Erlotinib Maintenance Therapy Research Articles

SC23.04 Cooperative Groups in China: The CSCO Experience

SC23.04 Cooperative Groups in China: The CSCO Experience

Toward a Science of Research Prioritization? The Use of Value of Information by Multidisciplinary Stakeholder Groups

In this issue of Medical Decision Making, Carlson and others describe the process of convening an external group of diverse stakeholders to identify 3 high-priority cancer genomics tests for further research and to rank these in order of priority for conducting further research. The external multidisciplinary stakeholder advisory group involved 13 members, including patient advocates, payers, test developers, a regulator, policy makers, and practicing oncologists. This group committed to meet over 2 years to help the South West Oncology Group (SWOG) leadership and investigators identify and prioritize future research areas and to help assess where scarce research funds would be best spent. The stakeholder group began by identifying 3 topics for research from a larger number of possible options in the area of cancer genomic tests. They were provided with a landscape review, and they developed priority-setting criteria in collaboration with the SWOG investigators to undertake this process. They identified 3 genomic tests for which further research would be useful: 1) ERCC1 expression testing for platinum-based adjuvant therapy in fully resected earlystage non–small cell lung cancer (NSCLC); 2) epidermal growth factor receptor (EGFR) mutation testing for erlotinib maintenance therapy after firstline chemotherapy in advanced NSCLC, and 3) breast cancer tumor markers (BC markers) for detection of recurrence after primary breast cancer therapy. The stakeholder group was subsequently provided with value of information (VOI) analyses to quantify the value of conducting further research on each of these genomic tests. More specifically, they were provided with expected value of perfect information (EVPI) analyses, which estimate the upper level dollar value of reducing the uncertainty about which strategy is the optimal intervention. Providing the stakeholder group with these analyses involved a number of complex steps: developing simulation models for each genomic test, calculating the EVPI, training the external group of stakeholders in understanding what these results mean and how to use them, and discussing the results and reranking their choices based on what they may have learned from the VOI analyses. Indeed, Carlson and colleagues describe how the stakeholder group ranking of the tests changed from 1) ERCC1, 2) EGFR, 3) BC markers to 1) ERCC1, 2) BC markers, 3) EGFR. The BC markers ranked higher relative to EGFR compared with the initial prioritization vote in part because the VOI analyses helped the stakeholders appreciate the benefits of studying a technology associated with high uncertainty. Of the stakeholders, 69% reported finding these analyses helpful and 53% reported that they changed their priority ranking because of the information provided by the VOI results. The science of research prioritization has made important advances over the past 20 years. Research prioritization has moved from an approach largely based on convening groups of experts for unstructured discussions to a scientific process that studies who and how to engage in priority-setting decisions and provides measurements of the value provided Received 11 March 2013 from Patient Centered Outcomes Research Institute (RLF); Department of Medicine, Department of Economics, and the Harris School of Public Policy Studies at the University of Chicago (DOM). Accepted for publication 20 March 2013.

Effects of erlotinib first-line maintenance therapy versus placebo on the health-related quality of life of patients with metastatic non-small-cell lung cancer

IntroductionMaintenance therapy can delay progression and prolong survival in metastatic non-small-cell lung cancer (mNSCLC). As treatment for mNSCLC is non-curative, its impact on patient health-related quality of life (HRQoL) is an important consideration. SATURN (Sequential Tarceva in Unresectable NSCLC) was a randomised, double-blind, placebo-controlled, multicentre study investigating the impact of erlotinib maintenance therapy on HRQoL in patients with locally advanced or recurrent NSCLC. Patients and MethodsEligible patients who had previously completed four cycles of platinum-based chemotherapy were randomised 1:1 to receive erlotinib 150mg/day or placebo until disease progression, unacceptable toxicity or death. Patient HRQoL was assessed using the Functional Assessment of Cancer Therapy-Lung questionnaire, in terms of time to symptom progression (TSP), time to deterioration (TTD) in Trial Outcome Index (TOI) and TTD. Exploratory analysis was based on time to analgesia and appearance of key symptoms (pain, cough and dyspnoea). ResultsCompared with placebo, erlotinib maintenance therapy prolonged progression-free and overall survival by 41% and 23%, respectively. At baseline, HRQoL measures were comparable between the two treatment groups. Maintenance therapy with erlotinib did not impact on deterioration in HRQoL: TSP (hazard ratio [HR]=0.91 [95% confidence interval (CI) 0.74–1.12]; n=785), TTD in TOI (HR=1.06 [95% CI 0.87–1.31]; n=781) and TTD in HRQoL (HR=0.96 [95% CI 0.79–1.16]; n=776). Time to pain and time to analgesic use were significantly delayed in patients receiving erlotinib compared with placebo (HR=0.61 [95% CI 0.42–0.88]; p=0.0080 and HR=0.66 [95% CI 0.46–0.94]; p=0.0199, respectively). A non-significant trend towards delayed time to cough and time to dyspnoea (HR=0.77 [95% CI 0.49–1.21] and HR=0.75 [95% CI 0.48–1.17], respectively) was also observed. ConclusionsErlotinib maintenance therapy significantly extends progression-free survival without compromising patient HRQoL in comparison with placebo, with some improvement in symptoms.

1219 - Cost-Utility Analysis of Maintenance Therapy with Either Gemcitabine or Erlotinib versus Observation with Predefined Second-Line Treatment after Cisplatin-Gemcitabine Induction Chemotherapy in Advanced Nsclc: Ifct-Gfpc 0502-ECO Phase III Study

ABSTRACT Rationale The IFCT–GFPC 0502 phase III reported prolongation of progression-free survival with maintenance with either gemcitabine or erlotinib versus observation after cisplatin-gemcitabine chemotherapy in advanced NSCLC. Their incremental cost-effectiveness ratio (ICER) was assessed in global population and in pre specified sub-groups. Methods A cost-utility analysis was performed to evaluate ICER of maintenance therapy with either gemcitabine or erlotinib, compared to observation. Direct medical costs (drugs costs, hospitalization, examinations, second-line treatments and palliative costs) were prospectively collected per patient alongside the trial, until death, from the third party payer perspective. Utility were extracted from literature. Sensitivity analyses were performed. Results ICER for maintenance therapy with gemcitabine and erlotinib were respectively 76 625 and 184 733 €/quality-adjusted life years (QALY). Gemcitabine maintenance therapy had favourable ICER in patients with PS = 0 (52 213 €/QALY), in responders to induction chemotherapy (64 296 €/QALY) and in patients with adenocarcinoma (62 292 €/QALY); erlotinib had favourable ICER if PS = 0 (94 908 €/QALY), in patients with adenocarcinoma (97 160 €/QALY) and objective response to induction (101,186 €/QALY), but it is not cost-effective in patients with PS = 1, other histology or if stable disease. Conclusion Gemcitabine and erlotinib maintenance therapy have acceptable ICER but with wide variation, function of histology, PS and response to the first line chemotherapy. Disclosure I. Borget: Honoraria from Roche for set up a class in health economy (no relation with the present study). M. Perol: consultant or advisory board with Roche, Lilly (myself) Honoraria from Lilly, Roche, Pfizer, Boehringer Ingelheim (myself) Research funding from Lilly, Roche (myself). D. Perol: Honoraria : Roche (myself). G. Zalcman: Honoraria from Lilly, Roche Research funding from Lilly, Roche. A. Vergnenegre: honoraria and research funding from Roche. C. Chouaid: Honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffman la Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis and Amgen Research funding from AstraZeneca, Lilly, Novartis and Amgen. All other authors have declared no conflicts of interest.

Cost-utility analysis of maintenance therapy with either gemcitabine or erlotinib versus observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC: IFCT-GFPC 0502-eco phase III study.

e16560 Background: The IFCT–GFPC 0502 phase III study reported a prolongation of progression-free survival with maintenance with either gemcitabine or erlotinib versus observation after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC. The aim of this analysis is to assess the incremental cost-effectiveness ratio (ICER) of these strategies in the global population and in pre specified sub-groups. Methods: A cost-utility analysis was performed to evaluate ICER of maintenance therapy with either gemcitabine or erlotinib, compared to observation, from randomization until end of follow up. Direct medical costs (including drugs costs, hospitalization, follow-up examinations, second-line treatment and palliative costs) were prospectively collected per patient alongside the trial, until death, from the third party payer perspective. Utility data were extracted from literature. Sensitivity analyses were performed. Results: The ICER for maintenance therapy with gemcitabine and erlotinib were respectively 84,011 and 183,261 euros per quality-adjusted life years (QALY). Gemcitabine maintenance therapy had a favourable ICER in patients with PS = 0 (51,168 €/Qaly), in responders to induction chemotherapy (65,554€/Qaly) and in patients with squamous cell carcinoma (44,884€/Qaly); erlotinib had a favourable ICER in patients with PS = 0 (162,371 €/Qaly) and objective response to induction (101,569 €/Qaly ). Conclusions: Gemcitabine and erlotinib maintenance therapy have acceptable ICER but with a wide variation function of histology, PS and response to the first line chemotherapy.

Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy

In the placebo-controlled phase III SATURN study, maintenance erlotinib after first-line chemotherapy demonstrated significantly prolonged progression-free survival (PFS) and overall survival (OS) in the overall study population of patients with advanced non-small-cell lung cancer (NSCLC). After four cycles of platinum-based doublet chemotherapy, patients without progressive disease (PD) were randomised to erlotinib (150 mg/day) or placebo until PD or unacceptable toxicity. In this pre-planned analysis, data are assessed according to response to first-line chemotherapy (complete/partial response [CR/PR] or stable disease [SD]). Following first-line chemotherapy, 889 non-PD patients were included in the intention-to-treat population (55% SD; 44% CR/PR; <1% unknown response). Erlotinib maintenance therapy significantly prolonged PFS in both the SD (hazard ratio [HR] = 0.68; P < 0.0001) and CR/PR (HR = 0.74; P = 0.0059) groups, while OS was significantly prolonged in the SD group only (HR = 0.72; P = 0.0019). The erlotinib-related OS benefit in the SD group remained significant across subgroups, irrespective of tumour histology and/or EGFR mutation status. The incidence of adverse events was similar in the SD group and the overall population, and erlotinib treatment did not negatively impact quality of life. Patients with advanced NSCLC and SD following first-line platinum-based doublet chemotherapy derive a significant OS benefit from maintenance erlotinib therapy.

Prospective Molecular Marker Analyses of EGFR and KRAS From a Randomized, Placebo-Controlled Study of Erlotinib Maintenance Therapy in Advanced Non–Small-Cell Lung Cancer

Prospective Molecular Marker Analyses of EGFR and KRAS From a Randomized, Placebo-Controlled Study of Erlotinib Maintenance Therapy in Advanced Non–Small-Cell Lung Cancer

Prospective Molecular Marker Analyses of EGFR and KRAS From a Randomized, Placebo-Controlled Study of Erlotinib Maintenance Therapy in Advanced Non–Small-Cell Lung Cancer

Prospective Molecular Marker Analyses of EGFR and KRAS From a Randomized, Placebo-Controlled Study of Erlotinib Maintenance Therapy in Advanced Non–Small-Cell Lung Cancer

Prospective Molecular Marker Analyses of EGFR and KRAS From a Randomized, Placebo-Controlled Study of Erlotinib Maintenance Therapy in Advanced Non–Small-Cell Lung Cancer

The phase III, randomized, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study found that erlotinib maintenance therapy extended progression-free survival (PFS) and overall survival in patients with advanced non-small-cell lung cancer (NSCLC) who had nonprogressive disease following first-line platinum-doublet chemotherapy. This study included prospective analysis of the prognostic and predictive value of several biomarkers. Mandatory diagnostic tumor specimens were collected before initiating first-line chemotherapy and were tested for epidermal growth factor receptor (EGFR) protein expression by using immunohistochemistry (IHC), EGFR gene copy number by using fluorescent in situ hybridization (FISH), and EGFR and KRAS mutations by using DNA sequencing. An EGFR CA simple sequence repeat in intron 1 (CA-SSR1) polymorphism was evaluated in blood. All 889 randomly assigned patients provided tumor samples. EGFR IHC, EGFR FISH, KRAS mutation, and EGFR CA-SSR1 repeat length status were not predictive for erlotinib efficacy. A profound predictive effect on PFS of erlotinib relative to placebo was observed in the EGFR mutation-positive subgroup (hazard ratio [HR], 0.10; P < .001). Significant PFS benefits were also observed with erlotinib in the wild-type EGFR subgroup (HR, 0.78; P = .0185). KRAS mutation status was a significant negative prognostic factor for PFS. This large prospective biomarker study found that patients with activating EGFR mutations derive the greatest PFS benefit from erlotinib maintenance therapy. No other biomarkers were predictive for outcomes with erlotinib, although the study was not powered for clinical outcomes in biomarker subgroups other than EGFR IHC-positive [corrected]. KRAS mutations were prognostic for reduced PFS. The study demonstrated the feasibility of prospective tissue collection for biomarker analyses in NSCLC.

Pancreatic adenocarcinoma-associated polymyositis treated with corticosteroids along with cancer specific treatment: case report

BackgroundAdenocarcinoma of the pancreas only rarely is associated with inflammatory myopathy. In this setting, polymyositis may be treated with glucocorticoids in combination with cancer specific treatment.Case presentationWe present the case of a 52-year-old man with stage IIA pancreatic tail adenocarcinoma who underwent surgical treatment and six months into therapy with gemcitabine he developed symmetrical, painful, proximal muscle weakness with peripheral oedema. Re-evaluation with imaging modalities, muscle histology and biochemistry conferred the diagnosis of polymyositis associated with pancreatic cancer progression. The patient was treated with glucocorticoids along with gemcitabine and erlotinib which resulted in complete remission within six months. He remained in good health for a further six months on erlotinib maintenance therapy when a new computer tomography scan showed pancreatic cancer relapse and hence prompted 2nd line chemotherapy with gemcitabine.ConclusionsPolymyositis associated with pancreatic cancer may respond to glucocorticoids along with cancer specific treatment.

Approval Summary: Erlotinib Maintenance Therapy of Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC)

On April 16, 2010, the U. S. Food and Drug Administration (FDA) approved erlotinib tablets (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY) for maintenance treatment of patients with stage IIIB/IV non-small cell lung cancer (NSCLC) whose disease had not progressed after four cycles of platinum-based first-line chemotherapy. In total, 889 patients received either erlotinib (150 mg) or placebo once daily. Progression-free survival (PFS), in all patients and in patients with epidermal growth factor receptor (EGFR)(+) tumors by immunohistochemistry (IHC), was the primary efficacy endpoint. Overall survival (OS) was a secondary sponsor endpoint but was the primary regulatory endpoint. Median PFS times were 2.8 months and 2.6 months in the erlotinib and placebo arms, respectively (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.62-0.82; p < .001). Median OS times were 12.0 months and 11.0 months, favoring erlotinib (HR, 0.81; 95% CI, 0.70-0.95). The PFS and OS HRs in patients with EGFR(+) tumors by IHC were 0.69 (95% CI, 0.58-0.82) and 0.77 (95% CI, 0.64-0.93), respectively. The PFS and OS HRs in patients with EGFR(-) tumors by IHC were 0.77 (95% CI, 0.51-1.14) and 0.91 (95% CI, 0.59-1.38), respectively. Following disease progression, 57% of placebo-treated patients received additional chemotherapy, compared with 47% of erlotinib-treated patients. Fourteen percent of placebo-treated patients received erlotinib or gefitinib, 31% received docetaxel, and 14% received pemetrexed. In total, 59% of placebo-treated patients who received treatment received FDA approved second-line NSCLC drugs. The most common adverse reactions in patients receiving erlotinib were rash and diarrhea.

Phase II trial of erlotinib maintenance therapy after platinun-based chemotherapy in advanced non-small cell lung cancer (NSCLC)

e19013 Background: phase II trial-efficacy &amp; toxicity of sequential erlotinib in advanced NSCLC after platinum-based CT Methods: Pts with adv NSCLC, PS 0/1, adequate renal, hepatic and bone marrow function, no PD after CT. Treatment: erlotinib 150 mg/day starting 3–4 weeks after CT until progression. Safety was evaluated monthly and tumor evaluation bimonthly. Results: 47 pts enrrolled:42(89%)stageIV &amp; 5(11%)wet IIIB, all valid for response &amp; toxicity. Median age 62 y(r:39 -77): 39(83%) males and 8(17%) females. Histology: adenocarcinoma 8(61.7%), bronquioloalveolar 3(6.4%), large cell 3(6.4%), squamous12(25.5%). PS 0: 23(49%), PS 1:24(51%). 38(81.9%) completed 6 cycles of CT. Response: CR: 1(2.1%), PR: 2(51.1%), EE: 22 (46%). Sequential erlotinib improved RR in 6 (12.8%), 23 (48.9) prolonged stabilization, 18 (38.3%) had progression. Median TTP and OS were 9.4 m (95% CI, 4.96–13–84), and 19.23 m (95% CI, 8.82–29.64). No significant differences in TTP according to age, sex, PS, histology or previous response to CT, but yes depending on RR to erlotinib: PR: 31.5 m (95% CI 15.37–47.63), EE: 12.8 m (95% CI, 10.58–15.03), PD: 6.3 m (95% CI, 5.36–7.3), p &lt; 0.001; and moreover depending on smoking status: Never: 21.67 m(95% CI, 5.39–37.94), previous smoker &gt; 5 years: 14.03 m(95% CI, 10.77–17.30), previous smoker 1 year: 7.77 m(95% CI, 7.62–7.91), current smoker: 5.9 m(95% CI, 5.12–6.34), p &lt;0.001. In Cox-regression model, smoking status ( p&lt; 0.001), and response to erlotinib (p=0.002) were associated with a significant difference in TTP. Similar results in OS, although in Cox-regression model only never smoker or &gt; 5 years previous smoker pts had a significant better survival. Toxicity: The most frequent was skin rash, grade (g) 1 in 11(23.4%), g 2: 16(34%) and g 3: 3(6.4%). Only 1 p had diarrea g 3, and no other side effects were observed. We found a significant benefit in p with g 2–3 skin toxicity respect g 0–1, in both TTP( p= 0.0003) and OS (p= 0.0014). Conclusions: Erlotinib-maintenance therapy after platinum-based CT had promising results. Pts with the best benefit were those with response to erlotinib, in never or past (&gt; 5 years) smokers and with g 2–3 skin toxicity. No significant financial relationships to disclose.

Biomarker analyses from the phase III placebo-controlled SATURN study of maintenance erlotinib following first-line chemotherapy for advanced NSCLC

8020 Background: The SATURN (BO18192) study investigated whether erlotinib maintenance therapy improved PFS in patients (pts) with advanced NSCLC who had obtained clinical benefit from 1st-line chemotherapy. This study included a prospective analysis of the prognostic/predictive value of several molecular markers. Methods: 889 pts with advanced NSCLC whose disease had not progressed following 4 cycles of 1st-line platinum-doublet chemotherapy were randomized to erlotinib 150 mg/day or placebo. Mandatory tumor specimens were collected at baseline and tested for EGFR protein expression using immunohistochemistry (IHC), EGFR gene copy number using fluorescent in-situ hybridization (FISH), and EGFR and KRAS somatic mutations using DNA sequencing. Pts were stratified according to EGFR IHC status (any membranous staining in ≥10% tumor cells used as cut-off); the co-primary endpoint was PFS in EGFR IHC+ pts. Baseline whole blood samples were obtained for genotyping of EGFR (intron 1 CA-repeat polymorphisms). Results: In the overall population, erlotinib significantly prolonged PFS vs placebo (HR 0.71, p&lt;.0001; primary endpoint). The co-primary endpoint was also met, with erlotinib significantly improving PFS in the EGFR IHC+ group (HR 0.69, p&lt;.0001). Many tumor samples were assessable for molecular marker status (see table). Biomarker data suggest that patients derived a PFS benefit with erlotinib irrespective of EGFR FISH or EGFR intron 1 CA-repeat status. The magnitude of benefit with erlotinib was similar in both KRAS-mutant and KRAS wild-type pts. Conclusions: This is the largest biomarker analysis performed for erlotinib in a randomized, placebo-controlled setting, and answers key scientific questions regarding the prognostic and predictive value of potential biomarkers of efficacy. Full data will be presented. [Table: see text] [Table: see text]

Disruption of the EGFR E884–R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity

Targeted therapy against epidermal growth factor receptor (EGFR) represents a major therapeutic advance in lung cancer treatment. Somatic mutations of the EGFR gene, most commonly L858R (exon 21) and short in-frame exon 19 deletions, have been found to confer enhanced sensitivity towards the inhibitors gefitinib and erlotinib. We have recently identified an EGFR mutation E884K, in combination with L858R, in a patient with advanced lung cancer who progressed on erlotinib maintenance therapy, and subsequently had leptomeningeal metastases that responded to gefitinib. The somatic E884K substitution appears to be relatively infrequent, and resulted in a mutant lysine residue that disrupts an ion pair with residue R958 in the EGFR kinase domain C-lobe, an interaction that is highly conserved within the human kinome as demonstrated by our sequence analysis and structure analysis. Our studies here, using COS-7 transfection model system, show that E884K works in concert with L858R in-cis, in a dominant fashion, to change downstream signaling, differentially induce MAPK-ERK1/2 signaling and associated cell proliferation, and differentially alter sensitivity of EGFR phosphorylation inhibition by ERBB family inhibitors in an inhibitor-specific fashion. Mutations of the conserved ion pair E884-R958 may result in conformational changes that alter kinase substrate recognition. The analogous E1271K-MET mutation conferred differential sensitivity towards preclinical MET inhibitors SU11274 (unchanged), and PHA665752 (more sensitive). Systematic bioinformatics analysis of the mutation catalog in the human kinome (COSMIC) revealed the presence of cancer-associated mutations involving the conserved E884 homologous residue, and adjacent residues at the ion pair, in known proto-oncogenes (KIT, RET, MET, FAK) and tumor suppressor gene (LKB1). Targeted therapy using small molecule inhibitors should take into account potential cooperative effects of multiple kinase mutations, and their specific effects on downstream signaling and inhibitor sensitivity. Improved efficacy of targeted kinase inhibitors may be achieved by targeting the dominant activating mutations present.

Phase I trial of neoadjuvant and postoperative paclitaxel (P), carboplatin (C) and erlotinib with concurrent accelerated hyperfractionation radiation (AHFR) followed by erlotinib maintenance therapy in stage III non-small cell lung cancer (NSCLC)

2091 Background: Erlotinib (E), a potent reversible Her1/EGFR tyrosine kinase inhibitor is a radiosensitizer in preclinical studies. Our study was conducted to determine the recommended dose of E when given with P, C and AHFR before/after surgery in patients (pts) with potentially resectable stage III NSCLC. Methods: Pts had biopsy-proven Stage III NSCLC, and ECOG performance status of 0/1. Treatment Plan was: 1) Induction AHFR (30 Gy/1.5 Gy BID), with concurrent P [50 mg/m2] C (AUC 2), weekly x 3, and E at 3 dose levels (DL); I: 50, II: 100, and III: 150 mg, orally once daily (qd) for 4 weeks (wks); 2) Surgery after 4 wks; 3) a second identical course of chemoradiotherapy (CRT) 4–6 wks postoperatively; 4) 2-year maintenance of a fixed dose of E (150 mg qd). 3 to 6 pts were treated at each DL of E. A dose level was deemed intolerable if greater than or equal to 2 of 6 pts develop a dose-limiting toxicity (DLT). Results: Between 8/03 and 11/04, 6 male and 3 female pts were enrolled, 4 at DL I, 3 at DL II, 2 at DL III. Median age was: 61(range 33–68) years. All pts completed induction treatment. 7 pts had surgery (3 lobectomy; 4 pneumonectomy). One patient (pt) progressed; 1 pt was deemed unresectable. 6 of 9 pts received postoperative CRT + E. No DLT was observed at DL I or DL II. One pt at DL 3 had prolonged postoperative recovery from respiratory failure (grade IV toxicity). Common grade I-II toxicities were, rash (6 pts), diarrhea (3 pts), and esophagitis (3 pts). One pt at DL I had reversible posterior leucoencephalopathy, thought to be unrelated to treatment. There were no unexpected surgical complications, and no treatment-related mortality. 4 pts were downstaged at surgery; to stage I: 1 pt, stage II: 2, and 1 pt had complete pathologic response. Maintenance E was started in 6 pts. 7 of 9 pts are progression free at a mean follow-up of 9.1 months (range: 5–15). Additional pts are being treated at DL III to further characterize toxicity. Conclusion: Erlotinib in combination with concurrent weekly P/C/AHFR is well tolerated. The recommended dose of E has not yet been determined. A phase II study is planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Genentech, Lilly Oncology, Pfizer, Bayer, Antigenics Amgen, Pfizer, Eyetech, Genentech, Genentech Genentech, Pfizer, Celgene, Antigenics, Amgen, Wyeth