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D. Moro-Sibilot



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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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      MO08.02 - Adjuvant pazopanib or placebo in resected stage I NSCLC patients: results of the NSCLC adjuvant randomized phase II trial (IFCT-0703) from the French collaborative Intergroup (ID 2274)

      16:20 - 16:25  |  Author(s): D. Moro-Sibilot

      • Abstract
      • Presentation
      • Slides

      Background
      Although UFT is approved in eastern countries, most guidelines do not recommend any adjuvant treatment in resected Stage I NSCLC. Pazopanib (P) is a potent, orally active multi-target receptor tyrosine kinase inhibitor of VEGFR-1, -2, -3, platelet derived growth factor (PDGFR) type-α and –β, approved in metastatic renal cell carcinoma and sarcoma. Neoadjuvant P demonstrated single-agent activity in patients with early stage NSCLC. We report the feasibility and tolerance of adjuvant P in stage I NSCLC.

      Methods
      In this double-blind randomized multicenter phase II/III trial, completely resected patients (pts) with stage I NSCLC (7[th] TNM edition) were randomized to receive either placebo or P 800 mg/d during 6 months. The Fleming’s two stage phase II primary endpoint was compliance (i.e. % of pts able to receive at least 3 months of P, whatever the dose). After 64 pts included (interim analysis), IDMC recommended to start with P 400 mg/d because of initial insufficient compliance. A one-step Fleming design was used with the new dose. Phase II design was not comparative.

      Results
      143 pts were randomized in 29 centers between March 2009 and August 2012, 71 and 72 in the placebo and P arms respectively. Most pts were male (61%) and smokers (91%), median age was 60. Pathological stage was IA in 111 pts (78%) and 16% were squamous cell carcinomas. Compliance for P800 was adequate in 38% (95% confidence interval [21-56]) vs. 87% [71-96] in placebo; for P400 in 69% [50-84] (p=0.01, compared to P800) vs. 93% [77-99] in placebo. Dose modifications were seen in 44% and 34% of P800 and P400 groups. The proportion of patient with at least one grade 3/4 toxicity was 53% [35-71] in P800 (13% [4-29] for placebo) and 38% [21-56] in P400 (27% [12-46] for placebo). No toxic deaths were observed. Only 2 pts has grade 4 toxicities in P800 (fatigue in P arm, GGT in the placebo arm). Most common toxicities G3 in P800 were diarrhea (9%), hypertension (9%), and increased transaminases (16% vs. 0% in P400); in P400 gastro-intestinal disorders (16%, 6% diarrhea) and hypertension (6%).

      Conclusion
      IFCT-0703 is the first feasibility study demonstrating that full dose of P is safe but not feasible in the adjuvant setting in NSCLC. Compliance and tolerance with reduced dose appeared acceptable for adjuvant settings.

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    MO24 - NSCLC - Chemotherapy III (ID 110)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO24.08 - Survival outcomes among NSCLC patients in Europe receiving platinum-based therapies as first-line treatment: results from the FRAME observational study (ID 1944)

      11:10 - 11:15  |  Author(s): D. Moro-Sibilot

      • Abstract
      • Presentation
      • Slides

      Background
      FRAME was a European non-interventional prospective observational study of patients with advanced or metastatic non-small cell lung cancer (NSCLC) initiating platinum-based therapies as first-line treatment (FLT).

      Methods
      Patients were enrolled between April 2009 and February 2011. Consenting adult NSCLC (Stage III/IV) patients initiating FLT with a platinum-based doublet chemotherapy, with or without an additional targeted agent, were eligible for the study. The choice of FLT was left to physician discretion, as per routine clinical practice. The primary objective of FRAME was to evaluate overall survival (OS) among different platinum-based treatment cohorts in patients with and without additional targeted therapy. Secondary objectives included the evaluation of OS in patients with different histological subtypes of NSCLC. Survival outcomes were assessed using Kaplan-Meier analysis, and unadjusted estimates are presented.

      Results
      A total of 1564 eligible patients from 11 EU countries were observed. Patient cohorts were: pemetrexed + platinum, gemcitabine + platinum, vinorelbine + platinum, taxanes + platinum and other therapy + platinum. Table 1 shows a subset of baseline patient characteristics, which varied across several parameters in the treatment cohorts, including age, performance status (PS), stage and histology. The median OS across the 4 main treatment cohorts was 10.3 months (95% CI: 9.5-11.2). A subset of overall survival estimates in the different treatment cohorts is shown in Table 1.

      Table 1. Select baseline patient characteristics and overall survival
      Baseline Patient Characteristics Overall Survival Estimates (unadjusted)
      Treatment Cohort[a] Age ≥70 Years (%) ECOG PS of 2/3 (%) Stage IV (%) Non-squamous Histology (%) All patients Median OS in Months (95% CI) Non-squamous Median OS in Months (95% CI) Non-squamous Cisplatin[b] Median OS in Months (95% CI)
      Pemetrexed + Platinum[b ](n=569) 23 18 86 97 10.7 (9.4-12.3) [n=569] 10.6 (9.4-12.0) [n=553] 11.6 (9.9-13.8) [n=374]
      Gemcitabine + Platinum[b] (n=360) 35 11 74 56 10.0 (8.4-11.8) [n=360] 8.4 (7.0-10.6) [n=201] 8.4 (6.7-10.8) [n=107]
      Taxanes + Platinum[b ](n=295) 36 23 75 64 9.1 (8.0-11.3) [n=295] 8.1 (7.4-10.1) [n=189] 9.6 (7.1-14.1) [n=44]
      Vinorelbine + Platinum[b] (n=300) 28 15 67 53 10.7 (8.9-12.8) [n=300] 10.1 (8.0-13.1) [n=160] 9.9 (7.2-13.4) [n=91]
      [a]A fifth cohort, the ‘other’ + platinum cohort contained a small number of subjects (n=40) and it was not included in the analyses presented here [b]Cisplatin is the platinum agent in the EMA approved prescription drug label

      Conclusion
      This observational study of first-line treatment for advanced NSCLC provides data describing patients and their survival outcomes in a real-world European practice setting between 2009 and 2012.

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    O04 - Molecular Pathology I (ID 126)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O04.01 - Identification of CD74-NRG1, a new recurrent fusion gene in invasive mucinous lung adenocarcinomas of never smokers (ID 4022)

      10:30 - 10:40  |  Author(s): D. Moro-Sibilot

      • Abstract
      • Presentation
      • Slides

      Background
      Lung adenocarcinoma (AD) of patients who have never smoked frequently bear targetable genome kinase alterations, such as EGFR mutations and translocations affecting ALK, ROS1, and RET genes. These mutations correlate with kinase inhibitor sensitivity in mouse models or in patients. Unfortunately, therapeutically relevant kinase alterations are not present in all lung cancer specimens. Thus, additional genome alterations need to be discovered in order to provide a therapeutic opportunity for the remaining patients.

      Methods
      We collected a cohort of 25 AD specimens of never smokers lacking mutations in KRAS or EGFR, in which we performed transcriptome sequencing with the aim of identifying new oncogenic driver genes.

      Results
      We were able to identify known kinase fusions affecting ALK, ROS1 and RET genes in 3 cases each. Moreover, we detected one sample carrying a novel chimeric transcript fusing the first six exons of CD74 to the EGF-like domain of the NRG1 III-β3 isoform, leading to the expression of its EGF-like domain in an otherwise NRG1-negative tumor tissue. The fusion gene was further detected in four additional cases out of 94 pan-negative* ADs of never smokers. In total, all 5 cases were identified in stage I invasive mucinous lung adenocarcinomas (IMA) of never smoker females. This tumor type frequently presents with multifocal unresectable disease, for which no effective treatment has been yet established. IMA is highly associated with KRAS mutations; indeed, out of 15 IMA analysed, 6 carried a KRAS mutation (40%), and 4 the CD74-NRG1 fusion (27%). Given the fact that NRG1 signals through ERBB3 and ERBB4 receptors, we aimed to determine which receptor CD74-NRG1 provides the ligand for. We observed that ERBB4 was not expressed in the index case, while ERBB3 was relatively highly expressed and this expression also correlated with a positive phospho-ERBB3 (p-ERBB3) signal in the tumoral tissue of all 5 CD74-NRG1 positive cases. In order to test if this phosphorylation of ERBB3 was statistically significant, we stained a cohort of 241 ADs and found that p-ERBB3 was only positive in 6 of them (p-value<0.0001). Additionally, although both EGFR and ERBB2 were expressed in the index case, only ERBB2 expression correlated with a p-ERBB2 positive signal. These data suggest that CD74-NRG1 might provide the ligand for ERBB3, which may form heterodimers with ERBB2, since ERBB3 is devoid of intrinsic kinase activity and cannot support linear signaling in isolation. This is in line with previous studies showing that NRG1 induces an oncogenic signal through ERBB2-ERBB3 heterodimers engaging the PI3K-AKT pathway. This was further supported by the activation of the PI3K-AKT, but not the MAPK pathway, in CD74-NRG1 transduced H2052 lung cells, after 24h starvation. *pan-negative: EGFR, KRAS, ALK, HER2, BRAF, ROS1 and RET wild-type

      Conclusion
      Altogether, these data shows that CD74-NRG1 is a new recurrent oncogenic fusion gene, highly associated with IMA of never smokers. It also suggests that CD74-NRG1 fusion protein signals through the ERBB2-ERBB3 receptors complex leading to the activation of the PI3K-AKT pathway, providing a therapeutic opportunity for a tumor type with, so far, no effective treatment.

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    O18 - Cancer Control and Epidemiology II (ID 133)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O18.03 - The BioCAST / IFCT-1002 study: a comprehensive overview of demographic, risk exposure and somatic mutations of non-small cell lung cancer occurring among French never smokers (ID 3293)

      10:50 - 11:00  |  Author(s): D. Moro-Sibilot

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer occurring in never-smoker (LCINS) is a particular entity. Although the definition is strict (less than 100 cigarette in lifetime) never-smokers are frequently misclassified and no study gives a comprehensive analysis of this group, particularly in a European setting.

      Methods
      All consecutive never-smoker patients diagnosed with a non-small cell lung cancer in one of the 75 participating centers throughout France, between November 2011 and January 2013, were included in this prospective survey. All patients underwent a detailed questionnaire supported by a trained staff during a phone interview. Somatic mutations and cancer clinical and histological data were also recorded from medical charts.

      Results
      Overall, 384 never-smokers were included and 336 interviews were completed. Most of them were women (n=319, 83.1%). The mean age at diagnosis was 69.8 ± 12.02 and 10.9% were under 55 years-old. None reported alternative smoking (pipe, cigar, water-pipe, gum, or cannabis). Most of them originated from Western and Southern Europe (90.5%). Overall, 219 (65.6%) reported a passive smoking exposure in a domestic setting (n=198; 59.3%), and/or at workplace (n=60; 18.0%). Patients had a personal history of pneumonia in 6.2%, tuberculosis in 8.3%, COPD in 13.0%, and a cancer at another site in 16.6%. Eighty patients reported at least two relatives with lung cancer (24.0%). Definite occupational exposure was observed in 12.0% (n=44) for diesel, 7,1% (n=26) for asbestos, 3.3% (n=12) for poly-aromatic hydrocarbons, 2.4% (n=9) for silica, 0.8% (n=3) for chrome, and 0.5% (n=2) for painting. Exposure to cooking oil was noted in 123 patients (36.8%) with a mean of 49.4 ± 356.7 cooking-dish year. Moreover, 79.7% (n=259) patients were ever exposed to solid fuel fumes for cooking or heating (21.2% during more than 50% of their lifetime). Among women, 91.7% already reached menopause (mean age 49.3 ± 5.6 years-old), 115 (41.7%) were ever-exposed to oral contraceptive (mostly oestrogen-containing drugs), and 25.5% to post-menopause hormone replacement therapy (oral or transdermal). Most of lung cancers were adenocarcinoma (n=327, 85.2%) followed by squamous cell carcinoma (n=29, 7.6%) and large cell carcinoma (n=17; 4.4%). Among adenocarcinoma, 71% were invasive, 4% in-situ, 2% minimally-invasive, 2% variant of invasive, and 20.0% were NOS. Cancer stage was I in 9.2%, II in 5.8%, III in 11.8% and IV in 73.2%. At least one biomarker was tested in 359 patients (93.5%). We found 148 patients with EGFR mutations (43.5% out of the EGFR-tested patients), 20 with KRAS mutations (6.8%), 24 with ALK translocation (12.5%), 10 with BRAF mutation (4.5%), 8 with HER2 mutation (4.0%) and 4 with PIK3CA (2.1%). Overall, 27.0% samples remain wild type, 2.1% with multiple mutations, 71.0% with a single mutation, and 20.6% with missing data.

      Conclusion
      We provide here the largest cohort of LCINS in a European setting with reliable data on tobacco intoxication, occupational exposure, and hormonal treatments, since collected by a trained staff through phone interview. In this perfectly clinically characterized cohort, molecular analyses showed that 72% of tumors exhibited oncogenic targetable mutations.

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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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      P3.02-010 - A PCR-based test detecting ectopic expressions of placenta/germline genes can predict aggressive lung tumours (ID 1648)

      09:30 - 09:30  |  Author(s): D. Moro-Sibilot

      • Abstract

      Background
      Cell transformation and tumour progression are associated with severe alterations of the epigenetic control of gene expression. Although the abnormal repression of tumour suppressor genes has been thoroughly investigated, the concept of tissue-specific gene aberrant reactivations in cancer is only starting to emerge. The extent of this process has not been reported yet, mainly because of the difficulties in detecting these expressions by the currently used transcriptomic analyses

      Methods
      We have developed a simple approach, exploiting genome wide expression data, which has enabled us to demonstrate that these "off-context" gene activations occur in any cancer, providing a universal source of cancer biomarkers. By applying this analysis to our series of lung cancer patients (n=297) with the corresponding precise clinical annotations and 5 to 10 years patient follow-up, we found that hundreds of germline-specific genes are ectopically expressed in the tumours and that a subset of 26 genes are specifically activated in a subgroup of highly aggressive metastatic-prone tumours, even at an early stage of the disease. This approach has enabled us to define and isolate a homogeneous group of very aggressive tumours called P3 with at least 3 genes ectopically expressed, independently of other prognosis parameters (histo-pathological or stage) (Rousseaux et al. Sci Transl Med 2013, 5 (186): 186ra66).

      Results
      Based on these data we setup a PCR based test to directly rank lung tumours by detection of the prognosis associated gene activations. This test was first validated on a series of 60 tumour samples from the same cohort (also analyzed by an affymetrix transcriptomic approach), which revealed the remarkable robustness of the PCR approach and showed a higher sensitivity of the PCR-based detections in tumour ranking. We then extended these PCR-based analyses to include additional patients with precise clinical and pathological annotations and 10 years follow-up but for whom transcriptomic data were not available. Here again we could show that our test successfully ranked the patients into groups with significantly different survival probabilities. we show here the intermediate analysis on a first group of 88 patients without lymph node metastasis treated by surgeryFigure 1

      Conclusion
      In conclusion we are ready to launch a prospective study based on this PCR test to evaluate its ability to predict tailored follow up of patients after surgery and also tumour sensitivity to design specific targeted therapies including immunotherapy since this ectopic activation may lead to very innovative treatment .

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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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      P3.10-002 - Resource utilization of NSCLC patients receiving platinum-based therapies across Europe; results from the FRAME observational study (ID 183)

      09:30 - 09:30  |  Author(s): D. Moro-Sibilot

      • Abstract

      Background
      FRAME was a non-interventional, prospective observational study of advanced or metastatic non-small cell lung cancer (NSCLC) patients initiating first-line treatment (FLT) with platinum-based therapies in a routine practice setting across 11 European countries.

      Methods
      Patient enrollment occurred between April 2009 and February 2011. Consenting adults with Stage IIIB or IV NSCLC receiving platinum-based doublet chemotherapy with or without an additional targeted agent as FLT were eligible for this study. Patients were under routine treatment for NSCLC by their doctors and treatment choice and resource use were at the discretion of the treating physician. Secondary objectives of the study included determining resource use during FLT. Hospitalizations, outpatient visits, concomitant therapy use, transfusions and the use of colony stimulating factors (CSFs) are reported here. Cohorts were not adjusted for multivariate parameters prohibiting statistical comparisons.

      Results
      Evaluable patients (n=1564) were categorized into 4 main cohorts based on their FLTs: pemetrexed + platinum (n=569), gemcitabine + platinum (n=360), taxanes + platinum (n=295) or vinorelbine + platinum (n=300). Forty of the evaluable patients received other platinum-doublet treatments and were excluded from the analyses presented here.Across the four main cohorts, 55% of patients were hospitalized.A majority (61%) of hospitalizations were preplanned (71% in the pemetrexed cohort, 45% in the gemcitabine cohort, 67% in the taxanes cohort and 53% in the vinorelbine cohort). Among the unplanned hospitalizations, 54% were related to an adverse event (54% in the pemetrexed cohort, 54% in the gemcitabine cohort, 55% in the taxanes cohort, and 55% in the vinorelbine cohort). The mean (95%-confidence interval) duration of hospitalizations was 13 days (11.6 to 14.6) for pemetrexed (median=9 days), 11 days (9.4 to 12.8) for gemcitabine (median=7 days),17 days (14.0 to 19.7) for taxanes (median=12 days), and 13 days (11.3 to 15.0) for vinorelbine (median=9 days). Nearly half of patients (47%) were seen in an outpatient setting with most outpatient visits (82%)planned for scheduled treatments. Nineteen percent of patients received ≥1 transfusion (16% in the pemetrexed cohort, 24% in the gemcitabine cohort, 15% in the taxanes cohort and 24% in the vinorelbine cohort). Nearly all (94%) of these patients received packed red blood cells. Nineteen percent of patients received ≥1 colony stimulating factor (CSF), which included G-CSF (69%), or erythropoietin (39%). During therapy, 82% of patients used antiemetics and antinauseants, 58% used steroids, 40% used analgesics, and 24% used antibiotics. Twenty-eight percent of patients received radiation during FLT and most often radiation was delivered concurrently with chemotherapy (66% overall, 66% in the pemetrexed cohort, 54% in the gemcitabine cohort, 68% in the taxanes cohort, and 73% in the vinorelbine cohort).

      Conclusion
      The FRAME study provides unique, real-life data reflecting prospectively collected information on resource use not accessible in a clinical trial setting. This study revealed several important findings regarding real-world resource use during NSCLC therapy including data on hospitalizations, outpatient visits, transfusions, concomitant treatments, and radiation.