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e18118 Background: In vitro and in vivo studies have demonstrated the antiproliferative effects of 1, 25 (OH)2D3 (calcitriol) as single agent and antitumor synergy with cisplatin. The goals of this Phase I/II study were to determine the maximum tolerated dose (MTD) of 1, 25 (OH)2 D3 in combination with cisplatin and docetaxel, and to evaluate the efficacy in patients (pts) with metastatic NSCLC.Methods: The study was a multicenter, open-label study in pts with metastatic NSCLC. Pts were adults 18 yrs., PS 0-1 with normal liver/kidney function. For the phase I study, pts (3–6 per cohort) received 1, 25 (OH)2 D3 I.V. every 21 days prior to docetaxel and cisplatin. The starting dose of 1,25 (OH)2D3 was 15 mcg/m2 at sequential ascending dose levels (DL) (15, 30, 60 and 80 mcg/m2) using a 3+3 design targeting a dose-limiting toxicity (DLT) rate of 2 and cisplatin 75mg/m2 following 1, 25 (OH)2 D3 for 4 cycles. We analyzed SNPs in the CYP24A1 gene.Results: 37 pts were enrolled (16 in phase I and 21 in phase II) with a median age of 54 (range 34–79) yrs.; M: F, 12:17. At the 80 mcg/m2 dose level, 2/4 pts had DLT of grade 4 neutropenia. There were no cases of hypercalcemia or azotemia. The MTD and recommended Phase II dose was 60 mcg/m2. Among 6 response-evaluable Phase I pts, and 21 phase II pts, there were: 2 confirmed partial responses (PR), 6 unconfirmed PRs and 10 pts with stable disease. The median time to progression was 6.9 months (95% CI 4.4, 12.9) and the median overall survival was 8.3 months (95% CI 5.8, 14.9). Of the CYP24A1 SNPs, the IVS4-308C>G was associated with progressive disease (Chi-Square=0.0062)Conclusions: The MTD of 1,25 (OH)2D3 in combination with docetaxel and cisplatin was 60 mcg/m2 IV every 21 days. Pre-specified endpoint of a 50% response rate was not met in the phase II study. However, disease control in 66% of patients argues for further study of 1,25 (OH)2D3 as maintenance therapy. The CYP24A1 polymorphism IVS4-308C>G may be associated with resistance to a 1,25 (OH)2D3 based therapeutic regimen

Background: The Epithelial-Mesenchymal Transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis. EMT cells have stem cells properties and possess the characteristics of cell motility, invasiveness and chemotherapy resistance. EMT expression profile correlates with poor outcome in multiple tumors and there is evidence suggesting an integral role of Notch pathway in mediating EMT. In this study, we investigated Notch activity and EMT status and the correlation with chemoressitance in non-small cell lung cancer (NSCLC). Results: Transduction of multiple NSCLC cell lines, NCI-H1299, NCI-H460, NCI-H358, NCI-H441 with a Notch GFP-reporter construct identified a subset of cells with high Notch activity (GFP-pos). We compared the tumor invasivness capacity of GFP-pos and GFP-neg cells utilizing a transwell invasion assay. Cells with high Notch activity, as evidenced by GFP expression, had multiple fold higher invasion capability compared to GFP-neg cells (p=0.0001). To evaluate whether Notch activity correlates with resistance to chemotherapy, we treated GFP-pos and GFP-neg cells with docetaxel or cisplatin and assessed Annexin V expression using flow cytometry. GFP-pos cells had five fold less apoptotic cells as compared to GFP-neg cells indicating resistance of GFP-pos cells to chemotherapy. When GFP-pos cells were exposed to a Notch signaling inhibitor inhibitor, gamma secretase inhibitor (GSI), these cells were rendered sensitive to cisplatin and docetaxel. RNA microarray analysis and RT-PCR analysis revealed an increased expression of EMT related genes (Vimentin, N-Cadherin, Snail-1,….) in GFP-pos cells as compared to GFP-neg cells. Furthermore, NOD/SCID mice with subcutaneous lung tumor xenografts treated with GSI showed decreased expression of downstream effectors of Notch as well as vimentin. This combination of GSI and docetaxel reduced tumor grwoth in mouse xenographs compared to GSI and docetaxel as single agents. Conclusion: These studies suggest that the Notch pathway is an important regulator of EMT status and that its inhibition may alter EMT chemo-resistance properties. The addition of a Notch inhibitor may enhance the efficacy of chemotherapy in the treatment of NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3309. doi:1538-7445.AM2012-3309

Purpose/Objective(s): A recent analysis from 7 RTOG trials suggested that patients treated more than 63 Gy in 1.8 - 2 Gy fractions was significantly associated with better outcome. This study aims to examine whether higher dose (.70 Gy) through personalized prescription can further improve local regional tumor control and overall survival, particularly in patients treated with concurrent chemotherapy. Materials/Methods: This is a secondary analysis of prospective trials from one single Institution. Patients received a definitive dose of fractionated RT, enrolled in imaging and treatment trials, with a minimum follow-up of 6 months were eligible. For the imaging trial,subjectswere treated per standard practice(60 - 70Gy) with or without concurrentchemotherapy basedon the stage of the diseases. For the treatment protocol, all subjects had an opportunity of receiving individualized higher dose RT based on the timing of treatment, and dosimetry of OARs (mainly the normal tissue complication probability of both lungs). Tumor local regional and distant progression free and overall survival (LRPFS, DPFS, and OS) were computed for tumor control outcome assessment. Results: A total of 85 consecutive patients treated between 2004 and 2010 were eligible. The median physical dose was 70 Gy (range60-86Gy)in2to3.8Gydailyfractionations.MinimumFUforsurvivalptswas6months.TheRTdosesweresignificantly associated with LRPFS,DPFS and OS,with hazard ratios of 0.92 (P=0.001),0.94 (P=0.016) and 0.91 (P=0.001),respectively. The median LRPFS (95%CI) was 9.9 (7.5, 12.4) and not reached (not reached) months (P\0.001), for PD\and .70 Gy, respectively. In patients with ‘‘no’’ chemotherapy, median LRPFS was 8.3 (5.8, 10.8) and not reached (P =0.2), for PD\70 Gy and.70 Gy, respectively. For patients treated with concurrent chemotherapy, median LRPFS was 10.7 (8.4, 13.0) months and not reached (not reached) months (P = 0.001), for PD\70 Gy and .70 Gy, respectively. The median OS (95%CI) was 18.2 (10.9, 25.4) and 41.9 (20.6, 63.1) months (P = 0.003), for PD\and .70 Gy, respectively. In those with ‘‘no’’ chemotherapy, median OS was 18.2 (0, 38.6) and not reached (P = 0.443), for PD\70 Gy and .70 Gy, respectively. For patients treated with concurrent chemotherapy, median survival was 15.5 (6.5 - 24.4) and 41.9 (18.3 - 65.5) months (P = 0.003), for PD\70 Gy and .70 Gy, respectively. Using 74 Gy PD (75 percentile of dose) as a cut-off, the median OS and LRPFS were also significantly better in the higher dose group (\74 Gy vs. $ 74 Gy). Conclusions: High dose (.70 Gy) RT improves local regional tumor control and overall survival in patients with and without concurrent chemotherapy. Randomized trials are needed to validate this promising result.

7537 Background: Aggressive EOL cancer care is a health care quality and cost issue. As lung cancer is the leading cause of cancer-related death in the U.S., and NCCN member institutions are consid...

Background: The cancer stem cell hypothesis postulates that tumors contain a subset of cells with stem cell properties that can initiate and recapitulate original tumor heterogeneity in serial xenotransplantation assays. A number of developmental signaling pathways, including Notch, have been implicated in regulating stem cell properties of self-renewal and differentiation. In this study, we investigated the role of Notch activity in lung cancer stem cells utilizing a Notch GFP-reporter construct and a gamma secretase inhibitor (MRK003), which inhibits the activation of Notch through preventing the cleavage of its intracellular domain (NICD). Results: Transduction of lung cancer cell line NCI-H1299 with a Notch GFP-reporter construct identified a subset of cells with high Notch activity (GFP-positive). We compared the tumor initiating capacity of GFP-positive and -negative cells and only cells with high Notch activity, as evidenced by GFP expression, were tumorigenic in serial transplantation assays in NOD/SCID mice. Furthermore, GFP-positive cells were capable of generating both GFP-positive and GFP-negative cell populations. In contrast, GFP-negative cells generated primary xenograft tumors only and failed to generate the GFP-positive population or secondary tumors in serial xenotransplantation. Furthermore, a single GFP-positive cell but not a GFP-negative cell was able to generate a xenograft in NOD/SCID mice. In vitro, the gamma secretase inhibitor MRK003 induced cell cycle inhibition and apoptosis in lung cancer cell lines NCI-H1299, NCI-H460, NCI-H358, and NCI-H82. To determine the specificity of MRK003, we introduced NICD expressing vectors that rescued the effects of MRK003, thus demonstrating a direct role in Notch inhibition. MRK003 treatment of mice with lung tumor xenografts (100mg/kg, 3 days per week) decreased the expression of downstream effectors of Notch. Furthermore, cells derived from MRK003 treated tumors failed to induce tumors upon secondary reimplantation in NOD/SCID mice, consistent with effects of this treatment on the cancer stem cell population. Utilizing multivariate analysis, we assessed the association of Notch pathway components with clinical outcome of 441 lung adenocarcinoma patients. We found a statistically significant correlation between poor overall survival and increased Notch ligands expression (p=0.042) or decreased expression of negative modulators (p=0.00016). Conclusion: These studies suggest that the Notch pathway is an important regulator of lung cancer stem cells and that its inhibition may specifically target the cancer stem cell population. The correlation between Notch pathway activation and patient survival, suggests a potential role for gamma secretase inhibitors in the treatment of lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 496. doi:10.1158/1538-7445.AM2011-496

7634 Background: The NCCN Clinical Practice Guidelines (GL) allow many systemic therapy options for patients (pts) with mNSCLC. The primary aims of this analysis were to identify first-line regimens for the treatment of mNSCLC pts and examine concordance with NCCN NSCLC GL. Methods: The database was queried to identify pts with mNSCLC treated with first-line systemic therapy at 8 NCCN institutions presenting between September 2006 and March 2009. Pt characteristics, regimens utilized, and GL concordance were analyzed. Systemic therapy was categorized as cytotoxic doublet (CD), combination cytotoxic/targeted therapy (C/T), targeted therapy alone (T), or cytotoxic single agent (SA). Results: A total of 983 eligible pts were identified, as follows: 51% male; median age 64 years; performance status (PS) was documented in 77% (82% PS 0 or 1; 11% PS 2; 7% PS 3 or 4). There were 729 pts (74%) treated with systemic therapy, 123 (17%) of which participated in a clinical trial. Most common reasons for not receiving...

e17509 Background: Esophageal uptake of FDG is commonly seen in patients with non-small cell lung cancer (NSCLC), but the relationship of the uptake to radiation esophagitis has not been delineated...

e18041 Background: The prognosis for patients (pts) with ES SCLC is poor, with a median progression-free (PFS) and overall survival (OS) of 5 mo. and 9 mo., respectively. This trial was designed to evaluate the efficacy/toxicity of maintenance sunitinib after platinum-based chemotherapy in pts with ES SCLC. Methods: Treatment consisted of cisplatin 75 mg/m2 IV or carboplatin AUC 5 on day 1 plus etoposide 100 mg/m2 IV on days 1-3 every 21 days for 4 cycles. If no evidence of disease progression was identified, sunitinib was given at 50 mg orally QD for 4 wks of a 6-wk cycle continuously until disease progression or unacceptable toxicity. The primary endpoint was proportion of pts progression-free 4 mo. after starting sunitinib. Treatment was deemed not interesting if the 4-mo. PFS rate after starting sunitinib was < 35%; target enrollment of 21 pts in first stage. Results: 16 pts were enrolled: median age 66 yrs (range 34-80); 8 men: 8 women; PS 0/1/2 = 5/10/1. Responses to platinum/etoposide were CR/PR/SD...

2528 Background: Vorinostat is an inhibitor of histone deacetylase 6, which results in the acetylation of tubulin and the stabilization of microtubules. Since taxanes bind to stabilized microtubules, the administration of vorinostat followed by docetaxel, we hypothesized, should result in synergistic cytotoxicity. A phase I trial was conducted to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in ≤ 30% of patients (pts). Methods: Eligible pts had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after ≥1 prior chemotherapy regimen not containing docetaxel, a performance status of 0–2 and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle. Docetaxel was given intravenously over 1 hour on day 4. The time-to-event continuous reassessment method guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m2, respectively. Blood was collected on days 1 and 4 of cycle 1 to measure drug levels by HPLC. Results: 12 pts were enrolled: median age 65 yrs (49–74); gender 9M:3F; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles was 2. 2 pts were treated at DL -1, 4 pts at DL 0, 5 pts at DL 1 and 1 pt at DL 2. 5 DLTs occurred in 5 pts: grade 4 neutropenic fever/sepsis (n = 2), anaphylactic reaction (n = 1), myocardial infarction (n = 1) and GI bleed (n = 1). Other toxicities included grade 4 neutropenia (n = 2), pulmonary embolus (n = 1) and GI bleed (n = 1). The estimated probability of DLT for DL -1 was .32 (90% posterior probability interval [PI], .11 to .53) for DL 0, .38 (90% PI, .16 to .58) and for DL 1, .43 (90% PI, .23 to .64). The trial was stopped due to excessive toxicity. No responses were noted. Conclusions: Combination vorinostat plus docetaxel was poorly tolerated with excessive DLTs requiring study termination. PK analysis will be presented. Supported in part by a grant from Merck & Co., Inc. [Table: see text]

22177 Background: Although Transforming growth factor-beta (TGF-β) is a key player, radiation-induced lung toxicity (RILT) involves numerous cytokines of multiple pathways. We hypothesized that TGF...

7548 Background: We hypothesized that the radiation induced elevation of transforming growth factor β1 (TGF-β1) during radiation therapy (RT) correlates with radiation-induced lung toxicity (RILT) ...

17089 Background: The prognosis for patients (pts) with ES SCLC is poor, with a median survival of 9 mo. This trial was designed to evaluate the efficacy and toxicity of cisplatin plus irinotecan followed by maintenance imatinib (Gleevec) in pts with c-kit positive ES SCLC. Methods: Immunohistochemistry for c-kit was performed on paraffin-embedded tissue prior to enrollment. Treatment consisted of irinotecan 65 mg/m2 IV on days 1 and 8 plus cisplatin 60 mg/m2 IV on day 1 repeated every 21 days for 4 cycles. If no evidence of disease progression was identified, Gleevec was given at 400 mg orally BID until disease progression or unacceptable toxicity. Results: 14 pts have been enrolled: median age 61 yrs (range 47–73); 9 men: 5 women; PS 0/1/2 = 3/10/1. 6 pts did not begin Gleevec due to disease progression (4), persistent grade 3 emesis (1), and referral for radiation therapy (1). 8 pts had a PR with cisplatin/irinotecan and received Gleevec. Median number of wks on Gleevec was 6.1 (range 4.6–25.1). Reasons for discontinuation of Gleevec were disease progression (7) and persistent neutropenia (1). Median progression-free survival was 4.7 mo. (range 0.7–16.3) for all pts and 5.5 mo. (range 4.7–16.3) for pts receiving Gleevec. There were no objective responses to Gleevec, but 3 pts (21%) had stable disease for 12, 15 and 25 wks. Median survival was 8.1 mo. (range 3.7–19.6) for all pts and 10.0 mo. (range 7.1–19.6) for those receiving Gleevec. Myelosuppression was mild (grade 1–2 ANC 13%, anemia 76%, platelets 13%) with one pt with grade 3 neutropenia. Non-heme toxicity included grade 1–2 nausea 76%, diarrhea 51% and peripheral edema 75%. Conclusions: Gleevec did not appear to maintain disease stability after response to chemotherapy in the majority of pts despite c-kit tumor positivity. Although disease stability with Gleevec was noted in 3 pts (12–25 wks) and therapy was well tolerated, this approach does not appear to warrant further clinical study. Supported by Novartis Pharmaceuticals. No significant financial relationships to disclose.

4090 Background: The prognosis for patients (pts) with CUP is poor, with a median survival of 4–6 mos. This trial was designed to evaluate the efficacy and toxicity of a novel chemotherapy combinat...

7102 Background: Weekly (DOC) is active and well tolerated in elderly or PS2 patients with advanced NSCLC. Cyclooxygenase-2 (COX-2) promotes tumor growth through the production of prostaglandin E2 (PGE2) and the induction of vascular endothelial growth factor (VEGF). Pre-clinical data show that celecoxib (CEL), a COX-2 inhibitor, has antitumor activity and enhances taxane efficacy.Methods: We are conducting a phase II study of CEL plus weekly DOC in elderly or PS2 pts with stage IIIB (pleural effusion)/IV NSCLC. Eligibility criteria include: age ≥ 70 yrs (PS 0–2) or age < 70 yrs with PS2; normal hepatic, renal and bone marrow function. CEL 400 mg po bid (daily) is started 7 days before the first dose of DOC 36mg/m2 IV given on days 1, 8, 15 of a 28 day cycle. Blood is collected pre-treatment, on day 8 of CEL, and on days 8 and 29 after first dose of DOC for VEGF and PGE2 levels. Results: 21 eligible pts have been treated: Median age 73 yrs (51–79 yrs); Gender 17M:4F; PS2 - 11; ≥70 yrs-14;PS2–11;adenocarci...

IntroductionThe aim of this study was to examine the effects of KRAS mutant subtypes on the outcome of patients with resected lung adenocarcinoma (AC).MethodsUsing clinical and sequencing data, we identified 179 patients with resected lung AC for whom KRAS mutational status was determined. A multivariate Cox model was used to identify factors associated with disease-free survival (DFS) and overall survival (OS). Publicly available mutation and gene-expression data from lung cancer cell lines and lung AC were used to assess whether distinct KRAS mutant variants have a different profile.ResultsPatients with KRAS mutation had a significantly shorter DFS compared with those with KRAS wild-type (p = 0.009). Patients with KRAS-G12C mutant tumors had significantly shorter DFS compared with other KRAS mutants and KRAS wild-type tumors (p < 0.001). In the multivariate Cox model, KRAS-G12C remained as an independent prognostic marker for DFS (Hazard ratio = 2.46, 95% confidence interval 1.51–4.00, p < 0.001) and for OS (Hazard ratio = 2.35, 95% confidence interval 1.35–4.10, p = 0.003). No genes were statistically significant when comparing the mutational or transcriptional profile of lung cancer cell lines and lung AC harboring KRAS-G12C with other KRAS mutant subtypes. Gene set enrichment analysis revealed that KRAS-G12C mutants overexpressed epithelial to mesenchymal transition genes and expressed lower levels of genes predicting KRAS dependency.ConclusionsKRAS-G12C mutation is associated with worse DFS and OS in resected lung AC. Gene-expression profiles in lung cancer cell lines and surgically resected lung AC revealed that KRAS-G12C mutants had an epithelial to mesenchymal transition and a KRAS-independent phenotype.

Introduction: The prognosis for patients with extensive-stage small cell lung cancer remains poor. This trial was designed to evaluate the efficacy and toxicity of maintenance sunitinib after platinum-etoposide chemotherapy. Methods: Patients who demonstrated objective tumor response or stable disease after four cycles of platinum plus etoposide chemotherapy were eligible. Sunitinib was given at 50 mg daily for 4 weeks of a 6-week cycle until disease progression or unacceptable toxicity. The primary end point was 4-month progression-free survival (PFS) rate from initiation of sunitinib. Results: Sixteen patients were enrolled. Responses to platinum-etoposide were complete response (CR)/partial response (PR)/stable disease (SD) = 3/11/2. The median number of weeks on sunitinib was 4 (range: 1.4–20). Reasons for sunitinib discontinuation were disease progression (50%), toxicity (31%), and patient request (19%). Median PFS from the start of sunitinib was 2.5 months (95% confidence interval [CI], 0.8–3.1). Further accrual would have failed to reach the target PFS rate, so the study was terminated. There were no objective responses to sunitinib, but four patients (25%) had disease stability for 15, 15, 17, and 20 weeks. Median PFS and overall survival from the start of chemotherapy were 6.2 months (95% CI, 4.1–6.5) and 8.2 months (95% CI, 6.2–14.7), respectively. Grade 3 to grade 4 toxicity included thrombocytopenia (25%), fatigue (19%), muscle weakness (13%), and hypothyroidism (6%). Conclusions: Sunitinib did not seem to maintain disease stability after response to chemotherapy. Sunitinib was discontinued in half of patients due to toxicity or request to stop therapy. Although disease stability with sunitinib was noted in four patients, this approach does not seem to warrant further clinical study.

18074 Background: Radiation dose is an independent prognostic factor for survival in patients with early stage non-small cell lung cancer (NSCLC). We hypothesized that radiation dose is also a significant independent factor associated with survival in patients with stage III disease treated with combined radiation and chemotherapy. Methods: This is an Institutional Review Board approved retrospective study. Eligible subjects included those with stage III NSCLC registered in the radiation oncology database at University of Michigan Hospital between January 1992 and July 2004. Radiation was given using 3-dimensional conformal technique with doses ranging from 30 to 102.9 Gy, corresponding to a bioequivalent dose (BED) of 39 to 124.5Gy. Median age was 65 years (range, 36–89). There were 80 males and 67 females. Median follow-up was 13.0 months (range, 2.7–145.9). Results: For patients treated with radiation alone (n=40), sequential chemoradiation (n=42), and concurrent chemoradiation (n=65), median survival was 8.6 (95% CI: 5.7–11.5), 12.8 (95% CI: 9.5–16.0) and 15.4 (95% CI: 12.7–18.0) months, respectively (P =0 .011). Multivariate Cox-regression analysis showed that BED (HR=0.96, 95% CI: 0.95–0.97, P0.05). To isolate the BED effect, multivariate analysis was performed separately in patients treated with and without chemotherapy: the hazard ratios of BED for the risk of death were 0.97 (95% CI: 0.95–0.99, P=0 .013) and 0.95 (95% CI: 0.93–0.98, P=0.001), respectively. BED also remained a significant independent prognostic factor in patients treated with chemotherapy and radiation in the dose range of 60–66 Gy (HR=0.91, 95% CI: 0.84–0.99, P=0.041). Conclusions: Radiation dose is significantly associated with survival in patients with stage III NSCLC treated with combined radiation and chemotherapy. No significant financial relationships to disclose.