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W.E.E. Eberhardt

Moderator of

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    O02 - NSCLC - Combined Modality Therapy I (ID 111)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Combined Modality
    • Presentations: 8
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      O02.01 - Geographic differences in the combined-modality treatment of stage III unresectable non-small cell lung cancer: Results from a global phase III trial of tecemotide (L-BLP25) (ID 2712)

      10:30 - 10:40  |  Author(s): N. Thatcher, F.A. Shepherd, P. Mitchell, M.A. Socinski, A. Paredes, M. Lambrechts, M. Thomas, J. Kollmeier, M. Zemanova, P. Sadjadian, N. Peylan-Ramu, C. Helwig, A. Schröder, C.A. Butts

      • Abstract
      • Presentation
      • Slides

      Background
      Chemo-radiotherapy (chemo/RT) is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC), but little is known about differences in clinical practice between regions of the world. The START trial is a global phase III trial of the MUC1-specific cancer immunotherapy tecemotide (L-BLP25), for which key efficacy and safety results have been reported previously. Here we report regional differences in diagnostic procedures and treatment of stage III NSCLC prior to enrolment in START.

      Methods
      The START trial recruited patients (performance status 0/1) with unresectable stage III NSCLC who had not progressed within 28–84 days of completing ≥2 cycles of platinum-based chemotherapy with concurrent or sequential radiotherapy (≥50 Gy). Baseline characteristics, diagnostic procedures and the initial chemo/RT administered of those recruited were compared between centers in different regions.

      Results
      From Jan 2007 to Nov 2011, 1513 patients were recruited at >250 centers in 33 countries: Western Europe 40.3%, Eastern Europe 26.0%, North America 21.8%, Latin America 5.7%, Asia 3.4%, Australia 2.8%. The majority of patients (92.1%) were Caucasian and median age was 61 years. Overall, 6.3% of patients were never-smokers with little inter-regional variation except for Asia (31.4%). The proportion of current smokers upon entry into the trial was highest in Eastern Europe (36.3%) and lowest in Australia (11.6%). Median tobacco consumption by region ranged from 36.2 (Eastern Europe) to 53.6 (Latin America) pack-years. The proportion of patients considered for the START trial who received concurrent rather than sequential chemo/RT varied widely between regions and was highest in North America and Australia, lower in Western Europe, Latin America and Asia, and lowest in Eastern Europe. There were also substantial variations in the diagnostic procedures between the regions, although pathological confirmation of N-status was infrequent in all regions. Detailed results by region for the time from diagnosis to randomization, duration of chemo- and radiotherapy, and chemotherapy agents used will be presented.

      Proportion of patients (%) with:
      Use of concurrent chemo/RT N-status determined with PET or PET/CT N-status determined with mediastinoscopy
      Australia (n=43) 100 74.4 2.3
      North America (n=330) 92.7 37.9 18.5
      Asia (n=51) 66.7 21.5 2.0
      Latin America (n=86) 65.1 7.0 5.8
      Western Europe (n=609) 67.2 32.2 6.9
      Eastern Europe (n=394) 28.9 7.3 3.6

      Conclusion
      Baseline data from the START trial suggest substantial variations in the management of unresectable stage III NSCLC between different regions of the world. While recruited patients from North American and Australian centers mostly received concurrent chemo/RT in accordance with current recommendations, a substantial proportion of patients in Europe, Latin America and Asia received sequential chemo/RT. More frequent use of concurrent chemo/RT as the recommended standard of care should be made across geographic regions.

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      O02.02 - Tecemotide (L-BLP25) in unresectable stage III non-small cell lung cancer in the phase III START study: Further endpoint and exploratory biomarker results (ID 2779)

      10:40 - 10:50  |  Author(s): P.L. Mitchell, C.A. Butts, M.A. Socinski, N. Thatcher, G. Wickart-Johansson, P.M. Ellis, O. Gladkov, J.R. Pereira, W.E.E. Eberhardt, K. Horwood, A. Szczesna, C. Helwig, A. Schröder, F.A. Shepherd

      • Abstract
      • Presentation
      • Slides

      Background
      The phase III START study evaluated the mucin 1 (MUC1) antigen-specific cancer immunotherapy tecemotide (L-BLP25) vs. placebo in patients with stage III unresectable non-small cell lung cancer (NSCLC) who did not progress following initial chemo-radiotherapy (chemo/RT). The primary objective of overall survival (OS) prolongation was not met, however, pre-defined subgroup analyses revealed a clinically meaningful prolongation of survival with tecemotide in patients previously treated with concurrent chemo/RT (p=0.016). Sensitivity analyses suggested the observed treatment effect may have been under-estimated due to a clinical hold, which resulted in a median suspension of recruitment and investigational treatment of about 4.4 months. Tecemotide was well tolerated and no safety concerns were identified.

      Methods
      From January 2007 to November 2011, 1513 patients with unresectable stage III NSCLC and stable disease or objective response following initial chemo/RT were randomized (2:1, double-blind) to subcutaneous tecemotide (806 µg lipopeptide) or placebo, weekly for 8 weeks and then 6-weekly until disease progression or withdrawal. A single dose of cyclophosphamide (300 mg/m2) or saline was given 3 days prior to first tecemotide/placebo dose. Primary endpoint, OS, and secondary endpoints progression-free-survival (PFS) and time-to-treatment-failure (TTF) used a Cox proportional hazards regression model adjusting for randomization strata. While RECIST 1.0 had to be observed for determination of disease progression, there was no formal imaging schedule to determine disease progression; this was done according to institutional practice. Exploratory analyses were done for treatment interaction for HLA-A02, -DRB4 and -B08. Baseline peripheral blood anti-nuclear antibodies (ANA), serum MUC1 (sMUC1), lymphocyte count and neutrophil:lymphocyte ratio (NLR) currently are being explored.

      Results
      The primary analysis population (N=1239) was defined prospectively to account for the clinical hold and prospectively excluded 274 patients randomized within 6 months prior to onset of the hold. Median PFS was 9.6 months with tecemotide vs. 7.7 months with placebo (HR 0.865, 95%CI 0.755–0.990, p=0.036). In keeping with OS data, tecemotide treatment effects on PFS were more pronounced in patients treated with concurrent chemo/RT (N=806; HR 0.826, 95%CI 0.696–0.980, p=0.029) vs. sequential chemo/RT (N=433; HR 0.947, 95%CI 0.756–1.187, p=0.638). Median TTF was 8.9 months with tecemotide vs. 7.2 months with placebo (HR 0.887, 95%CI 0.777–1.012, p=0.075). A prolongation of TTF with tecemotide was seen in patients with prior concurrent chemo/RT (HR 0.844, 95%CI 0.715–0.996, p=0.045), which was absent in the subgroup with prior sequential chemo/RT (HR 0.977, 95%CI 0.784–1.217, p=0.835). Detailed biomarker results will be presented.

      Conclusion
      While the primary endpoint of prolongation of OS was not met, secondary endpoints PFS and TTF support the previously-reported finding of a more favorable effect of tecemotide in patients treated with concurrent but not sequential chemo/RT. Any potential further clinical investigation of tecemotide in locally advanced NSCLC should focus on patients following concurrent chemo/RT therapy.

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      O02.03 - Value of Adding Erlotinib to Thoracic Radiation Therapy with Chemotherapy for Stage III Non-Small Cell Lung Cancer: A Prospective Phase II Study (ID 2436)

      10:50 - 11:00  |  Author(s): R. Komaki, P. Allen, X. Wei, G. Blumenschein, X.M. Tang, J..L.J. Lee, J.W. Welsh, I.I. Wistuba, D.D. Liu, W.K. Hong

      • Abstract
      • Presentation
      • Slides

      Background
      The molecular basis for radiation resistance seems to involve an enhanced survival response with increased capacity for DNA repair and suppressed apoptosis. Both properties are controlled in part by upstream signal transduction pathways triggered by activation of the epidermal growth factor receptor (EGFR). Hypothesizing that the response of non-small cell lung cancer (NSCLC) to current standard chemoradiotherapy can be improved through the addition of therapy targeted to the epidermal growth factor receptor (EGFR), we undertook a single-institution phase II trial to test whether adding the EGFR tyrosine kinase inhibitor (TKI) erlotinib to concurrent chemoradiation therapy for previously untreated, locally advanced, inoperable NSCLC would improve survival and response rates without increasing toxicity.

      Methods
      Forty-eight patients with previously untreated NSCLC received radiation (63 Gy/35 fractions) on Monday‒Friday, with chemotherapy (paclitaxel 45 mg/m², carboplatin AUC=2) given every Monday and erlotinib (150 mg orally 1/d) Tuesday–Sunday for 7 weeks, followed by two cycles of consolidation paclitaxel-carboplatin. The primary endpoint was time to progression; secondary endpoints were toxicity; response, overall survival (OS), and disease control rates; and whether any endpoint differed by EGFR mutation status.

      Results
      Of 46 patients (96%) evaluable for response, 40 were former or never smokers; 23 had adenocarcinoma; and 41 were evaluable for EGFR mutations (37 wild-type [wt] and 4 mutations [all adenocarcinomas]). Median time to progression was 14.5 months and did not differ according to EGFR status. Toxicity was acceptable (no grade 5, one grade 4, and eleven grade 3). Fourteen patients (31%) had complete responses (3 mutations and 11 wt), 24 (52%) partial (20 wt and 4 unknown EGFR mutation status), and 8 (18%) had stable or progressive disease (6 wt, 1 mutation and 1 unknown EGFR mutation status); 3 patients with mutations (75%) had complete response vs. 11 wt (30%) (p=0.07 for EGFR mutation vs wt groups). For alive patients, the median follow-up was 44.7 months’ follow-up (range, 29.3–54.6 months). OS rates were 82.6% at 1 year, 67.4% at 2 years, 48.5% at 3 years, and 32.2% at 4 years and did not differ by mutation status (wt vs mutation, p=0.17). For all patients the median follow-up was 30.6 months’ follow-up (range, 3.4–54.6 months). 14 patients were free from progression and 32 had local failure, distant failure, or both. Eleven of the 27 distant failures were in the brain (7 wt, 3 mutation, 1 unknown; P=0.04); the local control rate was 75% among the 4 patients with EGFR mutations. Median time to progression was 13.6 months (95% confidence interval 10.2-20) and did not differ by EGFR status (wt vs mutation p=0.39).

      Conclusion
      Overall survival was promising, but time to progression was disappointing. Toxicity was acceptable. The prevalence of distant failures underscores the need for more effective systemic therapy, perhaps including maintenance EGFR-TKI for patients with mutated EGFR.

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      O02.04 - DISCUSSANT (ID 3945)

      11:00 - 11:15  |  Author(s): E. Vokes

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      O02.05 - Major pathologic response (≤10% viable tumor) following neoadjuvant chemotherapy as a surrogate for overall survival in patients with pathologically documented stage IIIA (N2) lung adenocarcinomas (ID 2345)

      11:15 - 11:25  |  Author(s): J.E. Chaft, M.D. Hellmann, V.W. Rusch, W.D. Travis, M.G. Kris

      • Abstract
      • Presentation
      • Slides

      Background
      Neoadjuvant chemotherapy improves overall survival in patients with resectable stage IIIA lung adenocarcinomas. The gold-standard endpoint for clinical trials evaluating curative therapies is overall survival. Unfortunately, these trials take nearly a decade to complete and this prolonged timeline hinders the approval of promising therapies in the curative realm. Alternative endpoints that can act as a surrogate for overall survival have been evaluated, including nodal downstaging, nodal clearance, and pathologic response. We evaluated the degree to which these endpoints associate with overall survival in patients with pathologically proven stage IIIA(N2) lung adenocarcinoma treated with neoadjuvant chemotherapy.

      Methods
      An electronic database search engine was used to identify all patients with resectable stage IIIA(N2) lung adenocarcinoma treated with neoadjuvant chemotherapy at Memorial Sloan-Kettering Cancer Center between 1/2007-8/2012. Nodal downstaging was defined as no residual tumor tissue in the N2 nodes. Nodal clearance was defined as no residual tumor tissue in N1 and N2 nodes. Pathologic response was systemically assessed by a dedicated thoracic pathologist (WDT) who reviewed at least 1 section per centimeter of greatest gross tumor diameter. The percent viable tumor tissue in each slide was estimated to the nearest 10%. Major pathologic response (MPR) was defined as ≤10% viable tumor tissue. All pathologic analyses were performed by a dedicated thoracic pathologist (WDT). Patients with residual N2 disease at resection were offered post-operative radiation and routinely monitored thereafter. Survival proportions were estimated by the Kaplan-Meier method and compared using the log-rank test.

      Results
      69 patients with pathologically confirmed IIIA(N2) disease were identified and 46 (67%) ultimately underwent R0 resection. Among these patients, 16 had nodal downstaging, 14 had nodal clearance and 5 had a MPR. In both intention to treat analyses (N=69) and including only those who underwent resection, only MPR significantly associated with overall survival. The table below details findings from the population who had complete cancer resection.

      Endpoint (N=46) Yes (A) No (B) NA (C) HR (95% CI) ITT (A vs B+C) HR (95% CI) Resected(A vs B)
      Nodal downstaging 16 30 23 0.68 (0.32-1.56) 0.73 (0.24-2.10)
      Nodal clearance 14 32 23 0.57 (0.27-1.36) 0.96 (0.32-2.81)
      MPR 5 41 23 0.28 (0.1-0.78) 0.26 (0.07-0.95)
      NA = not assessable; ITT = intention to treat

      Conclusion
      MPR (≤10% viable tumor) effectively identifies patients with good clinical outcomes after neoadjuvant chemotherapy and can serve as a surrogate endpoint for overall survival. Furthermore, lack of MPR identifies a patient population at high risk of recurrence. Neither nodal downstaging nor nodal clearance effectively discriminated those with improved survival. Adaptive clinical trials designed to target those not achieving MPR are encouraged in attempt to improve the rate of cure in this disease.

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      O02.06 - Predictors of trimodality therapy use and overall survival in patients with stage III non-small cell lung cancer (NSCLC) in the National Cancer Database (ID 1736)

      11:25 - 11:35  |  Author(s): M.J. Fidler, M. Liptay, P. Bonomi, D. Sher

      • Abstract
      • Presentation
      • Slides

      Background
      The optimal locoregional therapy for stage III non-small cell lung cancer is controversial, with definitive chemoradiotherapy (CRT) and trimodality therapy (chemoradiotherapy followed by surgery, TMT) serving as competing strategies. The implementation of TMT and resultant survival outcomes in routine United States clinical practice has not been closely examined. In this study, we used the National Cancer Database (NCDB) to determine predictors of TMT and compare overall survival (OS) among a large cohort of stage III NSCLC patients treated with CRT or TMT.

      Methods
      Patients included were stage III NSCLC patients who received concurrent CRT with or without subsequent surgical resection at Commission on Cancer-accredited programs between 1998 and 2010; survival data were available for patients treated through 2005. High-volume (HV) center was defined as the upper decile. Per NCDB coding, treatment centers were stratified into academic, comprehensive, and non-comprehensive community cancer center (CCC). Logistic regression was used for univariable analyses, and multivariable models were prepared using stepwise selection to determine demographic, clinical and non-clinical predictors of TMT use and overall survival. Propensity score matching was used to estimate treatment effect and to minimize the effect of confounding variables.

      Results
      The overall cohort consisted of 49,534 patients, 25,679 of whom also had available survival data. Trimodality therapy was delivered in 7.8% of patients. Multivariable clinical predictors of TMT included: white race (OR 1.36), younger age (lowest [LQ] vs highest [HQ] quartile, OR 4.31), high school education or higher (HQ vs LQ, OR 1.37), stage IIIA vs IIIB, (OR 3.02) and squamous histology (OR 1.26). Non-clinical variables associated with TMT included: early treatment era (first vs last 3 years, OR 1.30), private insurance (OR 1.53), increasing distance from the treatment center (HQ vs LQ, OR 1.81), geography (Northeast vs. other, OR 1.35), treatment at academic research programs (ARP) over comprehensive CCC or non-comprehensive CCC (OR 1.53 and 2.01, respectively), and HV institution (OR 1.26). The median, 3- and 5-year OS were 12.3 months, 17% and 9.6%, respectively. Univariable comparison between CRT and TMT showed OS benefit with TMT (median 26.1 vs 11.7 months, log rank p<0.001). On MVA, stage IIIA (hazard ratio, HR, 0.85), squamous histology (HR 0.97), young age (HR 0.74) , female gender (HR 0.86), non-white race (HR 0.90), higher income (HQ vs LQ HR 0.76), farther distance from treatment center (HR 0.93), more recent treatment era (HR 0.80 vs. first 2 time periods) and TMT (HR 0.49) were significantly associated with improved OS. ARP was significantly associated with superior OS (HR 0.92 vs. CCP) if TMT was not in the Cox model. After propensity matching, TMT was still associated with improved OS (HR 0.62, p<0.001).

      Conclusion
      The use of TMT was strongly associated with markers of higher socioeconomic status and treatment at high-volume and academic centers. These data further support a significant survival benefit in patients undergoing TMT, and treatment at academic centers may improve OS via increased use of TMT.

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      O02.07 - Is there a survival benefit in patients with stage IIIA(N2) non-small cell lung cancer under neoadjuvant chemotherapy and/or radiotherapy followed by surgery administration: a systematic review and meta-analysis (ID 2164)

      11:35 - 11:45  |  Author(s): Y. Xu, B. Li, X. Xu, X. Yu, Q. Chen, W. Mao

      • Abstract
      • Presentation
      • Slides

      Background
      Optimal management of clinical stage IIIA (N2) non-small cell lung cancer (NSCLC) is controversial despite the conduct of several randomized controlled trials (RCTs). This article contributes to this problem by conducting a systematic review and meta-analysis of published RCTs.

      Methods
      A comprehensive literature search was performed in the Pubmed, Embase, Medline database (last search updated in May 2013) for relevant studies comparing patients with stage IIIA (N2)NSCLC undergoing surgery alone, chemotherapy and/or radiotherapy alone, or resection after neoadjuvant treatment with chemotherapy and/or radiotherapy. A systematic review and meta-analysis of available data were conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards.

      Results
      The comparison contained two components. In the comparison of neoadjuvant therapy followed by surgery and radical chemoradiotherapy/radiotherapy, a fine homogeneity (χ[2]=2.26, p=0.52, I[2]=0.0%) between four studies with a total of 803 selected cases was detected between the overall survival (OS), and the combined hazard ratio (HR) was 0.95 (95% confidence interval [CI]: 0.81-1.10; p=0.47). Progression-free survival (PFS) was investigated in two studies and there was also no significant difference for the combined HR was 0.90 (95% CI: 0.77-1.05; p=0.19). In the comparison of neoadjuvant chemoradiotherapy (Neo-ChRT) and neoadjuvant chemotherapy(Neo-ChT) alone, three studies with a total of 229 selected cases were detected, with the combined HR of OS and PFS 0.79 (95% CI: 0.57–1.09; p=0.15) and 0.67 (95% CI: 0.39-1.15; p=0.15) respectively, but it did not reach the statistical significance. Observing the short-term therapeutic effect, these studies revealed that Neo-ChRT had increased the rate of mediastinal pCR by 15.48% (OR: 3.61, 95%CI: 1.07–12.15; P = 0.04). Comparing the incidence of main complications and mortality, there was no significant difference between neoadjuvant therapy followed by surgery and radical chemoradiotherapy /radiotherapy alone. Neoadjuvant chemoradiotherapy followed by surgery achievered higher response rates and similar postoperative mortality as compared to neoadjuvant chemotherapy followed by operation, without adding significant adverse events.Figure 1

      Conclusion
      Neoadjuvant chemotherapy and/or radiotherapy followed by surgery is not superior to that followed by definitive radiotherapy. Neoadjuvant chemoradiotherapy dose not improve survival compared to neoadjuvant chemotherapy alone. But it can increase the rate of downstaging and mediastinal pCR which were correlated with the better PFS and OS. Neoadjuvant treatment has not increased the incidence of postoperative complication and motality. Further studies should be conducted to determine the patients who will benefit from various administrations.

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      O02.08 - DISCUSSANT (ID 3946)

      11:45 - 12:00  |  Author(s): E. Vallieres

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.14 - DISCUSSANT (ID 3939)

      17:30 - 17:40  |  Author(s): W.E.E. Eberhardt

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    O02 - NSCLC - Combined Modality Therapy I (ID 111)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Combined Modality
    • Presentations: 1
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      O02.02 - Tecemotide (L-BLP25) in unresectable stage III non-small cell lung cancer in the phase III START study: Further endpoint and exploratory biomarker results (ID 2779)

      10:40 - 10:50  |  Author(s): W.E.E. Eberhardt

      • Abstract
      • Presentation
      • Slides

      Background
      The phase III START study evaluated the mucin 1 (MUC1) antigen-specific cancer immunotherapy tecemotide (L-BLP25) vs. placebo in patients with stage III unresectable non-small cell lung cancer (NSCLC) who did not progress following initial chemo-radiotherapy (chemo/RT). The primary objective of overall survival (OS) prolongation was not met, however, pre-defined subgroup analyses revealed a clinically meaningful prolongation of survival with tecemotide in patients previously treated with concurrent chemo/RT (p=0.016). Sensitivity analyses suggested the observed treatment effect may have been under-estimated due to a clinical hold, which resulted in a median suspension of recruitment and investigational treatment of about 4.4 months. Tecemotide was well tolerated and no safety concerns were identified.

      Methods
      From January 2007 to November 2011, 1513 patients with unresectable stage III NSCLC and stable disease or objective response following initial chemo/RT were randomized (2:1, double-blind) to subcutaneous tecemotide (806 µg lipopeptide) or placebo, weekly for 8 weeks and then 6-weekly until disease progression or withdrawal. A single dose of cyclophosphamide (300 mg/m2) or saline was given 3 days prior to first tecemotide/placebo dose. Primary endpoint, OS, and secondary endpoints progression-free-survival (PFS) and time-to-treatment-failure (TTF) used a Cox proportional hazards regression model adjusting for randomization strata. While RECIST 1.0 had to be observed for determination of disease progression, there was no formal imaging schedule to determine disease progression; this was done according to institutional practice. Exploratory analyses were done for treatment interaction for HLA-A02, -DRB4 and -B08. Baseline peripheral blood anti-nuclear antibodies (ANA), serum MUC1 (sMUC1), lymphocyte count and neutrophil:lymphocyte ratio (NLR) currently are being explored.

      Results
      The primary analysis population (N=1239) was defined prospectively to account for the clinical hold and prospectively excluded 274 patients randomized within 6 months prior to onset of the hold. Median PFS was 9.6 months with tecemotide vs. 7.7 months with placebo (HR 0.865, 95%CI 0.755–0.990, p=0.036). In keeping with OS data, tecemotide treatment effects on PFS were more pronounced in patients treated with concurrent chemo/RT (N=806; HR 0.826, 95%CI 0.696–0.980, p=0.029) vs. sequential chemo/RT (N=433; HR 0.947, 95%CI 0.756–1.187, p=0.638). Median TTF was 8.9 months with tecemotide vs. 7.2 months with placebo (HR 0.887, 95%CI 0.777–1.012, p=0.075). A prolongation of TTF with tecemotide was seen in patients with prior concurrent chemo/RT (HR 0.844, 95%CI 0.715–0.996, p=0.045), which was absent in the subgroup with prior sequential chemo/RT (HR 0.977, 95%CI 0.784–1.217, p=0.835). Detailed biomarker results will be presented.

      Conclusion
      While the primary endpoint of prolongation of OS was not met, secondary endpoints PFS and TTF support the previously-reported finding of a more favorable effect of tecemotide in patients treated with concurrent but not sequential chemo/RT. Any potential further clinical investigation of tecemotide in locally advanced NSCLC should focus on patients following concurrent chemo/RT therapy.

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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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      P2.11-045 - TRY: A phase II study to evaluate safety and efficacy of combined trastuzumab and AUY922 in advanced non-small-cell lung cancer (NSCLC) with HER2 overexpression or amplification or mutation. (ID 3057)

      09:30 - 09:30  |  Author(s): W.E.E. Eberhardt

      • Abstract

      Background
      HER2 amplifications and/or mutations are rare genetic alterations in NSCLC accounting for approximately 4%. Preliminary clinical data suggested efficacy of trastuzumab in patients with HER2 IHC3+ status or FISH positivity. The heat shock protein HSP90 is a molecular chaperone that modulates stability and/or transport of intracellular client proteins including HER2. In breast cancer HSP90 inhibition has shown anticancer activity in HER2-positive patients after trastuzumab failure. Here we are investigating the efficacy of the combination of trastuzumab and the HSP90 inhibitor AUY922 in lung cancer patients with aberrant HER2.

      Methods
      This phase II study recruits metastatic NSCLC patients with HER2 overexpression (immunohistochemistry, DAKO-score 3+) or amplification (fluorescence in situ hybridization) or activating mutation after at least one previous standard treatment. In the first part of the study, patients are treated with trastuzumab only. CT scans are scheduled every 6 weeks during treatment. In case of disease progression, patients receive the combination of trastuzumab and AUY922.

      Results
      The study was initiated this year and NSCLC patients are screened within the Network of Genomic Medicine Lung Cancer on HER2 overexpression, amplifications and mutations. Until now, we tested 720 tumor samples by FISH and 63 by genomic sequencing. We identified 55 patients with HER2 amplification, 34 with HER2 overexpression (Dako score 3+) and 7 patients showed a mutation in the HER2 gene (1 exon 19; 6 exon 20).

      Conclusion
      HER2 overexpression, amplification or mutation is a rare genetic alteration in NSCLC patients. Data on treatment with HER2 antibody trastuzumab and HSP90 inhibitor AUY922 will be presented.

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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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      P3.10-028 - Pathologic complete remission after induction chemotherapy and intercalated Erlotinib in EGFR-mutated adenocarcinoma stage IIIA: Case report. (ID 1784)

      09:30 - 09:30  |  Author(s): W.E.E. Eberhardt

      • Abstract

      Background
      EGFR TKI treatment is standard of care in patients with metastasized NSCLC carrying an activating EGFR mutation. However, induction concepts in locally advanced NSCLC with EGFR mutation including TKI have not been studied extensively. Recently new focus has been shed on intercalated regimens of chemotherapy and TKI, showing improved PFS as well as OS. This concept was used as induction regimen in a female patient with activating EGFR mutation as well as p53 mutation and stage IIIA 3 multilevel.

      Methods
      Patient was diagnosed and worked up according to standard imaging, histology and immunohistology methods. EGFR, KRAS, BRAF, ALK and P53 mutation analysis was performed as described by Halbfass et al. Remission induction was measured by RECIST 1.1, regression grading by Junker criteria.

      Results
      A female caucasian 62 y.o. never smoker was diagnosed with TTF1+ adenocarcinoma G3 of the upper lobe of the lung, c2T3 (extension to mediastinal pleura) c2N2 (LN 2R and 4R) c2M0, UICC7 IIIA4 (Robinson). Molecular analysis after microdissection revealed WT for ALK, KRAS and BRAF, but an activating EGFR mutation Exon19 (p.Leu747_Ala750delinsPro), as well as a TP53 mutation in exon 8 (p.Val272Met (c.814G>A) (Sanger Sequencing). Induction therapy was started with erlotinib 150 mg/die p.o. days -12 to -2 in order to prove responsiveness of the tumour to TKI. On day 0 partial response was achieved. Therapy was continued with 3 cycles of Docetaxel 75 mg/m2 d1 and Cisplatin 50 mg/m2 d 1 and 2 qd22 with intercalated Erlotinib 150 mg/die p.o on days 4-19. Almost complete radiologic remission was achieved after 2 cycles The patient underwent R0 resection (upper lobe resection and radical lymphadenectomy) 4 weeks after day 1 of the 3[rd] cycle of chemotherapy, pathologic examination revealed T0N0 (mic+) with only one insula of tumor cells in an N2 lymph node, demonstrating regression grade III in the primary tumor and Grade IIB in the lymph nodes, according to the Junker classification. Molecular analysis of residual tumor cell insula revealed the same EGFR and p53 mutations as the primary tumour. The patient underwent postoperative radiotherapy of the mediastinum. No additional therapy, including TKI was administered postoperatively.

      Conclusion
      Intercalated TKI treatment might be a promising treatment choice in patients with EGFR mutated locally advanced NSCLC. A phase II trial is currently being planned to expand knowledge in this challenging field.