plasma radioactivity, indicating that the majority of the circulating radioactivity was from metabolites. BMS-690514 was metabolized via multiple oxidation reactions and direct glucuronidation. Circulating metabolites included a hydroxylated rearrangement product (M1), a direct ether glucuronide (M6), and multiple secondary glucuronide conjugates. None of these metabolites is expected to contribute to the pharmacology of BMS-690514. In summary, BMS-690514 was well absorbed and extensively metabolized via multiple metabolic pathways in humans, with excretion of drug-related radioactivity in both bile and urine.

Purpose The antiepidermal growth factor receptor (EGFR) antibody cetuximab shows activity in multiple epithelial tumor types; however, responses are seen in only a subset of patients. This study was conducted to identify markers that are associated with disease control in patients treated with cetuximab. Patients and Methods One hundred ten patients with metastatic colorectal cancer were enrolled onto a cetuximab monotherapy trial. Transcriptional profiling was conducted on RNA from mandatory pretreatment metastatic biopsies to identify genes whose expression correlates with best clinical responses. EGFR and K-ras mutation analyses and EGFR gene copy number analyses were performed on DNA from pretreatment biopsies. Results Gene expression profiles showed that patients with tumors that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab (EREG, P = .000015; AREG, P = .000025). Additionally, patients whose tumors do not have K-ras mutations have a significantly higher disease control rate than patients with K-ras mutations (P = .0003). Furthermore, patients with tumors that have high expression of EREG or AREG also have significantly longer progression-free survival (PFS) than patients with low expression (EREG: P = .0002, hazard ratio [HR] = 0.47, and median PFS, 103.5 v 57 days, respectively; AREG: P < .0001, HR = 0.44, and median PFS, 115.5 v 57 days, respectively). Conclusion Patients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.

S.N. Gettinger, M.D. Hellmann, F.A. Shepherd, S.J. Antonia, J. Brahmer, L.Q. Chow, J. Goldman, R. Juergens, H. Borghaei, N.E. Ready, D.E. Gerber, F. Nathan, Y. Shen, C.T. Harbison, N. Rizvi. Yale Comprehensive Cancer Center, Medical Oncology, New Haven CT, USA; Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service-Division of Solid Tumor Oncology-Department of Medicine, New York NY, USA; Princess Margaret Cancer Center, Cancer Clinical Research Unit, Toronto ON, Canada; H. Lee Moffitt Cancer Center & Research Institute, Thoracic Oncology Department, Tampa FL, USA; The Sidney Kimmel Comprehensive Cancer Center at John Hopkins, Division of Oncology, Baltimore MD, USA; University of Washington Division of Oncology, Department of Medicine, Seattle WA, USA; UCLA Jonsson Comprehensive Cancer Center, Hematology/ Oncology, Los Angeles CA, USA; Juravinski Cancer Center, Department of Oncology, Hamilton ON, Canada; Fox Chase Cancer Center, Medical Oncology, Philadelphia PA, USA; Duke University Medical Center, Division of Oncology, Durham NC, USA; UT Southwestern Medical Center, Division of Hematology/Oncology, Dallas TX, USA; Bristol-Myers Squibb, Clinical Research, Princeton NJ, USA; Bristol-Myers Squibb, Biostatistics, Princeton NJ, USA; Bristol-Myers Squibb, Immuno-Science Metabolic Diseases and Fibrosis, Princeton NJ, USA

8025 Background: NIVO, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has demonstrated durable responses and tolerability in heavily pretreated patients (pts) with advanced NSCLC. Th...

SummaryEukaryotic genomes are packaged into nucleosomes whose position and chemical modification state can profoundly influence regulation of gene expression. We profiled nucleosome modifications across the yeast genome using chromatin immunoprecipitation coupled with DNA microarrays to produce high-resolution genome-wide maps of histone acetylation and methylation. These maps take into account changes in nucleosome occupancy at actively transcribed genes and, in doing so, revise previous assessments of the modifications associated with gene expression. Both acetylation and methylation of histones are associated with transcriptional activity, but the former occurs predominantly at the beginning of genes, whereas the latter can occur throughout transcribed regions. Most notably, specific methylation events are associated with the beginning, middle, and end of actively transcribed genes. These maps provide the foundation for further understanding the roles of chromatin in gene expression and genome maintenance.

DNA-binding transcriptional regulators interpret the genome's regulatory code by binding to specific sequences to induce or repress gene expression1. Comparative genomics has recently been used to identify potential cis-regulatory sequences within the yeast genome on the basis of phylogenetic conservation2–6, but this information alone does not reveal if or when transcriptional regulators occupy these binding sites. We have constructed an initial map of yeast's transcriptional regulatory code by identifying the sequence elements that are bound by regulators under various conditions and that are conserved among Saccharomyces species. The organization of regulatory elements in promoters and the environment-dependent use of these elements by regulators are discussed. We find that environment-specific use of regulatory elements predicts mechanistic models for the function of a large population of yeast's transcriptional regulators.

We have determined how most of the transcriptional regulators encoded in the eukaryote Saccharomyces cerevisiae associate with genes across the genome in living cells. Just as maps of metabolic networks describe the potential pathways that may be used by a cell to accomplish metabolic processes, this network of regulator-gene interactions describes potential pathways yeast cells can use to regulate global gene expression programs. We use this information to identify network motifs, the simplest units of network architecture, and demonstrate that an automated process can use motifs to assemble a transcriptional regulatory network structure. Our results reveal that eukaryotic cellular functions are highly connected through networks of transcriptional regulators that regulate other transcriptional regulators.

First-Line Monotherapy With Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) in Advanced Non-Small Cell Lung Cancer (NSCLC): Safety, Efficacy, and Correlation of Outcomes With PD-L1 Status Metastatic Non-Small Cell Lung Cancer N.A. Rizvi, F.A. Shepherd, S.J. Antonia, J.R. Brahmer, L.Q. Chow, J. Goldman, R. Juergens, H. Borghaei, N.E. Ready, D.E. Gerber, Y. Shen, C. Harbison, A.C. Chen, and S. Gettinger; Memorial Sloan Kettering Cancer Center, New York, NY, Princess Margaret Cancer Centre, Toronto, ON, Canada, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, University of Washington, Seattle, WA, University of California, Los Angeles, Los Angeles, CA, Juravinski Cancer Centre at McMaster University, Hamilton, QC, Canada, Fox Chase Cancer Center, Philadelphia, PA, Duke University Medical Center, Durham, NC, UT Southwestern Medical Center, Dallas, TX, BristolMyers Squibb, Princeton, NJ, Yale Cancer Center, New Haven, CT

Other; Novartis, Roche, Boehringer-Ingelheim. M. Thomas: F. Honoraria; Lilly, Bristol Meyers Squibb, Roche. G. Consultant; Lilly, Bristol Meyers Squibb, Roche, Novartis. M. Schuler: E. Research Grant; Boehringer Ingelheim, Novartis. F. Honoraria; Boehringer Ingelheim, Celgene, GlaxoSmithKline, Lilly, Novartis, Pfizer. G. Consultant; AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer. G. Liu: G. Consultant; Astra Zeneca, Pfizer, Novartis. A. Santoro: None. M. Geraldes: A. Employee; Novartis Pharmaceuticals. M. Stock; Novartis Pharmaceuticals. A.L. Boral: A. Employee; Novartis Pharmaceuticals. A. Yovine: A. Employee; Novartis Pharma AG. A.T. Shaw: G. Consultant; Ignyta. K. Advisory Board; Novartis, Pfizer, Ariad, Chugai, Genentech.

Aim: Robust responses to nivolumab (Nivo, anti-PD1 antibody) are seen in both melanomas and NSCLCs. Both of these cancers are characterized by high somatic mutation burden, suggesting a potential link between mutational burden and immunogenicity. Since smoking-related NSCLCs have significantly greater mutation burden compared to never smokers, we hypothesized that smoking history may be associated with response to nivolumab in pts with NSCLCs. Methods: Smoking status, histology, and EGFR/KRAS genotype were recorded from 88 of 129 pretreated, advanced NSCLCs treated with Nivo monotherapy at 5 of 11 centers that participated in a previously reported study (NCT00730639, Topalian et al, NEJM 2012). Self-reported smoking history was categorized as never ( 5 pk-yrs, quit > 1 yr prior), or current smokers. In smokers, time-since-quitting was also recorded. Response was assessed every 8 wks by RECIST v1.0. Associations between smoking, histology, genotype, and response were assessed using the Fisher's exact, unpaired T-, log-rank tests. Results: The response rate was significantly higher in former/current smokers (20/75, 27%, 95% CI 17-38%) vs minimal/never smokers (0/13, 0%, 95% CI 0-25%) (p = 0.034). Responders had significantly more tobacco exposure than non-responders (median 50 pk-yrs [range 15-150] vs 36 pk-yrs [range 0-100], p=0.036). Among smokers, there was no association between response and time-since-quitting (Current smokers ORR 27%; Quit 1-15 yrs ago 24%; Quit >15 yrs ago 24%, p=0.18). There was no significant difference in response rate in adeno vs squamous histology (16 vs 21%, p=0.58). In adenos, response rates in EGFR muts vs KRAS muts vs all others were 1/9 vs 3/13 vs 4/27; the one EGFR mut responder was a 40 pk-yr current smoker. Conclusions: In advanced NSCLCs, the response rate to Nivo was significantly higher in former/current smokers compared to never/minimal smokers. There were no objective responses in never or minimal smokers in this subset of pts. Smoking history should be considered as a stratification factor for trials of PD-1 pathway inhibitors in lung cancer. Further work is needed to identify the underlying basis of this differential response rate. Disclosure: S.J. Antonia: Dr. Antonia receives research funding and/or serves as an advisor for Bristol-Myers Squibb. L. Horn: Dr. Horn receives research funding and/or serves as an advisor for Bristol-Myers Squibb; J.R. Brahmer: Dr. Brahmer receives research funding and serves as an advisor for Bristol-Myers Squibb; S. Gettinger: Dr. Gettinger receives research funding and serves as an advisor for Bristol-Myers Squibb; C. Harbison: Dr. Harbison is an employee and stock holder of Bristol-Myers Squibb; N. Rizvi: Dr. Rizvi receives research funding and serves as an advisor for Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Aim: We report interim data from a phase 1 study of nivolumab (N), a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, combined with PT-DC or ERL in advanced chemotherapy-naive NSCLC patients (pts). Methods: Pts (n = 56) were assigned by histology to receive N 10 mg/kg IV Q3W + concurrent IV gemcitabine 1250 mg/m2 + cisplatin 75 mg/m2 (squamous [sq]) or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 (non-sq), or N 5 or 10 mg/kg IV Q3W + IV paclitaxel 200 mg/m2 + carboplatin AUC6 (sq + non-sq). N + PT-DC was given for 4 cycles, with continued N to progression/unacceptable toxicity. EGFR mutant (EGFR MT) NSCLC pts (n = 21) received N 3 mg/kg IV Q2W + ERL 150 mg PO daily until progression/unacceptable toxicity. Objective response rate (ORR) was assessed by RECIST 1.1. Results: Across N + PT-DC arms (median follow-up [mF/U] 75 wks), grade 3–4 related AEs occurred in 45% of pts (25–73% across arms); 4 pts (7%) had grade 3–4 pneumonitis; 0–33% discontinued due to related AEs, any-grade pneumonitis (7%) most common. ORR with N + PT-DC was 33–47%; PD as best overall response (BOR) was infrequent (7%). Progression-free survival (PFS) rate at wk 24 was 38–71%; 1-yr OS rate was 50–87%. With N + ERL (mF/U 72 wks), grade 3–4 related AEs occurred in 5 pts; no pneumonitis was observed. Related AEs led to discontinuation in 4 pts (grade 3 AST ↑, grade 3 diarrhea, grade 2 nephritis, grade 2 flushing). ORR was 19% (median duration of response [DOR] not reached; range 60.1, 72.3+ wks); 24-wk PFS rate was 51%. Three of 20 pts (15%) with acquired ERL resistance achieved PR (DOR 60.1, 64.6 + , 70+ wks; 2 ongoing); 9/20 pts had BOR of SD, with 3/9 not progressed (time to progression/death 9.9+–53 wks); 1 pt had an ongoing unconventional response. One pt was EGFR TKI naive and achieved PR (DOR 72.3+ wks; ongoing). Conclusions: N + PT-DC demonstrated acceptable antitumor activity and safety reflecting additive nivolumab and PT-DC toxicities in pts with advanced NSCLC. N + ERL may provide durable clinical benefit and an acceptable safety profile in TKI-refractory, EGFR MT pts. These data support further evaluation of nivolumab combination regimens in pts with advanced NSCLC. Disclosure: S. Gettinger: Consultant advisor BMS; Honoraria for BMS advisory board; N. Rizvi: Consultant Advisor-BMS; Honoraria-BMS, Medimmune, Genentech/Roche; L.Q. Chow: BMS Stock; Research Funding-Bristol-Myers Squibb funding goes to University of Washington; H. Borghaei: Consultant advisor-Genentech, BMS; Research Funding- Pfizer, Arisaph, Millenium; Honoraria-Genentech; J.R. Brahmer: Consultant advisor BMS; Stock BMS; Research Funding BMS; R. Juergens: Research funding BMS; F.A. Shepherd: Consultant advisor (compensated), honoraria-BMS; J. Goldman: Research funding-BMS, Genentech; Y. Shen: BMS Employee; BMS Stock; C. Harbison: BMS-employee, stock; A. Chen: BMS-employee, stock; S.J. Antonia: Consultant advisor, honoraria, research funding for BMS MedImmune provides funding for clinical trials. All other authors have declared no conflicts of interest.