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The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis.In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability.A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group.Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).

Figure S1 shows the predicted ramucirumab concentration (μg/mL) over an 8-mg/kg dosing regimen to predicted steady-state.

Ramucirumab is an IgG1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure–efficacy and exposure–safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (Cmin,ss). Kaplan–Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (Cmin,ss)–efficacy relationship to overall survival (OS) and progression-free survival (PFS). Logistic regression analyses were used to evaluate exposure–safety relationships. Analyses included 321 ramucirumab + paclitaxel and 335 placebo + paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure–efficacy analysis showed ramucirumab Cmin,ss was a significant predictor of OS and PFS in both trials. Higher ramucirumab exposure was associated with longer OS and PFS. In RAINBOW, grade ≥3 hypertension, leukopenia, and neutropenia, but not febrile neutropenia, significantly correlated with Cmin,ss, with increased exposure leading to increased incidence. Exploratory exposure–response analyses suggest a positive relationship between efficacy and ramucirumab exposure with manageable toxicities at exposures generated from a dose of 8 mg/kg ramucirumab given every 2 weeks for patients with advanced gastric/GEJ cancer. These findings suggest an opportunity to further optimize benefit versus risk profiles of ramucirumab treatment in patients with gastric/GEJ cancer. Mol Cancer Ther; 16(10); 2215–22. ©2017 AACR.

Table S1 describes REGARD exposure-safety outcomes for Grade >=3 hypertension.

Background Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2). Methods Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed. Results Baseline AFP was confirmed as a continuous (REACH, REACH-2; p p p = 0.0042 continuous; p p p p p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p p Conclusions AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab. Clinical Trial Registration ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).

Phosphoinositide 3-kinase-δ (PI3Kδ) inhibitors are active in lymphoid malignancies, although associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82]; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43]; and other tumor types [n = 25]) who were treated with the recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1 months), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (AEs) occurred in 366 (98.7%) of 371 patients, with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade 3 or higher treatment-emergent AEs occurred in 189 (50.9%) of 371 patients and included neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferase levels (5.7%). Treatment-emergent serious AEs occurred in 95 (25.6%) of 371 patients. AEs of special interest were limited and included pneumonia (29 of 371 [7.8%]), noninfectious colitis (9 of 371 [2.4%]), and pneumonitis (4 of 371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died of AEs, none of which was deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.

Background Post-hoc analyses of AFP response and progression and their relationship with objective measures of response and survival were performed in patients from REACH. Methods Serum AFP was measured at baseline and every 3 cycles (2 weeks/cycle). Associations between AFP and radiographic progression and efficacy end points were analysed. Results Median percent AFP increase from baseline was smaller in the ramucirumab than in the placebo arm throughout treatment. Time to AFP progression (HR 0.621; P P P P = 0.0002). AFP response was higher with ramucirumab compared with placebo (P P Conclusions Treatment with ramucirumab prolonged time to AFP progression, slowed AFP increase and was more likely to induce AFP response. Similar benefits in radiographic progression and response correlated with AFP changes.

Background and Aim REGARD and RAINBOW were global, phase 3, randomized, double-blind trials of second-line ramucirumab for metastatic gastric or gastroesophageal junction adenocarcinoma. We describe exploratory subgroup analyses to assess the efficacy and safety of ramucirumab in REGARD and RAINBOW in young (≤45 and

Aim We describe a subgroup analysis assessing the efficacy and safety of ramucirumab monotherapy in East Asian (EA) patients from the REGARD trial. Methods Patients with advanced gastric or gastroesophageal junction adenocarcinoma with progressive disease were randomized 2:1 to receive ramucirumab (8 mg/kg) plus best supportive care (BSC) or placebo plus BSC every 2 weeks. Post hoc subset analyses were performed on the EA and non-EA intention-to-treat populations. Results Of 355 intention-to-treat patients, 26 patients from EA were randomized to ramucirumab (n = 18) or placebo (n = 8). Median overall survival was 6.5 months in the ramucirumab arm and 4.8 months in the placebo arm (hazard ratio [HR] 0.69; 95% confidence interval [CI], 0.27-1.82) for EA patients, and 5.2 months in the ramucirumab arm and 3.8 months in the placebo arm (HR 0.78; 95% CI, 0.60-1.02) for non-EA patients. The rate of disease control was numerically higher in ramucirumab patients versus placebo; 61% versus 38% respectively for EA patients, and 48% versus 22% for non-EA patients. The incidence of grade ≥3 treatment emergent adverse events was higher in the ramucirumab arm compared to placebo (39% vs 13%). Conclusion Despite limitations, this subgroup analysis suggests that ramucirumab monotherapy improves efficacy outcomes with a tolerable safety profile in EA patients with previously treated advanced gastric cancer.

Background Symptoms of advanced hepatocellular carcinoma (HCC) represent a substantial burden for the patient and are important endpoints to assess when evaluating treatment. Patient-reported outcomes were evaluated in subjects with advanced HCC and baseline alpha-fetoprotein (AFP) ≥400 ng/mL treated with second-line ramucirumab. Patients and methods Patients with AFP≥400 ng/mL enrolled in the REACH or REACH-2 phase 3 studies were used in this analysis. Eligible patients had advanced HCC, Child-Pugh A, Eastern Cooperative Oncology Group performance status 0/1 and prior sorafenib. Patients received ramucirumab 8 mg/kg or placebo once every 2 weeks. Disease-related symptoms and health-related quality of life (HRQoL) were assessed with the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL-5-Dimensions (EQ-5D) instruments, respectively. Time to deterioration (TTD) (≥3-point decrease in FHSI-8 total score;≥0.06-point decrease in EQ-5D score, from randomisation to first date of deterioration) was determined using Kaplan-Meier estimation and the Cox proportional hazards model. Both separate and pooled analyses for REACH AFP≥400 ng/mL and REACH-2 patients were conducted. Results In the pooled population with AFP ≥400 ng/mL (n=542; ramucirumab, n=316; placebo, n=226), median TTD in FHSI-8 total score was prolonged with ramucirumab relative to placebo (3.3 vs 1.9 months; HR 0.725; (95% CI 0.559 to 0.941); p=0.0152), including significant differences in back pain (0.668; (0.497 to 0.899); p=0.0044), weight loss (0.699; (0.505 to 0.969); p=0.0231) and pain (0.769; (0.588 to 1.005); p=0.0248) symptoms. TTD in EQ-5D score was not significantly different between ramucirumab and placebo groups (median 2.9 vs 1.9 months). Results in the individual trials were consistent with these findings. Conclusions Ramucirumab in second-line treatment of advanced HCC demonstrates consistent benefit in the delay of deterioration in disease-related symptoms with no worsening of HRQoL. Taken with previously demonstrated ramucirumab-driven survival benefits in this setting, these data may inform patient–clinician discussions about the benefit–risk profile of this therapy. Trial registration number NCT01140347 ; NCT02435433 , NCT02435433 .

Background: Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher. Methods: REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433. Findings: Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0–12·5), median overall survival (8·5 months [95% CI 7·0–10·6] vs 7·3 months [5·4–9·1]; hazard ratio [HR] 0·710 [95% CI 0·531–0·949]; p=0·0199) and progression-free survival (2·8 months [2·8–4·1] vs 1·6 months [1·5–2·7]; 0·452 [0·339–0·603]; p

Inadequate understanding of interpretation of quality of life (QoL) instruments leads to unsatisfactory data reporting and clinical decision-making, including in gastric cancer care.Pooled QoL data from two phase III studies of ramucirumab with or without paclitaxel in previously treated patients with gastric or gastroesophageal junction cancer were used to explore associations with clinical attributes, including tumour response, disease measurability and performance status (PS). The European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ)-C30 was used in both studies. Changes in QLQ-C30 scores from baseline to week 6 as a predictor of clinical outcomes and impacts of changes in clinical status on QoL were estimated by multivariate logistic regression and analyses of variance, respectively.Baseline QoL data were available for 989 patients. Fatigue, pain and appetite loss were prominent baseline symptoms. Disease progression resulted in worse QoL in all functional scales (p 0.0001 to p = 0.0306), global QoL (p = 0.0011) and symptom scales (fatigue, p 0.0001; nausea/vomiting, p = 0.0007; pain, p = 0.0052; appetite loss, p = 0.0061). Similar trends were seen with deterioration of PS on QoL. A 15- to 20-point change in global QoL and functional scale scores predicted change in tumour status as did change in fatigue, pain and appetite loss scores. Smaller QoL changes (5-15 points) predicted PS change. Results were similar in patients regardless of baseline disease measurability.Our study underscores the importance of disease control for maintaining or improving QoL. These data could improve future trial design and routine clinical care for patients receiving therapy for previously treated gastric cancer. NCT00917384, NCT01170663.

Background Elevated AFP in patients (pts) with HCC is associated with worse prognosis. Two placebo (P)-controlled trials (REACH, REACH-2) have studied ramucirumab (RAM, anti-VEGFR2 antibody) in pts with HCC after sorafenib, with REACH-2 enrolling only pts with baseline AFP ≥400ng/mL. In REACH-2 RAM treatment (trt) improved overall survival (OS) compared to P, consistent with REACH (AFP ≥400ng/mL) pts. Here we present post-hoc analyses assessing the prognostic and predictive value of baseline AFP in both studies. Methods Pts with HCC, Child-Pugh A, ECOG PS 0-1, and prior sorafenib were randomized to RAM 8mg/kg or P Q2W. The prognostic value of baseline AFP was assessed by Cox regression models with either continuous or dichotomous (≥400 vs Results Baseline AFP was confirmed as a significant continuous (REACH and REACH-2; p Conclusions The prognostic impact of baseline AFP is an important factor to consider in trial design. The findings suggest AFP may be predictive of RAM OS benefit. Results also confirm AFP ≥400ng/mL is appropriate selection criterion for RAM OS benefit. Clinical trial identification NCT01140347, NCT02435433. Editorial acknowledgement Nathalie Godinot, funded by Eli Lilly and Company. Legal entity responsible for the study Eli Lilly and Company. Funding Eli Lilly and Company. Disclosure A.X. Zhu: Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy: Roche/Genentech. P.R. Galle: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Schering Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sirtex Medical; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy: Bristol-Meyers Squibb; Advisory / Consultancy: MSD; Honoraria (self): Sillajen. J.M. Llovet: Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Celsion; Advisory / Consultancy: Incyte; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Glycotest; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Bayer Schering Pharma. R.S. Finn: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche Genentech; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Exelixis. Y. Kang: Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche Genentech; Advisory / Consultancy: Merck Serono; Advisory / Consultancy, Research grant / Funding (self): DAE HWA Pharmaceutical; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (self): LSK Biopharma. E. Assenat: Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Terasphere; Honoraria (self), Advisory / Consultancy: Sirtex Medical; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Servier. G. Brandi: Advisory / Consultancy: Eli Lilly and Company. K. Motomura: Honoraria (self): Eisai. I. Ohno: Advisory / Consultancy: Merck Serono; Speaker Bureau / Expert testimony: Taiho Pharmaceutical. B. Daniele: Honoraria (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Incyte; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Celgene. A. Vogel: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Delcath Systems; Honoraria (self), Advisory / Consultancy: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Baxalta; Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Sanofi; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD. T. Yamashita: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Eisai. C. Hsu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Taiho Pharmaceutical. T. Meyer: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy: Tarveda Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): BTG; Advisory / Consultancy: Beigene; Advisory / Consultancy: MSD; Research grant / Funding (institution): Bayer. R. Widau: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. W. Schelman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. C. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. Y. Hsu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. M. Kudo: Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Research grant / Funding (institution): AbbVie; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Gilead Sciences; Honoraria (self): Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: EA Pharma; Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Bristol-Myers Squibb Japan. All other authors have declared no conflicts of interest.

REGARD and RAINBOW were global, phase 3, randomized, double-blind trials of second-line ramucirumab for metastatic gastric or gastroesophageal junction adenocarcinoma. Exploratory subgroup analyses were described to assess the efficacy and safety of ramucirumab in REGARD and RAINBOW in young (≤ 45 and 65 years) and elderly (≥ 65, ≥ 70, and ≥ 75 years) patients.Patients were randomized 2:1 to receive ramucirumab plus best supportive care or placebo plus best supportive care (REGARD) or 1:1 to ramucirumab plus paclitaxel or placebo plus paclitaxel (RAINBOW). Subpopulation Treatment Effect Pattern Plots assessed efficacy and adverse events by age groups for ramucirumab versus placebo.The hazard ratios (HRs) for overall survival favored treatment with ramucirumab: REGARD ≤ 45 years (HR: 0.59, 95% confidence interval: 0.27-1.26), 65 years (0.80, 0.59-1.10), ≥ 65 years (0.72, 0.48-1.08), ≥ 70 years (0.73, 0.44-1.23), and ≥ 75 years (0.59, 0.25-1.37); and RAINBOW ≤ 45 years (0.56, 0.33-0.93), 65 years (0.78, 0.63-0.97), ≥ 65 years (0.88, 0.66-1.18), and ≥ 70 years (0.88, 0.60-1.28). The exception was elderly patients aged ≥ 75 years in RAINBOW (0.97, 0.47-2.01); however, patient numbers were low in this subgroup (n = 36). Similar findings were observed for progression-free survival, for which HRs numerically favored ramucirumab-treated patients. Adverse events (including grade ≥ 3) were not associated with age.In comparison with placebo, ramucirumab conferred improvements in efficacy across age groups with a tolerable safety profile. Despite some limitations, these exploratory analyses support the use of ramucirumab in advanced gastric cancer, irrespective of age.

This phase II trial examined the addition of ramucirumab, a vascular endothelial growth factor receptor-2 monoclonal antibody, to mFOLFOX6 as front-line therapy for patients with advanced gastric/GEJ or esophageal adenocarcinoma. A survival benefit was not observed in the ITT population, but an exploratory analysis suggested a potential benefit for ramucirumab in the gastric/GEJ cancer subgroup. Background We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ). Patients and methods Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure–response analysis was undertaken. Results Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69–1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure–response analysis indicated that patients with higher ramucirumab exposure had longer OS. Conclusion The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population. Clinicaltrials.gov identifier NCT01246960.

4073 Background: Oral multikinase inhibitors that have shown improvements in overall survival (OS) in HCC are associated with clinically important toxicities that commonly require dose adjustment or discontinuation (D/C) due to intolerance. REACH and REACH-2 studied RAM in patients (pts) with HCC who progressed on or were intolerant to sorafenib (SOR), and REACH-2 only enrolled pts with baseline AFP ≥400 ng/mL. In REACH-2 RAM treatment (trt) improved OS compared to placebo (P), supporting findings in REACH pts with baseline AFP ≥400 ng/mL. An exploratory analysis of outcomes by reason for D/C of SOR was performed. Methods: Pts had advanced HCC, Child-Pugh A, ECOG PS 0-1, and prior SOR. Pts were randomized to RAM 8 mg/kg or P Q2W. A pooled independent pt data analysis (stratified by study) of REACH-2 and REACH pts (AFP ≥400 mg/mL) was performed. Results are reported by reason for SOR D/C (intolerance or disease progression). OS and PFS were evaluated using Kaplan-Meier method and Cox proportional hazard model. Objective response rate (ORR), disease control rate (DCR) and safety are reported. Results: Baseline characteristics in the pooled population were generally balanced between trt arms in each subgroup. Median durations of prior SOR were 2.5 mo for SOR intolerant (n = 70) and 4.0 mo for SOR progressors (n = 472). Median OS (RAM v P) was 10.2 v 6.7 mo for SOR intolerant and 8.0 v 4.7 mo for SOR progressors (Table). Rates of D/C due to trt-related adverse events (AEs) (Table) (7% in each subgroup), and Grade ≥3 AEs (most frequently hypertension) were consistent with those observed in each study. Conclusions: Acknowledging limitations of sample size, the RAM trt benefit in SOR intolerant pts was consistent with that in the ITT population. RAM was well tolerated in SOR intolerant pts with low rates of D/C due to related-AEs. Clinical trial information: NCT01140347, NCT02435433. [Table: see text]

Summary Background Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. Methods We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24–87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384. Findings 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3–9·9) in patients in the ramucirumab group and 3·8 months (1·7–7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603–0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605–0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. Interpretation Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. Funding ImClone Systems.

Ramucirumab is an IgG1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure–efficacy and exposure–safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (Cmin,ss). Kaplan–Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (Cmin,ss)–efficacy relationship to overall survival (OS) and progression-free survival (PFS). Logistic regression analyses were used to evaluate exposure–safety relationships. Analyses included 321 ramucirumab + paclitaxel and 335 placebo + paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure–efficacy analysis showed ramucirumab Cmin,ss was a significant predictor of OS and PFS in both trials. Higher ramucirumab exposure was associated with longer OS and PFS. In RAINBOW, grade ≥3 hypertension, leukopenia, and neutropenia, but not febrile neutropenia, significantly correlated with Cmin,ss, with increased exposure leading to increased incidence. Exploratory exposure–response analyses suggest a positive relationship between efficacy and ramucirumab exposure with manageable toxicities at exposures generated from a dose of 8 mg/kg ramucirumab given every 2 weeks for patients with advanced gastric/GEJ cancer. These findings suggest an opportunity to further optimize benefit versus risk profiles of ramucirumab treatment in patients with gastric/GEJ cancer. Mol Cancer Ther; 16(10); 2215–22. ©2017 AACR.

Ramucirumab is a recombinant human IgG1 neutralizing monoclonal antibody specific for vascular endothelial growth factor receptor-2. Second-line ramucirumab, in conjunction with paclitaxel (ramucirumab 8 mg/kg or placebo in combination with 80 mg/m2 paclitaxel), has been shown to be effective and safe in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in RAINBOW, a global phase III randomized clinical trial. We conducted an exploratory exposure–response analysis of efficacy and safety of ramucirumab in East Asian patients from the RAINBOW trial. Using sparse pharmacokinetic samples collected in the RAINBOW trial, a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (C min,ss) using a nonlinear mixed-effect modeling approach. Kaplan–Meier and Cox proportional hazards analyses were conducted to evaluate ramucirumab exposure (C min,ss) and efficacy relationship by overall survival and progression-free survival. Exposure-safety relationships were assessed descriptively. Two hundred and twenty-two East Asian patients were included in this exposure–response analysis. Higher ramucirumab C min,ss was associated with longer overall survival (p = 0.0115) and progression-free survival (p = 0.0179) in this patient cohort. Patients with higher ramucirumab C min,ss (≥56.87 ng/ml median) had higher incidences of grade ≥3 leukopenia and neutropenia, but not febrile neutropenia or hypertension. This exploratory analysis suggests a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in East Asian patients from RAINBOW, consistent with the overall exposure–response analysis from this trial. A regimen with a higher dosage of ramucirumab warrants further consideration for East Asian patients with gastric/GEJ cancer.

Background The RAISE phase III clinical trial demonstrated that ramucirumab + (folinic acid plus 5-fluorouracil plus irinotecan) FOLFIRI significantly improved overall survival (OS) versus placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients failing bevacizumab- and oxaliplatin-based chemotherapy (hazard ratio [HR] = 0.84, 95% CI = 0.73–0.98, P = 0.022). Post hoc analyses of RAISE patient data examined the association of carcinoembryonic antigen (CEA) subgroups with efficacy parameters. Methods CEA subgroups (≤10 versus >10 ng/ml) were based on 2X upper limit of normal (ULN) (5 ng/ml). The Kaplan–Meier method estimated the median OS and the progression-free survival (PFS). Log-rank test compared the survival distributions within the subgroups. Hazard ratio (HR) (95% confidence interval [CI]) and treatment-by-subgroup interaction p-values were calculated by Cox proportional hazards model. Results Ramucirumab treatment prolonged survival for the CEA ≤10 subgroup (HR = 0.68; 95% CI = 0.50–0.92; P = 0.013) and CEA >10 subgroup (HR = 0.90; 95% CI = 0.76–1.07; P = 0.233). However, the ramucirumab OS benefit over placebo was greater for the CEA ≤10 subgroup than for the CEA >10 subgroup (median OS: 3.6 versus 0.8 months greater, respectively). The interaction P-value between CEA level and treatment effect on OS was 0.088. This trend was observed across randomisation strata and to a lesser extent for PFS (P = 0.594). Conclusions Although patients in both high- and low-CEA subgroups derive OS and PFS benefits from ramucirumab treatment, the low baseline CEA level may identify a subgroup of patients with mCRC who obtain greater benefit from ramucirumab.

326 Background: REACH-2 (NCT02435433) demonstrated a significant survival benefit with RAM vs placebo in the second-line treatment of patients with advanced HCC and AFP ≥ 400 ng/mL. This analysis investigated changes in AFP during treatment, as well as potential relationships with survival or progression. Methods: Patients were randomized (2:1) to RAM 8 mg/kg IV or placebo Q2W plus best supportive care until disease progression or unacceptable toxicity. Serum AFP levels were measured at baseline and every 3 cycles. Percent change in AFP from baseline was analyzed at each time point up to Cycle 12 with descriptive statistics and Wilcoxon rank sum test between treatment arms. AFP response was defined as ≥ 20% decrease from baseline. The association between AFP progression and radiographic progression in each time interval was assessed by odds ratio [OR] and Fisher’s exact test. Time to AFP progression and time to radiographic progression (TTP) were evaluated by the Kaplan-Meier method and compared between treatment arms using a stratified log-rank test. AFP progression was defined as ≥ 20% increase from baseline. Hazard ratio (HR) was generated using a stratified Cox regression model. Results: AFP response was significantly higher with RAM compared with placebo (42.1% vs 10.5%, p < 0.0001). Overall survival (OS) was longer in patients with AFP response (13.5 months) than in patients without (6.7 months), irrespective of treatment (HR 0.470, p < 0.0001). The median percent increase in AFP level from baseline was smaller in the patient population treated with RAM (0.4%, 6.1%, 15.4%, 10.8%) than with placebo (45.7%, 98.5%, 122.2%, 91.3%) at Cycles 3, 6, 9 and 12, respectively. Time to AFP progression (HR 0.422, p < 0.0001) and TTP (HR 0.427, p < 0.0001) favored a RAM benefit; subsequent analyses demonstrated a strong association between AFP progression and radiographic progression at 6 weeks (OR 2.44, p < 0.0084) and at 12 weeks (OR 1.89, p = 0.0430). Conclusions: Changes in AFP levels were associated with TTP and OS. RAM prolonged time to AFP progression and radiographic TTP, and slowed the rate of AFP increase during treatment. Clinical trial information: NCT02435433.

4047 Background: EORTC QLQ-C30 is a well-established QoL instrument for cancer patients (pts), but there is limited information for gastric cancer. To identify priority domains and describe meaningful changes, we explored data from 2 randomized ramucirumab phase 3 trials in pts with previously treated gastric or gastroesophageal junction cancer. Methods: Pts completed QLQ-C30 v3.0 at baseline and Q6W while on study. Data from all treatment arms were pooled (N=1020). Changes from baseline in QoL domains were compared by best overall response (BOR) and ECOG performance status (PS) using analysis of covariance. Odds ratios (ORs) for BOR and PS outcome groups per QoL unit (point) change were estimated by cumulative logit regression modeling, with OR≤0.85 considered meaningful. Results: Changes from baseline in QoL domains were significantly associated with BOR and PS outcomes (Table). ORs for BOR and PS outcomes for these domains were statistically significant (p

This molecular epidemiologic case-control study of lung cancer incorporated three complementary biomarkers: the glutathione S-transferase M1 (GSTM1) null genotype, a potential marker of susceptibility, and polycyclic aromatic hydrocarbon-DNA adducts (PAH-DNA) and sister chromatid exchanges (SCE), both indicators of environmentally induced genetic damage. Associations between biomarkers and lung cancer were investigated, as were possible gene-environment interactions between the GSTM1 null genotype and tobacco smoke exposure. Subjects included 136 primary non-small cell lung cancer surgical patients and 115 controls at the Columbia Presbyterian Medical Center. Questionnaire and Tumor Registry data, pre-treatment blood samples and biomarker measurements on blood were obtained. Overall, GSTM1 null genotype was significantly associated with lung cancer [odds ratio (OR) = 2.04, 95% confidence interval (CI) = 1.13-3.68]. ORs for GSTM1 and lung cancer were significant in females (2.50, 1.09-5.72) and smokers (2.25, 1.11-4.54) and not significant in males (1.4, 0.58-3.38) and non-smokers (0.88, 0.18-4.33). However, ORs for males versus females and smokers versus non-smokers did not differ significantly. The OR for GSTM1 and lung cancer in female smokers was 3.03 (1.09-8.40), compared with 1.42 (0.53-4.06) in male smokers. In contrast to PAH-DNA adducts in leukocytes, SCE did not differ between cases and controls. Neither biomarker differed significantly between the two GSTM1 genotypes. The combined effect of elevated PAH-DNA adducts and GSTM1 genotype on case-control status (16.19, 1.2-115) appeared multiplicative. Results suggest that the effect of the GSTM1 null genotype is greatest in female smokers, which is consistent with other evidence that indicates that women are at higher risk of lung cancer than males, given equal smoking. Persons with both the GSTM1 deletion and elevated PAH-DNA adducts may represent a sensitive subpopulation with respect to carcinogens in tobacco smoke and other environmental media.

P-postlabelling or immunoassay,this time exposure to polycyclic aromatic hydrocarbons have detected job-related increases in the levels of aromatic(PAH) decreased and the level of DNA adducts decreased and PAH types of DNA adducts, correlating to the level ofaccordingly. In the total group exposure was related to the exposure to PAH. The present study in this foundry haslevel of adducts. Adduct levels correlated with urinary 1- involved an annual sampling of workers and controls inhydroxypyrene (LOGU1OH), air benzo[a]pyrene, weekly November/December in four consecutive years, 1990–1993.working hours and daily cigarette consumption. In a Exposure and some 15 different end-points are being assessed.multivariatemodel1-hydroxypyrenehadaconsistenteffect. Several papers on DNA adducts and somatic cell mutations inNeither glutathione transferase M1 (GSTM1) nor the first year of the study have already been published (10–12).cytochrome P450 1A1 (CYP1A1) genotypes had clear The original objective of the study was to follow a homo-effects. Yet the individuals lacking GSTM1 had a stronger genous population, consisting of people exposed to variouseffect of LOGU1OH and some effect by other sources of levels of PAHs, over four years in order to analyse the levelsPAH, such as charcoal broiled food, although all these of the end-points, including DNA adducts. However, economicvariables were not significant in the multivariate model. slump in Finland with layoffs, shortened working hours andThe rare individuals with a CYP1A1 polymorphism MspI changed exposure partially defeated this original purpose.containing an amino acid change at isoleucine had an Instead, the changes in exposure provided a possibility to testincreased level of adducts. The results showed that the the detection levels of the biomarker assays used. To enablepostlabelling method used was able to detect an increase such an analysis, data on the possible confounding factorsin aromatic DNA adducts in leukocytes when exposure to were needed. Fortunately, at the time of blood sampling abenzo[a]pyrene in air was ~5 ng/m

668 Background: Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2. Overall survival (OS) and progression-free survival (PFS) in 2nd line FOLFIRI based treatment for metastatic colorectal cancer (mCRC) were improved with RAM therapy versus PBO in the RAISE trial. Recent work suggests mCRC primary tumor location is both prognostic and predictive; with improved OS and therapy-specific sensitivity observed in left (L)- vs right (R)-sided tumors. Given these findings, the RAISE trial data was subjected to post-hoc analysis to determine if sidedness influenced RAM efficacy. Methods: Primary tumor site was obtained. L-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum, while R-CRC included transverse, ascending colon and cecum. OS/PFS in L and R subgroups were analyzed via Kaplan-Meier method and unstratified log-rank test (treatments within subgroup), unstratified Cox proportional hazards model (estimate hazard ratio [HR] and 95% CI), and Wald test (treatment-by-subgroup interaction). Results: Tumor location was available for 1012/1072 (94%) patients, 699 L- and 313 R-CRC. Baseline characteristics were balanced between arms. RAM treatment enhanced L-CRC median OS by 2.5 mo (median 14.5 vs 12.0 mo) with a HR (95% CI) = 0.807 (0.675, 0.965), P = 0.019; compared to a 1.1 mo increase in median OS in R-CRC vs PBO (12.7 vs 11.6) with a HR (95% CI) = 0.971 (0.750, 1.258), P = 0.823; and, RAM enhanced L-CRC median PFS by 1.6 mo (6.0 vs 4.4 mo) and HR (95% CI) = 0.776 (0.664, 0.906), P = 0.001 compared to a 1.1 mo increase in median PFS R-CRC vs PBO (5.6 vs 4.5) with a HR (95% CI) = 0.855 (0.674, 1.084), P = 0.197. The treatment-by-subgroup interaction for both OS and PFS was not significant ( P = 0.276, 0.578, respectively). Conclusions: Despite L-CRC patients having longer OS/PFS and a seemingly stronger RAM treatment effect than R-CRC, the non-significant interaction test cannot verify sidedness as being predictive of RAM efficacy. The current study confirms ramucirumab benefits mCRC patients regardless primary tumor location. Clinical trial information: NCT01183780.

3 Background: REGARD and RAINBOW are two phase 3 studies which demonstrated significant survival benefits and manageable toxicity in patients with advanced gastric cancer (GC) randomized in the second-line setting to receive RAM or placebo. We examined outcomes by age (≤45, 45-70, ≥70, ≥75 years). Methods: Patients were randomized 2:1 to receive RAM 8 mg/kg + best-supportive care (BSC) or placebo (PL) + BSC (REGARD); or 1:1 RAM 8 mg/kg + paclitaxel (PTX) or PL + PTX (RAINBOW). Kaplan-Meier analysis and Cox proportional hazards regression were performed for overall survival (OS) and progression-free survival (PFS). Subpopulation treatment effect pattern plot (STEPP) assessed efficacy and the incidence of adverse events (AEs) across age subgroups. Results: Baseline characteristics were generally well balanced between arms amongst the age subgroups. Efficacy outcomes are summarized in the Table. STEPP analysis revealed no obvious patterns for differential risks in terms of efficacy and AEs (any grade or grade ≥3) according to age. Conclusions: Compared with PL, the efficacy of RAM was maintained in all age groups, with similar rates of toxicity. Despite some limitations regarding patient numbers in some age subgroups, this exploratory subgroup analysis supports the use of RAM for the treatment of GC, irrespective of age. Clinical trial information: NCT00917384 and NCT01170663. [Table: see text]

Purpose: To identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer. Materials and Methods: We pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum-and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters. Results: Of 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy

TPS178 Background: Ramucirumab, a human IgG1 monoclonal antibody directed to the ectodomain of VEGFR-2, prevents ligand binding to the receptor, blocking activation of downstream receptor-mediated pathways. Ramucirumab has demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) in 2 phase III registration studies (REGARD, RAINBOW) in patients in second-line treatment of gastric cancer. This global phase III trial will compare PFS in patients with HER2-negative, metastatic gastric or GEJ adenocarcinoma receiving ramucirumab with cisplatin/capecitabine (or 5-FU) versus placebo with cisplatin/capecitabine (or 5-FU) as first-line treatment. The trial is conducted in 137 sites in the Americas, Europe and Japan and is currently open to enrollment. Methods: Eligible patients will be randomized to receive ramucirumab (8mg/kg on days 1 and 8, based upon population pharmacokinetic modelling) or placebo with cisplatin/capecitabine every 21-day cycle until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary endpoint is PFS; OS is the key secondary endpoint. Efficacy will be considered at 3 analysis points: futility analysis for PFS, primary analysis of PFS & final analysis of OS. A gatekeeping strategy will be used to assess PFS and OS. The OS endpoint will only be tested if the PFS test is significant to control Type I error at 5% across both endpoints. An exposure/safety analysis will be done after 60 patients have started the 3rd cycle. The study has 90% power to demonstrate a PFS advantage assuming HR = 0.70 and 80% power to demonstrate an OS advantage assuming HR = 0.77. Other secondary endpoints include PFS2 (the time from randomization to disease progression after the start of additional systemic anticancer treatment, or death from any cause, whichever occurs first), objective response rate, safety and quality of life. As of 9/11/2015, 128 patients have been enrolled in 19 countries. The 1st exposure/safety analysis is underway. Clinical trial information: NCT02314117.

4028 Background: From 2009-2012, 1020 pts were enrolled in two phase III, randomized, double-blind studies of RAM in metastatic gastroesophageal junction and gastric adenocarcinoma following progre...

121 Background: We evaluated the E-R relationship of RAM in pts with advanced gastric cancer from the REGARD and RAINBOW trials. Methods: Pts received RAM (8 mg/kg) or placebo (PL) q2w in REGARD; or RAM (8 mg/kg) or PL q2w + paclitaxel (PAC) 80 mg/m2 on days 1, 8, and 15 (28-day cycle) in RAINBOW. Sparse pharmacokinetic (PK) samples were collected; a population PK analysis was conducted. A model-predicted minimum concentration after first RAM dose (Cmin,1) was used for correlation with efficacy and safety variables. Kaplan-Meier, Cox regression, and logistic regression analyses evaluated E-R relationships. Results: Analyses included 72 RAM and 35 PL pts from REGARD and 321 RAM+PAC and 335 PL+PAC pts from RAINBOW. Conclusions: Ram was safe and effective at 8 mg/kg q2w. Population PK suggests higher RAM exposures were associated with longer PFS and OS, better hazard ratios, and increased toxicity. Further studies to validate the PK model and evaluate RAM dosing are warranted. [Table: see text]

232 Background: REACH was a global, multicenter, randomized, double-blind, phase 3 study evaluating the efficacy and safety of RAM as a single agent for the treatment of pts with advanced HCC after prior sorafenib therapy. The primary outcome for REACH was presented at ESMO 2014. The overall survival (OS) HR for the ITT population (RAM 283; placebo [PBO] 282) was 0.866 (95% CI 0.717, 1.046; p=0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. The pre-specified subgroup analysis of baseline AFP (cutoff 400 ng/mL) suggested AFP is a predictive marker for RAM survival benefit. Methods: Pre-specified subgroup analysis was performed based on baseline AFP with a cutoff of 400 ng/mL. Additional analyses were conducted using stratified/unstratified cox regression models and corresponding log rank test to evaluate the relationship between baseline AFP and RAM treatment effect. Results: In 250 pts with baseline AFP ≥400 ng/mL (RAM 119; PBO 131), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059). Median OS was 7.8m for RAM vs 4.2m for PBO. In 417 pts with a baseline AFP ≥1.5 × upper limit of normal (ULN; RAM 205; PBO 212), mOS was 8.6m for RAM vs 5.7m for PBO and the HR was 0.749 (95% CI: 0.603, 0.930) (p=0.0088). The interaction testing of baseline AFP and RAM treatment effect on OS using both cutoffs (400 ng/mL and 1.5 xULN) are significant (p-value = 0.0272 and 0.0372, respectively). The safety profile in these pt populations was similar to that observed in the overall safety population. Additional REACH analyses demonstrating the predictive value of baseline AFP for RAM treatment effect on OS will be presented. Conclusions: A clinically meaningful improvement in OS was observed in populations with a baseline AFP ≥400 ng/mL or ≥1.5 × ULN. Additional analyses demonstrated a consistent RAM OS benefit for the pt population with baseline AFP over a wide range of values above the normal range. Baseline AFP is a likely predictive marker for RAM OS benefit. Clinical trial information: NCT01140347.

Transplacental exposure to carcinogenic air pollutants from the combustion of fossil fuels is a growing health concern, given evidence of the heightened susceptibility of the fetus. These mutagenic/carcinogenic pollutants include aromatic compounds such as polycyclic aromatic hydrocarbons that bind to DNA, forming chemical-DNA adducts. We have investigated the genotoxic effects of transplacental exposure in humans by analyzing aromatic-DNA adducts and the frequency of gene mutations at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in umbilical cord and maternal blood samples. Here we show, in a cross-sectional study of 67 mothers and 64 newborns from the Krakow Region of Poland, that aromatic-DNA adducts measured by (32)P-postlabeling are positively associated with HPRT mutant frequency in the newborns (beta = 0.56, P = 0.03) after controlling for exposure to tobacco smoke, diet, and socioeconomic status. In contrast to the fetus, HPRT mutations and DNA adducts do not reflect similar exposure periods in the mother, and the maternal biomarkers were not correlated. Adducts were higher in the newborn than the mother, indicating differential susceptibility of the fetus to DNA damage; but HPRT mutation frequency was 4-fold lower, consistent with the long lifetime of the biomarker. These results provide the first demonstration of a molecular link between somatic mutation in the newborn and transplacental exposure to common air pollutants, a finding that is relevant to cancer risk assessment.

X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD) are mainly involved in base excision repair (BER) and nucleotide excision repair (NER) of DNA repair pathways, respectively. Polymorphisms of DNA repair gene XRCC1 and XPD has recently been identified, and there is a growing body of evidence that these polymorphisms may have some phenotypic significance. To investigate the role of XRCC1 polymorphisms (codon 194 and codon 399) and XPD polymorphism (codon 751) in lung cancer, a population-based case-control study of 109 lung cancer patients and 109 healthy control subjects (individually matched on age and gender) in a Chinese population was conducted. XRCC1 and XPD genotypes were identified using PCR-restriction fragments length polymorphism technique. Conditional logistic regression analysis revealed that XRCC1 codon 194Trp/Trp genotype was associated with a borderline increased risk of lung cancer [adjusted odd ratio (OR) = 3.06; confidence interval (CI) 0.94-9.92]. The XPD 751 Lys allele (combined Lys/Lys and Lys/Gln genotypes) was associated with a significantly increased risk of lung cancer (OR = 3.19; CI 1.01-10.07). The risk of lung cancer increased more than additive interaction (adjusted OR = 8.77; CI 1.47-52.31) for the individuals with both putative high-risk genotypes of XRCC1 194 Trp/Trp and XPD 751 Lys allele. Our results suggested that the genotypes of XRCC1 194Trp/Trp and XPD 751 Lys allele might be the risk genotypes for lung cancer in Chinese population.

4057 Background: The REGARD trial demonstrated significant improvements in overall survival (OS), progression free survival (PFS), and disease control rates in pts receiving RAM, a human IgG1 recep...

Biomarkers such as DNA adducts have significant potential to improve quantitative risk assessment by characterizing individual differences in metabolism of genotoxins and DNA repair and accounting for some of the factors that could affect interindividual variation in cancer risk. Inherent uncertainty in laboratory measurements and within-person variability of DNA adduct levels over time are putatively unrelated to cancer risk and should be subtracted from observed variation to better estimate interindividual variability of response to carcinogen exposure. A total of 41 volunteers, both smokers and nonsmokers, were asked to provide a peripheral blood sample every 3 weeks for several months in order to specifically assess intraindividual variability of polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels. The intraindividual variance in PAH-DNA adduct levels, together with measurement uncertainty (laboratory variability and unaccounted for differences in exposure), constituted roughly 30% of the overall variance. An estimated 70% of the total variance was contributed by interindividual variability and is probably representative of the true biologic variability of response to carcinogenic exposure in lymphocytes. The estimated interindividual variability in DNA damage after subtracting intraindividual variability and measurement uncertainty was 24-fold. Inter-individual variance was higher (52-fold) in persons who constitutively lack the Glutathione S-Transferase M1 (GSTM1) gene which is important in the detoxification pathway of PAH. Risk assessment models that do not consider the variability of susceptibility to DNA damage following carcinogen exposure may underestimate risks to the general population, especially for those people who are most vulnerable.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: VEGF and VEGF receptor-2 mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 monoclonal antibody targeting VEGFR-2. We conducted a placebo-controlled, double-blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma progressing on 1st-line platinum- and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) or placebo (PL) every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Pts had disease progression within 4 months (m) after 1st-line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 12-wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were well balanced between arms. RAM significantly reduced all-cause mortality by 22% when compared to PL (Hazard Ratio [HR] for OS = 0.776; 95% CI, 0.603-0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The OS benefit for RAM appeared consistent across subgroups and after adjustment for other prognostic factors (multivariate HR = 0.774; 95% CI, 0.605-0.991). The HR for PFS was 0.483 (95% CI, 0.376-0.620; p < 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12-wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p < 0.0001). Use of anti-cancer therapy post-study: 32% RAM; 39% PL. The most frequent grade ≥3 AEs were: hypertension (7.6% RAM; 2.6% PL), fatigue (6.4% RAM; 9.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.9% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), decreased appetite (3.4% RAM; 3.5% PL), bleeding (3.4% RAM; 2.6% PL), and hyponatremia (3.4% RAM; 0.9% PL). Conclusions: Ramucirumab significantly prolonged survival in pts with advanced gastric or GE junction adenocarcinoma following progression on first-line therapy with an acceptable safety profile. These results validate VEGFR-2 signaling as a therapeutic target in gastric cancer. Clinical trial: [NCT00917384][1] Citation Format: Charles S. Fuchs, Jiri Tomasek, Jae Yong Cho, Dumitru Filip, Rodolfo Passalacqua, Chancal Goswami, Howard Safran, Lucas Vieira Dos Santos, Giuseppe Aprile, David Ferry, Bohuslav Melichar, Moustapha Tehfe, Eldar Topuzov, Josep Tabernero, John Raymond Zalcberg, Ian Chau, Minori Koshiji, Yanzhi Hsu, Jonathan Schwartz, Jaffer Ajani. REGARD: A phase III, randomized, double-blind trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line p [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-67. doi:10.1158/1538-7445.AM2013-LB-67 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00917384&atom=%2Fcanres%2F73%2F8_Supplement%2FLB-67.atom