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9519 Background: In a pilot phase II trial, we investigated the use of neoadjuvant immunotherapy to induce a pathologic response in patients with stage III/IV (M0) cutaneous squamous cell carcinoma of the head and neck (CSCC-HN). Here, we report the long-term outcomes according to pathologic response. Methods: Patients with newly diagnosed or recurrent stage III/IV (M0) (AJCC 8th Ed) CSCC-HN were treated with 2 doses of cemiplimab 350 mg intravenously every 3 weeks prior to surgery. The primary endpoint was overall response rate (ORR) per RECIST v1.1. Secondary endpoints included safety, pathologic response, disease-free and overall survival. Results: Of 20 patients enrolled, 7 (35%) had recurrent disease and 12 (60%) were stage IV on presentation. Neoadjuvant immunotherapy was generally well-tolerated and there were no surgical delays. Adverse events (AEs) were observed in 7 (35%) patients; 1 (5%) grade 3 diarrhea, 6 (30%) ≤ grade 2 AEs. ORR by RECIST was 30%. However, 85% (17/20) achieved a pathologic response (≤50% viable tumor), with pathologic complete response (pCR) in 11 (55%), major pathologic response (MPR, ≤10% viable tumor) in 4 (20%) and pathologic partial response (pPR, >10% and ≤50% viable tumor) in 2 (10%). Patients with a pCR did not receive planned radiotherapy after surgery. Patients who did not have a pathologic response (> 50% viable tumor) either progressed and died (1, 5%) or developed recurrence (2, 10%) despite surgery and adjuvant radiation or chemoradiation. At a median follow up of 34.5 months (range: 7.7-42.7), none of the patients who achieved a pathologic response have recurred. Conclusions: Consistent with other cancer types, pathologic response to neoadjuvant immunotherapy is durable in patients with advanced, resectable CSCC-HN. Adjuvant radiation therapy may be spared in patients who achieve a pCR and warrants further investigation. Clinical trial information: NCT03565783.

6067 Background: The American Joint Committee on Cancer (AJCC) TNM staging system defines the anatomical extent of disease and serves as a guide for treatment and prognosis. The favorable prognosis of p16+ oropharyngeal squamous cell carcinoma (OPSCC) compared to p16 negative counterpart led to major updates in the AJCC 8th edition. Its prognostic performance, however, warrants further validation. Methods: We included patients diagnosed with p16+ OPSCC enrolled in a prospective registry ( Stiefel) at The University of Texas MD Anderson Cancer Center between March 2015 and December 2018. Patients’ stage at diagnosis was classified according to the AJCC 7th (AJCC-7) and 8th (AJCC-8) editions. Overall survival (OS) and progression-free survival (PFS) was defined as time from diagnosis to death or to progression or death, respectively. The Kaplan-Meier method was used to calculate 1- and 3-year survival probabilities. Differences between groups were compared using the log-rank test. Prognostic discriminative performance of each staging system was evaluated using Harrel’s C-statistic. Survival differences between heavy (> 10 pack-years [PY]) vs. light/never smokers (≤ 10 PY) by AJCC-8 staging groups was assessed with the log-rank test. Results: Of 463 patients, the median follow-up was 34.7 months (2.3-169.74). Nearly 90% (N=413) of patients were down-staged from AJCC-7 to AJCC-8 with 69% of patients with IVA disease based on AJCC-7 (N=319) re-staged as stage I (N=196 [42%]), II (N=79 [17%]) or III (44 [10%]) according to AJCC-8. Over 60% (N=279) of patients were staged as I with AJCC-8. Compared to AJCC-7, AJCC-8 had improved prognostic ability (C-statistic, 0.58 for AJCC-7 vs. 0.63 for AJCC-8) and provided better discriminative survival probabilities at 1 and 3-year follow-up (Table). Similar results were observed for PFS. Smoking status did not impact OS when stratified by AJCC-8 staging groups: I, p=0.347; II, p=0.310; and III, p=0.532 for > 10 vs. ≤ 10 PY. Conclusions: Our cohort validates that the AJCC-8 provides better prognostic discriminative performance when compared to AJCC-7, however, a disproportionate number of patients were classified as stage I. Smoking was not associated with survival within each staging group.[Table: see text]

Purpose The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. Patients and Methods This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m2 on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m2 on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. Results Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m2 (schedule 1) and 105 mg/m2 (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. Conclusion An LY2606368 dose of 105 mg/m2 once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC.

6578 Background: Given the expected excellent prognosis of low-risk oropharyngeal squamous cell carcinoma (OPSCC), consideration of long-term toxicity and functional outcomes has become increasingly important. Activity monitors (e.g. FITBIT) are imperfect but have been shown to have reasonable validity in healthy adults. Here we aimed to test the feasibility of using medical grade longitudinal digital activity monitoring to better define objective functional outcomes after treatment of low-risk OPSCC. Methods: This prospective, observational parallel cohort study included patients with previously untreated stage I-III (AJCC 7) OPSCC eligible for standard of care single-modality treatment with either Intensity-Modulated Proton Therapy (IMPT) or TransOral Robotic Surgery (TORS). Objective Actigraph accelerometer data (Actigraph, Pensacola, FL) were collected continuously for 1 week at baseline, 3, 6 and 12 months after treatment along with subjective patient-reported outcome (PRO) measures. Results: Forty-four patients (34M, 10F) enrolled with median age 59 years (range: 42-78). Baseline, 3 and 6 month activity data were available for 40 patients (91%): 16 IMPT and 24 TORS. There was a significant decrease in mean percent of day performing moderate to vigorous physical activity (MVPA) (-0.78, 0.021) mean number of steps/minute (-1.1, p = 0.035), and mean kcals/day (-115.9, p < 0.001) from baseline to 3 months after treatment for the overall cohort. A significant decrease in mean kcals/day (-82.2, p = 0.004) persisted for the overall cohort at 6 months with no significant difference between groups. Conclusions: Longitudinal digital activity monitoring is feasible before and after treatment of low-risk OPSCC. This approach may offer objective functional endpoints for future de-escalation trials. Similar short-term decreases in objective activity measurements were observed after IMPT and TORS. Long-term (12 month) activity data and correlations to subjective PRO measures will be available at the time of presentation. Clinical trial information: 02663583 .

TPS6590 Background: Effective targeted therapies are needed for HNSCC that is lethal despite recent advances with immunotherapy. A major challenge to personalize treatment is that most genomic alterations are in tumor suppressors, including NOTCH1 that is mutated in ~20% of HNSCC. We recently published that HNSCC cell lines harboring NOTCH1 LOF mutations undergo cell death in vivo and in vitro following PI3K inhibition, in contrast to PIK3CA mutant cell lines that merely undergo cell cycle arrest when exposed to the same drugs. Based on these results we initiated a novel genomic biomarker-driven phase II clinical trial treating NOTCH1 mutant HNSCC pts with the dual PI3K/mTOR inhibitor bimiralisib (PQR309). Methods: The primary objective is to determine the objective response rate (ORR) of recurrent/metastatic HNSCC harboring NOTCH1 LOF mutations to bimiralisib. Pts who have already received standard platinum chemotherapy and immunotherapy will receive bimiralisib orally twice per wk unless progression or intolerable toxicity occurs. Tumors will be evaluated using RECIST q 6 wks. A Simon’s optimal two-stage design is used. To have 80% power to detect an ORR of 30%, (one-sided α = 0.05, β = 0.20) 10 pts will be enrolled in the first stage. If ≤1 pts respond, the trial will be closed for futility. If ≥2 pts have an OR, the study will enroll an additional 19 pts in the second stage. The null hypothesis (ORR ≤ 10%) will be rejected if ≥ 6 in 29 pts have an OR. Seven pts have enrolled. The algorithm for determining NOTCH1 mutation function is based on the patterns of mutations in HNSCC vs. leukemia where mutations are activating. It may be difficult to determine whether NOTCH1 mutations are homo- or heterozygous due to normal cell contamination. Therefore, levels of activated NOTCH1 in pretreatment tumors may be assessed by IHC with an antibody against activated NOTCH1 (NICD). In parallel with the trial, to further confirm NOTCH1 LOF, we can use site-directed mutagenesis to re-create NOTCH1 mutations from trial pts that will then be introduced into NOTCH1-null cell lines to assay for NICD and growth inhibition with culture on NOTCH1 ligand. All pts will have serial collection of blood for pharmacokinetics and for ctDNA to examine clonal evolution associated with acquired resistance. Samples with high NOTCH1 mutation ctDNA VAF will be analyzed by WES and compared with pretreatment tissue. In the second stage, IHC and WES may be performed on pre- and post- treatment (day 15 and progression) tissue to examine pharmacodynamics and mechanisms of resistance. Clinical trial information: NCT03740100 .

6008 Background: Anti-PD-1/PD-L1 are active in metastatic oropharynx squamous cell carcinoma (OPC). Durvalumab (durva) and tremelimumab (tremi) target respectively PD-L1 and CTLA-4, which in combination may be synergistic. Here we report the safety and interim results of durva vs. durva+tremi prior to surgery in a window of opportunity trial in OPC. Methods: Pts were randomized 1:1 to durva 1500 mg or durva 1500 mg + tremi 75 mg IV Q4W x 2 cycles. The primary objective was to quantify pre- and post-treatment differences in CD8+ tumor infiltrating lymphocytes for the two arms. Secondary objectives included safety, toxicity, ORR by RECIST, fraction of patients undergoing surgery at 8 wks, and percentage viable tumor cells in the surgical specimen. Serial pre- and post-treatment blood and tumor specimens were collected for ongoing correlative analyses. Results: 28 pts enrolled: median age 64y, 27 (96%) male, 19 (68%) newly diagnosed, most (63%) at stage IVA (AJCC 7th Ed), 9 (32%) had locoregional recurrence, 24 (86%) p16 positive, and 22 (79%) had ≤ 10 PPY smoking history. Median follow-up was 7.6 months. The most common AEs were fatigue (36%), leukopenia/lymphopenia (25%), transaminitis (25%), and rash (21%). Grade 3 AEs occurred in 4 (14%) pts: 2 elevated lipase, 1 diarrhea, and 1 hepatitis, all were manageable. There were no grade >3 AEs. ORR was 43%: 50% had SD (including 29% tumor shrinkage in 1 pt). Treatment effect in the surgical specimen was observed in 19 (79%) of 24 evaluable pts; 2 pts had major pathologic response (≤ 10% viable tumor) at the primary site. Efficacy was equivalent in both arms. The 2 pts with PD and 1 pt with SD were switched to chemotherapy after durva +/- tremi before resection; interestingly, each achieved a pCR in the primary. Most pts (57%) didn’t receive radiotherapy after surgery. There was a statistically significant association between ORR and treatment effect (p=0.014). The median percentage of viable tumor in the primary was 37.5% in pts with PR, and 82.5% in SD (p=0.003). Conclusions: Durva +/- tremi prior to surgery was well tolerated in OPC pts. Activity is encouraging with treatment effect seen in 79% of pts. The primary endpoint and complete efficacy data will be presented. Clinical trial information: NCT03144778.

6017 Background: In a single-arm, phase 2 study, we previously demonstrated that in pts with R/M HNSCC, cisplatin, docetaxel and E improved progression-free survival (PFS) compared to historical data (Kim et al., ASCO 2006). Herein, we evaluated this regimen in a single center, randomized, phase 2 trial. Methods: Pts with R/M HNSCC, with a performance status (PS) 0-2, were randomized (1:1) to receive up to 6 cycles of first-line chemotherapy with cisplatin 75 mg/m2 (or carboplatin AUC 6) and docetaxel 75 mg/m2 i.v. on day 1 every 21 days, plus placebo (P) vs. E 150 mg p.o. daily, followed by maintenance P or E until disease progression. The primary endpoint was PFS. With 120 pts, the study had 80% power to detect an improvement in median PFS from 3.0 to 4.9 months with a two-sided type I error rate of 0.1. Results: From 05/2010 to 07/2015, 120 pts were randomized to the P (N = 60) or E (N = 60) groups. All pts but one initiated treatment and were eligible for evaluation of the primary endpoint – 92 males; median age 62 years; 52 oropharynx, 40 oral cavity, 19 larynx, 8 hypopharynx cancer pts; 86 current/former smokers; 43 with recurrence within 6 months of completion of local treatment; 27 with prior exposure to EGFR inhibitors. Median PFS was 4.4 vs. 6.1 months for the P and E groups, respectively (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.42-0.95 months, p = 0.026). Response rates were 44% vs. 56% for P vs. E (p = 0.21). Median overall survival (OS) for P- and E-treated pts was 13.7 vs. 17.0 months (HR = 0.67, 95% CI 0.43-1.04, p = 0.07). Benefits from E on PFS and OS were more pronounced in pts with oropharyngeal tumors (p≤0.05 for interaction). In the E group, first-cycle rash grade 2-4 (34% pts) was associated with longer OS (HR = 0.40, p = 0.02). E-treated pts experienced a higher incidence of grade 3-4 adverse events (33.9 vs. 53.3%), including diarrhea (3 vs.17%), dehydration (5 vs. 15%), nausea (5 vs. 14%), rash (0 vs. 12%). Conclusions: This study met its primary endpoint. Addition of E to first-line platinum/docetaxel improved PFS and OS. This regimen may warrant further evaluation in randomized, phase 3 trials. Clinical trial information: NCT01064479.

e20077 Background: Intra-tumor heterogeneity (ITH) may be present in all molecular levels. Genomic ITH at the exome level has been reported in many cancer types, but comprehensive gene expression ITH has not been well studied. Methods: We collected 35 samples from 10 NSCLC patients (3 or 4 regions/tumor) including lung adenocarcinoma (n = 6), squamous cell carcinoma (n = 2), large cell carcinoma (n = 1) and pleomorphic carcinoma (n = 1). Using Affymetrix Gene 1.0 ST arrays, we generated the gene expression data for each sample. Diverse gene expression signatures associated with clinical outcomes were tested for ITH. Results: Inter-tumor heterogeneity was generally higher than intra-tumor heterogeneity, but some tumors showed a substantial level of ITH. The analysis of various clinically relevant gene expression signatures including molecular subtype, EMT and immunotherapy response signatures also revealed heterogeneity between different regions of the same tumor. The gene expression ITH we observed was associated with heterogeneous tumor microenvironments represented by stromal and immune cells infiltrated. Conclusions: Our data suggest that RNA-based prognostic or predictive molecular tests should be carefully conducted in consideration of the gene expression ITH.

6001 Background: We designed a randomized phase II trial to determine the efficacy of two induction chemotherapy (ICT) cetuximab (C) containing regimens with demonstrated efficacy and acceptable to...

2597 Background: Although C and D both demonstrate activity resistance can develop. Preclinical studies demonstrated that activation of MET requires c-SRC. We hypothesized that a c-SRC inhibitor (D...

6033 Background: The epidermal growth factor receptor (EGFR) and Src family kinases are upregulated in HNSCC. EGFR interacts with cSrc to activate oncogenic STAT3 signaling; dual targeting is syner...

6030 Background: The incidence of oropharyngeal cancer (OPC) has increased 5% per year over the past decade due to a rise in human papilloma virus (HPV)-driven OPC. HPV+ OPC is clinically and molecularly distinct from HPV- head and neck squamous cell carcinomas (HNSCC). However, there are currently no validated therapeutic targets for HPV+ HNSCC. Methods: Reverse phase protein array (RPPA) was performed on HNSCC tumors from The Cancer Genome Atlas to measure cancer-associated pathways and targets. Differences in individual markers and proteomic pathway scores between HPV+ and HPV– tumors were assessed by t-test in the overall group and for the subset of OPC. Results: Significant proteomic differences were observed in 14 HPV+ and 186 HPV- HNSCC. Of 160 proteins, the top marker overexpressed in HPV+ HNSCC was p16, an established clinical biomarker of HPV status (p

11044 Background: A variety of methods for isolation of CTCs of epithelial origin are available; most employ antibodies to epithelial cell adhesion molecule (EpCAM). Using classic phenotypic definition, a CTC is nucleated, cytokeratin CK(+), CD45(-) cell. However, some CTCs may elude capture as they originate from primary tumor cells which have undergone epithelial-mesenchymal transition (EMT). We report here the use of ApoStream, a novel dielectrophoresis field-flow-assisted, antibody-free method to isolate CTCs from blood. Methods: Blood was collected from consented NSCLC patients and processed using ApoStrea. For CTC enumeration comparison, CellSearch FDA-approved kit was used. Isolated cells were evaluated with multiplexed immunofluorescent assay and laser scanning cytometry analysis were applied to identify multiple combinations of positive and/or negative staining for CK/CD45/DAPI and EpCam. To determine specific EGFR mutations from captured CTCs, samples were analyzed using Improved and Complete Enrichment with CO-amplification at Lower Denaturation temperature (ICE COLD-PCR). Results: Blood samples from 32 NSCLC patients and 3 healthy volunteers were processed. ApoStream isolated 0 to 65 CK(+)/CD45(-) CTCs(n=32) and CellSearch isolated 0 to 13 EpCAM(+)/CK(+)/CD45(-) CTCs(n=7). Additionally, ApoStream™ recovered 37-3536 CK(-)/CD45(-) and 4-10702 CK(+)/CD45(+) cells. EpCAM expression was detected in 7-100% of CK(+)/CD45(-) and 0-5% of CK(-)/CD45(-) cells, and 18-100% of CK(+)/CD45(+) cells. EGFR mutations [exon 19 deletion and exon 21 L858R] were determined and found to be concordant when compared to tumor tissue analysis by Sanger sequencing. Conclusions: The ApoStream platform enriched EpCAM(+) and EpCAM(-) CTCs from the blood of NSCLC patients demonstrating utility in recovering cancer cells with multiple phenotypes. From recovered CTCs, detection of EGFR mutations was possible indicating the clinical relevance and potential utility of CTCs as an alternative to tissue biopsy. Complete mutation analysis will be presented.

8102 Background: In preclinical models, combining EGFR and Src inhibition has been shown to have at least additive and possibly synergistic effects. In this phase I/II (phI/II) trial, we combined EGFR inhibitor E with D, a multi-targeted tyrosine kinase inhibitor with activity against Src. Primary endpoint of PhI was to determine maximum tolerated dose (MTD) of the combination of E and D; primary endpoint of PhII was progression free survival (PFS) at 12 weeks. Methods: In preclinical models, combining EGFR and Src inhibition has been shown to have at least additive and possibly synergistic effects. In this phase I/II (phI/II) trial, we combined EGFR inhibitor E with D, a multi-targeted tyrosine kinase inhibitor with activity against Src. Primary endpoint of PhI was to determine maximum tolerated dose (MTD) of the combination of E and D; primary endpoint of PhII was progression free survival (PFS) at 12 weeks. Results: 53 pts were enrolled between 2/09 and 4/12. 6 were not eligible. Of the 47 eligible pts (12 in PhI, 35 in PhII): median (range) age was 62 yrs (44-88), 26 pts (45%) were female. 6 pts in PhI and all 35 pts in PhII had NSCLC: adeno 25 pts, squamous 11, NSCLC NOS 5. Other tumor types enrolled in PhI: head and neck cancer (2), adenoid cystic carcinoma (1), mesothelioma (2), small cell lung cancer (1). 47% of pts were chemo-naïve. 8 pts had activating EGFR mutations (6 exon 19 deletions, 2 L858R mutations). The PhI starting dose E150/D100 was not well tolerated as 2 of 3 pts experienced grade 3 hypophosphatemia as a dose limiting toxicity. MTD was found to be E150/D70. 11% achieved PR and 44% SD. All observed responders had EGFR mutations. 9 pts (19%) stopped treatment early and were unevaluable. Median time on treatment was 43 days (range 1-262). Median time on treatment for the 8 pts with activating EGFR mutations was 144 days. Conclusions: Combination of E and D is safe and feasible in NSCLC, with MTD E 150 mg PO daily and D 70 mg PO daily. Rate of PR and SD were 11%,and 44%, respectively. Biomarker and pharmacokinetic studies will be reported. Clinical trial information: NCT00826449.

2530 Background: OSI-906 is a potent inhibitor of IGF-1R and IR tyrosine kinase activity. Increased IGF-1R activity is observed in human malignancies and implicated in resistance to chemotherapy. M...

e19069 Background: Early determination of therapeutic failure can potentially spare a pt ineffective and toxic treatment. We previously reported in a retrospective study the use of CT within 4 weeks of initiation of chemotherapy in advanced NSCLC to assess response and progression by RECIST (Bruzzi et al. JTO 2006). Here, we prospectively assess whether CT imaging after the first cycle of pemetrexed in advanced NSCLC has a role in evaluating response and management. Methods: We accrued pts with PS 2 or 3 advanced NSCLC receiving at least one dose of 1st or 2nd line pemetrexed. A repeat CT prior to a 2nd course was required. Pts with progression by RECIST were to come off study. CT scans were done using multislice CT technology (GE Lightspeed Plus), and images were reconstructed with slice thicknesses of 3.75mm or less. All images were reviewed using a PACs workstation (Stentor iSite) and measurements were done with electronic calipers. RECIST criteria: progression, an increase in the tumor's longest dimension by 20%, response, a decrease by 30%. Results: Thirty pts had a median age of 68 years (45 - 81). PS 2/3, 1st/2nd line, and F/M were 16/14, 17/13, and 12/18 respectively. Pts received 1–8 cycles (median 2). Twelve pts received only 1 course of whom 7 pts had f/u CTs at a median of 20 days (12–25) after 1st chemo dose. Of these pts, 5/7 had progression by RECIST and the other 2/7 pts had stable disease with 1 pt who came off due to serial PEs and 1 pt who opted off for reasons of travel. Two of the 5 pts who had progression by CT had no detectable change by CXR. Of 5/12 pts treated with only 1 course without f/u CT, 2 pts died, 2 pts had progression by CXR, and 1 pt stopped after treatment for pneumonia. All 18 pts receiving ≥2 cycles had a repeat CT prior to their 2nd course. Conclusions: The results of this prospective trial support earlier retrospective findings that short-term follow-up using CT in pts with advanced NSCLC can detect tumor progression and impact patient management. We will also present f/u CTs in pts who received ≥ 1course to determine whether early signs of progression predict later RECIST determined progression. [Table: see text]

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]

14042 Background: SPRYCEL™ is a potent, orally active, multi-targeted kinase inhibitor, active against BCR-ABL and SRC family kinases. We report the results of a Phase I dose-escalation study evaluating safety, tolerability, pharmacokinetics, and biomarkers of dasatinib in pts with advanced solid tumors. Methods: Pts with adequate hematologic, renal, cardiac and liver function received oral dasatinib once daily for 7 days per week. Three doses and schedules were examined: 90 mg BID; 140 mg QD; and 180 mg QD. Pharmacokinetics and pharmacodynamic biomarkers were collected on Days 1 and 26 of Cycle 1. Tissue biomarkers were assessed at screening. CT was performed at least every 8 weeks, and FDG-PET at weeks 4, and 8. Results: 26 pts [M=15, F=11] ECOG PS ≤ 2 with epithelial tumors (n=14) or other solid tumors (n=12) have been treated in escalating dose levels. Toxicity was generally mild; most patients came off study for progressive disease. DLTs of pleural effusions were seen in 3/9 subjects on the 180 mg cohort, 2 of whom had pre-existing effusions. Patients with pleural effusion have been excluded from future enrollment. The maximum tolerated dose has not been identified. There have been no objective responses on CT. Six patients have had stable disease with continued study treatment for 2–10 months. Conclusions: Dasatinib can be safely administered at doses of 140 and 180 mg QD. Clinical efficacy, pharmacokinetics, and correlative studies of tumor biopsy material and early FDG-PET results will be reported. No significant financial relationships to disclose.

6026 Background: The role of the epithelial-mesenchymal transition (EMT) is crucial to invasive and progression of several epithelial malignancies. The role of this process in head and neck squamous cell carcinoma (HNSCC) remains poorly defined. Methods: Eleven head and neck squamous cancer cell lines and 50 primary tumor specimens formed the materials for this study. We used Western blotting, immunohistochemistry, RT-PCR cell motility assay to determine the expression and the functional implications of several cell adhesions and singling molecular associated with EMT in these tumors. Results: Our results showed Src and E-Cadherin to be paradoxically overexpressed in the majority of cell lines and in primary tumor tissues relative to normal squamous mucosa. In both cell lines and tumor tissues elevation of activated Src was accompanied by down-regulation of E-Cadherin and vimentin detection. In-vitro inhibition of Src led to the increased E-Cadherin of expression and cell proliferation in squamous carcinoma cell lines. Immunophenotypic analysis of the protein products of these genes in primary tumor tissues demonstrated a spectrum of changes that correlated significantly with the differentiation, invasive patterns, sarcomatoid transformation and lymph node status. Our results show that high activated Src and low E-Cadherin expression were correlated with finger-like invasive pattern, poor differentiation, sarcomatoid transformation and lymph node metastasis in HNSC. Conclusions: Our study indicates that Src and E-Cadherin play a major role in EMT invasion and progression of head and neck squamous carcinoma. These proteins may be targeted in the therapeutic intervention of patients with HNSCC. No significant financial relationships to disclose.

18119 Background: Irinotecan has significant activity in small-cell lung cancer. Randomized trials comparing IP to EP have yielded conflicting results. Our phase I study of alternating weekly therapy with IP and EP with granulocyte colony-stimulating factor (G-CSF) support found this regimen to be tolerated and active in untreated small cell lung cancer.(Johnson et al Clin Lung Cancer 2003) Methods: Based on these findings we conducted a phase II study to estimate the efficacy of weekly combination therapy in previously untreated patients with extensive disease small-cell lung cancer (ED-SCLC). Patients received 12 weeks of therapy with cisplatin (20 mg/m2) on day 1 and irinotecan (100 mg/m2) on day 1 and G-CSF days 2–5 (IP) alternating with cisplatin (20 mg/m2) on day 1 and etoposide 60 mg/m2 on days 1–3 with G-CSF on days 4–7 (EP). Patients with asymptomatic brain metastases were included. The primary end point was overall survival. Results: 38 patients were enrolled from 7/2001 to 7/2006. The median age was 60 years (range 37–73) and 55% were female. ECOG performance was 0 in 11 patients, 1 in 25 patients and 2 in 2 patients. 87% of patients completed 12 weekly cycles of chemotherapy (range 1–12) with 90% of the planned dose intensity of irinotecan delivered. The objective response rate in 33 evaluable patients was 87% (0 CR, 30 PR). Median follow-up time was 43.7 months. Median progression free survival was 6.4 months (95% CI 5.16–7.59 months). The median survival was 10.9 months (95% CI 8.61–13.5 months). The 2 year survival rate was 19% (95% CI 5–31%). Grade 3–4 non-hematologic toxicities included diarrhea (8%), hyponatremia (5%), dehydration (3%), and neutropenic fever (5%).Grade 3–4 hematologic toxicities included anemia (13%), neutropenia (5%), and thrombocytopenia (3%). There was 1 therapy related death due to sepsis. Conclusions: Weekly therapy with IP alternating with EP with growth factor support was well tolerated in patients with untreated ED- SCLC, but did not show improved progression-free or overall survival when compared with historical controls at our institution. No significant financial relationships to disclose.

6084 More effective systemic treatment is needed for HNSCC. The taxoids are the most efficacious single agents identified. Epidermal growth factor receptor (EGFR) is almost universally expressed by HNSCC tumors but inhibitors have only modest activity as single agents in clinical studies. However, the combination of the taxoids with EGFR inhibition has additive anti-tumor effects in HNSCC in vitro and in animals. Despite similar pre-clinical data in lung cancer, clinical trials showed no benefit when EGFR inhibitors were added to chemotherapy. In vitro studies in lung, breast and colon cancer cell lines demonstrate that the separation of EGFR TKI from chemotherapy and the order in which these agents are administered influences efficacy. We sought to determine if a similar sequence-dependent effect exists in HNSCC in order to help design future clinical trials with these agents. We chose three human HNSCC cell lines with diverse levels of basal EGFR expression and activation. None had EGFR mutations, which are very rare in HNSCC. Cells were treated with single agent docetaxel or erlotinib or combinations for 72 h and cytotoxicity was measured with an MTT assay. Concurrent treatment with docetaxel and erlotinib resulted in more cytotoxicity than single agents and calculated combination indices demonstrated additive effects. When erlotinib was added 4 to 24 h prior to docetaxel, the efficacy was similar to or less than that of concurrent therapy regardless of whether the erlotinib was washed off prior to the docetaxel or left in the cell medium. In contrast, when docetaxel was added ≥ 10 h prior to erlotinib, cytotoxicity was enhanced as compared to concurrent therapy. The most efficacious combination was docetaxel treatment for 24 h followed by erlotinib for 48 h. This combination was chosen for further analysis. Consistent with previously published studies in other cell types, erlotinib resulted in G1 cell cycle arrest and docetaxel in G2-M arrest. On-going studies to investigate the mechanism for the sequence-dependent cytotoxicity include examination of the effects of the sequence on cell cycle and apoptosis, tubulin expression, and cell signaling molecules that mediate pro-survival signals from EGFR. [Table: see text]

7713 Background: Malignant pleural mesothelioma (MPM) is a lethal disease with few effective therapeutic options. We sought to determine whether Src, a non-receptor tyrosine kinase, could be a new therapeutic target in MPM and to establish the potential therapeutic use of pharmacologic Src inhibitors in this disease. Methods: We analyzed four MPM cell lines (MSTO-211H, NCI-H28, NCI-H2052, and NCI- H2452) for immunohistochemical (IHC) expression of total and phosphorylated Src (Tyr 419, Tyr 530). These cell lines were treated with dasatinib, a Src inhibitor, and evaluated for apoptosis, cell cycle analysis, and migration and invasion. Downstream signaling events were studied by Western blot analysis. We also conducted IHC analyses with total Src, phosphorylated Src Tyr 419 (p-Src Tyr 419), and phosphorylated Src Tyr 530 on 46 archived MPM tumor specimens and correlated the biomarker results with the clinical outcome. Results: All four MPM cell lines expressed total and activated Src (p-Src Tyr 419). Three of the four cell lines were sensitive in vitro to cytotoxicity by dasatinib with inhibition of migration and invasion, cell cycle inhibition, and apoptosis. Treatment with dasatinib inhibited several pathways downstream of Src. In the archived MPM tumor specimens, Src protein was highly expressed on IHC analysis in tumor cells, but that expression did not correlate with overall or progression-free survival. However, expression of activated Src (p-Src Tyr 419) on the tumor cell membrane was higher in patients with stage 4 disease; the presence of metastasis correlated with higher membrane (P = 0.03) and cytoplasmic (P = 0.04) expression of p-Src Tyr 419. MPM nodal involvement at N1 was associated with the highest membrane expression of inactive Src (p-Src Tyr 530) (P = 0.02), whereas N2 disease was associated with the lowest expression. No gene mutations in Src exon 12 were found in the cell lines or tumor specimens. Conclusions: Activated Src may have an important role in survival, metastasis, and invasion in MPM, and targeting Src may be an important therapeutic strategy. No significant financial relationships to disclose.

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...