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87 Background: Cancer-associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (WL, skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer. Methods: The SLR was conducted following PRISMA guidelines. Embase and PubMed were searched to identify articles published in English between 1 Jan 2016 and 10 Oct 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by International Consensus (IC) diagnostic criteria (Fearon et al., Lancet Oncol 2011;12:489–95) or a broader definition of any WL. Included publications were of studies in ≥100 patients with colorectal or pancreatic cancer. Results: Twenty-six publications in patients with colorectal (n=13) or pancreatic cancer (n=13) met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 studies (58%) reported any WL. An association between survival and cachexia/WL was assessed across studies using multivariate (n=23) or univariate (n=3) analyses and within each study across multiple WL categories. Cachexia/WL was associated with a statistically significantly poorer survival in at least one WL category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Conclusions: Cachexia/WL was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two-thirds of the studies. The classification of WL varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could inform early disease management strategies that may improve prognosis.

Outcomes for patients with lung cancer have been improved substantially through the integration of surgery, radiation, and systemic therapy for patients with early-stage disease. Meanwhile, advances in our understanding of molecular mechanisms have substantially advanced our treatment of patients with advanced lung cancer through the introduction of targeted therapies, immune approaches, improvements in chemotherapy, and better supportive care. However, the majority of these advances have occurred among patients with good functional status, normal organ function, and with the social and economic support systems to be able to benefit most from these treatments. The aim of this article is to bring greater attention to management of lung cancer in patients who are medically compromised, which remains a major barrier to care delivery. Impaired performance status is associated with poor outcomes and correlates with the high prevalence of cachexia among patients with advanced lung cancer. CT imaging is emerging as a research tool to quantify muscle loss in patients with cancer, and new therapeutics are on the horizon that may provide important adjunctive therapy in the future. The benefits of cancer therapy for patients with organ failure are poorly understood because of their exclusion from clinical trials. The availability of targeted therapy and immunotherapy may provide alternatives that may be easier to deliver in this population, but clinical trials of these new agents in this population are vital. Patients with lower socioeconomic status are disproportionately affected by lung cancer because of higher rates of tobacco addiction and the impact of socioeconomic status on delay in diagnosis, treatment, and outcomes. For all patients who are medically compromised with lung cancer, multidisciplinary approaches are particularly needed to evaluate these patients and to incorporate rapidly changing therapeutics to improve outcomes.

9623 Background: The Lung Cancer Master Protocol (Lung-MAP) is designed to evaluate novel targeted therapies in patients with advanced squamous lung carcinoma. In the S1400F sub-study (non-match), we tested whether combined CTLA-4 and PD-1 inhibition with durvalumab plus tremelimumab (D+T) could overcome primary or acquired resistance to anti-PD-(L)1 therapy. Response, progression-free (PFS) and overall survival, and safety in the acquired resistance cohort are reported herein. Methods: Patients with previously treated squamous lung carcinoma, performance status (PS) 0-1, and adequate organ function that developed disease progression after ≥24 weeks of anti-PD-(L)1 monotherapy were eligible. Prior severe immune-related toxicities, intervening systemic therapy and combination chemo-immunotherapy were not permitted. Patients received D1500 mg + T75 mg IV q28 days for 4 cycles then D maintenance until disease progression. The primary endpoint was best objective response (RECIST 1.1). Interim analysis for futility was planned after 20 patients evaluable for response were enrolled. If no responses were observed, the cohort would stop enrolment. Results: 30 eligible patients were accrued to the acquired resistance cohort. Median age was 68 years, 60% of patients were male, 33% PS 0 and had received a median of 2 prior lines of therapy (maximum 4). Best response to prior anti-PD-(L)1 therapy was CR/PR/SD in 3/7/20 patients, with a median duration of anti-PD-(L)1 therapy of 8.6 months (5.2-30.4). No objective responses were seen with D+T; 47% had SD as best response. Median PFS was 2.0 months (95% CI 1.6-2.9) and survival 7.5 months (95% CI 5.3-8.7). Among the 14 patients with SD as best response, the median PFS calculated from first disease assessment is 2.8 months (95% CI: 1.4-3.9). Grade≥3 adverse events at least possibly related to protocol therapy were seen in 10/30 patients. These include 1 treatment-related death due to pneumonitis and 1 death not otherwise specified. Other adverse events include grade 3 confusion (1), dehydration (2), diarrhea (3), encephalopathy (1), weakness (1), hyperglycemia (1), hypoxia (1), lymphopenia (1), nausea, (1), neutropenia (1), thrombocytopenia (1), rash (1), vomiting (1), grade 4 dyspnea (1), leucopenia (1) and lymphopenia (1). Conclusions: D+T did not demonstrate activity in patients with acquired resistance to PD-1 checkpoint inhibitors and pretreated advanced squamous lung carcinoma. Clinical trial information: NCT03373760 .

e21683 Background: Combination chemo-immunotherapy is a well-established frontline therapeutic option for treatment naïve NSCLC. Dual immune checkpoint blockade (ICB) with nivolumab (nivo) and ipilimumab (ipi) has demonstrated improved clinical outcomes compared with chemotherapy alone in this setting. Combination dual ICB with low-dose chemotherapy may have advantages of preventing early disease progression and potentiating immunogenic response to treatment. Methods: We are conducting a single arm phase II clinical trial of nivo 360 mg IV Q3 weeks, ipi 1 mg/kg IV Q6 weeks, and weekly paclitaxel 80 mg/m2 IV on d1 and d8 of a 21 day cycle in ECOG 0-1 patients (pts) with treatment naïve NSCLC. Paclitaxel is stopped after a total of 4-6 cycles. The primary endpoint of the trial is progression free survival (PFS) with secondary endpoints of safety and objective response rate (ORR) by independent radiologic review. Interim results are presented from the first 23 evaluable pts, of a planned sample size of 49. Results: 23 pts were enrolled and evaluable with a mean age 63.8 years, 56.5% ECOG 0, 87% current/previous smoking history, and 70% adenocarcinoma. PDL1 score for < 1%, 1-49%, ³ 50% was seen in 9 (39.1%), 4 (17.4%), and 10 (43.5%) pts, respectively. Median time of follow up was 6.5 months (range 1.4–15.0). Partial response was observed in 14 pts, stable disease was seen in 8 pts, and 1 pt progressed during cycle 1, resulting in an ORR of 61%. Grade 3 or higher toxicity at least possibly attributed to study treatment was seen in 47.8% of 23 AE evaluable patients, of which included 4 cases of secondary adrenal insufficiency. Other toxicity rates were as expected for the respective agents. Conclusions: This is the first trial to evaluate weekly paclitaxel with nivo plus ipi in pts with untreated NSCLC. This regimen has demonstrated highly encouraging clinical activity with a manageable toxicity profile. The study is ongoing and updated results will be presented at the annual meeting. Clinical trial information: NCT03573947.

3102 Background: BRAF alterations (alts) account for ~4% of non-small cell lung cancers (NSCLC) with 50% being non-V600 alts. Because these alts are functionally heterogeneous and have a poorly characterized genomic landscape, determining appropriate treatment strategies is a challenge. Methods: The Guardant360 clinical database was queried for NSCLC patients (pts) with BRAF alts. Alts were categorized by clonality, type and class (1 and 2: BRAF monomer and dimer signaling; 3: requires co-occurring upstream RAS-mediated signaling). Functionality and drug screen assays were performed in Ba/F3 cells. Pts with non-V600 mutations were analyzed for sensitivity to MEK +/- BRAF inhibitors (M+Bi). Results: 306 unique BRAF alts were identified and the majority were observed once (233/306; 76%). Amplifications (806/1663; 48.5%) and missense alts (795/1663; 47.8%) were the most common occurrences. Missense alts were predominantly clonal (58%), and of known functionality (428/795; 54%). All class 1-2 alts were activating in Ba/F3 cells, while class 3 alts were found to have variable functionality (activating: 4/9). Functionality was correlated with clonality as demonstrated by class 1-3 alts having higher clonality compared to variants of unknown significance (VUS) (1: 56%; 2: 54%; 3: 45%; VUS: 38%; P

Purpose Erlotinib is clinically effective in patients with non–small-cell lung cancer (NSCLC) who have adenocarcinoma, are never or limited former smokers, or have EGFR mutant tumors. We investigated the efficacy of erlotinib alone or in combination with chemotherapy in patients with these characteristics. Patients and Methods Patients with advanced NSCLC (adenocarcinoma) who were epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy naive never or light former smokers (smokers of > 100 cigarettes and ≤ 10 pack years and quit ≥ 1 year ago) were randomly assigned to continuous erlotinib or in combination with carboplatin and paclitaxel (ECP) for six cycles followed by erlotinib alone. The primary end point was progression-free survival (PFS). Tissue collection was mandatory. Results PFS was similar (5.0 v 6.6 months; P = .1988) in patients randomly assigned to erlotinib alone (arm A; n = 81) or to ECP (arm B; n = 100). EGFR mutation analysis was possible in 91% (164 of 181) of patients, and EGFR mutations were detected in 40% (51 of 128) of never smokers and in 42% (15 of 36) of light former smokers. In arm A, response rate (70% v 9%), PFS (14.1 v 2.6 months), and overall survival (OS; 31.3 v 18.1 month) favored EGFR-mutant patients. In arm B, response rate (73% v 30%), PFS (17.2 v 4.8 months), and OS (38.1 v 14.4 months) favored EGFR-mutant patients. Incidence of grades 3 to 4 hematologic (2% v 49%; P < .001) and nonhematologic (24% v 52%; P < .001) toxicity was greater in patients treated with ECP. Conclusion Erlotinib and erlotinib plus chemotherapy have similar efficacy in clinically selected populations of patients with advanced NSCLC. EGFR mutations identify patients most likely to benefit.

Overview: Although advances in the molecular biology of lung cancer have rapidly impacted management of patients with advanced stage non-small cell lung cancer (NSCLC), the principal treatment in the adjuvant setting of early stage NSCLC remains platinum-based chemotherapy regimens. The evidence available from clinical trials demonstrates a similar benefit of adjuvant chemotherapy in fit, older patients as well as younger patients. Observational studies suggest that adjuvant chemotherapy for older patients provides comparable survival benefit, along with increased toxicity. The lower use of chemotherapy in the older population also suggests that the selection of appropriate patients remains an important part of the decision process. Carboplatin therapy may be substituted for cisplatin in selected older patients, and different options exist for the second cytotoxic chemotherapy agent. As in all patients, and particularly in this vulnerable population receiving cytotoxic chemotherapy, supportive care is vital. Increasing enrollment of the older population in clinical trials will be important to improve the evidence for our decision-making in the future.

11500Background: DT is a rare cancer of connective tissue affecting young patients (pts), arising in any location, with a wide natural histories. DT is locally infiltrative and may cause pain, loss of mobility, bowel obstruction and visceral organ compromise. Death is rare. There is no standard of care (SoC), but surgery, observation and systemic therapies are used. S is an oral drug inhibiting VEGFR2/PDGFRB/RAF, showing activity in DT in case series. Methods: We conducted an international prospective study to evaluate efficacy of S (400 mg qd) in unresectable progressive (PD) or symptomatic DT. Pts were randomized 2:1 (S:P) and crossover to S upon RECIST 1.1 PD. Stratification: pain-level and disease site. Primary endpoint was progression-free survival (PFS). 75 pts yielded 90% power (1-sided α = 0.025, 1 interim analysis) to detect a hazard ratio (HR) of 0.4 (favoring S), assuming 6 month (mo) median (md) PFS for P and 15 mo for S, requiring 52 PFS events. Other endpoints: response rates (RR); toxicity ...

9086Background: Early assessment of the effect of treatment for advanced NSCLC can prevent unnecessary exposure to toxic and costly therapy while aiding in decision making to change treatment if ne...

e21088Background: Body composition is an integral component of cachexia, which impacts function and treatment outcomes in patients with NSCLC. Our aim was to evaluate weight loss, lean body mass (L...

Purpose Although numerous clinical trials have demonstrated the efficacy and tolerability of erythropoiesis-stimulating agents (ESAs) in patients with chemotherapy-induced anemia (CIA), results of some recent trials and one meta-analysis have suggested that ESAs may negatively impact survival and/or disease control in patients with cancer. Methods To assess the benefits and risks of ESAs in CIA, we conducted a pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials in 2,122 patients with CIA receiving darbepoetin alfa (DA; n = 1,200) or placebo (n = 912). Results DA did not increase mortality (hazard ratio = 0.97; 95% CI, 0.85 to 1.1) and had no effect on progression-free survival (hazard ratio = 0.93; 95% CI, 0.84 to 1.04) and disease progression (hazard ratio = 0.92; 95% CI, 0.82 to 1.03), but, as expected, increased the risk for thromboembolic events (hazard ratio = 1.57; 95% CI, 1.10 to 2.26). Overall and progression-free survival were not affected by baseline hemoglobin and seemed better in patients who achieved hemoglobin more than 12 or more than 13 g/dL. Transfusions and rates of hemoglobin increase (> 1 g/dL in 14 days; > 2 g/dL in 28 days) owing to transfusions were associated with an increased risk for death and disease progression in both treatment groups; in the absence of transfusions, rates of hemoglobin increase did not appear to increase the risk for adverse outcomes. Compared with placebo, DA significantly reduced the risk of receiving one or more transfusion. Conclusion There seemed to be no association between DA and risk of death or disease progression in this meta-analysis of individual patient data from DA studies conducted in CIA, the approved indication for ESAs in oncology.

Purpose The purpose of this study was to investigate the relationship between socioeconomic status (SES) and the use of intentionally reduced doses of chemotherapy in the adjuvant treatment of breast cancer. Patients and Methods Patients with breast cancer treated with a standard chemotherapy regimen (n = 764) were enrolled in a prospective registry after signing informed consent. Detailed information was collected on patient, disease, and treatment, including chemotherapy doses. Zip code level data on median household income, proportion of people living below the poverty level, and educational attainment were obtained from the US Census. Doses for the first cycle of chemotherapy lower than 85% of standard were considered to be reduced. Univariate analyses and multivariate logistic regression were performed to identify factors associated with the use of reduced first cycle doses. Results In univariate analysis, individual education attainment, zip code SES measures, body mass index, and geographic region were all significantly associated with receipt of intentionally reduced doses of chemotherapy. In multivariate analysis, controlling for geography, factors independently associated with reduced doses were obesity (odds ratio [OR], 2.47; 95% CI, 1.36 to 4.51), severe obesity (OR, 4.04; 95% CI, 1.46 to 11.19), and education less than high school (OR, 3.07; 95% CI, 1.57 to 5.99). Conclusion Social disparities in breast cancer outcomes may be in part the result of lower quality chemotherapy doses in the adjuvant treatment of breast cancer. Efforts to address such prescribing patterns may help reduce SES disparities in breast cancer survival.

PurposeTo evaluate the efficacy and toxicity of bortezomib ± docetaxel as second-line therapy in patients with relapsed or refractory advanced non–small-cell lung cancer (NSCLC).Patients and MethodsPatients were randomly assigned to bortezomib 1.5 mg/m2(arm A) or bortezomib 1.3 mg/m2plus docetaxel 75 mg/m2(arm B). A treatment cycle of 21 days comprised four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, docetaxel on day 1. Patients could receive unlimited cycles. The primary end point was response rate.ResultsA total of 155 patients were treated, 75 in arm A and 80 in arm B. Baseline characteristics were comparable. Investigator-assessed response rates were 8% in arm A and 9% in arm B. Disease control rates were 29% in arm A and 54% in arm B. Median time to progression was 1.5 months in arm A and 4.0 months in arm B. One-year survival was 39% and 33%, and median survival was 7.4 and 7.8 months in arms A and B, respectively. Adverse effect profiles were as expected in both arms, with no significant additivity. The most common grade ≥ 3 adverse events were neutropenia, fatigue, and dyspnea (4% and 53%, 19% and 26%, and 17% and 14% of patients in arms A and B, respectively).ConclusionBortezomib has modest single-agent activity in patients with relapsed or refractory advanced NSCLC using this schedule, with minor enhancement in combination with docetaxel. Additional investigation of bortezomib in NSCLC is warranted in combination with other drugs known to be active, or using different schedules.

Purpose To determine whether BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor (MMPI), added to systemic chemotherapy improved survival in advanced non–small-cell lung cancer (NSCLC). In early phase studies, BMS- 275291 was not associated with dose-limiting joint toxicity seen with other MMPIs. Patients and Methods Chemotherapy-naive patients with stage IIIB/IV NSCLC, performance status (PS) 0 to 2, and adequate organ function were eligible. All patients received paclitaxel 200 mg/m2 plus carboplatin (area under the curve, 6 mg/mL-min) intravenously every 21 days for up to 8 cycles, and were randomly assigned to receive BMS-275291, 1,200 mg orally daily, or placebo until disease progression. The primary study end point was survival (OS); secondary end points included progression-free survival (PFS), response rates (RR), toxicity, and quality of life. Results From 2000 to 2002, 774 patients were randomly assigned. Pretreatment characteristics were well balanced between arms: median age, 61 years; male sex, 73%; stage IV, 79%; PS 0 to 1, 88%. Interim safety analysis revealed no survival advantage and increased toxicity in the experimental arm, and study treatment was stopped. Median OS, PFS and RR in the final analysis in the BMS-275291 arm were 8.6 months, 4.9 months, and 25.8% respectively, and in the control arm 9.2 months, 5.3 months, 33.7%. Toxicity was significantly higher in the BMS-275291 arm, including flu-like symptoms, rash, hypersensitivity reactions (8.6% v 2.4%), and febrile neutropenia (9.7% v 5.5%). Conclusion BMS-275291 added to chemotherapy increases toxicity and does not improve survival in advanced NSCLC.

Purpose To prospectively determine the maximum-tolerated dose of accelerated hyperfractionated conformal radiotherapy (RT; 1.6 Gy bid) for unresectable locally advanced lung cancer (IIB to IIIA/B) following induction carboplatin/paclitaxel (C/T) or carboplatin/vinorelbine (C/N). Methods Induction chemotherapy, C/T or C/N, was followed by escalating doses of conformally-planned RT (73.6 to 86.4 Gy in 6.4-Gy increments). Concurrent boost methods delivered 1.6 and 1.25 Gy bid to the gross and clinical target volumes, respectively. Results Between November 1997 and February 2002, 44 patients were enrolled (median age, 59 years; 59% male; stage III, 98%; median tumor size, 4 cm). Thirty-nine patients completed induction chemotherapy: 19 had a partial response, seven progressed, 15 had no response, and three were not assessable. Chemotherapy-associated toxicities were similar in the two chemotherapy groups. The incidence of grade ≥ 3 RT-induced toxicity was 1/13, 2/14, and 4/12 at 73.6, 80, and 86.4 Gy, respectively, thus defining the maximum tolerated dose at ≈80 Gy. Toxicities were in both lung and esophagus and were similar in the two chemotherapy arms. With a median followup of 34 months in the survivors, the actuarial 2-year survival was 47%, the median survival was 18 months. Fifteen patients had tumor relapse: 5 local failures in the high-dose volume, 2 regional failures outside of the high-dose volume, and 8 distant metastases. Conclusion High-dose conformal twice-daily radiation therapy to approximately 80 Gy appears tolerable in well-selected patients with unresectable lung cancer following either C/T or C/N. Dose-limiting toxicities are mainly pulmonary and esophageal.

Purpose: This retrospective study was undertaken to assess practice patterns in adjuvant chemotherapy for early-stage breast cancer (ESBC) and to define the incidence and predictive factors of reduced relative dose-intensity (RDI). Patients and Methods: A nationwide survey of 1,243 community oncology practices was conducted, with data extracted from records of 20,799 ESBC patients treated with adjuvant chemotherapy. Assessments included demographic and clinical characteristics, chemotherapy dose modifications, incidence of febrile neutropenia, and patterns of use of colony-stimulating factor (CSF). Dose-intensity was compared with published reference standard regimens. Results: Dose reductions ≥15% occurred in 36.5% of patients, and there were treatment delays ≥7 days in 24.9% of patients, resulting in 55.5% of patients receiving RDI less than 85%. Nearly two thirds of patients received RDI less than 85% when adjusted for differences in regimen dose-intensity. Multivariate analysis identified several independent predictors for reduced RDI, including increased age; chemotherapy with cyclophosphamide, methotrexate, and fluorouracil, or cyclophosphamide, doxorubicin, and fluorouracil; a 28-day schedule; body-surface area greater than 2 m 2 ; and no primary CSF prophylaxis. CSF was often initiated late in the chemotherapy cycle. Conclusion: Patients with ESBC are at substantial risk for reduced RDI when treated with adjuvant chemotherapy. Patients at greatest risk include older patients, overweight patients, and those receiving three-drug combinations or 28-day schedules. Predictive models based on such risk factors should enable the selective application of supportive measures in an effort to deliver full dose-intensity chemotherapy.

9054 Background: Lung-MAP (S1400) is a National Clinical Trials Network “umbrella” trial for previously-treated SqNSCLC. Sub-study S1400B included patients (pts) with tumors harboring PI3K mutations.Taselisib (GDC-0032), a potent, small molecule inhibitor of Class 1 PI3K with beta isoform sparing selectivity, has been shown to be a potent inhibitor in preclinical models of PIK3CA-mutant tumors. Methods: Eligibility stipulated progressive SqNSCLC after primary platinum-based therapy and presence of a PIK3CA mutation as determined by Foundation Medicine (FMI+) NGS. . The primary analysis population was a subgroup of the total PIK3CA mutation group (GNE+) with alterations limited to substitutions: E542K, E545A, E545G, E545K, E545Q, H1047L, H1047R, H1047Y. Primary endpoint was response rate (RR) in GNE+ pts. The initial protocol randomized PIK3 mt (+) pts to taselisib 4 mg po daily or docetaxel, but was amended to single arm phase II trial of taselisib with interim analysis based on first 20 eligible GNE+ pts evaluable for response, stipulating closure for futility if < 2 responses were observed. Results: 26 eligible pts, 7% of those registered to S1400, received taselisib; of these , 21 (81%) were GNE+. Of the 20 eligible, response-evaluable GNE+ pts, one pt with PIK3CA E545K gene alteration responded (5% RR, 95% Confidence Interval [CI] 1%, 24%). 13 pts had stable disease. Median PFS was 2.5 mos (95% CI, 1.7-4.0 mos) and 2.7 mos (95% CI, 1.8-3.4 mos) among GNE+ and FMI+ pts, respectively. 26 FMI+ pts were evaluable for toxicity: two grade 5 events (cardiac arrest, respiratory failure), neither clearly attributable to treatment, were recorded, along with one instance each of grade 4 AEs (dyspnea, thrombocytopenia, pneumonitis). Grade 3 AEs included 5 pts each with hyperglycemia or diarrhea, and 3 with lymphopenia. Overall survival data is premature. Conclusions: Study S1400B failed to meet its primary endpoint and was closed December 2016 at interim analysis for futility. Toxicities were manageable. The trial is unique in cataloguing the diversity of mutations in the PI3K pathways in SqNSCLC Clinical trial information: NCT02785913.

26 Background: Ipilimumab (Ipi) is a humanized CTLA-4 antibody that blocks binding of CTLA-4 to B7, permitting T cell activation through CD28. Phased in Ipi added to chemotherapy (C) may enhance efficacy in NSCLC. Methods: Patients with stage 2 or 3A NSCLC received neoadjuvant carboplatin AUC6 plus paclitaxel 200 mg/m2 every 21 days for 3 cycles and Ipi (10 mg/kg) was given on day 1 for cycles 2 and 3. Blood for immune profiling of circulating T cells was collected at baseline, after chemotherapy alone, and after chemotherapy plus Ipi. Tumor infiltrating lymphocytes (TIL) were derived from 7 available tumors. Polychromatic flow cytometry (PFC) analyses were performed on peripheral blood mononuclear cells (PBMC) and TIL. Objective response rates were assessed according to RECIST 1.1 criteria. Results: Of the 24 patients enrolled on this study, objective responses after 3 cycles of neoadjuvant C plus ipi included 2 PD, 8 SD, and 14 PR. Phenotypic analyses revealed that PBMC from all 24 patients were highly activated following two cycles of Ipi (cycle 3) as evidenced by significantly increased frequencies of CD28, ICOS, HLA-DR, PD-1, and CTLA-4 expressing CD4+ cells; and ICOS, HLA-DR, and CTLA-4 expressing CD8+ cells. The frequencies of Tregs were highly variable among the 24 participants. Two of the 24 participants had levels of MDSC cells above 15%. TIL contained far greater frequencies of activated CD4+ and CD8+ cells than found in the PBMC at cycle 3. Tumor associated antigen (TAA)-specific CD4+ or CD8+ cells were detected at baseline in 4 patients (24%), but their relative frequencies remained unaltered by Ipi therapy. No patients developed detectable de novo TAA reactivities while on Ipi therapy. Conclusions: Combined neoadjuvant Ipi plus chemotherapy produced significantly increased frequencies of highly activated CD4+ and CD8+ populations in the peripheral blood and the tumor microenvironment. TAA-specific CD4+ or CD8+ cells were detected in PBMC at baseline in a subset of patients. No TAA-reactive T cells were detected among the 7 TIL samples analyzed. Analysis for predictive or pharmacodynamic biomarkers is ongoing. Clinical trial information: NCT01820754.

PURPOSE: To explore the use of SD/01 (a polyethylene glycol–conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS: Thirteen patients with non–small-cell lung cancer were randomized to receive daily filgrastim (5 μg/kg/d) or a single injection of SD/01 (30, 100, or 300 μg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed. RESULTS: Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 μg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 μg/kg. Dose-limiting toxicities were not noted. CD34+ cells were mobilized in all cohorts. CONCLUSION: A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34+ cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.

PURPOSE: To confirm the promising phase II results of docetaxel monotherapy, this phase III trial was conducted of chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC) who had previously failed platinum-containing chemotherapy. PATIENTS AND METHODS: A total of 373 patients were randomized to receive either docetaxel 100 mg/m2 (D100) or 75 mg/m2 (D75) versus a control regimen of vinorelbine or ifosfamide (V/I). The three treatment groups were well-balanced for key patient characteristics. RESULTS: Overall response rates were 10.8% with D100 and 6.7% with D75, each significantly higher than the 0.8% response with V/I (P = .001 and P = .036, respectively). Patients who received docetaxel had a longer time to progression (P = .046, by log-rank test) and a greater progression-free survival at 26 weeks (P = .005, by χ2 test). Although overall survival was not significantly different between the three groups, the 1-year survival was significantly greater with D75 than with the control treatment (32% v 19%; P = .025, by χ2 test). Prior exposure to paclitaxel did not decrease the likelihood of response to docetaxel, nor did it impact survival. There was a trend toward greater efficacy in patients whose disease was platinum-resistant rather than platinum-refractory and in patients with performance status of 0 or 1 versus 2. Toxicity was greatest with D100, but the D75 arm was well-tolerated. CONCLUSION: This first randomized trial in this setting demonstrates that D75 every 3 weeks can offer clinically meaningful benefit to patients with advanced NSCLC whose disease has relapsed or progressed after platinum-based chemotherapy.

Recombinant human erythropoietin has enjoyed a high profile status throughout its history in medicine. The isolation and purification of erythropoietin and the subsequent cloning of the humanprotein,followedbyclinicaltrialsdemonstratingthereversal of anemia in renal dialysis patients in the 1980s ushered in the era of biotechnology. 1 In the 1990s, randomized clinical trials demonstrated that recombinant human erythropoietin was also effectiveintreatmentofanemiaincancerpatientsreceivingchemotherapy. 2 Subsequent open label trials described the impact of erythropoietic therapy in patients with anemia related to cancer chemotherapy. 3-5 While these trials lacked a control group, the results were very high profile because of the thousands of patients treated. These data correlated the relationship, not only between rising hemoglobin and reduction in transfusion requirement, but also in defining the relationships between anemia, fatigue, and quality of life measures. 6 These results were further validated in a subsequent randomized placebo-controlled study. 7 These open label trials also were fundamental to defining the incremental improvement in quality of life measures with increasing hemoglobin levels in cancer chemotherapy patients, with an optimum hemoglobin level of 12 g/dL. 8 Based on these data and extensive

PURPOSE The primary objective of this randomized prospective study was to compare the survival of limited-stage small-cell lung cancer (SCLC) patients treated with chemotherapy alone or chemotherapy plus thoracic radiotherapy (TRT). A secondary objective was to determine the effect of consolidation chemotherapy on survival. PATIENTS AND METHODS This multiinstitutional phase III study included 386 patients with limited-stage SCLC. All patients received cyclophosphamide 1,000 mg/m2, doxorubicin 40 mg/m2, and vincristine 1 mg/m2 (CAV) every 3 weeks for six cycles. Irradiated patients received 30 Gy in 10 fractions during weeks 1 and 2 of chemotherapy. Fifteen Gy in five fractions was administered during week 7 (total dose, 45 Gy). Following CAV, responding patients were randomized to receive two cycles of consolidation chemotherapy (cisplatin 20 mg/m2/d for 4 days plus etoposide 100 mg/m2/d for 4 days) or observation. RESULTS Complete (46% and 38%; P = .14) and overall response rates (67% and 64%; P = .58) were not statistically significantly different. Although not significantly different, median (14.4 v 12.8 months) and 2-year survival (33% v 23.5%) rates favored the irradiated patients. Grade 4 hematologic toxicity was greater in irradiated patients (60% and 39%; P < .001). Patients given consolidation chemotherapy experienced superior median (21.1 v 13.2 months; P = .028) and 2-year survival (44% v 26%; P = .028) rates. CONCLUSION The concurrent use of TRT and CAV chemotherapy as administered in this study failed to improve the survival of limited-stage SCLC patients compared with CAV alone. Life-threatening hematologic toxicities were more frequent with combined-modality therapy. The survival of limited-stage patients treated with CAV (with or without TRT) was improved with two cycles of cisplatin and etoposide consolidation therapy. Whether similar survival results could be achieved with cisplatin and etoposide alone requires additional study.

6521 Background: Metastatic breast cancer (MBC) is a responsive but heterogeneous disease with generally a poor prognosis. The clinical importance of chemotherapy dosing and schedule in this settin...

9618 Background: Cancer induced muscle wasting is a selective and progressive cancer related symptom that begins early in the course of malignancy. Greater than 50% of NSCLC patients have muscle wa...

TPS8130 Background: Non-Small Cell Lung Cancer (NSCLC) is a heterogeneous disease forwhich patients (pts) may benefit from targeted therapies. RANK ligand (RANKL) and its receptor RANK are expresse...

9607 Background: A prediction model was previously developed that estimates the risk of SN or FN during the first cycle of chemotherapy (ctx) based on pt characteristics, disease characteristics, a...

e17612 Background: G-CSF treatment is associated with improved relative dose intensity of chemotherapy, which may be associated with improved outcomes (Lyman et al. Ann Oncol. 2013;24:2475-84). How...

7506 Background: Sunitinib (S) inhibits small cell lung cancer (SCLC) targets VEGFR1-3, PDGFR, and KIT. We tested whether giving S after chemotherapy (C) for extensive stage SCLC improves progression free survival (PFS). Methods: CALGB 30504 was a randomized, double-blind, placebo (P) controlled phase II study for untreated SCLC, performance status 0-2, adequate organ function, and no S risk factors: bleeding, hypertension, or brain metastases. Enrollment was prior to C: cisplatin 80 mg/m2 or carboplatin AUC5 day 1 plus etoposide 100 mg/m2days 1-3 every 21 days 4-6 cycles. Patients without progression after C were stratified cisplatin vs carboplatin, and 4-5 vs 6 cycles C, and randomized 1:1 to P or S 37.5 mg daily until progression assessed every 6 weeks. Prophylactic cranial irradiation was offered to responders (CR or PR) to start about 4-6 weeks after C. S was held during radiation. Crossover from P to S was allowed at progression. Primary endpoint was PFS (from time of randomization) for maintenance (M) P vs S using a 1-sided log rank test with a=0.15; 80 randomized and treated patients provide »89% power to detect a hazard ratio (HR) of 1.67. Results: Between 5/09 and 12/11, 144 enrolled and 138 received C. Ninety five were randomized to P vs S; 10 did not receive M due to progression, refusal, and AE (5 each arm). Eighty five received M, 41 P and 44 S. Demographics were balanced. M toxicities grade > 3 and incidence > 5% included (%): grade 3 (S: fatigue 19, neutrophils 10, leukocytes 7, platelets 7) (P: fatigue 5); grade 4 (S: 1case GI hemorrhage, 1case lipase) P zero; grade 5 zero both arms. Efficacy (90% CI): PFS on maintenance after C was P 2.3 mo (CI: 1.7-2.6) and S 3.8 mo (2.7-4.4) (HR=1.54, CI 1.03-2.32, p=0.04). Overall survival (OS) was P 6.7 mo (5.5-9.5) and S 8.8 mo (8.0-9.8) (HR=1.10, CI 0.71-1.70, p=0.36). At progression on P, 17 received S and among 14 evaluable 10 (71%) had stable disease receiving 2-9 cycles S. Conclusions: The primary objective was met showing improved PFS for maintenance S. There was a non-significant trend toward improved OS despite crossover design. S was well tolerated. Further study of sunitinib after chemotherapy for SCLC is justified. Clinical trial information: NCT00453154.

8039 Background: CALGB (Alliance) 30406 was a randomized phase II trial that investigated erlotinib alone or in combination with carboplatin and paclitaxel in patients (pts) with a never or light smoking history with advanced NSCLC. Tissue collection was mandatory. Methods: Between August 2005 and April 2009 188 pts were enrolled. Tumor specimens were assessed using ALK immunohistiochemistry (IHC; clone D5F3; Cell Signaling); KRAS and HER2 mutations were tested. Results: The rate of mutations was: KRAS 10% (17/164), HER2 2% (3/164), and ALK + 7% (8/114). Given the small numbers of KRAS, HER2 and ALK positives, the analysis combines data from both arms. Pts with ALK + compared to ALK- NSCLC had an inferior ORR and PFS (Table). No statistically significant differences in ORR, PFS, OS between pts with KRAS or HER2 mutant and wild-type NSCLC were observed. In multivariate analysis pts with ALK+ compared to ALK- tumors experienced a statistically significant worse PFS (HR=2.67, p=0.0114) but not OS (HR=1.48, p=0.3217). One pt was identified as having an EGFR exon 21 mutation and ALK +; the pt experienced a best response of progressive disease, a PFS of 2.9 months, and OS of 17.4 months. Conclusions: (1) Pts with ALK+ compared to ALK- NSCLC have a lower ORR, worse PFS, but not OS with erlotinib alone or with carboplatin and paclitaxel. (2) The prevalence ALK+, KRAS and HER2 mutations observed was 7%, 10% and 2%, respectively. Clinical trial information: 00126581. [Table: see text]

e19100 Background: Although muscle wasting and cancer cachexia occur in > 80% of patients with advanced cancer, few well-powered scientifically-based trials have been conducted. Using enobosarm, a novel SARM, we have now enlisted 650 patients (pts) with advanced NSCLC in two phase III trials. Recent studies indicate major advantages for supportive care in NSCLC at chemotherapy initiation (Temel, NEJM 2010).This presentation examines the feasibility of pt enlistment at chemo initiation, the major characteristics of these pts and trial design for the prevention and treatment of muscle wasting. Methods: Both double-blind, placebo-controlled, international trials evaluate the effect of enobosarm in NSCLC. ˜300 pts with stage III or IV NSCLC were randomized in each trial at initiation of first-line chemo to receive additionally enobosarm or placebo for 5 months. Pts were males and postmenopausal females ≥30 years, ECOG ≤1. First line chemo: a platinum + taxane (Power 1) or platinum + non-taxane (Power 2). Co-primary endpoints at Day 84 are physical function assessed by stair climb power (SCP) and lean body mass (LBM) by DXA. Baseline characteristics are available on 634 pts (98%), as in the Table. Results: See Table. Conclusions: These results indicate that it is feasible to enlist pts receiving first-line chemo in trials designed to prevent or treat muscle wasting and cachexia; their presenting characteristics are typical for NSCLC. Median weight loss at baseline was 5% even though weight loss was not required for study inclusion. LBM and SCP were lower than typically observed in healthy individuals indicating significant functional decline before starting chemo for NSCLC. These phase III trials will determine the effect of enobosarm on preventing and treating muscle wasting in NSCLC. Clinical trial information: NCT01355484 and NCT01355497. [Table: see text]

e20564 Background: Advanced disease stage has been identified as an independent risk factor for the development of febrile neutropenia (FN), which continues to be associated with substantial morbidity. We report here results from two clinical trials on the impact of pegfilgrastim (PEG) in patients with advanced stage solid tumors. Methods: Patients were pooled from two placebo-controlled trials: a) a phase III trial of 928 patients with breast cancer, randomized to placebo or PEG 6 mg on day 2 of each 21-day cycle (Vogel CL, et al. JCO 23:1178-84, 2005); and b) a phase II trial of 241 patients with colorectal cancer (CRC), randomized to placebo or PEG 6 mg on day 4 of each 14-day cycle (Hecht JR et al. Clin CRC 9:95-101, 2010). Patients were grouped by disease stage at baseline: advanced (stage III, IIIA, IIIB, IV) or limited (stage I, II, IIA, IIB). Grade 3/4FN was defined as a temperature of ≥ 38.2°C and an ANC of 9/L. The Cochran-Mantel-Haenszel test was used to evaluate the association between PEG and grade 3/4 FN, odds ratio (OR) for FN was estimated by logistic regression, and a trend in the number of FN events per patient was estimated using a Cochran-Armitage test. Results: Characteristics of the 982 patients with advanced stage cancer are shown in the table. PEG was associated with significantly fewer grade 3/4 FN events (p < 0.001), with OR for PEG vs placebo of 0.12 (95% CI: 0.07, 0.22). The percentage of patients with 0, 1, and ≥ 2 FN events was 97%, 3%, and 0% with PEG and 81%, 18%, and 0.4% with placebo, and PEG significantly reduced the number of FN events (p< 0.001). Conclusions: Patients with advanced stage cancer are at considerable risk for developing FN, and PEG prophylaxis reduced that risk. Assessment of FN risk is essential in the advanced/metastatic treatment setting. [Table: see text]

6534 Background: The value of chemotherapy and supportive care for advanced cancer has been questioned. Two systematic reviews were conducted to study the impact of chemotherapy-induced myelosuppression and supportive care on subsequent survival. Methods: Phase 1 identified trials evaluating the relationship of chemotherapy associated with myelosuppression and subsequent survival in patients with cancer. Phase 2 evaluated randomized controlled trials (RCTs) chemotherapy with or without G-CSF support for advanced cancer. Outcomes included hazard ratios (HR), relative risk (RR) and absolute risk (AR) ±95% CI. Results: In Phase 1, 11 of 25 identified studies were conducted in patients with advanced/metastatic disease with 10 in patients with solid tumors. Among the 7 studies in patients with solid tumors reporting survival outcomes, a consistent association between chemotherapy-associated myelosuppression and reduced mortality was observed (HR=0.69; 0.61-0.77; P

e22166 Background: Hypoxia is a characteristic of many tumors and portends a worse prognosis in lung, cervical, prostate, and rectal cancers. Unlike the others, lung cancers present a unique challenge in measuring hypoxia, with invasive biopsies and higher rates of complications. Noninvasive imaging studies detecting hypoxia using isotopes of copper-diacetyl-bis (N4-methylthiosemicarbazone), CuATSM, have predicted prognosis and treatment outcomes in some small feasibility trials. These images, however, may not identify all areas of hypoxia. Hence, we hypothesize that the addition of another positron emission tomography (PET) imaging agent, copper-pyruvaldehyde-bis (N4-methylthiosemicarbazone), 62CuPTSM, which can detect areas of perfusion, can augment the information obtained in 62CuATSM PET scans. Methods: In order to characterize tumors based on both perfusion and hypoxia, ten patients were studied using both 62CuATSM and 62CuPTSM PET scans. All patients signed informed consent; the protocol was approved by the Duke University Medical Center institutional review board. 62CuATSM and 62CuPTSM SUV values at steady state were tabulated and the ratios of 62CuATSM to 62CuPTSM calculated. In addition, proteomic arrays looking at specific proangiogenic, survival, and proinflammatory targets were assessed. Results: Six out of ten patients had fully evaluable PET scans. Our initial experience of characterizing lung tumor hypoxia using 62CuATSM/62CuPTSM PET scans showed that visualization of areas with hypoxia normalized for perfusion is feasible. All studied tumors exhibited some hypoxia. Despite the small sample size, a positive relationship was noted between serum epidermal growth factor (EGF) levels and 62CuATSM detected hypoxia. Conclusions: This initial series of 62CuATSM/62CuPTSM PET scans demonstrate that evaluating pulmonary lesions by visualizing hypoxia and perfusion is a feasible and novel technique to provide more information. Further investigation is warranted to assess the potential role of 62CuATSM and 62CuPTSM PET imaging techniques combined with proteomics as alternatives to invasive biopsy techniques in clinical care.

6129 Background: Myelosuppression remains the major dose-limiting toxicity of cancer chemotherapy. The risk of myelotoxicity is associated with the specific drugs, doses and schedule utilized along with patient differences in drug metabolism and tolerance. Several retrospective studies have suggested that patients surviving early myelosuppression may experience improved disease-free and overall survival. Methods: A literature search was conducted of studies published between 1980 - 2011 reporting a relationship between chemotherapy-associated myelosuppression and cancer recurrence and/or mortality. Eligibility was restricted to adult cancer patients receiving chemotherapy and reporting disease recurrence or mortality in relationship to myelosuppression. Dual blinded study identification and data extraction were employed. Hazard ratio (HR) estimates for clinical outcomes were based on random effects models. Results: A total of 1,896 studies were identified in the initial search. A total of 25 studies analyzing results in 14,029 (range 23 – 4,626) patients were deemed to be eligible. Studies included cancers of the breast (7), lung (8), ovary (3), gastrointestinal (5), and Hodgkin lymphoma (2). Overall, neutropenia was observed in 7,577 (54%) patients. Overall survival was reported in 17 studies, recurrence or progression free survival in 11, and both in 5. Outcomes were based on HRs in 16, median survival in 14 and neither in 2. The HRs for survival and progression/recurrence free survival with and without myelosuppression were 0.66 [95%CI: 0.56-0.78; P

9135 Background: Neutropenic complications remain important dose-limiting toxicities of cancer chemotherapy associated with considerable morbidity, mortality and cost. The risk of the initial neutropenic event is greatest in the first cycle when most patients are receiving full dose chemotherapy. Methods: A prospective cohort study of adult patients with solid tumors or lymphoma receiving a new chemotherapy regimen was conducted at 115 U.S. practice sites between 2002 and 2006. Chemotherapy-associated toxicities were captured in up to 4 cycles including severe neutropenia (SN), febrile neutropenia (FN), and infection. Documented interventions included colony-stimulating factor (CSF) and antibiotics use and reductions in chemotherapy relative dose intensity (RDI). Results: Results are available on 3,638 patients starting chemotherapy of which 3,301, 2,937, and 2,199 went on to cycles 2, 3, and 4, respectively. The majority of neutropenic and infection events occurred in cycle 1. A significant inverse relationship was observed between subsequent reductions in neutropenic and infectious events and efforts to reduce these complications (Table). Most patients with stage 4 solid tumors underwent reductions in chemotherapy RDI. Patients with lymphoma and stage 1-3 solid tumors were less likely to undergo dose reductions with half or more receiving prophylactic CSFs during treatment. Approximately 15% of patients also received prophylactic antibiotics. Conclusions: While the risk of neutropenic complications remains greatest during the initial cycle of chemotherapy, clinician efforts to reduce the risk of these events vary with cancer type and stage. Reduced dose intensity is evident in two-thirds of patients with advanced solid tumors whereas the CSFs are employed in half to two-thirds of patients with early stage solid tumors or lymphoma. [Table: see text]

1062 Background: ESBC is commonly treated with myelosuppressive chemotherapy, and high relative dose intensity (RDI) correlates with improved overall survival. A retrospective analysis of patients with ESBC treated from 1997–2000 showed that 56% received an RDI < 85% (Lyman et al. JCO. 2003;21:4524-4531). To determine current practice, we evaluated ESBC treatment patterns at 24 US community- and hospital-based oncology practices. Methods: Data were abstracted from medical records of 532 patients with ESBC treated from January 2007–December 2009. Inclusion criteria included surgically resected ESBC (stage I-IIIA); ≥ 18 years old; and completion of at least 1 standard chemotherapy cycle on an every 2 or 3 week schedule. The primary endpoint was RDI over planned cycles. Other endpoints were incidence of dose delays ≥ 7 days, dose reductions ≥ 15% from standard, grade 3/4 neutropenia (SN), febrile neutropenia (FN), FN-related hospitalization, granulocyte-colony stimulating factor (G-CSF) use, and antimicrobial therapy. Descriptive statistics were generated for all endpoints. Results: In this study, mean (range) age was 55 (29–85) years. Relative to previously published results, chemotherapy regimens have shifted from mainly doxorubicin + cyclophosphamide (AC) (previously 35%) to docetaxel + cyclophosphamide (TC; n = 221; 42%) and AC followed by paclitaxel (AC-T; n = 163; 31%). Mean RDI is now higher (93% for both TC and the most common AC-T schedule [dose dense AC-T; n = 84] vs 79% previously); the incidence of dose delays (16% vs 25% previously) and dose reductions (21% vs 37% previously) have decreased; and primary prophylactic use of G-CSF has increased (76% vs 3% previously). In this study, 40% of patients had SN, 3% had FN, 2% had an FN-related hospitalization, and 30% received antimicrobial therapy. These measures were not available in the previously published results. Conclusions: The observed changes between the two studies are noteworthy though inferential comparisons are limited by changes in treatments and other factors. RDI has improved over time, but 16% of patients in this study received an RDI < 85%. Further evaluation is needed to identify factors associated with lower RDI and determine outcomes for these patients.

5084 Background: Although considerable progress has been made in the treatment of advanced ovarian cancer, complications of both disease and treatment limit long term survival. Further research is ...

Lathia et al comment on our meta-analysis of granulocyte colony-stimulating factor (G-CSF) primary prophylaxis reported in Journal of Clinical Oncology in 2007, demonstrating significant reductions in infection-related mortality, all-cause early mortality, and febrile neutropenia in patients randomly assigned to receive primary G-CSF prophylaxis compared with those receiving secondary G-CSF prophylaxis or untreated controls. Among the 17 eligible randomized controlled trials, relative risk for febrile neutropenia was 0.54 (95% CI, 0.43 to 0.67) overall and 0.61 (95% CI, 0.53 to 0.72) for filgrastim. Despite the use of different statistical programs and exclusion of certain trials, Lathia et al arrived at estimates of treatment effect nearly identical to ours. To consider all relevant studies, we included the study by Zinzani et al, because it reported clinically relevant infections during the period of neutropenia, a better approximation for febrile neutropenia than the alternative of including all neutropenic events. As Lathia et al confirm, removal of the Zinzani et al study from the meta-analysis would not only reduce heterogeneity but also have no clinically meaningful impact on estimated treatment effect, nor would it alter any study conclusions. No significant heterogeneity was observed in filgrastim studies, regardless of the inclusion of the study by Zinzani et al. In addition, because Zinzani et al reported no meaningful beneficial effect of G-CSF on early mortality or infection-related mortality, inclusion of this study in the meta-analysis is the more conservative approach. For each trial using a 2 2 factorial design, rather than assessing the visual effect of point estimates as Lathia et al suggest, we formally assessed interaction between randomization strata. Statistically significant interaction between subgroups was determined by comparing the ratio of the difference in the natural logarithm of relative risks and the SE of the difference in log relative risks with the standard normal distribution. Significant interaction was observed for survival between chemotherapy and G-CSF assignments in the Osby et al study but not in the Fossa et al study. Therefore, separate comparisons of the results for the Osby et al study were included. Although we recognize that investigators may differ in their approaches to the analysis in this circumstance, no meaningful differences in effect estimates were observed with either approach. The minimal differences in estimated rates for the two studies noted by Lathia et al are most likely attributable to rounding differences, use of differing statistical programs, and varying presence of updated study information. Overall, it is gratifying that Lathia et al have essentially replicated and confirmed the results of our meta-analysis.

6056 Background: The recently established VA Oncology Registry (VAOR) offers the ability to identify newly diagnosed patients with cancer treated at VA Medical Centers, for whom detailed clinical information can be linked to VA electronic medical data to evaluate treatment and outcomes of care. Methods: We compared male Veterans in the Pacific Northwest VAOR to male subjects in the Puget Sound Surveillance, Epidemiology, and End Results (SEER) Registry for the period 2000 through 2006. Women were excluded as they comprised 47% of SEER data but only 3% of VA patients with lung cancer. Results: We identified 1,715 Veterans and 7,864 men diagnosed with lung cancer in the Puget Sound SEER region between 2000 and 2006. Stage IV disease was common among Veterans and the SEER population (37% VAOR; 39% SEER) although stage information was missing for more subjects from SEER. Veterans were more likely to be diagnosed at an earlier age than the SEER population. Over 97% of Veterans were current or former smokers. T...

9141 Background: To evaluate the impact of G-CSF support on overall mortality in cancer patients receiving CT, a systematic review of randomized controlled trials (RCTs) was conducted. Methods: Ele...

e18003 Background: The incorporation of prognostic and predictive microarray-based biomarker assays in clinical trials or routine clinical practice is challenging. We report the methodology and design of prospective, phase II, gene expression based, directed chemotherapy trials in NSCLC. Methods: Using an Affymetrix platform, we developed genomic signatures of sensitivity to chemotherapy in NSCLC. Retrospective studies validated the sensitivity and specificity of these signatures. We initiated two prospective phase II clinical trials in NSCLC. TOP0703 is an adjuvant study that stratifies between cisplatin + pemetrexed or cisplatin + vinorelbine using genomic predictors of pemetrexed and vinorelbine in non-squamous histology. TOP602 is an advanced stage study stratifying by predicted sensitivity to cisplatin and histology: cisplatin sensitive (cisplatin + pemetrexed for non-squamous or cisplatin + gemcitabine for squamous) and cisplatin resistant (pemetrexed + gemcitabine for non-squamous or docetaxel + ge...

7072 Background: The International Association for the Study of Lung Cancer (IASLC) recently recommended changes to the TNM classification of lung cancers. For early-stage disease, increasing tumor...

7611 Background: Tobacco exposure has a profound influence on the molecular biology of NSCLC. In this study, gene expression arrays were used: 1) to define distinct molecular sub-phenotypes that dr...

11001 Background: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities between normal/embryonic stem cells and mature tumor cells, specific to lung cancer, are a result of underlying biologic processes, such as specific molecular pathways and regulatory networks. Methods: Using a large cohort of lung cancer cell lines with associated gene expression data, genes associated with an embryonic stem cell identity were used to develop a ‘signature’ representative of embryonic stemness (ES) activity specific to lung adenocarcinoma. Differential biology was evaluated using Gene Set Enrichment Analysis (GSEA) and signatures of oncogenic pathway deregulation. The ES signature was applied to three independent early (stage I - IIIa) lung adenocarcinoma data sets (N = 634) with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin sensitivity was also evaluated. Results: Using Bayesian regression analysis, a 100 gene signature representative of ES activity in lung adenocarcinoma was developed and validated in a leave-one-out-analysis. GSEA identified gene sets significantly represented in the ES signature: signature of neoplastic transformation, signature of undifferentiated cancer, BRCA pathway, and fibroblast serum response pathway, all associated with cancer invasiveness. Adenocarcinomas with ES demonstrated increased activation of RAS (p = 0.0002), MYC (p = 0.0057), wound healing (angiogenesis) (p < 0.0001), chromosomal instability (p < 0.0001), and invasiveness (p < 0.0001) gene signatures. Adenocarcinomas (N= 634) with ES had a decreased survival (p No significant financial relationships to disclose.

6552 Background: Myelosuppression is a major cause of dose-limiting toxicity in patients receiving cancer chemotherapy. A meta-analysis of randomized controlled trials of prophylactic colony-stimul...

634 Background: Reductions in chemotherapy relative dose intensity (RDI) in patients with early stage breast cancer (ESBC) have been shown to compromise disease-free and overall survival. A previous risk model identified factors associated with neutropenic events in patients with ESBC during the first cycle of treatment. The current analysis extends these observations to include the initial neutropenic event over multiple cycles. Methods: From 115 community oncology practices, 1,473 breast cancer patients starting a new chemotherapy regimen were enrolled in a prospective study and followed over the first 4 cycles of treatment. The primary outcome was febrile neutropenia (absolute neutrophil count (ANC)

20577 Background: Anemia is a common complication of cancer chemotherapy associated with considerable morbidity and cost. Guidelines recommend consideration of erythroid stimulating agents (ESAs) f...

4052 Background: While the risk of colorectal cancer (CRC) as well as comorbidities increase with age, systemic chemotherapy has become a mainstay of treatment across age groups. Trends in chemothe...

16508 Background: Chemotherapy represents a central component of effective multidisciplinary management of women with ovarian cancer. The study reported here was conducted to evaluate the delivery ...