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R. De Las Peñas



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    MO08 - NSCLC - Early Stage (ID 117)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO08.01 - First analysis of toxicity and treament compliance in customized postoperative chemotherapy based on BRCA1 levels after NSCLC resection: SCAT (Spanish Customized Adjuvant Therapy) trial. Spanish Lung Cancer Group/GECP (ID 2454)

      16:15 - 17:45  |  Author(s): R. De Las Peñas

      • Abstract
      • Presentation
      • Slides

      Background
      Customization is feasible in adjuvant setting (tissue availability). SCAT trial has completed planned recruitment with 500 p. For resected NSCLC with nodal involvement adjuvant platinum-based CT improves outcomes but survival remains suboptimal. Compliance may be a key issue for efficacy in adjuvant setting. mRNA BRCA1 levels are prognostic in early NSCLC and could be a predictive marker for CT activity. In advanced disease patients with low BRCA1 benefit from cisplatin doublets meanwhile p with high levels attained longer survival with taxanes.

      Methods
      Phase III trial testing 4 cycles non-selected vs customized adjuvant CT. Entry criteria: NSCLC, R0 resection, pN1 or pN2, KI > 70, recovered from surgery, adequate hematologic, renal and liver functions, no prior CT or RT, age > 18 y, informed consent. Stratification: N1 vs N2, histology (squamous vs non-squamous), resection (lobectomy vs pneumonectomy). Central lab mRNA BRCA1 levels and quartile distribution. Primary end-point: OS. Secondary end-points: DFS, toxicity, recurrence pattern. Design: R: 1:3. Control treatment: Cis-Docetaxel (CD). Experimental arm: Q1: Cis-Gemcitabine (CG); Q2-3: Cis-Docetaxel; Q4: Docetaxel (D). PORT in pN2 patients. Compliance treatment and toxicity profile analyzed by arm and correlation with potential prognostic factors explored

      Results
      500 included p; 108 control arm, 392 experimental arm. Median follow-up 18.6 m (2-59 m). Median mRNA BRCA1 levesl 15.78 (0.73-132) Q1 212 (42.4%), Q2-3 150 (30%), Q4 138 (27.6%). Mean BRCA1: Adenocarcinoma: 8.45 vs Squamous 19.6 (p< 0.001). Overall low levels BRCA1: 43.8%. EGFR mut 5.6% 297 p evaluated for compliance planned adjuvant treatment: M/F ratio: 82.5/17.5%. Median age: 62 (range 36-80). PS 0/1/2: 55.9/43,1/1%. Histology: Adenocarcinoma 47.5%, Squamous 44.1%. Stages: IIA/IIB/IIIA: 11.1/38.4/50.2%. Surgical procedure: Lobectomy 72.1%; Pneumonectomy 27.9%.. Toxicity. G3-4 AE: Neutropenic fever: CD 10% vs D 4.4% vs CG 0%. (p=0.0056); Nausea/vomits: CG 11.1% vs CD 10.4% vs D 0%. (p=0.0198); Hypersensitivity: D 5.97% (NS). Dose-reduction: 34.24% control vs 18.30% experimental (p=0.0044). Full 4 cycles CT compliance: CD control 80.83%, CG 91.2%, CD experimental 79.2%, D 88.1% (p=0.052). No differences in dose-reductions. CT compliance lobectomy 86.4% vs 85.5% pneumonectomy (NS). CT compliante < 70 y 91.1% vs 66.6% > 70 y (p<0.01)PORT compliance 55.31% of planned cases.

      Conclusion
      Planned trial recruitment achieved with median f-u 18.6 m. Majority of resected NSCLC showed low levels expression BRCA1. Adenocarcinoma lower levels than Squamous. Safety profiles differences observed between treatment schedules: neutropenic fever (CD), nausea/vomits (CG). Customized treatment requires less dose-reductions. Trend to poor compliance with Cis-Doc. No relation between extensión of surgery and adjuvant Tx compliance . Compliance CT significantly lower for age > 70 y. Low compliance for PORT.

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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.01 - Interim analysis of the Spanish Lung Cancer Group (SLCG) randomized phase II trial of thoracic radiotherapy (RT) concurrent with cisplatin (P) plus oral vinorelbine (OV) or etoposide (E) for unresectable locally advanced (LA) stage III non-small cell lung cancer (NSCLC). (GECP10/02). (ID 2658)

      10:30 - 12:00  |  Author(s): R. De Las Peñas

      • Abstract
      • Presentation
      • Slides

      Background
      Chemoradiation is the standard of care for the treatment of unresectable LA-NSCLC. Cisplatin plus either etoposide or vinorelbine are two of the chemotherapy (CT) regimens widely used for the disease concurrently with radiotherapy. Oral vinorelbine is a formulation which has achieved comparable results to the IV vinorelbine. The purpose of the study is to evaluate the efficacy and safety of cisplatin when combined with etoposide or oral vinorelbine with radical radiation for the management of stage III NSCLC.

      Methods
      Patients (pts) between 18 and 75 years, with histologically proven untreated and unresectable LA stage IIIA/IIIB NSCLC, adequate bone marrow, hepatic and renal function, ECOG PS 0-1, were randomized to: Arm OV-P: OV 60 mg/m[2] D1, D8 cycle 1 and 80 mg/m[2] cycle 2 (if no grade 3-4 toxicity) plus P 80 mg/m[2] D1 every 3 weeks for 2 cycles as induction; patients without progression received OV 40 mg/m[2] D1, D8, and P 80 mg/m[2] D1 every 3 weeks for 2 more cycles (4 cycles in total). Arm E-P: E 50 mg/m[2] intravenously D1 to D5 plus P 50 mg/m[2] D1, D8 every 4 weeks for 2 cycles. Both regimens administered with concurrent RT 66 Gy in 6.5 weeks. The primary endpoint was progression free survival using RECIST 1.1, and secondary endpoints were overall response rate, overall survival, and safety profile. To guarantee an overall type-1 α error (one side) no greater than 0.05 and a type II (β) error 0.1 for the primary endpoint of PFS, a sample size of 134 pts allocated in a 1:1 ratio is planned.

      Results
      Since August 2011 77 pts have been recruited. 46 pts have been included in the interim analysis, 23 pts have been randomly allocated to each treatment arm. Patient’s characteristics were: Male 91.3%; median age 64 (range 44-75); PS1 56.5%; smokers 46.8%; adenocarcinoma 40.4% / squamous 55.3%; stage IIIA 46.8% / IIIB 53.2%. Median of months between initial diagnosis and study start was 1 (range 0.3-15.7). Safety: 118 cycles (cy) were analysed, 79 in arm OV-P and 39 in arm E-P. Hematological toxicities arms OV-P/E-P (% cy): grade (g) 3/4 neutropenia 8.9%/13.1%; g3 thrombocytopenia 0%/5.3%; g3 anemia 0%/2.6%; febrile neutropenia 3 cases on OV-P arm (all during induction CT on cy 1) and 1 case on E-P arm (during concurrent chemoradiation). Non-hematological toxicities arms OV-P/E-P (% cy): g3 esophagitis/mucositis 1.3%/15.5%; g3 infection without neutropenia 1.3%/5.1%. No treatment-related deaths were reported. There was no remarkable difference in other toxicities between both arms. 39 pts completed the treatment as per protocol, 19 in arm OV-P and 20 in arm E-P. Overall response rates were 73.7% and 50% for the OV-P and the E-P arm, respectively.

      Conclusion
      This interim analysis shows that OV-P and E-P when administered concurrently with RT have a manageable safety profile with efficacy. Safety data is consistent with other studies reported for both chemoradiation regimens. Based on these positive results for safety, accrual is ongoing. Clinical trial information EudraCT 2010-022927-31.

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    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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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)

      10:30 - 12:00  |  Author(s): R. De Las Peñas

      • 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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    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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      P1.11-046 - Women with lung cancer harboring epidermal growth factor (EGFR) mutations: prevalence, clinical characteristics and EGFR tyrosine kinase (TKI) treatment-related outcomes. Results from the Spanish WORLD07 database (ID 3078)

      09:30 - 16:30  |  Author(s): R. De Las Peñas

      • Abstract

      Background
      EGFR mutations define a distinct molecular subset of non-small-cell lung cancer patients (p). Prevalence, baseline clinical characteristics and outcomes for women with lung cancer harboring EGFR mutations would be of interest.

      Methods
      We analyzed the clinical characteristics of women with lung cancer harboring EGFR mutations included in the WORLD07, a Spanish prospective, multicenter, epidemiologic female-specific e-database.

      Results
      A total of 2081 newly-diagnosed women with lung cancer from 38 Spanish centers were included in the WORLD07 e-database from October/2007 to October/2012. Overall 915 p were evaluated for EGFR mutation status, and 342 of them were found to have EGFR mutation (16% of all p in the e-database, 37% of p tested). EGFR-mutated p characteristics: median age 64.6 years; 86% had offspring; 8.2% had used oral contraceptives; smoking habit: 72% never smokers, 14% current smokers, 13% former smokers; for those never smokers, second-hand smokers 35%; histology: 91% adenocarcinoma, 1.5% squamous cell carcinoma, 2% large-cell carcinoma, 5% other; EGFR mutation type: 60% deletions in exon 19, 32.5% L858R mutations, 8% exon 20 mutations, 1% exon 18 mutations, 14% unknown. Sixty-nine percent of p had stage IV disease. A total of 184 EGFR mutated p received an oral EGFRTKI as 1[st] line (ECOG PS: 0 in 24%, 1 in 53%, 2 in 13%, 4 in 4%, unknown in 5%) achieving a 59% response rate (RR), 20% stable disease (SD), 10% progression (PD) and 11% not evaluable (NE); with a median follow-up of 12 months, median overall survival for these p was 21 months. A total of 72 p received an EGFRTKI as 2[nd] line with 37% RR, 34% SD, 19% PD and 10% NE. Only 16 p received an EGFRTKI as 3[rd] line, achieving a 38% RR, 19% SD, 31% PD and 12.5% NE. For those EGFR mutated women receiving an EGFRTKI as 1[st] line, RR to an EGFRTKI was 70% in those women harboring deletion in exon 19, and 45% in those with L858R mutation; median overall survival was 24 months in those with deletion in exon 19, and 17 months in those with L858R mutation. Response rate to an EGFRTKI as 1[st] line treatment was 59% in never-smoker p and 53% in current-smoker/former-smoker p with a median overall survival of 23 months and 21 months, respectively.

      Conclusion
      According to our prospective e-database of women with lung cancer, not selected for clinical trials and including all histologies, a high proportion harbor an EGFR mutation (16% of non-selected women, 37% of those tested). The vast majority of women with lung cancer harboring EGFR mutation are never smokers, have adenocarcinoma histology and outcomes similar to those previously reported in the literature. Additional epidemiologic and treatment data will be presented at the meeting.

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    P2.22 - Poster Session 2 - Epidemiology, Etiology (ID 167)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.22-008 - Analysis of family history of cancer in women with lung cancer (WLC) from the Spanish WORLD07 database (ID 2430)

      09:30 - 16:30  |  Author(s): R. De Las Peñas

      • Abstract

      Background
      Gender differences in lung cancer (LC) have been reported, but with many unresolved issues . Family history of cancer might play an important role in lung cancer, especially in never-smoker patients. The aim of this study was to analyze potential clinical, molecular and epidemiological differences between WLC with or without family history of cancer.

      Methods
      WORLD07 is a Spanish prospective, multicenter, epidemiologic female-specific LC database sponsored by ICAPEM, a professional association committed with WLC research. Clinicopathologic data, tumor genotype, family and personal history of cancer were collected and analyzed in order to detect differences between both groups.

      Results
      From October/2007 to November/2012, 2081 WLC were included in an e-database from 32 centers. Family history of cancer was common (49.4%, in first-degree was 77%), family history of lung cancer was present in 33%, of breast cancer in 25% and of colorectal cancer in 17%. No differences in median age of diagnosis of LC, previous hormonal therapy, number of children, menstrual status, tumor histology or stage at diagnosis were observed between WLC with or without family history of cancer. WLC with family history of cancer were ever smokers in a higher percentage (63% vs 56%, p=0.006), with no differences in passive smokers. The presence of EGFR mutations was similar in WLC with family history of cancer versus WLC without family history (38% vs 37%), although WLC patients with family history of cancer had a higher rate of exon 21 mutation (36% vs 28%), both in smokers WLC (32% vs 16%, p=0.220) and in never smokers WLC (43% vs 32%, p=0.094). The median overall survival was 25 months (CI95% 21.0-29.0) for WLC with family history of cancer and 22.0 months (CI95% 19.4-24.5) for patients without family history of cancer (p=0.027). Of note, the median overall survival was 34.8 months (CI95% 22.9-46.6) for WLC with family history of LC and 22.5 months (CI95% 20.5-24.5) for patients without family history of LC (p< 0.001).

      Conclusion
      The presence of familiar history of cancer in WLC patients included in the WORLD07 database was high (49.4%), being lung cancer the most common, followed by breast cancer. No clinical or pathologic characteristic differences were observed between patients with or without family history of cancer. The presence of EGFR mutations was similar, although WLC patients with family history of cancer had a higher rate of exon 21 mutation. The median overall survival was significantly higher in WLC patients with family history of cancer and LC. Family history of cancer, especially of LC, might have a role in LC development and deserves further studies focused in inherited genetic alterations related with an increased susceptibility to LC.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-035 - Study of the correlations between SNPs in angiogenic genes and treatment response/ outcome in patients with advanced NSCLC (non-squamous histology) treated in first line with carboplatin, paclitaxel and bevacizumab (CPB). The ANGIOMET study. (ID 2664)

      09:30 - 16:30  |  Author(s): R. De Las Peñas

      • Abstract

      Background
      It has been demonstrated that the addition of bevacizumab to paclitaxel plus carboplatin (CPB) in the treatment of advanced NSCLC improves survival. Even though, there is a high variability in drug efficacy between patients, leading to different response rates. ANGIOMET is an exploratory study promoted by the SLCG in advanced NSCLC, non-squamous histologies (NS-NSCLC) treated in first line with a combination scheme based in CPB, designed to investigate the relationship between angiogenic mediators and the outcome and response to treatment. The primary end-point was progression-free survival (PFS), and the secondary end-points are the follows: OS, response-rates and toxicity profiles.

      Methods
      In this multicentric study, patients with stage IIIB/IV NS-NSCLC (ECOG status 0–2) were included and treated in first line with CPB. Peripheral blood samples were collected before treatment administration and DNA was purified from the leukocyte fraction. Ten SNPs of VEGF-pathway genes were genotyped in 186 samples by RT-PCR in duplicate. SNPs were related to PFS and OS (Kaplan-Meir method, log-rank test) and to response rate.

      Results
      10 SNPs were determined in 186 DNA samples. In this preliminary analysis there were data from 108 patients valid for PFS and OS analysis. Baseline characteristics of the patients were: median age, 63 years [37-80]; 74.5% male; 94.1% ECOG PS 0-1; 14% never-smokers, 100% caucasian; 89.7% adenocarcinomas, 2.8% large cell carcinomas; median number of CPB cycles was 4. There was no response assessment in 27 patients (25%), 30.6% PR, 31.5% SD and 13.0% PD. The SNP rs833061 (CC) in VEGFA correlated with lower response rates to CPB than the other genotypes (p=0.07). SNPs in KRAS and VEGFR2 were associated with PFS and/or OS in our cohort. The KRAS SNP rs10842513 (TT+CT) was associated with shorter PFS compared with the CC genotype (median: 5.39 vs 6.81 months; p=0.04, respectively). The VEGFR2 SNP rs2071559 (AA) was significantly associated with longer PFS and OS (Table 1). No significant differences in PFS or OS were observed according to other SNPs analyzed. Table 1: PFS and OS for VEGFR2 SNPrs2071559.

      PFS
      % Median (months) 95%CI p
      VEGFR2 (rs2071559)
      AA 25.6 9,408 5,084 - 13,732 0.01
      GG+AG 74.0 5,724 4,902 - 6,546
      OS
      % Median (months) 95%CI p
      VEGFR2 (rs2071559)
      AA 25.6 NR ---- 0.001
      GG+AG 74.0 12,270 8,760 – 15.780

      Conclusion
      These preliminary data indicate that genetic variation in VEGFR2, SNP rs2071559 variant AA, is associated with prognosis in advanced NS-NSCLC patients treated with CPB and may have predictive implications as biomarkers in patients treated with chemotherapy with bevacizumab. On behalf of the Spanish Lung Cancer Group (SLCG)