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D. Galetta



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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-056 - The Elderly Patient Individualized Chemotherapy Trial (EPIC): A Randomized Phase III Multicenter Trial of Customized Chemotherapy versus Standard of Care for 1st Line Treatment of Elderly Patients with Advanced Non-Small-Cell Lung Cancer (ID 1117)

      09:30 - 09:30  |  Author(s): D. Galetta

      • Abstract

      Background
      This is an ongoing phase III multicenter randomized trial comparing first line pharmacogenomic-driven chemotherapy based on Excision-Repair-Cross-Complementing-1 (ERCC1), Ribonucleotide Reductase subunit M1 (RRM1) and Thymidylate Synthase (TS) gene expression, versus standard first line treatment in elderly patients (pts) with advanced non-small-cell lung cancer (NSCLC). Chemotherapy selection based on an individual patient’s molecular profile is a potentially promising approach to optimize efficacy with the already available cytotoxic drugs. In older pts this is particularly relevant owing to their rapid deterioration of symptoms and their increased propensity to suffer therapy-induced toxicity.

      Methods
      Pts aged >70 years, with ECOG Performance Status (PS) 0 or 1, previously untreated for stage IV NSCLC will be evaluated. In a 2:1 fashion, pts will be randomized to experimental arm (A) or standard arm (B). They must have measurable disease and EGFR negative mutational status. In arm A, treatment with single or dual-agent chemotherapy will be based on histology, ERCC1 (E), RRM1 (R) and TS (T) expression at the mRNA level. Expression of E, R and T is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. The cut off for high or low expression have been previously defined. Pts with squamous NSCLC who are: E low/R high will be treated with single agent carboplatin, E high/R low with single agent gemcitabine, E low/R low with carboplatin and gemcitabine and E high/R high with docetaxel or vinorelbine. In non-squamous NSCLC pts: E low/T high will be treated with carboplatin, E high/T low with pemetrexed, E low/T low with carboplatin and pemetrexed, E high/T high/R low with gemcitabine and E high/T high/R high with docetaxel or vinorelbine. In arm B treatment will be standard of care at the discretion of the care provider. The primary endpoint is overall survival (OS). The secondary endpoints are progression-free survival (PFS), disease response according to RECIST 1.1 and tolerability (using CTCAE version 4.0). Feasibility of treatment selection based on pharmacogenomic parameters will also be assessed. Treatment will continue to a maximum of 6 cycles if tolerated or until disease progression. Switch maintenance treatment is not allowed in either arm. Continuation maintenance (one or more of the agents used in the initial regimen) is allowed at the discretion of the investigator. Treatment upon progression is at the discretion of the care provider. Assuming an exponential survival distribution for both treatment arms and a median survival time of 8 months in the control arm we anticipate to detect an improvement of 3 months in the median survival time in the experimental arm. To have 90% power to detect a three-month improvement in median survival at a significance level of 5% (2-sided) and assuming a 10% failure rate in gene analyses or loss to follow up rate, a sample size of 567 patients is planned to be enrolled.

      Results
      Not Applicable

      Conclusion
      We hypothesize that such tailored approach will improve survival decreasing the exposure to ineffective toxic agents in advanced NSCLC elderly pts. To our knowledge this is the first pharmacogenomic-driven randomized trial in this population.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-033 - Afatinib in EGFR mutant non-small-cell lung cancer patients with acquired resistance to reversible EGFR-TKIs (ID 2285)

      09:30 - 09:30  |  Author(s): D. Galetta

      • Abstract

      Background
      Afatinib, an irreversible EGFR-HER2 dual inhibitor, demonstrated superiority versus standard platinum-based chemotherapy as front-line therapy in non-small-cell lung cancer patients (NSCLC) with activating Epidermal Growth Factor Receptor (EGFR) mutations. In pretreated NSCLC afatinib failed to improve survival when compared to placebo in patients refractory to gefitinib or erlotinib and not selected for EGFR status. Aim of the present study was to evaluate clinical efficacy of afatinib in EGFR mutant NSCLC patients (pts) with secondary resistance to reversible EGFR-TKIs.

      Methods
      We retrospectively analyzed a cohort of 97 EGFR mutant lung cancer pts resistant to EGFR-TKI according to criteria used in the LUX-Lung 1 trial (Miller VA, Lancet Oncol 2012) and treated with Afatinib at the daily dose of 40-50 mg. The drug was given as compassionate use.

      Results
      The study included individuals with a median age of 62,5 year. The majority were females (N=63/64.9%), never/former smokers (N=94/96,9%), with good performance status (ECOG PS 0-1; N=90/90.2%) and pretreated with > 3 therapy lines (N=68/70.0%). EGFR status was assessed in tumor tissue obtained at the time of original diagnosis. The majority of pts (N=64, 66%) harbored a deletion in exon 19, while T790M mutation was detected in two cases including one case with double exon 19 and T790M mutation. Among the 95 pts evaluable for toxicity, 54.7% had any grade skin rash, including 11.6% with grade 3, and 50,5% had any grade of diarrhea, with grade 3 recorded in 10,5%. Among the 87 pts evaluable for efficacy, response rate (RR) was 11.5%, with a median progression free-survival and overall survival of 3.9 months and 7.3 months respectively. In 25 pts a tumor biopsy was repeated immediately before starting Afatinib therapy and 1 patient out of 5 individuals harboring T790M mutation showed a short extracerebral partial response, with following brain progression.

      Conclusion
      Our findings suggest that afatinib is modestly effective in EGFR mutant NSCLC with acquired resistance to reversible EGFR-TKIs.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-038 - Comparison of expression profiling of circulating and tissue miRNAs looking for possible non-invasive biomarkers for the treatment of metastatic NSCLC patients: preliminary results. (ID 2787)

      09:30 - 09:30  |  Author(s): D. Galetta

      • Abstract

      Background
      Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Although some progress has been made in the development of its treatment, most patients are diagnosed at advanced stage and have a short overall survival rate. Just as specific genes have to be analyzed before selecting a targeted therapy, microRNAs (miRNAs) are emerging as biomarkers for NSCLC diagnosis and prognosis. miRNAs are small oligonucleotides that regulate target mRNAs in the post-transcriptional step driving the expression of some genes involved in the tumorigenesis of NSCLC. Due to their resistance to nuclease digestion, miRNAs can be detected both in lung tissue samples and in body fluids as circulating factors. Our aim was to identify specific non-invasive cancer biomarkers involved in NSCLC tumorigenesis regulation.

      Methods
      33 NSCLC patients, 19 male and 14 female, were enrolled. The mean age was 63.3 and 66% were smokers. 88% of patients had advanced stage (IIIb-IV) tumors of which 23 were adenocarcinoma and 10 squamous cell carcinoma. We collected serum before chemotherapy and, when available, tissue samples from biopsy. MiRNA expression profiling of 33 serum and 10 tissue paired samples and 10 serum samples from normal volunteers were investigated by Affymetrix GeneChip miRNA Array. meV software was used for statistical analysis, and target genes identified by deregulated miRNAs were analyzed through the miRWalk database.

      Results
      Statistical analysis revealed 47 miRNAs differentially expressed in NSCLC serum samples compared to control serum (p<0.05) and 29 miRNAs deregulated in NSCLC tissue samples compared to their normal counterparts. 326 miRNAs resulted differentially expressed between the serum and the tissue of NSCLC patients. Among these deregulated miRNAs, the Venn diagram comparing tumor/normal serum, tumor/normal tissue and tumor serum/tissue samples showed that the serum of NSCLC patients was characterized by 22 miRNAs, while 10 miRNAs identified the tumor tissue of NSCLC patients. Only one miRNA, miR-133a, was detected both in NSCLC serum samples and in tissue ones. Focusing on miRNAs involved in NSCLC pathogenesis, of 22 miRNAs miR-486-5p had a lower mean expression ratio (MER) in tumor vs normal serum (8.70±3.28 vs 10.78±1.35), as did let7b which had a MER of 5.28±2.63 in tumor serum vs 7.14±1.8 in normal serum samples. Of 10 miRNAs, miR-200c had the lowest MER in tumor vs normal tissue (1.25±0.10 vs 2.37±0.09 respectively) as did miR-29c* which had a MER of 2.18±0.08 in tumor tissue samples vs 2.34±0.11 in normal tissues. miR-133a had a comparable MER in tumor serum vs tumor tissue (2.41±0.17 vs 2.46±0.17 respectively). These miRNAs are able to target PIK3CA and PTEN genes, according to the miRWalk database, which are involved in the EGFR-related pathway.

      Conclusion
      Our results highlighted specific miRNA expression profiles, both in the serum and in the tissue of NSCLC patients, able to identify circulating miRNAs that could be used as non-invasive biomarkers for early diagnosis, or to predict prognosis in NSCLC patients thus improving personalized therapy. These data are preliminary to a prospective clinical validation in a multicentric trial.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-023 - BE-Positive: Gefitinib in first-line treatment of advanced non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. A combined retrospective and prospective analysis from Italian patients. (ID 1881)

      09:30 - 09:30  |  Author(s): D. Galetta

      • Abstract

      Background
      Advanced NSCLC patients have an extremely poor prognosis with a 5-year survival rate of less than 5%. In 2009, the European Medicines Agency approved gefitinib, a reversible EGFR tyrosine kinase inhibitor, at the dose of 250 mg daily for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations. As the first-line EGFR mutation positive data at that time were mainly in Asian populations a prospective phase IV, open-label, single-arm study of first-line gefitinib in Caucasian patients was presented: this trial confirmed the activity and efficacy of gefitinib in 106 Caucasian patients (Douillard EMCTO 2013). In the same way, we initially collected retrospectively, continuing then prospectively, the data of NSCLC EGFR-mutation positive Italian patients treated with first-line gefitinib, with the aim to evaluate the therapeutic outcomes and the approaches beyond progression in a “real life population”.

      Methods
      We collected data of patients who started gefitinib from June 2009 until May 2013. Primary endpoint was the evaluation of first line outcomes, in terms of: objective response rate (ORR), duration of treatment, progression-free survival (PFS), overall survival (OS) and safety. Secondary endpoint is the evaluation of the outcomes beyond progression to gefitinib. Here we report the results of first-line gefitinib of a large number of Caucasian patients.

      Results
      Data of 203 patients from 23 Italian Institutions were collected. The main patients characteristics were: median age 67 (range: 33-87), male/female 76/127, ECOG performance status (PS) 0/1/2/3/4 in 89/92/18/2/2 patients, 90.6% adenocarcinoma (in our study the percentage of carcinoma non otherwise specified was 1.5%), never/former/current smoker in 129/64/10, del19/L858R/uncommon in 128/57/18. In one case a T790M mutation ex novo was found in association with the deletion of the exon 19 (not all the patients were tested for this mutation at baseline). A median time for obtaining the EGFR test result was 8-15 days (more than 30% of the patients got the results in less than one week). Patients evaluable at the time of data lock were 168, of these 3 (1.8%) patients achieved a complete response, 72 (42.9%) a partial response for an ORR of 44.7%, 54 (32.1%) patients were stable. Median treatment with gefitinib was 38 weeks. Main toxicities were: grade 3-4 skin rash and diarrhea in 1.8% and 4.2%, respectively. Treatment was definitely stopped due toxicity in 4.2% of patients. After progression in 5 cases a re-biopsy was performed and 94 (56%) received a second-line treatment.

      Conclusion
      BE-Positive is the first study reporting results of first-line gefitinib in a large "real life population" of Caucasian patients. Data were firstly collected in a retrospective fashion, than in a prospective way. This study shows that Caucasian patients reported lower ORR when indirectly compared to Asian counterparts, but this is probably due to the partial analysis of the patients, excluding at this time those who are still on treatment. However, the tolerability profile was excellent and the median time of treatment is quite overlapping to literature data. The outcomes of PFS, OS and treatment beyond gefitinib progression will be reported when mature.

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    P2.24 - Poster Session 2 - Supportive Care (ID 157)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P2.24-007 - First-line Pemetrexed plus Cisplatin followed by maintenance Pemetrexed vs Carboplatin-Paclitaxel plus Bevacizumab followed by maintenance Bevacizumab (ERACLE) in advanced non squamous non-small Cell Lung Cancer : a Quality of Life-oriented, multicenter randomized phase III trial of the GOIM (Gruppo Oncologico Italia Meridionale). (ID 749)

      09:30 - 09:30  |  Author(s): D. Galetta

      • Abstract

      Background
      Chemotherapy (CT) for advanced non-squamous non-small cell lung cancer (NS-NSCLC) without oncogenic drivers remains palliative with suggested similar efficacy and survival among different regimens. Histotype, maintenance therapy (m) and quality of life (QoL) have been explored to improve patients (pts) outcome. The ERACLE trial (NCT01303926), a QoL-oriented phase III trial, was designed to compare the QoL for two CT regimens.

      Methods
      Pts with stage IIIB/IV NS-NSCLC (ECOG 0/1) were randomized (1:1) to receive first-line CT. Arm A received 6 cycles of Cisplatin (C) (75 mg/m[2])/Pemetrexed (P) (500 mg/m[2]) q3w, followed by mP (500 mg/m[2]), while Arm B received Carboplatin (Cb) AUC 6/Paclitaxel (T) 200 mg/m[2] plus Bevacizumab (Be) 15 mg/kg q3w for 6 cycles, followed by mBe 15 mg/kg. Both treatments were administered until progression, unacceptable toxicity or death. Stratification was based on Study Centre and disease stage. Co-Primary endpoints were EQ5D Index (EQ5D-I) and EQ5D-VAS (Euro-QoL questionnaire). Quality of life data were collected at three time points during the induction phase and at 12 and 18 weeks during the maintenance phase. Secondary endpoints were QoL over time, safety and activity of CT arms. A sample size of 49 pts per arm (that have not progressed during initial CT and during maintenance therapy for at least 12 weeks) would have 91% chance to have 12-point Minimal Interesting Difference (MID) between arms for EQ5D-VAS, and 87% chance to find 0.137 MID between arms for EQ5D-I. It is assumed that about 20% of pts in both arms experience progressive disease before the evaluation of the primary endpoint. The study sample was then increased to 118.

      Results
      From 1/2011 to 3/2012, 118 pts were randomized to Arm A (n=60) or Arm B (n=58). Baseline demographics were well balanced across arms; Arm A/Arm B male: 70%/77.6%, PS 0: 78.3%/79.3%, stage IV 95%/93%, smokers: 63%/52% . Seventy four pts (62,7%) received maintenance chemotherapy. Treatment differences (mean change from baseline), EQ5D-VAS = 1.82 (95%CI -8.60 to 12.24; P=0.73), EQ5D-I = 0.15 (95%CI 0.01 to 0.29), favoured arm A. Safety was as expected without relevant haematological toxicity and with a significant impact of G3/4 alopecia (p=0.002) and G 1-3 neurotoxicity in ARM B (p=0.008) during induction. Response rates were (Arm A/Arm B) partial responses 40%/51%; stable disease 48.3%/27.6%. The Hazard Ratio (HR) for Progression Free Survival Arm A/Arm B [Cox's analysis] was 0.62 (95%CI 0.41 to 0.95) p=0.03 and HR for Overall Survival Arm A/Arm B [Cox's analysis] was 0.69 (95%CI 0.61 to 1.04) p=0.08.

      Conclusion
      Arm A showed better (over the MID) health profile (EQ5D-I) as compared to Arm B. EQ5D-VAS didn’t find any significant difference between treatment arms. By assuming equal activity, the choice of a treatment for advanced NSCLC should be mainly based on QoL.