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406 Background: Chemotherapy combined with inhibitors of VEGF signaling is associated with improved outcomes, but biomarkers of therapeutic benefit have been elusive. Cediranib (Ced) is an oral VEGFR tyrosine kinase inhibitor that has been investigated as a treatment for metastatic colorectal cancer (mCRC). Methods: 215 patients with progressive disease and no prior VEGF inhibitor therapy were enrolled in a randomized phase II study of FOLFOX + Ced 20mg/d, Ced 30mg/d or bevacizumab (Bev) 10mg/kg (Cunningham D, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4028). 36 CAFs were analyzed at 3 time points (baseline, wk 4, wk 8). Groups were dichotomized by median CAF value. Hazard ratios (HRs) were estimated from a Cox model with a single term. Results: Data were available for > 85% patients for each CAF. When pooled across all arms, several baseline CAFs including VEGF, interleukin (IL)-2Rα, IL-8 and PDGF were associated with improved PFS (Table). Low and high baseline CAF subgroups were evaluated for potential predictive CAFs. Pts with elevated baseline IL-8 did better with Ced 30mg/d than Bev (HR 0.6 for PFS, CI 0.3-1.0) while low IL-8 was associated with greater benefit from Bev than Ced (HR 2.1, CI 1.0 to 4.2). For Ced 20mg/d, PFS HRs were 0.9 (CI 0.5, 1.6) and 1.7 (CI 0.9, 3.2) for elevated and low baseline IL-8 respectively. Hepatocyte-growth factor (HGF) demonstrated a similar relationship, while a trend for the inverse association was seen with IP-10. Distinct patterns of cytokine modulation were seen between Ced and Bev during the 8 wks, including decreases of sVEGFR2, IL-13 and increases in osteopontin. Conclusions: Several potential prognostic factors for second-line mCRC therapy were identified including VEGF and IL-8. Further work in larger placebo-controlled studies is required to further evaluate predictive markers for VEGF signaling inhibitors. [Table: see text] [Table: see text]

Purpose: Diet and certain dietary supplements are postulated to influence the development and progression of prostate cancer. Angiogenesis and inflammation are central to tumor growth and progression, but the effect of diet on these processes remains uncertain. Procedure: We examined changes in 50 plasma cytokines and angiogenic factors (CAFs) in 145 men with prostate cancer enrolled in a pre-operative, randomized controlled phase-II trial with four arms: control (usual diet); low-fat (LF) diet; flaxseed-supplemented (FS) diet; and flaxseed-supplemented, low-fat diet. The mean duration of dietary intervention was 30 days. While two CAFS changed significantly in the FS arm (eotaxin and IL-16), 11 CAFs, including proangiogenic factors (vascular endothelial growth factor [VEGF], stromal-cell derived-1α) and myeloid factors (granulocyte-colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage-colony-stimulating factor) changed significantly in the LF arm compared to controls with virtually all of these factors decreasing. Results: Significant decreases in body mass index occurred in the LF arms and correlated with VEGF decreases (P Conclusions: Low-fat diets may reduce levels of specific inflammatory cytokines and angiogenic factors via the NF-κB mediated pathway. Citation Information: Cancer Prev Res 2010;3(12 Suppl):PR-09.

4522 Background: In a phase II RCC study of pazopanib (VEG102616) a response rate of 34.7% and disease control rate (CR + PR +SD) of 80% were observed (Hutson, JCO 2009). Previous analysis using AVANTRAT Biochips (Decision Biomarkers) in a subset of 129/215 patients (pts) with greatest versus least tumor shrinkage (TS) identified that lower baseline levels of plasma HGF, IL-6, and IL-8 were significantly correlated with greater TS, while elevated E-Selectin and lower IL-6 were associated with longer progression-free survival (PFS) (Heymach, ACCR-NCI-EORTC 2009). The validation was conducted using Searchlight (SL) (Aushon) and ELISA (EL) assays. Methods: Candidate markers (HGF, IL-6, IL-8, E-Selectin, and VEGF) were validated in 215 pts including the initial 129 pts. Spearman correlations were performed across the three platforms. CAF levels were correlated with maximum change from baseline in TS by linear regression; PFS by Cox regression; baseline tumor burden using baseline sum of longest tumor diameter...

Introduction: A Phase II RCC study (VEG102616) demonstrated activity with a response rate = 34.7% (CI 95%, 28.4 – 40.9) and disease control rate (CR + PR +SD) = 80% [ASCO 2008, #5046]. An analysis of plasma cytokines and angiogenic factors (CAFs) was undertaken with the objective of identifying patients who were the most likely to respond to pazopanib. Methods: A subset (n=129/217) of available plasma samples were selected based on extremes of tumor shrinkage from baseline. CAF levels were correlated with dichotomized tumor shrinkage (DTS) by logistic regression, with continuous tumor shrinkage (CTS) by linear regression, and with progression-free survival (PFS) by Cox regression. ROC analysis was performed using a stratified random sample of 97 patients in a training set and 32 pts in a test set. Results: Elevated levels of HGF, IL-8, and IL-6 were significantly correlated with less tumor shrinkage. Lower levels of E-Selectin and elevated IL-6 were associated with shorter PFS. ROC curve analysis for HGF resulted in an AUC of 0.668 with an optimal cutoff of 638.5 pg/ml. Using this cutoff, HGF-based predictions in the test set had an overall accuracy of 53%, positive predictive value of 67% and negative predictive value of 50%. Conclusion: CAF profiling showed that lower baseline levels of plasma HGF, IL-6, and IL-8 are correlated with greater tumor shrinkage in renal cell carcinoma pts treated with pazopanib. Also, elevated levels of E-Selectin and lower levels of IL-6 were associated with longer PFS. CAF1 p-value Fold Change2 Dichotomized HGF 0.006 Fold change: 1.3 Tumor Shrinkage IL-8 0.036 Fold change: 3.0 (Logistic regression) IL-6 0.039 Fold change: 1.5 TIMP1 0.047 Fold change: 1.2 Continuous HGF 0.029 Not Applicable - NA Tumor Shrinkage IL-8 0.048 NA (Linear Regression) IL-6 0.031 NA PFS (Cox Proportional E-Selectin 0.017 NA Hazards Model) IL-6 0.005 NA 1 The following CAF analysis were performed: Angio-10 (VEGF, VEGF-R2, ICAM-1, TIE-2, PLGF, TIMP-1, HGF, FGF basic, E-Selectin, and IL-8) and Cyto-8 (IL-1 beta, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12, TNF alpha) BIOCHIPS (Biomarker Workstation, Decision Biomarkers, Inc). Only the significant results were displayed above. 2 Fold change = (median CAF level for group with less tumor shrinkage) / (median CAF level for group with greater tumor shrinkage). Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A11.

e19015 Background: Lung cancer is the leading cause of cancer-related deaths. Better systemic therapies are needed. One potential therapeutic target is c-Src which is expressed and activated in NSCLC patient tumors where it can mediate invasion, angiogenesis, and proliferation. Additionally, epidermal growth factor receptor (EGFR) and c-Src cooperate to promote NSCLC survival. We are conducting a phase II study of dasatinib, a tyrosine kinase inhibitor of c-Src, Abl, c-Kit, PDGFR, Btk, and EphA2. The primary objective is to determine the rate of progression free survival at 12 weeks in patients with metastatic NSCLC treated with dasatinib as front line therapy. Methods: Patients with metastatic NSCLC were treated with dasatinib (100 mg BID), with PET/CT scans every 6 weeks. KRAS and EGFR mutations, EGFR copy number, and pSrc expression were measured in pre-treatment biopsies. Blood was collected pretreatment and on day 21 to measure drug exposure (PK), pharmacodynamics (PD), and serum cytokine levels. Results: Twenty five patients have enrolled on study. Of the 16 patients evaluable for response: 1 had a partial response (PR) with no evidence of recurrence for at least 18 months (male smoker with adenocarcinoma and KRAS mutation); 6 patients had stable disease (SD) which includes 3 patients with prolonged stable disease for 4, 6, and 18 months; 9 had progressive disease (PD). Only 4 patients had a significant change in SUV (>25%): decreased in 2 with PR and SD and increased in 2 with PD and SD. There is currently no clear association between EGFR and KRAS mutational analysis and response, although the sample number is small. Only 2 patients have activating EGFR mutations: one with SD and one with PD. PK, PD, and cytokine data will be presented. The most common grade 3/4 toxicity is dyspnea/pleural effusion that has led to a reduced dasatinib starting dose in subsequent patients. Conclusions: Dasatinib as a single agent has activity in a subset of patients with NSCLC. Planned correlative studies may lead to the discovery of biomarkers that predict response. Toxicities observed were consistent with prior dasatinib phase I studies in solid tumor patients. Supported by NCI/CTEP (NIH contract N01-CM-62202), The Commonwealth Foundation for Cancer Research and Bristol-Myers Squibb. [Table: see text]

5114 Background: SR, an oral inhibitor of Raf kinase, RET-receptor (R), VEGFR-1, 2, and 3, PDGFR-β, FLT-3, and c-KIT tyrosine kinases, has been shown to prolong progression-free survival (PFS) in mRCC after cytokine failure. In a phase II trial, mRCC pts were randomized to first line treatment with SR vs. SR plus interferon (IFN) to assess whether combination therapy improved PFS. Both treatment arms showed similar outcomes (Tannir et al, ASCO. 2008). Here we investigated predictive and prognostic biomarkers in plasma. Methods: Pts received SR 400 mg PO BID or same dose SR plus IFN 0.5 MU SC BID. Plasma was collected from 69 pts at baseline (BL; SR 34, SR+IFN 35), 59 on day (D) 28, and 57 pts on D56. We used multiplex bead suspension arrays to measure concentrations of 54 CAFs, including VEGF, PDGFbb, EGF, HGF, MMP-9, and multiple chemokines and interleukins (IL). Osteopontin (OPN), soluble carbonic anhydrase 9 (sCA9), placental growth factor (PlGF), collagen type IV (ColIV) and sVEGFR-2 were measured by ELISA. The primary objective of this analysis was to establish a CAF signature based on a set of individual markers at BL with a significant and differential impact on the association between treatment arm and PFS. Results: Among 52 CAFs available at BL, higher than median EGF concentrations associated with poor outcome independently of treatment arm, whereas low IL-2 had the opposite effect (p = 0.003 for both). Only OPN showed a significant treatment by factor interaction at BL (p < 0.01), suggesting that OPN has a differential effect on PFS in the two arms. Pts with high OPN benefitted more from single agent SR (7.74 vs. 3.93 mos for the combination; p = 0.007), but no differences were found for those with low OPN. Lower than median on-treatment increases in sCA9 (D28, p = 0.01) and GRO-alpha (D56, p = 0.04) on SR only were also associated with a better outcome. A 6-marker CAF signature at BL containing OPN, sCA9, VEGF, sVEGFR-2, ColIV, and TRAIL demonstrated predictive value on PFS. Conclusions: A CAF signature showed potential value in predicting differential benefit from single agent SR vs. SR+IFN in mRCC. Broad-based screening of circulating CAFs may identify predictive and prognostic biomarkers in the context of clinical trials. [Table: see text]

9596 Background: A randomized phase II trial (JCO 26:5407–15, 2008) compared carboplatin-paclitaxel (CP) with vandetanib (VEGFR-EGFR inhibitor) monotherapy (V) and V plus CP (VCP) 1st-line for advanced NSCLC (N=181). PFS was superior for VCP vs CP (HR 0.76). We performed analyses of quality of life (QOL) and its correlations with plasma concentrations of cytokines and angiogenic factors (CAF) among the participants in this trial. Methods: QOL was serially measured by Functional Assessment of Cancer Therapy-Lung (FACT-L) and Trial Outcome Index (TOI) scores. Concentrations of 35 plasma CAFs were measured at baseline and multiple timepoints during treatment with multiplexed bead suspension arrays and ELISAs. We performed exploratory analyses for the following associations: (1) QOL with plasma CAF levels at baseline; (2) changes in QOL with changes in plasma CAF levels. Spearman correlation coefficient, log-rank test and mixed linear models were applied in the analyses. P-value < 0.05 was considered significant. Results: Baseline QOL and plasma samples were both available for 120 patients. Lower baseline FACT-L scores (inferior QOL) were associated with higher pre-treatment plasma levels of INF-γ, IL-1RA, IL-6, IL-12, IL-15, TNF-α, RANTES, MIG, MIP-1β, MMP-9, bFGF, VEGF and sVEGFR-2 (all P [Table: see text]

7568 Background: Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR and c-kit. In a single-arm phase II trial (NCT00367679; VEG105290), patients received pazopanib 800 mg QD for 2–6 weeks before scheduled surgery. Tumor volume measurements were performed using high resolution CT images before and after treatment. An exploratory analysis was planned to describe the modulation of C/AFs during pazopanib treatment and identify potential predictive plasma markers. Methods: Plasma samples were collected pre- treatment and on the last day of pazopanib dosing. Levels of 52 C/AFs were measured by suspension bead multiplex assays (BioRad) or ELISA. Results were correlated with change in tumor volume. Statistical analyses included Wilcoxon tests and Pearson correlation tests. Results: 19 paired samples have been analyzed. Pazopanib treatment was associated with a significant modulation of 13 C/AFs, including a decrease in soluble VEGFR-2 (p

8008 Background: We previously developed a serum Matrix-Assisted Laser Desorption/Ionization- Time of Flight Mass Spectrometry (MALDI-TOF MS) proteomic algorithm (VeriStrat) that can reliably predi...

8010 Background: In the first phase of BATTLE clinical study, 72 pts with advanced, previously treated NSCLC were characterized into one of four biomarker groups (BGs) based on their pre-treatment tumor biomarker profile. BGs included the following: EGFR (mutation & gene copy number), angiogenesis (VEGF and VEGFR-2 by IHC), K-ras/B-raf mutations and RXR/Cyclin D-1 (IHC and gene copy number). We performed exploratory analysis of plasma levels of 59 C/AFs to investigate potential correlation with pathway activation from pretreatment tumor specimens. Methods: 62/72 pts consented to the optional blood collection for C/AF analysis. We used multiplex bead assays to measure 53 plasma C/AFs, including VEGF, basic FGF, HGF, E-selectin, MMP-9, multiple chemokines and interleukins (IL). Total and free IGF-1, IGFBP-3, osteopontin (OPN) and sVEGFR-1&2 were measured by ELISA. To evaluate the association between plasma C/AFs and pretreatment tumor markers, Wilcoxon test was performed. Results: A significantly higher sco...

5093 Background: Sorafenib was shown to significantly prolong progression-free survival (PFS) in pts with mRCC after cytokine failure. We have previously shown that low-dose interferon alfa (IFN-α)...

7593 Background: VAN (ZD6474) is an oral inhibitor of VEGFR, EGFR and RET. In a phase II trial, 181 patients with advanced NSCLC were randomized to 1st-line treatment with VAN, CP or VAN + CP. Progression free survival (PFS) was prolonged for VAN + CP vs CP (Heymach et al, submitted for ASCO 2007). Exploratory subgroup analyses suggest gender differences in PFS benefit for VAN + CP vs CP (HR 0.47 in females vs 1.05 in males). We performed exploratory analyses of plasma levels of 35 C/AFs to investigate gender differences and potential prognostic or predictive markers. Methods: Plasma was collected at baseline (n = 123; VAN 55, CP 32, VAN + CP 36), day (D) 8 (n = 104), D22 (n = 95), and D43 (n = 83). We used multiplex bead assays to measure 33 plasma C/AFs, including VEGF, basic FGF, EGF, HGF, E-selectin, ICAM-1, MMP-9, multiple chemokines and interleukins (IL). Osteopontin and sVEGFR-2 were measured by ELISA. Cox models were applied on PFS to identify prognostic/predictive markers after rank transformation and adjusted for covariates. Results: Significant gender differences in baseline C/AF levels were seen for IL-15, IL-1RA, IL-2R, MIG, and MIP-1A (all higher in females, all p = 0.022). Controlling for gender and treatment, high baseline E-selectin (p = .01), IL-6 (p = 0.018), and IL-2R (p = 0.008) were adverse prognostic indicators for PFS. Controlling for gender, the tests for treatment by factor interactions (to assess whether treatment effect was different in patients with low and high C/AF levels) were significant for baseline HGF (p = 0.04) and IL-2R (p = 0.008). For both HGF and IL- 2R, low levels were associated with prolonged PFS in the VAN arm, but were not associated with differences in the CP or VAN + CP arms. Significant changes in VEGF (rise) and sVEGFR-2 (decrease) occurred with treatment in the VAN arm; IL12, IL-1RA, MMP-9 and MCP-1 changed in the CP and VAN + CP arms. Conclusions: There are gender differences in PFS benefit from VAN and in plasma C/AF profile. Several C/AFs were of prognostic value, whereas low HGF and IL-2R were predictive of benefit in the VAN but not CP and VAN + CP arms. These gender differences and markers warrant further investigation. [Table: see text]

3079 Background: Targeted therapeutics are highly promising in combination because they are both well tolerated and interact with the signals that cause cancer. We propose a direct functional scree...

7022 Background: A multicenter phase I/II study found that inhibition of VEGF and EGFR with the combination of bevacizumab and erlotinib had significant antitumor efficacy in NSCLC, including activ...

1005 Background: High level of IGF-I is associated with increased susceptibility for several types of cancer, whereas high levels of IGFBP-3 and vitamin E tend to attenuate the risk. This study was...

7257 Background: SCLC cell lines commonly express c-kit and its ligand, suggesting an autocrine loop promoting cell growth. IM inhibits c-kit kinase activity. SCLC cells treated with IM in vitro undergo cell cycle arrest. In this study we investigated the feasibility of combining IM with cytotoxic chemotherapy for extensive disease SCLC. Methods: Six patients received P (30 mg/m2) and I (65 mg/m2) on days 1 and 8 every 21 days for four cycles. IM (300 mg) was given daily during chemotherapy and then as maintenance until progression of disease. Immunohistochemistry (IHC) for potential IM targets was done on patients' pre-treatment biopsies. Results: The first 3 patients experienced significant neutropenia that required GCSF support. One patient died during treatment from neutropenic fever. GCSF was added prophylactically to the subsequent 3 patients who did not experience significant neutropenia. Five patients had grade 2 diarrhea and one had grade 3 diarrhea. One patient had a deep vein thrombosis. This p...

2050 Background: Erlotinib is a novel, oral EGFR-TKI that has demonstrated activity as a single agent in pts with advanced NSCLC. Preclinical studies have shown additive efficacy when E was combine...

Endostatin is a novel antiangiogenic agent currently in phase I trials. In the context of this trial, we are evaluating the use of non-invasive imaging with PET to determine the relationship between tumor blood flow and glucose metabolism in imaged tumors from treated patients.Ten patients have been treated with escalating daily iv Endostatin doses of 30 to 180 mg/m(2). PET images were obtained before the start of therapy and again after 28 days of treatment. Each patient was scanned with Oxygen-15 labeled water for estimation of tumor blood flow and Flourine-18 labeled FDG to estimate tumor metabolic activity. In most cases, two distinct tumor-bearing sites were analyzed in each patient. Thus, a total of 19 tumors were imaged. Regional blood flow and standard uptake values (SUV) were computed at baseline and 28 days post treatment and the percentage change in blood flow and SUV plotted as a function of Endostatin dose.Both blood flow and glucose metabolism in the imaged tumors were observed to increase in patients treated with

The purpose of this study was to determine if the first-pass of FDG can be used to measure regional blood flow in tumors in the absence of perfusion imaging with a known blood flow tracer. PET scans were obtained in patients being evaluated for tumor perfusion and metabolism in a Phase I dose escalating protocol for Endostatin, a novel antiangiogenic agent. A two minutes perfusion scan was done with a bolus injection of 60 mCi of O-15 labeled water followed by a 10 mCi dose of FDG and four sequential scans consisting of a first pass two minutes scan and three 15 minutes scans. Regions of interest were drawn on two tumor sites for each scan. Blood flow was computed using a one-compartment model previously published by the authors. Linear regression analysis was carried out between the first pass FDG measured blood flow and O-15 measured blood flow (Figure 1) Download : Download high-res image (49KB) Download : Download full-size image Figure 1 . . Blood flow estimated from the first pass of FDG was linearly correlated with O-15 measured blood flow with an intercept of 0.01, slope of 0.86, and r squared regression coefficient of 0.74 (R = 0.86) for blood flow values of up to 0.6 ml/min/gm of tissue. These results suggests that in the absence of a perfusion tracer, the first pass of FDG provides an estimate of perfusion in a tumor within the limitations of incomplete extraction of FDG compared to O-15 water.

The unpredictable intestinal absorption and erratic bioavailability of oral busulfan (Bu) has limited the drug's use in high-dose pretransplantation conditioning therapy. To standardize drug delivery, we solubilized Bu for parenteral use. This new intravenous (i.v.) Bu formulation was combined with oral Bu and cyclophosphamide (Cy) to evaluate (1) the human acute toxicity of i.v. Bu and its solvent system and (2) the pharmacokinetics of Bu in patients undergoing hematopoietic progenitor cell transplantation (HPCT). One dose of i.v. Bu (escalating from 0.08 to 0.8 mg/kg) was given over 2 hours by pump; 6 hours later, an oral Bu regimen was begun, consisting of 1 mg/kg every 6 hours for 15 doses, followed by Cy, 60 mg/kg daily for 2 days. After 1 day of rest, HPCT was performed. The i.v. Bu dose was well tolerated and did not produce any acute toxicity reaction that could be attributed to the solvent system of dimethylacetamide and polyethylene glycol (PEG)-400. All observed treatment-related toxicity was as would be expected after high-dose oral Bu plus Cy. When the i.v. Bu was used as reference solution, the pharmacokinetic analysis indicated an average bioavailability of oral high-dose Bu of 69%, ranging from

Background On 30 January 2012, the US FDA approved vismodegib (Erivedge®, Genentech, CA, USA) for the management of both metastatic and locally advanced basal cell carcinoma. Objective Our objective was to identify evidence of hepatotoxicity with vismodegib in the FDA Adverse Event Reporting System (FAERS) in treated patients in two National Cancer Institute Comprehensive Cancer Centers. Methods FAERS was searched for reports dated 1 January 2009 through 31 December 2015 using terms including hedgehog pathway and vismodegib and hepatic-related terms such as liver, jaundice, and hepatitis, among others. Disproportionality analyses with estimates of proportional reporting ratio and empirical Bayesian geometric mean were conducted. A comprehensive literature review was conducted, and the clinical databases at the University of Texas MD Anderson Cancer Center and Robert H. Lurie Comprehensive Cancer Center of Northwestern University were searched. Results Two cases of severe liver dysfunction were published (Common Terminology Criteria for Adverse Events [CTCAE] class III), and 94 reports of adverse events (AEs) were detected in FAERS, 35 of which were serious AEs. Safety notifications related to hepatotoxicity have not been issued by the manufacturer or the FDA, although vismodegib is listed in LiverTox and the European Medicines Agency website. Conclusion We identified a detectable safety signal for hepatotoxicity for vismodegib within 4 years of FDA approval. Vismodegib should be used in patients with severe liver disease only after careful consideration, and concomitant hepatotoxic medications should be avoided. Rapid dissemination of such safety concerns is expected to result in fewer serious hepatotoxic AEs and more optimal outcomes for patients with cancer receiving vismodegib. Electronic supplementary material The online version of this article (doi:10.1007/s40268-016-0168-2) contains supplementary material, which is available to authorized users.

4042 Background: T is a reversible and highly selective allosteric inhibitor of MEK1/MEK2. The addition of T to G did not improve overall survival (OS) as first-line treatment for pts with metastatic adenocarcinoma of the pancreas (ASCO GI 2013 #291). CAF profiles have shown potential for identification of prognostic and predictive markers in cancer pts (Tran, Lancet, 2012). Methods: Plasma samples (n = 144 baseline [BL]; n = 112 day 15) from pts who consented to participate in MEK113487 study were analyzed for 30 CAFs (ANG2, IGFBP3, IL2R, IP10, MMP2, MMP9, OPN, PDGFBB, SCF, TIMP1, IL6, MIP1B, SDF1, TRAIL, VEGF, MIP3A, MCP2, FGFB, IL8, VEGFR1, IL10, IL1A, IL12P40, PIGF, EGF, IL1B, TNFA, IL4, MIP1A, MCP3) using SearchLight multiplex assays in a CLIA-certified laboratory. Change from BL was assessed using either paired t tests or Wilcoxon tests. BL and change from BL CAF levels were tested for association with clinical outcome using proportional hazards regression within arm (P < .01 for significance) and between arms (treatment arm by CAF level interaction, P < .05 for significance). Results: Lower levels (< median) of BL ANG2, IL6, TIMP1, and IL8 were associated with an average of 5 mo longer OS in both the T+G and G arms. Lower BL levels (less than first quartile) of IGFBP3 and PDGFBB were associated with 6 mo longer OS in the T+G arm, while higher levels (greater than third quartile) of IGFBP3 and PDGFBB were associated with 4.8 mo longer OS in the G arm. A combined model of low IGFBP3 and/or PDGFBB showed improved survival for T+G vs G (median OS, 10.3 vs 5.6 mo). Decreases of ANG2 and IL2R levels at day 15 from BL were observed in the T+G arm only; additional results will be presented. Conclusions: This study suggests that plasma CAF profiling may aid in the prognostic evaluation of pts, assessing therapeutic response, and identifying pathways modulated by treatment in pancreatic cancer pts. Low IGFBP3 and PDGFBB may identify patients who receive greater benefit from T+G compared with G in this population and merit further investigation as predictive markers. Clinical trial information: NCT01231581.

8532 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) are being explored in resectable non-small cell lung cancer (NSCLC). Here, we studied the composition and changes in the T cell repertoire in a cohort of NSCLC patients (n = 44) treated with neoadjuvant nivolumab (N) alone or in combination with ipilimumab (NI) followed by surgery (NEOSTAR trial). Methods: Sequencing of the variable CDR3β chain of the T cell receptor (TCR) involved in antigen binding was performed in pre-treatment and surgical tumors, matched adjacent uninvolved lung specimens, as well as paired longitudinal blood at baseline, prior to each dose of therapy, prior to surgery, and within 8 weeks post-surgery. T cell repertoire density, diversity, and clonality (reactivity) were evaluated in addition to tumor PD-L1 expression pre- and post-neoadjuvant treatment. Results: Median T cell diversity in the blood post-therapy was 3.3-fold higher in NI- compared to N-treated patients (40,993 [NI, n = 3] vs 12,177 [N, n = 4] unique TCR rearrangements, n.s.). However, median T cell clonality in the blood was 3.5-fold higher in N- than NI-treated patients post-therapy (0.093 [N, n = 4] vs 0.026 [NI, n = 3], n.s.). Median clonality was 3.8-fold higher in the tumor post-therapy in patients receiving NI than in those receiving N (0.076 [NI, n = 7] vs 0.020 [N, n = 5], n.s.). Interestingly, diversity in the blood at baseline and in the tumor post-therapy were positively correlated ([n = 7], r = 0.82; p = 0.023), which may reflect an influx of cells from the periphery following ICIs. Importantly, higher baseline T cell clonality in the blood was associated with a lower % of viable tumor at time of surgery in both treatment arms ([n = 7], r = -0.77; p = 0.04). Conclusions: Our study is the first to assess the TCR repertoire in NSCLC patients treated with combination neoadjuvant NI and highlights potential mechanistic differences compared to N alone. Neoadjuvant NI is associated with higher clonality in tumors and lower clonality in blood post-therapy, suggesting increased T cell trafficking into the tumor. Finally, lower pre-treatment clonality in the periphery was correlated with higher % viable tumor post-neoadjuvant ICIs. Clinical trial information: NCT03158129.