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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...

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.

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]