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BACKGROUND. We conducted a phase 2, multicenter, open-label study of erlotinib plus bevacizumab in patients with malignant pleural mesothelioma who had previously received 1 prior chemotherapy regimen. These agents have activity in non–small cell lung cancer, but their role in mesothelioma is unclear. The primary endpoint is response rate. Secondary endpoints include time to progression, survival, and toxicity. METHODS. Eligible patients with mesothelioma who had previously received 1 chemotherapy regimen were treated with erlotinib 150 mg per os daily and bevacizumab 15 mg/kg administered intravenously on Day 1 of a 21-day cycle. Treatment continued until disease progression or development of significant toxicity. Tumor response was assessed after every 2 cycles using previously established mesothelioma response criteria from Byrne and Nowak. RESULTS. Twenty-four eligible patients initiated therapy with erlotinib and bevacizumab between February 2004 and October 2006. There were no complete or partial responses, although 12 patients achieved stable disease for at least 2 cycles of treatment. The median time to progression was 2.2 months (95% confidence interval [CI], 1.4 months-5.9 months). The median survival was 5.8 months (95% CI, 2.8 months-10.1 months). The most common toxicities were rash and diarrhea. There were no treatment-related deaths, intracranial bleeding, or hemoptysis. CONCLUSIONS. The combination of erlotinib and bevacizumab was tolerated reasonably well, but there was no evidence of radiographic response. This study demonstrates the feasibility of conducting trials in mesothelioma patients who have failed first-line therapy. More therapeutic studies with effective agents are needed for these patients. Cancer 2008. © 2008 American Cancer Society.

PURPOSE/OBJECTIVES To evaluate a nurse-led intervention to enhance medication knowledge and adherence using the Multinational Association for Supportive Care in Cancer Oral Agent Teaching Tool (MOATT). DESIGN Longitudinal, descriptive feasibility study. SETTING An ambulatory thoracic oncology disease center located at the Dana-Farber Cancer Institute in Boston, MA. SAMPLE 30 adult patients with lung cancer who received the oral agent erlotinib. METHODS Structured, nurse-led education sessions using the MOATT were provided, with a 72-hour follow-up telephone contact. Participants completed a Knowledge Rating Scale (KRS) and adapted Morisky Medication Adherence Scale-8 (MMAS-8) at the end of the first cycle of oral chemotherapy. MAIN RESEARCH VARIABLES Knowledge and adherence; feasibility. FINDINGS Twenty-seven participants completed the study outcome measures reporting high knowledge levels and MMAS-8 scores. Structured, nurse-led education and follow-up monitoring sessions ranged from 14-30 minutes. Several participants also initiated contact for assistance with prescription procurement and symptom management. Participants reported a median of two side effects. CONCLUSIONS The structured, nurse-led teaching, using the MOATT tool, and follow-up nurse contacts were feasible as integrated into the thoracic oncology setting. Adherence and knowledge outcomes were encouraging. Additional studies should include objective adherence measures and strategies for delivering supportive care to patients at home. IMPLICATIONS FOR NURSING Structured teaching with patients is important to enhance proper oral anticancer medication knowledge and adherence, including follow-up monitoring of administration and side effects at 72 hours.

Purpose: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non–small-cell lung cancer (NSCLC), we conducted a phase I clinical trial.Patients and Methods: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 × 106, 4 × 106, or 1 × 107cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals.Results: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/106cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed.Conclusion: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.

// David M. Jackman 1, 2, * , Leigh A. Cioffredi 4 , Lorraine Jacobs 5 , Farhana Sharmeen 1 , Linda K. Morse 1 , Joan Lucca 1 , Scott R. Plotkin 2, 6 , Paul J. Marcoux 1, 2 , Michael S. Rabin 1, 2 , Thomas J. Lynch 7, 8 , Bruce E. Johnson 1, 2 , Santosh Kesari 3, * 1 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 2 Harvard Medical School, Boston, MA, USA 3 Department of Neurosciences, Translational Neuro-Oncology Laboratories, Moores UCSD Cancer Center, University of California, San Diego, La Jolla CA, USA 4 Georgetown University School of Medicine, Washington, DC, USA 5 Eurofins Medinet B.V., Breda, The Netherlands 6 Stephen E. & Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA 7 Smilow Cancer Hospital at Yale-New Haven, Yale Cancer Center, New Haven, CT, USA 8 Yale University, New Haven, CT, USA * These authors have contributed equally to this work Correspondence to: David M. Jackman, e-mail: djackman@partners.org Santosh Kesari, e-mail: skesari@ucsd.edu Keywords: non-small cell lung carcinoma, epidermal growth factor receptor, meningeal carcinomatosis, kinase inhibitors Received: September 20, 2014 Accepted: December 09, 2014 Published: February 25, 2015 ABSTRACT Introduction: There are few effective treatment options for leptomeningeal metastasis (LM) in non-small-cell lung cancer (NSCLC). This study assessed the feasibility of high-dose gefitinib in patients with LM from NSCLC harboring EGFR mutations or prior systemic response to EGFR-TKI. Methods: This phase I open-label trial of a novel gefitinib dosing schedule employed a 3+3 design. Eligible NSCLC patients with LM had known EGFR mutations and/or prior response to EGFR-TKI. Patients alternated 2 weeks of high-dose daily gefitinib (dose levels: 750 mg, 1000 mg, 1250 mg) with 2 weeks of maintenance therapy (500 mg daily). Primary endpoints were safety and toxicity. Secondary endpoints included overall survival (OS), neurological progression-free survival, radiological response, and cytological response in cerebrospinal fluid (CSF). Results: Seven patients were treated: 3 at 750 mg dose level, 4 at 1000 mg dose level. There were no DLTs at the 750 mg dose level, and one DLT (toxic epidermal necrolysis) at the 1000 mg dose level. The study was closed due to slow accrual. Median neurological PFS was 2.3months (range 1.6–4.0 months); median OS was 3.5months (range 1.6–5.1months). Though there were no radiologically documented remissions of LM disease, four patients had improvement in neurological symptoms. One patient cleared their CSF of NSCLC cells, while 2 others had decrease in malignant cells in CSF. Conclusion: Although the MTD was not defined due to slow accrual, this study provides important information about the tolerability and CSF penetration of high-dose gefitinib as a therapeutic option for modest palliation for NSCLC patients with LM and a known EGFR mutation.

8076 Background: Erlotinib is a first-line therapy for patients (pts) with advanced EGFR mutant non-small cell lung carcinoma (NSCLC). However, tumors develop acquired resistance; choice of further...

To determine the maximum-tolerated dose of docetaxel (DOC) in combination with carboplatin (CAR) and thoracic radiotherapy (RT), in the setting of trimodality treatment of patients with stage III non-small cell lung cancer (NSCLC).Thirty-two patients with biopsy-proven stage IIIA (n = 20) or IIIB (n = 12) NSCLC were given two initial cycles of CAR (area under the curve = 6) and DOC (75 mg/m(2)), subsequent RT (54 Gy) with concurrent weekly CAR (area under the curve = 2), and DOC at six dose levels from 10 to 40 mg/m(2), then surgery if the patient's disease was resectable.Three patients did not complete induction computed tomography (CT). Twenty-nine patients received concurrent CT/RT. Fifteen patients were eligible for surgery. Dose-limiting toxicities occurred in 2 patients, at dose levels two (atrial fibrillation) and three (transaminitis). The maximum-tolerated dose, as defined by the protocol, was not reached, although grade 3 and 4 toxicities were encountered at all dose levels. The most common more than or equal to grades 3 toxicities were neutropenia, nausea, vomiting, and fatigue. Four patients (13.3%) responded to induction CT. Ten patients (38.5%) responded to CT/RT. Eight surgical patients (57.1%) were downstaged, including 3 pathologic complete responses. Median relapse free and overall survivals are 8.5 and 12 months. One-year and estimated 2-year survival rates are 56.3 and 34.3%.This new regimen for stage III NSCLC of induction CAR/DOC, then weekly CAR/DOC with concurrent RT followed by surgery, can be safely administered and offers encouraging results. DOC at 30 mg/m(2) in combination with CAR and RT is recommended for Phase II study.

7099 Background: Despite response to initial therapy, SCLC has high rates of relapse or distant metastasis and limited 2nd-line therapeutic options. Angiogenesis is an essential part of cell invasion, dissemination, and outgrowth of distant metastases and therefore is a potential therapeutic target in SCLC. Pazopanib (Votrient, GSK) is a potent, competitive inhibitor of the tyrosine kinase activity of VEGFR-1, VEGFR-2, VEGFR-3, PDGF, and c-kit. We initiated a phase II single-arm trial of pazopanib in relapsed or refractory SCLC to determine impact on disease progression. Methods: Patients were eligible if they had progressive disease following up to two lines of prior therapy. Patients were treated at the FDA-approved dose of 800 mg pazopanib once daily. The primary endpoint was progression-free rate (PFR) at 8 weeks. Secondary endpoints included median progression-free survival, overall survival, and safety. The trial followed a Simon 2-stage design to limit accrual if no therapeutic benefit was observed. Results: To date, 27 of 30 planned subjects have been enrolled since October 2010. Two did not complete cycle 1 and were considered inevaluable for response. Major toxicities (mostly grade 1/2) were those previously described including nausea, fatigue, hypertension, electrolyte abnormalities, and AST/ALT elevations (grade 3 in 4 subjects). Three subjects were removed from study due to toxicity: 1 with grade 3 nausea, 1 with grade 3 drop in the cardiac ejection fraction, and 1 with multiple grade 2 toxicities including diarrhea, fatigue, and nausea. A fourth was removed due to grade 1 hemoptysis despite clinical response. The PFR at 8 weeks of 21 subjects evaluable for response to date was 52%; 4 of these 11 subjects had chemo-refractory disease. There were no confirmed responses, but tumor regressions ranged from 2-20%. Median progression-free survival is 14.1 weeks. Conclusions: In patients with SCLC, single-agent pazopanib demonstrated a notable rate of stable disease (including among chemo-refractory patients) and a median PFS that exceeds that of historical PFS rates of < 2 months on ineffective 2nd-line therapies. These data suggest that the potential for pazopanib in SCLC treatment should be further investigated.

Background: XL765 is an oral, selective inhibitor of Class I PI3Ks, as well as TORC1 and TORC2. The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mediator of resistance to EGFR inhibitors. In preclinical studies, XL765 has demonstrated dose-dependent target modulation in tumor xenograft models. In an ongoing Phase 1 single agent clinical study, XL765 has exhibited robust pharmacodynamic activity in diverse solid tumors. Methods: Pts with advanced solid tumors are enrolled in successive cohorts of 3 to receive escalating doses of XL765 in combination with erlotinib. Cycles consist of 28 days of XL765 and erlotinib, each given qd. During the ongoing dose-escalation phase of the study there is a 14-day run-in period of erlotinib monotherapy. Cycle 1 safety data determine dose limiting toxicities (DLTs). Tumor response is evaluated every 8 weeks. Results: As of 24Aug2009, 14 pts with advanced solid tumors have been enrolled: NSCLC (11), CRC (1), liposarcoma (1), and endometrial adenocarcinoma (1). Most of the NSCLC pts have been previously treated with erlotinib before entering the study. Pts have been treated at 2 dose levels of XL765 (30 and 50 mg) administered once-daily in combination with 100 mg erlotinib. No DLTs or study treatment-related SAEs have been reported. As of 03Aug2009, AEs have been reported for 7 pts. Grade 3 adverse events of nausea, vomiting, and anorexia considered related to study treatment were observed in one pt dosed at 30 mg qd. The PK of XL765 given in combination with erlotinib is consistent with that observed for XL765 given alone (Exelixis study XL765-001). Likewise, XL765 does not appear to alter the PK of erlotinib. In skin biopsies, substantial post-dose reductions were evident in phosphorylation of AKT, the mTOR substrate 4EBP1, and EGFR. For example, progressive pharmacodynamic effects were evident in serial skin biopsies from a pt with EGFR-mutant NSCLC previously treated with erlotinib who has remained on study through 26 weeks, culminating in decreases in pAKT-T308 (72%), p4EBP1 (57%), pERK (73%), and pEGFR (50%) at Day 85 post-start of combination dosing (50 mg XL765/100 mg erlotinib). Pharmacodynamic analyses of paired tumor biopsies are in progress. Of the first 9 patients enrolled, five have remained on study for at least 12 weeks. Conclusions: XL765 in combination with erlotinib is generally well tolerated at doses up to 50 mg XL765/100 mg erlotinib, with no apparent drug-drug PK interaction, and results in robust simultaneous inhibition of PI3K and EGFR signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A254.

8065 Background: This single-arm phase II study explored the role of clinical characteristics (female gender, adenocarcinoma histology, no tobacco within 1 year) in selecting pts for 1st-line therapy w/ erlotinib. Available tissue for EGFR mutation analysis was required to assess its impact on outcomes. Methods: Eligible pts were chemotherapy-naïve women, stage IIIB/ IV, PS 0–2, adenocarcinoma, and w/ available tissue for analysis of EGFR mutation status. Pts received erlotinib 150 mg PO daily until disease progression or unacceptable toxicity. Primary endpoint was response rate (RR). Secondary endpoints included toxicity, time to progression (TTP), overall survival (OS), and impact of EGFR genotype on clinical outcomes. Results: From 11/04 - 12/08, 84 pts were treated. Median age 68 (range 34–88); 59 PS 0, 24 PS 1, 1 PS 2; race: 79 white, 3 Asian, 2 black; 16 pts had BAC or predominant BAC features; smoking status: 35 never, 49 former. Tox: Rash (90%; 21% grade 3) and diarrhea (69%; 7% grade 3) were the most common toxicities. 32 pts developed toxicity grade 3+ felt likely related to erlotinib. 2 deaths may be treatment-related (1 DIC, 1 hepatic failure). There were also 3 pts w/ PE's (1 fatal). Efficacy: Response (n=84): 0 CR, 27 PR (RR 32%), 27 SD, 23 PD. 7 pts not evaluable (5 tox, 1 non-progression death, 1 withdrawn consent). Median TTP was 5.6 months (95% CI 4.1–7.4 mos), and median OS was 22.7 months (95% CI 15.8 - 26.0 mos). At the time of analysis, there were 36 deaths, 16 pts on treatment w/o progression, and 5 pts lost to follow-up. Compared to smokers, never-smokers trended toward improved RR (43% vs 22%, p=.06), w/ improved TTP (HR .59; 95%CI .36-.96) but no improvement in OS (HR 1.15, 95%CI .58–2.27). Genotype had a more obvious impact on outcomes: compared w/ 37 known wild-type EGFR, 33 pts w/ known sensitizing mutations had a higher response rate (70% vs 0), and significantly improved hazard ratios for both TTP (.20, 95%CI .11-.36) and OS (.36, 95% CI .18 - .73). Results will be updated and outcomes for rarer mutations will be reported. Conclusions: Clinical characteristics may help select appropriate pts for first-line erlotinib when EGFR mutation status is unavailable. However, when available, EGFR genotype is superior to clinical phenotype in selecting pts for first-line erlotinib. [Table: see text]

7591 Background: Erlotinib is associated with a survival benefit over placebo for pts with advanced NSCLC who had received 1–2 prior regimens. Its role as initial therapy in clinically defined subgroups or in pts prospectively tested for EGFR mutations is less clear. Methods: Chemotherapy-naive women with adenocarcinoma, stage IIIB/IV, PS 0–1, who had formerly or never smoked, were enrolled and treated with erlotinib 150 mg PO daily, until the time of disease progression or unacceptable toxicity. Response rate was the primary endpoint. Secondary endpoints included overall survival, progression-free survival and toxicity. Tumor tissue adequate for genomic analysis was mandated and prospectively collected for determination of EGFR and KRAS mutations by direct sequencing. Results: From 11/04 to 10/06, 40 women were treated. Demographics: median age 65 yrs (range 36–87); 38 white, 1 black, 1 Asian; 30% PS 0, 70% PS 1; 20% BAC or adenoCA w/ predominant BAC features, 80% adenoCA w/o BAC features; smoking status: 63% former, 37% never. Toxicity: Rash (95%; 30% grade 3) and diarrhea (73%; 10% grade 3) were the most common toxicities. 50% of pts developed toxicity of grade 3 or greater. 5 pts were discontinued due to toxicity, with 2 deaths that were possibly treatment-related: 1 DIC, 1 hepatic failure. There were also two pts with PE (one fatal). Response: CR 0, PR 12 (30%), SD 11 (28%), and PD 10 (25%), 7 not evaluable. To date, 27 patients have progressed, with 14 deaths. Median PFS was 5.6 months; median overall survival has not yet been reached and exceeds 23 months. Of 32 patients sequenced for EGFR to date, there were 9 exon 19 deletions, 3 L858R mutations, and 1 exon 20 insertion. For the 12 pts prospectively determined to have classic EGFR mutations, RR was 75% (9 PR, 2 SD, 1 not evaluable). Of 15 pts w/ wild-type EGFR, only 1 response (7%) was achieved. The pt w/ the exon 20 insertion developed PD. Of 28 pts evaluated to date for KRAS, 6 KRAS mutations were found, w/ no responses in this group (2 PD, 4 SD). Conclusions: Preliminary results suggest that first-line erlotinib monotherapy may be a useful treatment strategy for women with adenocarcinoma and a limited smoking history. Response rate is particularly impressive for those subjects prospectively found to have an EGFR mutation, and poor for those with KRAS mutations. No significant financial relationships to disclose.

7168 Background: Elderly patients derive survival benefit but significant toxicity from chemotherapy for NSCLC. Erlotinib is associated with reasonable toxicity and has a survival benefit for relapsed patients previously treated with 1–2 chemotherapy regimens. This targeted agent may prove an effective and well-tolerated first-line therapy in elderly patients with advanced disease. Methods: 80 patients (chemo-naïve, age ≥ 70, PS 0–2, stage IIIB/IV NSCLC) were treated with erlotinib 150 mg/d as part of a phase II study. Primary endpoint was survival. QoL was a secondary endpoint, as assessed by LCSS at baseline and q4 weeks until progression. The primary endpoint of QoL analysis was to determine changes from baseline in LCSS score. Patients were eligible for QoL analysis if they completed an LCSS questionnaire at baseline and ≥ 1 other monthly follow-up visit. Each of 9 items was assessed on a 100mm visual analog scale from 0 (best) to 100 (worst); symptom improvement or worsening was based on a change of ≥ 10mm, with decreased scores implying improvement. Score differences between the baseline and best follow-up response of each subscale and total LCSS are assessed by the signed rank test. Results: 64 patients (80%) were eligible for QoL analysis. There was a trend towards improvement in QoL, based on the total LCSS score. Statistically significant improvements in dyspnea, cough, fatigue, and pain were seen, both in terms of median changes from baseline and the proportion of patients improved (Table). No patients were symptomatic for hemoptysis at baseline, so improvement could not be calculated. Conclusions: Erlotinib in elderly patients with advanced NSCLC was associated with encouraging survival (10.9 mo), a trend towards improved QoL, and statistically significant improvements in key symptoms of dyspnea, cough, fatigue, and pain. Mixed effects longitudinal modeling showing changes in LCSS over time will be presented at the conference. [Table: see text] [Table: see text]

7148 Background: Chemotherapy for patients ≥ 70 with advanced NSCLC is associated with survival benefits but with increased toxicity compared with younger patients. Erlotinib has shown promising activity and a tolerable side effect profile, and it has been approved in the treatment of patients who have failed prior chemotherapy. We have conducted a single center, phase II trial of erlotinib in patients ≥ 70 years with previously untreated advanced NSCLC. Methods: Patients who were chemotherapy-naive, IIIB/IV, PS 0–2, were enrolled and treated with erlotinib, 150 mg p.o.q.d, until evidence of disease progression or toxicity. Median survival is the primary endpoint. Secondary endpoints include response rate, toxicity, quality of life (measured by LCSS), and gene sequencing for EGFR and K-ras mutations, and EGFR copy number (CN). Results: From 3/03 to 8/04, 58 patients were treated; all were evaluable for survival and toxicity; 55 were evaluable for response. Demographics: median age 76 (range 70–91); 55% ma...

2031 Background: E7070 is a novel sulfonamide cell cycle inhibitor, demonstrating preclinical synergy with irinotecan. A phase I study was designed to determine the MTD of E7070 in combination with...

7080 Background: Chemotherapy for patients ≥ 70 years of age with advanced NSCLC can be associated with greater toxicities than in younger patients. The identification of an efficacious therapy with minimal systemic toxicity would be particularly beneficial to elderly subjects. Erlotinib (Tarceva™) has shown promising activity, and a tolerable side effect profile, in the treatment of patients who have failed prior chemotherapy. We thus chose to conduct a single center phase II trial of erlotinib in patients ≥ 70 with previously untreated advanced NSCLC. Methods: Patients: chemotherapy naive, IIIB (w/malignant effusion)/IV, PS 0–2; treated with erlotinib, 150 mg p.o. q.d., until evidence of disease progression or toxicity. Primary endpoint: median survival; secondary endpoints: response rate, quality of life (using LCSS), changes in FDG-PET, and analysis of EGFR signaling pathway from pre-treatment tumor specimens. Results: From 3/03 to 12/03, 36 pts were treated; 30 evaluable for toxicity and response; 1 ...