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F. Shepherd



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    Best of Posters - IASLC Selection - Part 2 (ID 263)

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
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      P2.11-024 - Efficacy Analysis for Molecular Subgroups in MARQUEE: a Randomized, Double-blind, Placebo-controlled, Phase 3 Trial of Tivantinib (ARQ 197) Plus Erlotinib versus Placebo plus Erlotinib in Previously Treated Patients with Locally Advanced or Metastatic, Non-squamous, Non- small Cell Lung Cancer (NSCLC) (ID 2909)

      10:00 - 10:05  |  Author(s): F. Shepherd

      • Abstract
      • Slides

      Background
      MARQUEE, a Phase 3 study which investigated the role of tivantinib, a c-MET inhibitor, in previously treated non-squamous NSCLC, collected EGFR and KRAS genotype on >90% of randomized patients, and MET expression was determined for 42%. In the ITT population, addition of tivantinib to erlotinib significantly improved PFS and ORR but did not show benefit in OS. Additional efficacy analyses in the pre-defined molecular subgroups are presented.

      Methods
      Patients with locally advanced or metastatic non-squamous, EGFR inhibitor naive NSCLC previously treated with 1 or 2 lines of systemic therapy, including a platinum-doublet, were stratified by number of prior therapies, sex, smoking history, and EGFR and KRAS mutation status, then randomized to oral tivantinib (360 mg twice daily) + erlotinib (150 mg once daily) or placebo + erlotinib until disease progression. Primary endpoint was OS with one interim analysis for futility/superiority. MET was assessed centrally by IHC using CONFIRM (SP44) antibody. Based upon a stability study, tumor tissue must have been sectioned within 90 days prior to MET immunostaining to be considered reliable. MET High was pre-specified as ≥50% of tumor cells staining with 2+ or 3+ intensity.

      Results
      From 1/2011 to 7/2012, 1048 patients were randomized to tivantinib + erlotinib (TE, n=526) or placebo + erlotinib (PE, n=522). Baseline characteristics were median age = 62 years (range, 24-89), prior therapies = 1 (66%) or 2 (34%), ECOG performance status = 0 (32%) or 1 (68%), EGFR mutant (10.4%), and KRAS mutant (27.1%). In 9/2012, the data monitoring committee recommended trial discontinuation because the pre-planned interim analysis of OS crossed the futility boundary. At the 12/2012 data cutoff, median OS was 8.5 months and 7.8 months for TE and PE, respectively (hazard ratio [HR] = 0.98; 95% CI, 0.84-1.15; p = 0.81). Median PFS was 3.6 months and 1.9 months, respectively (HR = 0.74; 95% CI, 0.62-0.89; p < 0.0001). Overall response rate (ORR) improved to 10.3% for TE compared with 6.5% for PE (p < 0.05). MET expression was obtained for 445 patients. In the pre-specified, MET High subgroup (n = 211), median OS improved to 9.3 months for TE vs 5.9 months for PE (HR = 0.70; 95% CI, 0.49-1.01; p = 0.03). In the MET Low subgroup (n = 234), median OS was 8.5 months for TE and 7.7 months for PE (HR=.90, 95% CI, 0.64-1.26, p=.53). OS did not differ between treatments in KRAS wildtype (n=702), KRAS mutant (n=284), and EGFR wildtype (n=937) subgroups; OS was immature for the EGFR mutant (n=109) subgroup at the cut-off time. Consistent with ITT, PFS was increased with TE vs PE across all molecular subgroups. Common adverse events (TE vs PE, respectively) included rash (33.1% vs 37.3%), diarrhea (34.6% vs 41.0%), and asthenia/fatigue (43.5% vs 38.1%), which occurred at similar rates between treatments; neutropenia (Grade 3/4: 10.0% vs 1.0%) was more common with TE.

      Conclusion
      Tivantinib significantly improved PFS and OS in the prospectively defined MET High subgroup. Further investigation of tivantinib in MET High selected, non-squamous NSCLC is warranted.

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    E10 - Targeting KRAS in Lung Cancer (ID 10)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Biology
    • Presentations: 1
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      E10.2 - Predictive or Prognostic Role of KRAS (ID 419)

      14:30 - 14:55  |  Author(s): F. Shepherd

      • Abstract
      • Presentation
      • Slides

      Abstract
      KRAS mutations are found in ~30% of adenocarcinomas and ~5% of squamous NSCLC. They are more common in current or former smokers. Most KRAS mutations in NSCLC occur on codon 12 and less frequently codons 13 and 61. Prognostic Value of KRAS The prognostic significance of KRAS has been investigated extensively. Results have been inconsistent with heterogeneity among studies including differing endpoints and patient populations studied. A large meta-analysis of 28 studies reported that KRAS mutation was a negative prognostic factor for OS (p=0.01) when all cancers were considered, in adenocarcinoma (HR 1.52, CI 1.30-1.78, p=0.02) but not squamous histology (HR 1.49, CI 95%: 0.88–2.52; p=0.48). The International Agency for Research on Cancer assessed KRAS in 762 patients with resected NSCLC. Mutations were detected in 18.5%; KRAS was not prognostic for PFS (p=0.26). The LACE-Bio group performed a pooled analysis of 1,543 patients from four randomized trials of adjuvant chemotherapy vs observation. KRAS mutations were present in tumors of 300 patients (codon 12 275, codon 13 24, and 1 codon-14). This was the first study to assess the prognostic effect of different KRAS mutations. In observation patients, there was no prognostic difference for OS for codon-12 (HR=1.04) or codon-13 (HR=1.01) mutations, nor for specific codon-12 amino acid substitutions. KRAS was not prognostic in the adenocarcinoma subgroup (HR=1.0, p=0.97). This group was the first to report that OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR=2.76, p=0.005). This observation requires validation. Predictive Value of KRAS Mutation for Chemotherapy Several studies have assessed the predictive value of KRAS in NSCLC patients treated with chemotherapy, but few have had untreated control arms to be able to isolate the predictive from the prognostic effects of mutation status. Rodenhuis et al. assessed KRAS in 83 patients with advanced adenocarcinoma treated with ifosfamide/carboplatin/etoposide; 26% had mutations.[10 ]The presence of KRAS mutation was not significantly associated with response rate, PFS or OS (p=0.486, p=0.22 and p=0.29, respectively). The TRIBUTE trial in advanced NSCLC compared first-line carboplatin/paclitaxel +/- erlotinib. KRAS mutations were present in 21% of samples tested. Response rates in the chemotherapy-alone arm were 26% and 23% for patients with wild-type and mutated KRAS, respectively, with no significant survival difference (median OS 13.5 and 11.3 months, respectively). In a neo-adjuvant chemotherapy study, Boermann et al[12] reported ORRs of 80% and 77% in patients with KRAS wild-type and mutated tumors, respectively. PFS was longer in patients with wild-type tumors compared to those with mutations (PFS 21 vs 9 mo, p=0.003) although there was no difference in OS (p=0.07). The LACE-BIO pooled analysis revealed no significant effect of KRAS mutation on benefit from adjuvant chemotherapy with respect to OS or DFS, even in adenocarcinoma (interaction p=0.99). Analysis by KRAS subtype revealed a non-significant benefit from ACT in patients with wild-type KRAS (HR=0.89, p=0.15) but not codon-12 mutations (HR=0.95, p=0.77); with codon-13 mutations, ACT was deleterious (HR=5.78, p=0.001, interaction p=0.002). There was a trend towards benefit from ACT for codon-12 G12A or G12R (HR=0.66 p=0.48) but not G12C or G12V (HR=0.94 p=0.77) or G12D or G12S (HR=1.39 p=0.48), (comparison of 4 HRs, including WT p=0.76). Predictive Value of KRAS Mutation for Epidermal Growth Factor Receptor Inhibitors In TRIBUTE, patients with KRAS mutant tumors who received chemotherapy+erlotinib had shorter median TTP than those treated with chemotherapy+placebo (3.4 vs 6 months, p=0.03). OS also was significantly shorter in the KRAS mutant subgroup treated with chemotherapy+erlotinib than those treated with chemotherapy+placebo (4.4 vs 13.5 months, p=0.019). In the NCIC CTG BR.21 trial of erlotinib vs placebo in advanced NSCLC, KRAS mutations were found in 15% of response-evaluable patients in the erlotinib arm. Response rates were 10% and 5% for patients with wild-type and mutated KRAS, respectively (p=0.69). There was no significant difference in survival benefit from erlotinib based on KRAS status (interaction p=0.09) on multivariable analysis (p=0.13), despite a trend in univariate analyses (KRAS mutant HR 1.67, p=0.31; KRAS wild-type HR 0.69, p=0.03). In the ATLAS trial that compared maintenance bevacizumab+placebo to bevacizumab+erlotinib, 93 patients had tumors with KRAS mutations. There was no significant PFS benefit for bevacizumab+erlotinib (HR 0.93, p=0.7697), while in wild-type KRAS, there appeared to be some benefit for the combination (HR 0.67, p=0.01).[14] In the SATURN trial, stable and responding patients were randomized to receive maintenance erlotinib or placebo. KRAS mutation was detected in 18%. Modest PFS benefit from erlotinib was seen both in patients with mutant KRAS and wild-type tumors (interaction p=0.95). Data are limited regarding KRAS mutation subtype and response to EGFR-TKIs in NSCLC. One recent investigation of KRAS mutation status and response to EGFR-TKI in EGFR wild-type advanced NSCLC demonstrated that patients with codon 13 KRAS mutations had worse PFS (p=0.04) and OS (p=0.005) than patients with codon 12 mutations. However, there were only 14 and four patients having mutations in codons 12 and 13, respectively. Two meta-analyses have evaluated the association between KRAS and EGFR TKIs in NSCLC. Linardou et al. assessed 17 trials (1008 patients, 165 with KRAS mutation). Mutation was significantly associated with lack of response to TKIs. Mao et al. included 22 studies; 16% (231/1470) had KRAS mutations. ORRs were higher for KRAS wild-type compared to mutation (26% and 3%, respectively). The pooled relative risk for response was 0.29 (p<0.01). In Asians, relative risk was 0.22 (p=0.01), and 0.31 (p<0.01) in Caucasians. In BMS-099, advanced NSCLC patients were randomized to receive taxane/carboplatin +/- cetuximab. KRAS mutations were found in 17% of assessable samples. There was no significant association between KRAS status and response, PFS or OS. The FLEX study compared cisplatin/vinorelbine +/- cetuximab in EGFR-expressing NSCLC. KRAS mutations were detected in 19% of assessable samples. The addition of cetuximab to chemotherapy did not significantly affect survival, PFS or response in patients with KRAS wild-type or mutated tumors. Summary KRAS is at most, a weak prognostic marker in NSCLC. It should not be considered a tool to select patients for treatment at this time.

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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O01.01 - Genetic polymorphisms of inflammatory and DNA repair pathways, radiation-related esophagitis and pneumonitis in definitive chemoradiation treated non-small cell lung cancer patients. (ID 2997)

      10:30 - 10:40  |  Author(s): F. Shepherd

      • Abstract
      • Presentation
      • Slides

      Background
      The benefits of concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC) are tempered by treatment toxicity. Germline genetic variants have been associated with intrinsic radiosensitivity and radiotoxicity in various cancer settings. We investigated whether variants in genes involved in inflammation response and DNA repair pathways independently influence radiation-induced phenotypes of esophagitis and pneumonitis. From 19 candidate genes, 52 polymorphisms, directed by literature and by tagging procedures, were systematically selected for assessment. The candidate genes were involved in DNA repair (double-strand breaks, homology directed, nucleotide excision) and pro/anti-inflammatory signaling. The this investigation sought to evaluate the association of genetic sequence markers for two clinically significant radiation-induced toxicities - esophagitis and pneumonitis – seen in NSCLC patients treated with a curative intent.

      Methods
      From 312 patients treated at PMCC between 2005-12, a training cohort was defined consisting of 92 definitive concurrent chemoradiation/radiation-treated NSCLC patients with genotype information on the 52 polymorphisms. A second, validation cohort consisted of 209 patients. Multivariate logistic regression was performed for each polymorphism of interest, adjusting for known clinical and dosimetric prognostic factors on the dichotomized outcomes of radiation esophagitis (Grades 0-2 vs 3-5) and pneumonitis (Grades 0-1 vs 2-5). The CTCAEv4.03 grading criteria were used. Additive genetic models were used for genetic association analysis. In the training set, genetic variants, genotyped by IlluminaGoldenGate, with p<=0.05 were identified for validation; HWE was set at p>0.01, a criteria met by all polymorphisms with statistical significance.

      Results
      In the combined training and validation datasets, 63% were males, with median age of 65 years. Specifically in the training dataset, 65% were male, with median age of 62, median mean lung doses of 15.9, median max esophageal dose of 67.1 and median V20 of 27.6. For esophagitis, the final models were adjusted for concurrent chemotherapy, V20 and max esophageal dose. Five genetic variants linked to TNF and IL6 were significantly associated with outcome (each using wild-type genotype as reference) (Table 1). For pneumonitis, the final models adjusted for V20 and smoking status. Eight genetic variants found within four genes (ATM, BRCA2, IL1alpha, IL1RN) were associated with significant pneumonitis (Table 1).

      ESOPHAGITIS
      Function / Pathway Gene refSNP OR 95% CI P value
      pro-inflammatory cytokine TNF rs3093662 3.54 1.9-10.6 0.02
      pro-inflammatory cytokine TNF rs3093664 3.42 1.2-10.2 0.03
      pro-inflammatory cytokine TNF rs3093665 4.95 1.2-21.1 0.03
      anti-inflammatory cytokine IL6 rs1800797 2.53 1.0-6.2 0.04
      anti-inflammatory cytokine IL6 rs1800795 2.45 1.0-5.9 0.046
      PNEUMONITIS
      Function / Pathway Gene refSNP OR 95% CI P value
      double-strand break repair ATM rs664143 2.67 1.3-5.6 0.01
      double-strand break repair ATM rs664677 2.37 1.2-4.7 0.01
      homology-directed repair BRCA2 rs1799955 2.59 1.3-5.3 0.01
      homology-directed repair BRCA2 rs1801406 2.42 1.2-4.8 0.01
      homology-directed repair BRCA2 rs1799943 2.09 1.0-4.2 0.04
      anti-inflammatory cytokine IL1alpha rs17561 2.63 1.2-5.7 0.01
      anti-inflammatory cytokine IL1alpha rs2856863 2.60 1.1-5.9 0.02
      anti-inflammatory cytokine IL1RN rs3087263 0.17 0.04-0.8 0.04

      Conclusion
      In our 92 patient training set, genetic variations in TNF and IL6 are associated with radiation esophagitis, while genetic variations in ATM, BRCA2, IL1alpha and IL1RN are associated with pneumonitis. Results from the 209 patients in the validation dataset will be presented at the meeting (A.H. and G. L are co-senior authors).

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-038 - Long-term outcome after resection of non-small cell lung cancer invading the thoracic inlet (ID 2929)

      09:30 - 09:30  |  Author(s): F. Shepherd

      • Abstract

      Background
      Non-small cell lung cancer (NSCLC) of the thoracic inlet accounts for less than 5% of all lung cancers. Due to the lack of efficient treatment and the complexity of the anatomical structures commonly invaded, these tumors were deemed historically unresectable and fatal. In this study, we reviewed our surgical experience and long-term outcome after resection of NSCLC invading the thoracic inlet

      Methods
      All consecutive patients from a single center who underwent resection of NSCLC invading the thoracic inlet were reviewed with data retrieved retrospectively from the charts.

      Results
      A total of 65 consecutive patients with a median age of 61 years (range 32 to 76) underwent resection of NSCLC invading the thoracic inlet from 1991 to 2011. Tumors were located in the previously described (Reference) five zones of the thoracic inlet as follows: zone 1 or anterolateral (n=5, 8%), zone 2 or anterocentral (n=7, 11%), zone 3 or posterosuperior (n=12, 18%), zone 4 or posteroinferior (n=22, 34%) and zone 5 or inferolateral (n=7, 11%). Fifty-two (80%) patients had induction therapy, mostly two cycles of cisplatin-etoposide and 45 Gy of concurrent radiation. All patients underwent en bloc resection of the lung and chest wall. Lobectomy was performed in 60 patients (92%). A median of three ribs were resected (range 1 to 5) and included the first rib in all patients. Twenty-four patients (37%) had an additional vertebral resection of up to five levels (median 3). Considering the most extended vertebral resection, total vertebrectomy with anterior-posterior spinal stabilization was required in 6 patients (25%), hemi-vertebrectomy with posterior spinal stabilization in 15 (62%), and partial vertebrectomy without stabilization in 3 (13%). Arterial resections were performed in seven patients (11%) and included subclavian artery (n=5), vertebral artery (n=1) and combination of sublclavian and carotid arteries (n=1).The median postoperative length of stay was 11 days (range 4 to 173). Postoperative morbidity and mortality were 46% and 6%, respectively. Pathologic response to induction treatment was complete (n=19) or near complete (n=12) in 31 patients (49%). Pathologic stages were 0 in 19 patients (29%), IB in 1 (2%), IIB in 28 (43%), IIIA in 15 (23%) and IIIB in 2 (3%) patients. After a median follow-up of 20 months (range 0 to 193), 34 patients were alive without recurrence. The overall 3- and 5-year survivals reached 58% and 52%, respectively. Results of the Cox regression and log-rank/Breslow tests identified the site of tumor (zone 1/3 vs 2/4/5, p=0.050) and the response rate to induction treatment (complete/near complete vs partial, p=0.004) as significant predictors of survivals. A trend toward shorter survival was found in case of arterial resection (p=0.063).

      Conclusion
      Survival after resection of NSCLC invading the thoracic inlet in highly selected patients reached 52% after five years. Tumor location within the thoracic inlet and pathologic response to induction therapy were significant predictors of survivals. Reference: de Perrot M, Rampersaud R. Surgical approaches to apical thoracic malignancies. J Thorac Cardiovasc Surg. 2012 Jul;144(1):72-80.