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A. Vergnenegre



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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.09 - Feasibility and clinical impact of re-biopsy in advanced non-small cell lung cancer: a prospective multicentric study in real world setting (GFPC study 12-01) (ID 1045)

      17:00 - 17:05  |  Author(s): A. Vergnenegre

      • Abstract
      • Presentation
      • Slides

      Background
      In case of progression under initial treatment, repeat biopsy is a new option procedure in advanced non-small cell lung cancer (NSCLC). Its justification is based on the assessment of biological markers (comparison to the initial status, emergence of resistance to chemotherapy or new biomarkers). The aim of this pragmatic prospective multicenter study was to assess feasibility and clinical utility of re-biopsy in real world setting in advanced NSCLC.

      Methods
      Patient’s main inclusion criteria was advanced NSCLC with an indication of repeat biopsy by the referent clinician. The primary outcome was the percentage of successful procedures; secondary outcomes were localization of the new biopsy, type of procedure, new biological status (comparison to initial status, new biomarkers, resistance biomarkers) and tolerance of the procedure.

      Results
      From May 2012 to May 2013, 18 centers included 102 patients. The characteristics of the 67 first patients were: male: 40%; age: 64.8 ± 10.9 years; PS 0/1: 87%; adenocarcinoma: 85%; EGFR mutated: 46.2%; no biological available assessment: 16.4%; controlled disease as best response to first line: 70%. Repeat biopsy was possible in 80.6%. The main failure reasons were: inaccessible lesion: 4.5%, medical contraindications: 14.9%. Main procedures were: bronchial endoscopy: 48.1%, trans thoracic needle biopsy: 24.1%. The procedure permits to find, in EGFR wild type population, 3 patients with a driver oncogene (1 HER2, 1 Ros1, 1 EML4 ALK); in EGFR mutated patients, 2 T790M mutations and to obtain in 3 patients with no biological data’s at the diagnosis, a biological profile. Complications were very low: 2 cases of moderate bleeding and 1 case of pneumothorax.

      Conclusion
      Repeat biopsy is a feasible procedure with acceptable adverse events. Recommendations should be realized on the indications of re-biopsy, the timing and the recommended site (primary versus metastasis, progressive target versus no progressive). Analysis of the complete population (n=102) will be presented at the meeting. Supported by an academic grant from Boehringer Ingelheim Company and Hoffmann-La Roche Company.

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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.05 - Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients with acquired resistance to erlotinib. (ID 1426)

      10:50 - 10:55  |  Author(s): A. Vergnenegre

      • Abstract
      • Presentation
      • Slides

      Background
      NSCLC patients with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs) but ultimately relapse. Sub-genomic molecular studies indicate that the EGFR T790M mutation and the activation of MET, PI3K, AXL, HER2 and MAPK can lead to acquired resistance to EGFR TKIs. To date, no integrated comprehensive genomic investigation of EGFR TKI resistance has been reported.

      Methods
      FFPE biopsies of erlotinib-sensitive and erlotinib-resistant tumors were obtained from 13 EGFR mutant NSCLC patients. The samples were analyzed by whole exome sequencing and whole transcriptome sequencing utilizing the Illumina HiSeq2500 platform. In addition, targeted gene sequencing was performed with the Illumina TruSeq Amplicon-Cancer Panel and run on the MiSeq system.

      Results
      Erlotinib resistant NSCLC specimens harbored known resistance drivers, including EGFR T790M mutations (9/13; 69%), MET amplification (3/13; 23%), HER2 amplification (3/13; 23%), and AXL upregulation (3/13; 23%). Differential expression analysis between resistant and pre-treatment states revealed enrichment in the pre-treatment tumors of immune signaling pathways, and in the resistant tumors upregulation of ERBB2, mTOR, PI3 kinase and ribosomal signaling pathways. PI3K/AKT pathway upregulation also occurred through somatic mutations in AKT and LKB1 in the resistant tumors. Copy number analysis demonstrated both large scale and focal amplifications and deletions in the resistant tumors, including the focal loss of EGFR and gain of c-Myc and NKX2-1. There was strong correlation between the copy number changes observed and the expression mRNA levels of the involved cancer-associated genes. Of note, each resistant tumor exhibited greater copy number similarity to the corresponding matched pre-treatment sample compared to other tumors within the resistance cohort.

      Conclusion
      We conducted the first ever comprehensive integrated genomic analysis of EGFR TKI resistant NSCLC patients, and identified both known and potentially novel drivers of EGFR TKI resistance. This study demonstrated the feasibility and utility of comprehensive genomic analysis in the clinical management of NSCLC receiving targeted therapy. Together, our data provide unprecedented insight into the molecular pathogenesis of escape from EGFR oncogene inhibition in NSCLC. We are now conducting a prospective observational study in additional NSCLC patients on targeted therapy.

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    MO26 - Anatomical Pathology II (ID 129)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO26.08 - The concomitant presence of echinoderm microtubule associated protein like 4 - anaplastic lymphoma kinase (EML4-ALK) EML4-ALK fusion gene in EGFR-mutant non-small-cell lung cancer (NSCLC) patients treated with erlotinib or chemotherapy in the EURTAC trial</b> (ID 1109)

      11:10 - 11:15  |  Author(s): A. Vergnenegre

      • Abstract
      • Presentation
      • Slides

      Background
      Activating mutations in the epidermal growth factor receptor (EGFR) confer sensitivity to gefitinib and erlotinib in patients with NSCLC. However, response is often short-lived, and patients ultimately relapse, indicating that other concomitant actionable mutations could influence outcome in these patients. The EML4-ALK fusion gene has recently been identified in a subset of NSCLCs, but its specific role remains unclear. We have evaluated the frequency and impact of the concomitant presence of EML4-ALK in patients included in the randomized phase III EURTAC trial.

      Methods
      The EURTAC study enrolled 173 EGFR-mutant NSCLC patients who were randomized to receive erlotinib or standard chemotherapy with cisplatin or carboplatin plus docetaxel or gemcitabine. Tumor specimens were available from 95 of these patients for the analysis of EML4-ALK. EML4-ALK variants 1 and 3 (v1, v3) were analyzed by an independent single round of PCR followed by sequencing, using cDNA as a sample.

      Results
      EML4-ALK was detected in 15 samples (15.79%). Nine tumors contained v1 (E13;A20) and six v3 (E6;A20). No significant differences were found in baseline characteristics between patients with and without EML4-ALK. Progression-free survival was 10.4 months (m) for patients harboring the EML4-ALK fusion gene compared to 7.1 m for those without EML4-ALK. Overall survival (OS) was not reached in patients with EML4-ALK, compared to 22.9 m in those without. Complete data on outcome according to treatment arm will be presented.

      Conclusion
      Our findings indicate that the EML4-ALK rearrangement is concomitant with EGFR mutations in a considerable number of NSCLC patients and may affect outcome.

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    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 3
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      O15.02 - The Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized phase III trial of customized chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) (NCT00617656/GECP-BREC) (ID 1157)

      10:40 - 10:50  |  Author(s): A. Vergnenegre

      • Abstract
      • Presentation
      • Slides

      Background
      RAP80, a component of the BRCA1 complex, influenced outcome both in p with low BRCA1 expression treated with cisplatin (cis)/gemcitabine (gem) and in p with intermediate/high BRCA1 levels treated with cis/docetaxel (doc) or with doc alone in the SLCG phase II customized chemotherapy trial (NCT00883480). Based on these findings, the SLCG and the French Lung Cancer Group performed a prospective, randomized phase III trial in metastatic NSCLC patients to compare non-customized cis/doc with customized therapy customized according to BRCA1 and RAP80 mRNA expression levels.

      Methods
      From 2008 to 2013, patients with wild-type EGFR were randomized 1:1 to the control or experimental arm. Planned accrual was 391 patients. Treatment in the control arm was cis/doc, while patients in the experimental arm received treatment according to their BRCA1 and RAP80 levels: 1) those with low RAP80, regardless of BRCA1 levels, received cis/gem; 2) those with intermediate/high RAP80 and low/intermediate BRCA1 received cis/doc; and 3) those with intermediate/high RAP80 and high BRCA1 received doc alone. The primary endpoint was progression-free survival (PFS).

      Results
      At 15 October 2012, 279 patients had been included and the planned interim analysis was performed. PFS was 5.49 months (m) in the control and 4.38 m in the experimental arm (P=0.07). Overall survival (OS) was 12.66 m in the control and 8.52 m in the experimental arm (P=0.006). Response rate (RR) was 37.3% in the control and 27% in the experimental arm (P=0.07). In the multivariate analysis including PS, treatment arm, BRCA1, RAP80, histology, smoking status and metastatic site, only extrathoracic metastases were associated with an increased risk of progression (HR, 1.78; P=0.02). In a post hoc analysis restricted to patients with ECOG PS 0, PFS was 3.91 m in the control and 7.47 m in the experimental arm (P=0.01) for those with low RAP80 levels (experimental group 1). PFS for patients in experimental groups 1, 2 and 3 was 7.47, 7.01 and 3.22 m, respectively (P=0.02). OS for patients in experimental groups 1, 2 and 3 was 28.88, 15.86 and 11.81 m, respectively (P=0.04).

      Conclusion
      Based on the negative results for PFS at the interim analysis, accrual was closed on this study. The negative results may be due to the poor predictive capacity of RAP80 and/or to the inclusion of doc alone as a treatment in the experimental arm. In addition, doc/cis may not have been the ideal combination for the control arm. Customized chemotherapy could be further encouraged in oncogene-driven pan-negative patients with PS 0.

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      O15.03 - Phase III, randomized, multicenter study comparing in elderly patients (≥70 years) with stage IV non small-cell lung cancer (NSCLC) a standard strategy of treatment allocation (carboplatin based bi-therapy or monotherapy with docetaxel) based on performance status (PS) and age with an experimental strategy allocating the same chemotherapies or best supportive care (BSC) according to a comprehensive geriatric assessment (CGA) - Study ESOGIA-GFPC-GECP 08-02. (ID 694)

      10:50 - 11:00  |  Author(s): A. Vergnenegre

      • Abstract
      • Presentation
      • Slides

      Background
      Incidence of advanced NSCLC in the elderly is increasing. The use of a CGA is recommended to detect the patient’s vulnerability but its integration in treatment decision making has never been prospectively evaluated. The main objective of this study was to show that, compared to a standard strategy based on PS and age, the use of a CGA can improve the management of NSCLC in first line.

      Methods
      Randomized, multicentric, prospective phase III study in patients ≥70 y, PS 0-2 with stage IV NSCLC. We compared in arm A a standard algorithm of chemotherapy allocation based on PS and age: carboplatin based doublet in PS≤1 and age ≤75y, mono-therapy in PS =2 or age >75y with in arm B an experimental strategy of treatment allocation based on CGA: carboplatin based doublet for fit patients, mono-therapy for vulnerable patients and BSC for frail patients. Carboplatin (AUC5,d1), was associated to pemetrexed (500 mg/m2,d1) in non-squamous tumors and to gemcitabine (1000 mg/m2, d1-8) in squamous tumors, monotherapy was docetaxel 38 mg/m2 (d1-8). Four cycles of chemotherapy were to be given every three weeks. The main endpoint was time to failure treatment (TTF=duration between the date of randomization and the date the patient was withdrawn from treatment for any reason (progression, toxicity, death), secondary endpoints were Overall Response Rate (ORR), overall survival (OS), toxicity and quality of life (QoL), survival adjusted on QoL .

      Results
      493 patients were randomized from 01/2010 to 01/2013 by 45 centers. Patients characteristics were: male: 74%, median age: 77 (70-91) years, non-squamous histology: 71.8%, PS 0-1: 81.4%, ADL<6:13.9%, IADL<4:27.5%, Charlson’s index ≥2: 23%, score GDS 5≥3:2.5%. The 2 arms were well-balanced for patients characteristics except for ADL<6 (17.4% in arm A vs 10.3% in arm B). Respectively in arms A and B, 34.4% and 47% patients received a carboplatin based doublet, 65.6% and 31.5% received docetaxel and in arm B 21.5% received BSC. There was no significant difference in terms of TTF, respectively for arm A and arm B: median TTF was 99 days (d), 95%CI:[89; 126] vs. 98 d, 95%CI:[81;135], p=0.7149 and in terms of mOS: 196 d in arm A, 95%CI [171;231] vs. 185 d in arm B ,95%CI [148;235], p=0.7784. All grades toxicities were significantly less frequent in arm B than in arm A (93% vs.86.2%, p=0.016), but there was no difference in terms of grade 3-4 toxicities. All the secondary endpoints data will be updated at time of the meeting.

      Conclusion
      this large phase III study failed to show a superiority of a CGA based strategy of treatment allocation in terms of TTF. In experimental arm, 21.5% of frail patients according to Balducci’s criteria were enrolled and received an exclusive BSC management. Carboplatin-based doublets with pemetrexed and gemcitabine according to histology are feasible with a good profile of tolerance in selected elderly patients. This study will help to precise the most relevant geriatric tools and their cut-off in order to improve the management of the elderly with advanced NSCLC.

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      O15.06 - Randomized Phase III Trial of Gemcitabine (G)/Carboplatin (C) with or without Iniparib (I) in Patients (Pts) with Previously Untreated Stage IV Squamous Lung Cancer (ID 3322)

      11:25 - 11:35  |  Author(s): A. Vergnenegre

      • Abstract
      • Presentation
      • Slides

      Background
      Iniparib is an agent originally thought to function as an inhibitor of the DNA repair enzyme PARP-1, which is overexpressed in squamous lung cancers. Promising phase II activity and safety were reported with iniparib in combination with GC in pts with metastatic triple-negative breast cancer (O’Shaughnessy, NEJM 2011); however, subsequent phase III data were negative. Further study of iniparib’s mechanism of action suggests that this agent induces DNA damage, cell cycle arrest in the G2/M phase, and potentiates DNA-damaging chemotherapies not through PARP inhibition. Herein we report the final results from an international Phase III trial (NCT01082549) of first-line chemotherapy and iniparib in pts with advanced squamous lung cancer.

      Methods
      Pts were randomized 1:1 to GC or GCI. All pts received G 1000 mg/m[2] IV days (D) 1 and 8, and C AUC=5 IV D1 of each 21-D cycle. Iniparib was dosed 5.6 mg/kg IV D 1, 4, 8, and 11. All pts were assessed for response per RECIST 1.1 every 6 weeks. Pts without evidence of progressive disease (PD) or other reason for discontinuation could remain on treatment beyond 6 cycles. Accrual of 780 pts provides 89% power to detect an improvement in survival from 8 months (mos) anticipated with GC to 10.7 mos with GCI (HR of 0.75). Eligibility: Pts with newly diagnosed stage IV (M1a and M1b) squamous lung cancer, ECOG PS 0-1. Exclusion criteria included: history of recent cardiac disease, untreated brain metastases, and treatment for early-stage lung cancer within 12 months of study entry. The primary endpoint was overall survival (OS). Interim analyses for safety and futility were performed by an independent data safety monitoring board.

      Results
      780 pts were enrolled and randomized (GC, 390), (GCI, 390) from March 2010 to May 2012. Baseline characteristics were well balanced between groups (GC/GCI): median age 66 years (21-86); 74%/73% male; 30%/33% ECOG 0; 28%/33% current smokers; 66%/62% past smokers. The median number of cycles for GC/GCI were 4 (1-26)/5 (1-32). Dose reductions, dose intensity, and discontinuations due to tumor progression or adverse events were similar in both arms. The median OS for GC/GCI was 8.9 v. 8.9 months, HR 1.08 (0.92-1.28), p=.348. 1-year OS was 41 v. 40%. The median progression-free survival (PFS) for GC vs GCI was 4.9 v. 4.8 months, HR 0.99 (0.83-1.19), p=.92. The objective response rate (ORR) for GC v GCI was 34 v. 32%, p=.648. The safety profile was similar in both arms; anemia (28/26%), neutropenia (31/35%), thrombocytopenia (27/28%), and fatigue (6/9%).

      Conclusion
      The addition of iniparib did not improve the efficacy of GC in the treatment of pts with advanced squamous lung cancer. Further development of iniparib in squamous lung cancer is not recommended.

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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O16.03 - Cost-utility analysis of first-line treatment with erlotinib versus chemotherapy in EGFR-mutant advanced non-small-cell lung cancer (NSCLC): economic analysis of EURTAC trial (ID 1100)

      10:50 - 11:00  |  Author(s): A. Vergnenegre

      • Abstract
      • Presentation
      • Slides

      Background
      The impact of tyrosine kinase inhibitors (TKIs) in EGFR-mutant advanced NSCLC is poorly documented. Two studies (Jacob et al, ISPOR2010, Brown et al, Health Technol Assess, 2010) are based on modelisation and indirect comparisons. The present study reports a cost-utility analysis of a phase III randomized trial (EURTAC).

      Methods
      A three state Markov model (first line PFS, second line PD and death) was built. Clinical data and resource assessment (drugs, drug administration, adverse events, second-line treatment) were collected from the trial. Utility values were derived from Nafees et al, as previously published (Vergnenegre et al. JTO 2011). Incremental cost-utility ratios (ICUR) were calculated for the first-line treatment and the overall strategy until death from the perspective of different countries (2013 actualized euros). Sensitivity analyses researched the main cost drivers.

      Results
      The quality-adjusted life-years gained was 0.124 with erlotinib, which showed an improvement in the quality of life for these patients. Despite the extra treatment costs of second-line erlotinib in the chemotherapy arm, there was a cost benefit for erlotinib first, resulting in fewer patients receiving second-line pemetrexed along with other therapy. Cost gain in favor of first-line erlotinib was 8,918 Euros. The main results are depicted in Table1.

      First-line erlotinib First-line chemotherapy
      Average cost of first-line (euros 2013)
      Drugs 21,679 1030
      Administration 329 4,455
      Adverse events 546 2,686
      Cost of post-first progression care 40,467 67,281
      ICUR (erlotinib versus chemotherapy)
      ICUR France negative
      ICUR Spain negative
      ICUR Italy negative
      Sensitivity analyses will be presented at the meeting.

      Conclusion
      ICUR favored first-line erlotinib in EGFR-mutant patients with advanced NSCLC, which is the widely accepted treatment compared to chemotherapy. The cost-utility of the overall strategy remained beneficial in three different European countries. On behalf GFCP,GEPC and AIOT groups

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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-001 - Phase II study of concurrent chemo-radiotherapy (CRT) with weekly cisplatinum plus oral vinorelbine in fit elderly patients with nonresectable locally advanced non-small-cell lung cancer (NSCLC) assessed by Standardized Geriatric Assessment (RACCOSA, GFPC 08-06 study): interim analysis. (ID 233)

      09:30 - 09:30  |  Author(s): A. Vergnenegre

      • Abstract

      Background
      Few studies are dedicated to elderly patients with unresectable stage IIIA/B. We used a Standardized Geriatric Assessment (SGA) to select fit elderly patients and assess if this population can benefit from standard of care, namely concurrent CRT.

      Methods
      The aim of this multicentric phase II opened-study was to assess CRT in patients older 70 years with locally advanced NSCLC, evaluated as “fit” according to SGA.CRT associated oral vinorelbine (30 mg/m²/week) and IV cisplatinum (30 mg/m²/week) during 6 weeks concurrently with radiotherapy (66 Gy, 33 fractions, 6,5 weeks). Main inclusion criterias were : PS ≤ 1, weight loss < 10%, creatinine clearance ³ 50 ml/mn abreviated, VEMS ³ 40%, PaO2 ³ 60 mm Hg, KCO ³ 60% and patient classified as fit according to SGA. The principal end-point was early treatment tolerance (number of patients with adverse event grade ³ 3 (except nausea and vomiting) or grade 4 for hematologic toxicity and asthenia. Secondary end-points were RECIST response 4 weeks after treatment, quality of life, tolerance, progression-free survival and overall survival. Using a Simon's optimal plan in 2 steps, the total number of patients to be included was 59 with an intermediate analysis after 19 patients. Toxicities and serious adverse events were monitored by an independent peer committee.

      Results
      Interim analysis was done after 23 inclusions in 19 evaluable patients: males 84% , mean age 74.6 (70 to 83) years, 3 patients didn’t end the treatment (1 disease progression, 1 cons-indication for radiotherapy, 1 patient choice). Four patients had adverse event ≥ 3 (except nausea and vomiting) or grade 4 hematologic toxicity and asthenia. Treatment efficacy was: 1 RC, 10 RP, 5 SD, 1 PD. Two patients were not evaluable (1 early death, 1 patient’s refusal to further treatment). The independent peer committee judged that toxicities were acceptable and consistent with what was expected. Study is ongoing with 44 enroled patients currently.

      Conclusion
      The interim analysis of a phase II study of CRT in fit elderly patients with no resecable locally advanced NSCLC assessed by SGA showed an acceptable toxicity. Results will be upgraded for the congress.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-013 - Randomized non comparative multicenter phase II study of sequential erlotinib with docetaxel versus docetaxel alone in patients with non small cell lung cancer (NSCLC) after failure of first line chemotherapy (TARSEQ): a GFPC 10.02 study. (ID 972)

      09:30 - 09:30  |  Author(s): A. Vergnenegre

      • Abstract

      Background
      Erlotinib and docetaxel are approved in second line treatment of advanced NSCLC. Concomitant administration of a tyrosine kinase inhibitor (TKi) of EGFR with standard chemotherapy in first line did not improve survival compared to chemotherapy alone. Preliminary studies support a possible efficacy of sequential administration of EGFR TKi and chemotherapy. Objective: This open randomized phase II trial (Tarseq) was designed to assess the efficacy and tolerability of second-line sequential erlotinib plus docetaxel in advanced NSCLC.

      Methods
      Patients were randomized (1/1, stratified by center, disease status: recurrent or refractory (no response observed after 4 cycles of first-line chemotherapy))between sequential erlotinib 150 mg/d (day 2-16) + docetaxel (75 mg /m2 d1- 21) (arm A) versus docetaxel (75mg/m2 d1) alone (arm B) until disease progression or unacceptable toxicity. Primary endpoint was the rate of patients with progression-free survival at 15 weeks (PFS15) ; second endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and tolerability. Main eligibility criteria were advanced NSCLC, EGFR wild type or unknown, performance status 0 to 2, failure of first line cisplatin based chemotherapy; main exclusion criteria were more than 2 lines of treatment, previous anti-EGFR or docetaxel treatment. Statistical analysis was based on a Simon’s optimal two stage design . The primary endpoint is rejected if the number of efficacy is less 33 over 66 pts (25+ 41) at the end of the two stages.

      Results
      147 patients were randomized by 33 centers: median age: 60 ± 8 years, PS 0/1/2 (44/83/20 pts) ; male: 78%, EGFR status: wild type 66%, unknown: 34%; recurrent patients: 65% (arms A/B :66%/65%), nonsquamous: 86% (arms A/B : 84%/90%), smoking status: smokers 35%, formers 57,5%, never 7,5%. Baseline characteristics were balanced between 2 arms. In ITT, the primary objective was not meet with 18/66 pts without progression at 15 weeks in arm A, 17 /66 pts in arm B. In arm A and B, median PFS was 2,2 (CI95% 1,6-2,8) and 2,5 (CI 95% 1,7-2,8) months and median OS was 6,6 (CI 95% 4,3-10,3) and 8,4 (CI 95% 4,5-11,3) months respectively. Toxicity was acceptable in both arms with 60.2 % and 54% of G3/4 toxicity in arms A and B, respectively.

      Conclusion
      The sequential combination of erlotinib with docetaxel did not demonstrate any benefit in second-line treatment of EGFR wild type or unknown advanced NSCLC, despite acceptable toxicity. The Pharmacological hypothesis of synergism between erlotinib given sequentially and standard chemotherapy is not confirmed in the present study. Clinical trial information: NCT01350817 / Supported by an academic grant from Roche, Chugai, Sanofi Aventis,with the help of clinical research direction ( Limoges University Hospital)

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-009 - <b>ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer (NSCLC) patients with the EGFR T790M mutation</b> (ID 1395)

      09:30 - 09:30  |  Author(s): A. Vergnenegre

      • Abstract

      Background
      Molecular cross-talk between EGFR and other signaling pathways creates alternative means of tumor cell proliferation and promotes resistance to single-agent erlotinib therapy in NSCLC driven by EGFR mutations. ROR1 knockdown inhibited the growth of NCI-H1975 cells (harboring EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling in cooperation with AKT has been demonstrated. We have assessed ROR1 expression in 45 patients from the EURTAC trial (clinicaltrials.gov NCT00446225), 27 of whom harbored pretreatment concomitant EGFR T790M mutations, and correlated results with outcome.

      Methods
      ROR1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles; patients were classified as having low/intermediate or high ROR1 expression. The T790M mutation was determined by Taqman with a PNA to inhibit amplification of the wild-type (wt) allele. Tumor samples were run in octuplicates; this method can detect 1 mutated allele among 10,000 wt alleles.

      Results
      Median age 65; 68.9% female; 57.8% never-smokers; 95.6% ECOG PS <2; 91.1% adenocarcinoma; 68.9% exon 19 deletion. No differences in baseline characteristics were observed according to ROR1 expression levels. 24 patients (53.3%) were treated with erlotinib and 21 (46.7%) with chemotherapy. 10 (41.7%) erlotinib-treated patients and 6 (28.6%) chemotherapy-treated patients had high ROR1 mRNA levels. Among erlotinib-treated patients, response rate (RR) was 40% for the 10 patients with high ROR1 levels vs 71.4% for the 14 with low/intermediate levels (P=0.058). Among chemotherapy-treated patients, RR for the 15 patients with low/intermediate ROR1 levels was 6.7%; the 6 patients with high ROR1 levels did not respond. Progression-free survival (PFS) was 11.8 months (m) for erlotinib-treated patients with low/intermediate ROR1 levels vs 5.8 m for those with high levels. PFS for chemotherapy-treated patients was 5.6 and 9 m, respectively (P=0.0165). 15 erlotinib-treated patients harbored concomitant T790M mutations; for these patients, PFS was10.8 m for those with low/intermediate ROR1 levels vs 2.7 m for those with high levels (P=0.0138).

      Conclusion
      ROR1 expression has a differential effect on outcome to erlotinib and chemotherapy in EGFR-mutant NSCLC patients. High ROR1 expression significantly limits PFS in erlotinib-treated patients with T790M mutations and ROR1-directed therapies can enhance the efficacy of treatment. In contrast, high ROR1 expression confers longer PFS to chemotherapy in the same group of patients. The role of chemotherapy and erlotinib in EGFR-mutant NSCLC patients with high ROR1 expression warrants further investigation.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-041 - Impact of a Comprehensive Geriatric Assessment on management strategies in elderly patients with advanced no small cell lung cancer (NSCLC): a polled analysis of two phase 2 prospective study of the GFPC group. (ID 2418)

      09:30 - 09:30  |  Author(s): A. Vergnenegre

      • Abstract

      Background
      The impact of a systematic use of a Comprehensive Geriatric Assessment (CGA) on management strategies in elderly patients with no small cell lung cancer (NSCLC) is not well established. The objective of this study was to analyze if items of CGA may predict overall survival of elderly patients with NSCLC treated by chemotherapy or erlotinib in first or second lines setting.

      Methods
      Individuals data’s of GFPC 0504 study (population of fit elderly patients) and GFPC 0505 study (population of frail elderly patients) were pooled. The aim of these two prospective phase 2 trials were to compare a strategy using chemotherapy (doublet in fit patients, monotherapy in frail patients) in first line followed by erlotinib in second line to the reverse strategy (erlotinib in first line, followed by chemotherapy), in terms of progression-free survival (PFS) in second line period. Secondary outcomes were to compare first-line PFS, overall survival (OS), tolerance and costs. All patients had a complete comprehensive geriatric assessment, evaluating diverse areas as functional status, nutritional status, cognition, psychological functioning, and social support, at randomization. Predictive factors associated with OS were searched using Kaplan-Meier curves and logrank tests in the univariate analysis. A Cox model was used for the multivariate analysis.

      Results
      195 patients were included. Mean age was 77 years. 135 (70%) patients were males, 172 (89%) were stage IV and 109 (56%) were no or ex-smokers. At CGA assessment, 176 patients (70%) had an IADLD score of 3 or 4, 129 pts (66%) had a 0 or 1Charlson score, 167 pts (86%) had a simplified Charlson score < 8, 19 pts had a MMS score < 30, 146 pts (75%) had a situational score >10, 33 (17%) had a nutritional score <8. Factors predicting OS in the univariate analysis were 1-3 PS scores (1.5 [1.1 – 2.0], p=0.01); no or ex-smoker (0.70 [0.52–0.95], p = 0.02); 2-4 Charlson score (2.0 [1.4 – 2.7], p<0.0001, Simplified Charlson score ≥ 8 (1.50 [1.10–2.07],p=0.03), nutritional score>8 (0.60 [0.42 – 0.91], p= 0.01); 2 level mobility score (0.15 [0.04 – 0.62], p = 0.009). In the multivariate analysis, remained 1-3 PS (1.4 [1.02 – 1.9], p = 0.04), 2-4 Charlson score (1.46 [1.07 – 1.99], p=0.02), >8 nutritional score (0.69 [0.46 – 1.04], p= 0.07), level 2 mobility score level (0.25 [0.06 – 1.01], p = 0.06)

      Conclusion
      Comorbidities, nutritional and mobility scores, in this specific elderly population are predictive of OS. Prospective studies using large prospective cohort are needed to better select the more relevant management for elderly with advance NSCLC.