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M.A. Socinski



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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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      MO06.12 - Efficacy and safety of paclitaxel and carboplatin with bevacizumab for the first-line treatment of patients with nonsquamous non-small cell lung cancer (NSCLC): analyses based on age in the phase 3 PointBreak and E4599 trials (ID 2879)

      17:20 - 17:25  |  Author(s): M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background
      A post hoc analysis of NSCLC patients (pts) aged ≥70 y in the pivotal E4599 trial found increased adverse events (AEs) and numerically decreased overall survival (OS) benefit associated with bevacizumab (BEV) compared with pts <70 y. We evaluated the efficacy and safety of BEV by age in pts in a pooled dataset from the E4599 and PointBreak (PB) trials.

      Methods
      Pts randomized to the PC (paclitaxel and carboplatin ) + BEV arms of E4599 and PB received P 200 mg/m[2], C AUC 6, and BEV 15 mg/kg q3w for 6 (E4599) or 4 (PB) cycles; Eligible pts received maintenance BEV alone q3w until disease progression or unacceptable toxicity. OS, progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety were assessed in pts grouped according to age (<65 y, 65–74 y, 70–74 y, <75 y, and ≥75 y). Pt-level data from the PC + BEV arms of E4599 and PB were pooled and compared with data from pts in the PC-alone arm of E4599.

      Results
      PB and E4599 randomized 467 pts and 434 pts to PC + BEV, respectively, while 444 were randomized to receive PC alone on E4599. Baseline characteristics were balanced between age groups. OS and PFS hazard ratios (HRs) and increases in grade ≥3 AEs for the pooled pt cohort relative to E4599 PC-alone arm are shown (Table). Outcomes were similar in pts <70 y and ≥70 y, and data from the pooled population were similar to those seen in each individual trial (data not shown). ORR for pts <75 y was 39% with PC + BEV vs 26% with PC (P<.01). For pts ≥75 y, ORR was 33% vs 30% (P=.71). DCR in pts <75 y was 70% with PC + BEV vs 53% with PC (P<.01). For pts ≥75 y, DCR was 60% vs 67% (P=.37).

      Conclusion
      In a pooled exploratory analysis of pt data from E4599 and PB, the statistically significant benefit associated with the addition of BEV to PC appeared consistent across all age groups <75y, while pts ≥75 y receiving PC + BEV had no statistically significant survival benefit. Pts receiving PC + BEV had an increase in grade ≥3 AEs compared with pts receiving PC-alone in all age groups.

      PB + E4599 <65 y n=735 65–74 y n=453 70–74 y n=203 <75 y n=1188 ≥75 y n=157
      HR for OS 95% CI P 0.75 0.62–0.89 <.01 0.80 0.64–1.00 .05 0.68 0.48–0.96 .03 0.78 0.68–0.89 <.01 1.05 0.70–1.57 .83
      HR for PFS 95% CI P 0.71 0.60–0.85 <.01 0.62 0.49–0.78 <.01 0.68 0.48–0.96 .03 0.69 0.60–0.79 <.01 0.95 0.62–1.44 .80
      E4599 n=499 n=277 n=129 n=776 n=102
      Δ Grade ≥3 AEs,[a ]% P 13 <.01 21 <.01 23 <.01 15 <.01 25 <.01
      [a]Relative to PC-alone arm.

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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.08 - KDR (VEGFR-2) copy number gains and mutations are targetable alterations in non-small cell lung cancer (ID 1466)

      17:00 - 17:05  |  Author(s): M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background
      Therapeutic regimens targeting the vascular endothelial growth factor (VEGF) pathway have been extensively tested in the treatment of malignancies including non-small cell lung cancer (NSCLC). VEGF pathway inhibitors including bevacizumab or VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have been shown to prolong progression-free survival (PFS) and/or overall survival (OS). These benefits, however, have been modest, occurring only in subsets of patients. Therefore, predictive markers to identify patients likely to derive benefit are critically needed. Although expression of VEGFR-2, also known as KDR, was initially thought to localize primarily on endothelial cells, VEGFR-2 has been detected on malignant cells. We recently observed that KDR copy number gains (CNGs) were detectable by FISH in ~30% of both adenocarcinoma and squamous cell carcinoma and were associated with poor clinical outcome in early stage NSCLC patients treated with adjuvant chemotherapy. In addition to CNGs, mutations and polymorphisms within the KDR gene were also observed. The impact of these alterations is unknown. Here, we investigated KDR CNGs, polymorphisms, and mutations in NSCLC and their effects on sensitivity to VEGFR targeting agents in preclinical models and in NSCLC patients.

      Methods
      Cell migration was evaluated by Boyden chamber assay. NSCLC cell lines were treated with VEGF pathway inhibitors for 24 hours, and protein lysates where collected. HIF-1α levels were evaluated by ELISA assay. VEGFR, p38, and p70s6K were evaluated by Western blotting. Tumor DNA and peripheral blood DNA, were analyzed in duplicate using Affymetrix Genome-Wide SNP Array 6.0. Transformation of Ba/F3 cells was evaluated by an IL-3-independent growth assay.

      Results
      In tumor cells with KDR CNG, VEGF stimulation induced activation of p38 and p70S6K, and VEGFR TKIs including sorafenib and vandetanib effectively inhibited VEGF-mediated signal transduction. In tumor cell lines with KDR CNG, exogenous VEGF ligand increased cell motility and this was inhibited by VEGFR blockade with TKIs including sunitinib, sorafenib, and axitinib. Various receptor tyrosine kinases have been shown to drive HIF-1α levels, and NSCLC cells with KDR CNG express elevated levels of HIF-1α in normoxia compared to NSCLC cell lines without KDR CNG. In NSCLC cell lines with KDR CNG, VEGFR TKIs decreased protein levels of HIF-1α and HIF-1α regulated proteins. Furthermore, we report a clinical case in which a NSCLC patient with KDR CNG had a partial response to the VEGFR inhibitor, sorafenib. In addition to gene amplification, mutations and polymorphisms within the KDR gene were also observed. KDR mutation 1586A>T and polymorphism 1416A>T effectively transformed Ba/F3 cells. Finally, we report two clinical cases in which NSCLC patients with the 1416A>T polymorphism had a partial response the VEGF pathway inhibitor, bevacizumab.

      Conclusion
      Collectively, our data indicate that KDR amplification promotes downstream signaling events including activation of the p38, mTOR, and HIF pathways and are targetable by VEGF pathway inhibitors. KDR gene alterations may be predictive markers for VEGF pathway inhibitors.

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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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      MO24.07 - nab-Paclitaxel plus carboplatin in patients (pts) with squamous cell (SCC) non-small cell lung cancer (NSCLC): analysis of pts treated beyond 4 cycles in a pivotal phase 3 trial (ID 3438)

      11:05 - 11:10  |  Author(s): M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background
      Continuous maintenance is defined as continuation of ≥ 1 first-line agents after 4-6 cycles of induction therapy in pts who have not progressed. In a pivotal phase 3 trial, first-line treatment to progression with nab-paclitaxel (nab-P, 130-nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C resulted in a 68% improvement in response rate (41% vs 24%; P < .001) and a trend toward improved survival (median, 10.7 vs 9.5 months; P = .808) in the subset of pts with SCC. This unplanned exploratory analysis examined outcomes in pts with SCC receiving > 4 cycles of nab-P/C to assess the feasibility of the nab-P/C regimen in the maintenance setting in SCC.

      Methods
      Pts with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on days 1, 8, 15 or sb-P 200 mg/m[2] on day 1 every 21 days; both arms received C AUC 6 on day 1. Overall response rate and progression-free survival (PFS) were determined by blinded centralized review. To allow comparison of the results of this analysis with maintenance studies, PFS is expressed from day 1 of cycle 5 (C5D1).

      Results
      229 pts with SCC received nab-P/C and 221 received sb-P/C in this study. In the nab-P/C arm, 60% (n = 138) of pts with SCC were progression-free at the end of cycle 4 and entered cycle 5 (the study population). In these pts, the median PFS was 3.4 months (range 2.8 – 4.2) from C5D1. The median OS from randomization in these pts was 13.8 months (range 12.4 – 16.8). Survival at 1year was 59% (51% – 67%). The median number of treatment cycles was 7 (range 5 – 31). A total of 125 (91%), 64 (46%) and 35 (25%) pts were treated for up to 6, 8 and 10 cycles, respectively, with a median weekly dose of 75 mg/m[2 ]for nab-paclitaxel in each group, and carboplatin AUC of 6, 4.75, and 4.5, respectively. Preliminary safety findings in this population revealed that the most common grade 3/4 treatment-related adverse events were neutropenia (49%), anemia (31%), and thrombocytopenia (27%). The overall rate of grade 3 peripheral neuropathy in the nab-P/C arm was 4% (with no grade 4); 1%, 3%, and 0% of pts had grade 3 peripheral neuropathy at cycle 6, 8, and 10, respectively.

      Conclusion
      Continued treatment with nab-P/C to progression was feasible, well tolerated, and effective in pts with advanced SCC who had not progressed after 4 cycles of first-line therapy. Future randomized, prospective studies are warranted to further evaluate the activity of nab-P/C as maintenance therapy in SCC pts.

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

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Combined Modality
    • Presentations: 2
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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): M.A. Socinski

      • 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): M.A. Socinski

      • 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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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.02 - Randomized Phase-3 trial (INSPIRE) of Necitumumab plus Cisplatin-Pemetrexed versus Cisplatin-Pemetrexed Alone as First-Line Therapy in Stage IV Non-Squamous NSCLC (ID 2337)

      10:40 - 10:50  |  Author(s): M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background
      Necitumumab is a human IgG1 anti-EGFR1 monoclonal antibody that competes for the binding of natural ligands to this receptor and prevents receptor activation. EGFR1 is detectable in approximately 85% of advanced NSCLC tumors. This phase 3 study investigated necitumumab in combination with first-line chemotherapy in advanced non-squamous NSCLC.

      Methods
      Patients with histologically or cytologically proven stage IV non-squamous NSCLC were randomized 1:1 to either Arm A: cisplatin 75mg/m[2] i.v.-pemetrexed 500mg/m[2] i.v. (Cis + PEM) on Day 1+ necitumumab 800mg i.v. on Days 1 and 8 of a 21-day cycle or Arm B: Cis+PEM alone. Patients received these regimens for up to six cycles. For patients in Arm A with at least stable disease, necitumumab continued until PD or intolerable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and EGFR protein expression level by immunohistochemistry (H-score) utilizing archived tumor tissue based on a mandatory tissue collection. The planned sample size of this study was 947 patients (assuming a hazard ratio [HR] of 0.8 would allow 85% power at 2-sided alpha level of 0.05). After 633 patients, enrollment was stopped (after Feb 2011) following an Independent Data Monitoring Committee (IDMC) recommendation.

      Results
      Between Nov 2009 and Feb 2011 633 patients were randomized (315 Arm A; 318 Arm B). Baseline characteristics were balanced between the arms; 67.0% were male and 33.0% female; ECOG-PS 0/1 94.2 % and PS 2 5.7 %. No difference between treatment arms was observed for OS (median 11.3 vs 11.5 months; HR 1.01 95%-CI [0.84, 1.21]), PFS (median 5.6 vs 5.6 months, HR 0.96 95%-CI [0.80, 1.16]) and ORR (31.1 vs 32.1%; Odds ratio 0.96 95%-CI [0.68, 1.34]). The exploratory analysis in 490 patients assessable for H-score revealed no association between H-score and differences in efficacy between treatment arms (H-score < 200: mOS 8.97 vs 9.72 months, HR 1.07, mPFS 4.90 vs 4.76 months, HR 0.95, ORR 27.1 vs 26.0%; H-score ≥ 200: mOS 15.01 vs 13.34 months, HR 1.03, mPFS 5.59 vs 5.62 months, HR 0.94, ORR 39.6 vs 39.4%). Grade ≥ 3 treatment-emergent adverse events (AEs) occurring more frequently in Arm A included skin or subcutaneous disorders (14.1 vs 0.3%), thromboembolic events (9.5 vs 6.4%), hypomagnesaemia (7.6 vs 2.2%), asthenia (6.9 vs 1.9%), vomiting (6.6 vs 3.2%), dyspnea (5.3 vs 2.6%) and diarrhea (4.3 vs 2.2%). The frequency of study drug related deaths was 4.9% and 2.9% in Arms A and B, respectively.

      Conclusion
      In this study, the addition of necitumumab did not improve the efficacy outcome over cisplatin plus pemetrexed alone in advanced non-squamous-NSCLC. The EGFR H-score did not seem to predict the efficacy outcomes of necitumumab in combination with cisplatin plus pemetrexed. The addition of necitumumab resulted in a higher frequency of grade ≥ 3 AE (skin reaction, GI, asthenia and other) and an imbalance of grade ≥ 3 thromboembolic events. Further biomarker studies are ongoing.

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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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      O15.06 - Randomized Phase III Trial of Gemcitabine (G)/Carboplatin (C) with or without Iniparib (I) in Patients (Pts) with Previously Untreated Stage IV Squamous Lung Cancer (ID 3322)

      11:25 - 11:35  |  Author(s): M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background
      Iniparib is an agent originally thought to function as an inhibitor of the DNA repair enzyme PARP-1, which is overexpressed in squamous lung cancers. Promising phase II activity and safety were reported with iniparib in combination with GC in pts with metastatic triple-negative breast cancer (O’Shaughnessy, NEJM 2011); however, subsequent phase III data were negative. Further study of iniparib’s mechanism of action suggests that this agent induces DNA damage, cell cycle arrest in the G2/M phase, and potentiates DNA-damaging chemotherapies not through PARP inhibition. Herein we report the final results from an international Phase III trial (NCT01082549) of first-line chemotherapy and iniparib in pts with advanced squamous lung cancer.

      Methods
      Pts were randomized 1:1 to GC or GCI. All pts received G 1000 mg/m[2] IV days (D) 1 and 8, and C AUC=5 IV D1 of each 21-D cycle. Iniparib was dosed 5.6 mg/kg IV D 1, 4, 8, and 11. All pts were assessed for response per RECIST 1.1 every 6 weeks. Pts without evidence of progressive disease (PD) or other reason for discontinuation could remain on treatment beyond 6 cycles. Accrual of 780 pts provides 89% power to detect an improvement in survival from 8 months (mos) anticipated with GC to 10.7 mos with GCI (HR of 0.75). Eligibility: Pts with newly diagnosed stage IV (M1a and M1b) squamous lung cancer, ECOG PS 0-1. Exclusion criteria included: history of recent cardiac disease, untreated brain metastases, and treatment for early-stage lung cancer within 12 months of study entry. The primary endpoint was overall survival (OS). Interim analyses for safety and futility were performed by an independent data safety monitoring board.

      Results
      780 pts were enrolled and randomized (GC, 390), (GCI, 390) from March 2010 to May 2012. Baseline characteristics were well balanced between groups (GC/GCI): median age 66 years (21-86); 74%/73% male; 30%/33% ECOG 0; 28%/33% current smokers; 66%/62% past smokers. The median number of cycles for GC/GCI were 4 (1-26)/5 (1-32). Dose reductions, dose intensity, and discontinuations due to tumor progression or adverse events were similar in both arms. The median OS for GC/GCI was 8.9 v. 8.9 months, HR 1.08 (0.92-1.28), p=.348. 1-year OS was 41 v. 40%. The median progression-free survival (PFS) for GC vs GCI was 4.9 v. 4.8 months, HR 0.99 (0.83-1.19), p=.92. The objective response rate (ORR) for GC v GCI was 34 v. 32%, p=.648. The safety profile was similar in both arms; anemia (28/26%), neutropenia (31/35%), thrombocytopenia (27/28%), and fatigue (6/9%).

      Conclusion
      The addition of iniparib did not improve the efficacy of GC in the treatment of pts with advanced squamous lung cancer. Further development of iniparib in squamous lung cancer is not recommended.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 3
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      P1.10-004 - Exploratory Subset Analysis in African Americans from the PointBreak Study (Randomized Phase 3 Pemetrexed + Carboplatin + Bevacizumab Followed by Maintenance Pemetrexed + Bevacizumab Versus Paclitaxel + Carboplatin + Bevacizumab followed by Maintenance Bevacizumab in Patients with Stage IIIB/ IV   Nonsquamous Non-Small Cell Lung Cancer) (ID 249)

      09:30 - 09:30  |  Author(s): M.A. Socinski

      • Abstract

      Background
      African Americans (AA) have a higher rate of lung cancer than Caucasians per 100,000 population (74.7 versus 64.4) but are underrepresented in randomized clinical trials. In the PointBreak study, AAs were enrolled at the same rate as the US incidence of non-small cell lung cancer (NSCLC) for AAs in 2011 (13%; now 15% in 2013). Post-hoc analyses of the AA subgroup were conducted from this study to evaluate efficacy and safety, as well as these outcomes by treatment center.

      Methods
      All patients (N=939) were chemonaive with an ECOG performance status (PS) of 0/1. AAs were analyzed against Caucasians for efficacy/safety in the pemetrexed (Pem) arm only. Subgroup analyses of AAs alone were conducted for efficacy/safety (between arm comparisons) as well as academic versus community settings (pooled two treatment arms). Hazard ratios and p-values were derived from a multivariate Cox-PH model, adjusting for disease stage, gender, PS and measurable/nonmeasurable disease. Response rates and adverse events (AEs) were compared using the exact test.

      Results
      Patients had stage IIIb (with pleural effusion)/IV nonsquamous NSCLC, according to AJCC edition 6. There were 94 AAs (42 = Pem arm; 52 = Paclitaxel [Pac] arm) and 805 Caucasians in the treated population. Demographics were statistically comparable between AAs and Caucasians in the Pem Arm, respectively: 62%/53% male, 71%/53% ≤65 years, 98%/89% ever smokers, 81%/90% Stage IV disease, with ECOG PS of 0/1, 33%/67%, versus 44%/56%. Median OS was similar between AAs and Caucasians in the Pem arm at 12.4 versus 12.3 months. Median PFS for AAs and Caucasians was 4.6 months versus 6.0 months (HR 1.229 (0.864 – 1.749; p=0.251). Overall response rate (ORR) for AAs was higher, though not statistically, at 38.1% versus 33.3% (p=0.607). Efficacy among AAs was fairly similar with median OS for Pem arm at 12.4 versus 13.7 months for Pac arm (p=0.1208). Median PFS by arm was 4.6 versus 5.1 months (p=0.6699). ORR among AAs was 38% in both arms. AAs showed a heavy trend (80%) for enrollment in community centers (n=74) versus academic center (n=20). Efficacy among AAs by setting showed a higher median OS at academic sites at 16.5 months versus 11.4 months, p=0.1906 (HR=0.6605; 95% CI: 0.355 – 1.229). Median PFS was also higher at academic sites at 6.9 months versus 4.6 months, p=0.9149 (HR =0.9690; 95% CI: 0.544 – 1.726). Drug-related grade 3/4 AEs in the Pem arm showed higher percentages for Caucasians with the exception of neutropenia, as follows: anemia (7.3%/15.9%), thrombocytopenia (9.8%/25.5%), fatigue (4.9%/11.5%), neutropenia (31.7%/25.3%), febrile neutropenia (0%/1.6%). Among AAs in the Pem/Pac Arm respectively, drug-related grade 3/4 AEs were: anemia (7.3%/0%), thrombocytopenia (9.8%/4.0%), fatigue (4.9%/4.0%), neutropenia (31.7%/44.0%), and febrile neutropenia (0%/4.0%).

      Conclusion
      There were no significant differences between AAs and Caucasians for OS, PFS, and ORR. Among AAs, median OS was not superior for either arm. PFS and OS were similar for academic and community settings among AAs. Caucasians had a significantly higher incidence of Grade 3/4 thrombocytopenia (p=0.0217), but this should be interpreted with caution due to the sample size for the AAs.

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      P1.10-018 - nab-Paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC): analysis of peripheral neuropathy (ID 1022)

      09:30 - 09:30  |  Author(s): M.A. Socinski

      • Abstract

      Background
      Peripheral neuropathy (PN) is a common side effect associated with taxane treatment. In a phase III trial, nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C significantly improved ORR (primary endpoint; 33% vs 25%; P = 0.005), with a trend toward improved OS and PFS in patients with advanced NSCLC. Here, we report on the PN profile of nab-P/C vs sb-P/C.

      Methods
      Patients with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on d 1, 8, 15 or sb-P 200 mg/m[2] q 1 q21d; both arms received C AUC 6 day 1 q21d. PN was assessed by Standardized MedDRA Query (SMQ) for neuropathy (broad scope) unless otherwise indicated. Patient-reported taxane-related neuropathy symptoms were assessed by the Functional Assessment of Cancer Therapy (FACT)-Taxane Additional Concerns scale.

      Results
      nab-P/C was associated with significantly less PN vs sb-P/C (all grade: 46% vs 62%; P < 0.001) and grade 3/4 treatment-related PN (3% vs 12%; P < 0.001). Grade 4 PN occurred in 2 patients in the sb-P/C arm vs 0 patients in the nab-P/C arm. PN led to taxane dose reductions in 2% vs 7% and delays in 3% vs 8% of patients in the nab-P/C vs sb-P/C arm. Physician assessment of PN based on NCI CTCAE grade showed fewer instances of worsening with nab-P/C vs sb-P/C. At baseline, ≥ 95% of patients in both arms were assessed with grade 0 PN, but at final evaluation, significant treatment differences favoring the nab-P/C arm were observed, with fewer nab-P/C−treated patients shifting from grade 0 to grades 1-4 (38%) relative to the sb-P/C arm (58%; P < 0.001). Fewer patients receiving ≤ 6 cycles (median number of cycles = 6) in the nab-P/C vs sb-P/C arms experienced all-grade PN (41% vs 60%); 2% vs 10% of these patients experienced grade 3/4 PN (no patients in the nab-P/C arm experienced grade 4 PN). Median time to PN onset of any grade was longer with nab-P/C vs sb-P/C, 49 vs 38 days (P < 0.001); grade 2-4, 105 vs 78 days (P = 0.04) and grade 3/4, 121 vs 106 days (P = 0.723). The median time to improvement of grade 3/4 PN to grade 1 was 38 vs 104 days (P = 0.326) with nab-P/C vs sb-P/C. Patient-reported FACT-Taxane PN subscore at final evaluation also demonstrated a statistically significant treatment effect favoring nab-P/C (P < 0.001). Most patients completed the FACT-Taxane questionnaire at baseline (98%) and provided follow-up assessments (94%) at each cycle. Deterioration in patient-reported PN subscore at or after the development of grade 3/4 PN was lower for nab-P/C vs sb-P/C (median change from baseline 4.5 vs 10).

      Conclusion
      In this trial, nab-P/C was associated with lower rates PN compared with sb-P/C. PN occurred later during treatment with nab-P/C vs sb-P/C, and the majority of patients experienced improvement of PN symptoms within approximately 1 month. Patients receiving ≤ 6 cycles of therapy with nab-P/C had less PN compared with those receiving sb-P/C.

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      P1.10-044 - nab-Paclitaxel in combination with carboplatin as first-line therapy in diabetic patients with advanced non-small cell lung cancer (NSCLC) (ID 2446)

      09:30 - 09:30  |  Author(s): M.A. Socinski

      • Abstract

      Background
      Diabetes and other age-related comorbidities frequently occur together in patients with NSCLC and may affect treatment efficacy and tolerability. Several studies demonstrated that diabetic patients have worse outcomes than those without diabetes. Additionally, studies have suggested that metformin may enhance the effects of chemotherapy, leading to improved outcomes. In a phase III trial, nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) significantly improved the primary endpoint of overall response rate (ORR) from 25% to 33% (P = 0.005), with a trend toward improved overall survival (OS) and progression-free survival (PFS) vs solvent-based paclitaxel (sb-P) + C in patients with advanced NSCLC. This exploratory analysis examined efficacy and safety outcomes in diabetic patients with advanced NSCLC.

      Methods
      Patients with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on d 1, 8, 15 or sb-P 200 mg/m[2] d 1 q21d; both arms received C AUC 6 d 1 q21d. ORR and PFS were determined by blinded, centralized review. P values for ORR were based on chi-square test, and those for OS and PFS were based on log-rank test. Multiple sensitivity analyses were performed to confirm treatment differences and to rule out confounding effects from other baseline covariates.

      Results
      31 patients in the nab-P/C and 30 patients in the sb-P/C arms were included in this analysis. Similar to the intent-to-treat (ITT) population, most diabetic patients were male (75%), white (62%), with ECOG PS 1 (79%), and stage IV disease (85%). In these patients, ORR for nab-P/C vs sb-P/C was 52% vs 27% (response rate ratio 1.935; P = 0.046), median PFS was 10.9 vs 4.9 months (HR 0.416; P = 0.016), and median OS was 17.5 vs 11.1 months (HR 0.553; P = 0.057). Treatment difference in PFS remained significant (P ≤ 0.026) after adjusting for baseline characteristics (including histology, region, stage, and age). For OS, region, stage, race, and age were not observed to be confounding factors on treatment effect. Metformin was concomitantly used in 29% and 37% of diabetic patients in the nab-P/C vs sb-P/C arms, respectively. The percentage of patients experiencing ≥ 1 adverse event (AE) was similar between the diabetic and ITT populations. Among diabetic patients, the most common grade 3/4 AEs in the nab-P/C vs sb-P/C arms were neutropenia (53% vs 55%), anemia (23% vs 10%), peripheral neuropathy (PN, 7% vs 23%), thrombocytopenia (20% vs 7%), and fatigue (7% vs 10%); differences were not statistically significant. Safety findings were similar to those observed in the ITT population; however, the incidence of grade 3/4 PN was slightly higher for both arms in the diabetic population compared with the ITT population (for nab-P/C vs sb-P/C, 3% vs 12%; P < 0.001).

      Conclusion
      In this analysis, nab-P/C demonstrated improved efficacy and was well tolerated in diabetic patients with advanced NSCLC. These findings warrant further study in a larger diabetic patient population. The relationship between the efficacy of nab-P and glucose level/metformin use also merits additional study.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-038 - nab-Paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC): analysis of predictive factors (ID 2462)

      09:30 - 09:30  |  Author(s): M.A. Socinski

      • Abstract

      Background
      Identification of predictive factors is critical for appropriate selection of patients and chemotherapy regimen. In a phase III trial, nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C significantly improved ORR (primary endpoint; 33% vs 25%, P = 0.005), with a trend toward improved OS and PFS in patients with advanced NSCLC. nab-P/C vs sb-P/C was associated with less severe peripheral neuropathy, arthralgia, and myalgia, but more anemia and thrombocytopenia. This exploratory analysis examined the correlation between several key patient and clinical factors and clinical outcomes with nab-P/C vs sb-P/C.

      Methods
      Patients with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on d 1, 8, 15 or sb-P 200 mg/m[2] d 1 q21d; both arms received C AUC 6 d 1 q21d. ORR and PFS were assessed by blinded, centralized review. P values for ORR were based on chi-square test, and those for OS and PFS were based on log-rank test. Factors, including sex, age (< 70 and ≥ 70 y), histology (squamous and nonsquamous), stage (IIIB/IV), and geographic region (North America, Eastern Europe, and Asia/Pacific), baseline ECOG score, smoking status, diabetes, body mass index, number and location of metastatic sites, were analyzed for association with outcomes; of these, the first 5 were prespecified stratification factors for the trial.

      Results
      The hazard ratio (HR)/risk ratio favored nab-P/C for ORR, PFS, and OS for most factors analyzed. Significant quantitative treatment-by-predictive factor interactions were noted for several key factors, including number of metastatic sites, diabetes, histology, and age, with respect to outcomes, and the comparative treatment effect was maintained in all other subgroups. In patients with ≥ 4 metastatic sites, significant treatment differences favoring nab-P/C were noted for ORR (response rate ratio [RRR] 3.40; P = 0.003) and OS (HR 0.562; P = 0.009) and trended in favor of nab-P/C for PFS (HR 0.735; P = NS). In patients with diabetes, significant treatment differences favoring nab-P/C were noted for ORR (RRR 1.935; P = 0.046) and PFS (HR 0.416; P = 0.016) and trended in favor of nab-P/C for OS (HR 0.553; P = NS). In patients with squamous NSCLC, significant treatment differences favoring nab-P/C were noted for ORR (RRR 1.68; P < 0.001) and trended in favor of nab-P/C for OS (HR 0.890; P = NS). In patients ≥ 70 y, significant treatment differences favoring nab-P/C were noted for OS (HR 0.583; P = 0.009) and trended in favor of nab-P/C for ORR (RRR 1.385; P = 0.196) and PFS (HR 0.687; P = NS). No treatment differences significantly favoring sb-P/C were observed.

      Conclusion
      A trend toward improved outcomes was noted with nab-P/C vs sb-P/C in most factors analyzed. Squamous NSCLC, diabetes, age ≥ 70 y, and ≥ 4 metastatic sites were predictive of improved outcomes with nab-P/C vs sb-P/C. These predictive factors should be taken into consideration when selecting the appropriate treatment for patients with advanced NSCLC.

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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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      P3.10-043 - nab-Paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): an economic analysis (ID 2479)

      09:30 - 09:30  |  Author(s): M.A. Socinski

      • Abstract

      Background
      In a phase III trial in first-line, advanced NSCLC, nab-paclitaxel + carboplatin (nab-P/C) significantly increased tumor response rates, with comparable overall survival (OS) vs solvent-based paclitaxel + carboplatin (sb-P/C). However, nab-P/C improved OS in prespecified, stratified subgroups of pts, including those aged ≥­ 70 y (19.9 vs 10.4 mo; P = 0.009) and in North American pts, (12.7 vs 9.8 mo; P = 0.008). Based on the data from this trial, nab-P/C was approved by the US Food and Drug Administration (FDA) as a first-line treatment in advanced NSCLC, a condition for which no drug has demonstrated a clinically meaningful survival advantage vs platinum doublets in an unselected population in FDA registration trials. Here, we report results of a cost-effectiveness analysis that was conducted from the US payer perspective, with resource use data collected during the trial.

      Methods
      Cost-of-care estimates were applied to patient-level data on chemotherapy, drug delivery, patient monitoring, supportive care drugs, and treatment of dose-limiting toxicity. Cost-effectiveness outcomes were presented as incremental cost per life year ($/LY) gained with nab-P.

      Results
      Use of colony stimulating factors and treatment discontinuations due to toxicity were comparable between experimental and control arms. Taxane dose intensity was higher with nab-P vs sb-P (79.6% vs 61.8%). For all pts, the nab-P/C group had a $25,868 higher cost compared with sb-P/C ($35,179 vs $9,310) and an incremental $/LY gained in excess of $100K, comparable with $/LY gained estimates published for other recently approved NSCLC agents. However, in the subsets of pts aged ≥ 70 y and those from North America, the cost differential was reduced to $18,244 and $19,941, respectively. $/LY gained was reduced to $23,000 and $83,000, respectively, which compares favorably with published incremental $/LY gained for other NSCLC agents based on their OS advantage in patient subpopulations. Similar results were observed in a post hoc analysis of the subgroup of pts aged ≥ 60 y.

      Conclusion
      Weekly nab-P/C can be considered a clinically and economically attractive treatment option for US payers for first-line advanced NSCLC, particularly in the North American and elderly subsets. Future clinical trials are needed to validate these findings.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-039 - Exploration of patient health status as measured by the generic preference-based questionnaire EQ-5D alongside the START trial of tecemotide (L-BLP25) in non-small cell lung cancer (ID 2744)

      09:30 - 09:30  |  Author(s): M.A. Socinski

      • Abstract

      Background
      Tecemotide (L-BLP25) is a mucin 1 (MUC1) antigen-specific cancer immunotherapy investigated in patients not progressing after primary chemo-radiotherapy for stage III non-small cell lung cancer (NSCLC) in the phase III START study. The objective of this analysis was to explore patients’ health status alongside the study.

      Methods
      From January 2007 to November 2011, 1513 patients with unresectable stage III NSCLC that did not progress after chemo-radiotherapy (platinum-based chemotherapy and ≥50 Gy) were randomized (2:1; double-blind) to tecemotide (806 μg lipopeptide) or placebo SC weekly x 8 then Q6 weeks until disease progression or withdrawal. The analysis population (n=1239) was defined prospectively to account for a clinical hold of the study. The impact on patient health status was assessed as an exploratory endpoint using the EuroQoL 5 Dimensions (EQ-5D), a widely used generic preference-based questionnaire covering 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). EQ-5D index score can be calculated for which perfect health is given a value of 1 and death a value of 0. EQ-5D was collected at baseline, weeks 2, 5 and 8 and then every 6 weeks until end of treatment (EOT) visit (i.e. at time of disease progression), the EOT visit and every 12 weeks afterwards. Analysis of covariance (ANCOVA) was carried out to explore the change of EQ-5D index score over time in the overall population for patients on treatment. The change of EQ-5D to EOT visit was also estimated. Change of EQ-5D index score was explored using all data (i.e. collected both before and after EOT visit) using a linear growth curve model, with random intercept and slope, considering time as a continuous variable.

      Results
      EQ-5D compliance rates (percentage of patients still in the study who completed the questionnaire) were consistently above 85% for all visits of the treatment period in both treatment arms. Mean baseline EQ-5D score was 0.79 (sd=0.19) for both tecemotide and placebo arms. The results from ANCOVA on the overall population did not show any significant difference between the two arms during the treatment phase. Change in the EQ-5D index score from baseline to EOT visit was –0.102 (95%CI: –0.134, –0.071) for tecemotide and –0.136 (95%CI: –0.177, –0.095) for placebo. The linear growth model including the EQ-5D assessments before and after EOT showed that the EQ-5D index score decreased significantly over time in both treatment arms, but that the decrease was slightly slower in the tecemotide than in the placebo arm: –0.0076 per month in tecemotide patients vs. –0.01 in placebo (p=0.0498).

      Conclusion
      During treatment, there was no statistical difference in health status with tecemotide vs. placebo. This supports the good tolerability profile of tecemotide, with a lack of significant toxicity as compared to placebo. Disease progression was associated with a notable deterioration of patient health status, regardless of the treatment. Considering data from both before and after disease progression, patients’ health status appeared to worsen slightly over time, at a slower rate for patients treated with tecemotide.

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    PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)

    • Event: WCLC 2013
    • Type: Plenary Session
    • Track:
    • Presentations: 1
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      PL03.07 - Treatment with Therapies Matched to Oncogenic Drivers Improves Survival in Patients with Lung Cancers: Results from The Lung Cancer Mutation Consortium (LCMC) (ID 2444)

      09:21 - 09:33  |  Author(s): M.A. Socinski

      • Abstract
      • Slides

      Background
      Detecting and targeting the oncogenic drivers EGFR and ALK have transformed the care of patients with lung adenocarcinomas. The LCMC was established to use multiplexed assays to test tumors for alterations in 10 genes and provide the results to clinicians to select treatments and clinical trials matched to the driver detected.

      Methods
      Fourteen LCMC sites enrolled patients with metastatic lung adenocarcinomas and tested their tumors in CLIA laboratories for activating mutations in 10 oncogenic driver genes.

      Results
      Tumors were tested from 1,007 patients for at least one gene and 733 for all 10 genes. An oncogenic driver was found in 466 (64%) of fully-genotyped cases. Among these 733 tumors, drivers found were: KRAS 182 (25%), sensitizing EGFR 122 (17%), ALK rearrangements 57 (8%), “other” EGFR 29 (4%), two genes 24 (3%), HER2 19 (3%), BRAF 16 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), AKT1 0. For cases with any genotyping, we used results to select a targeted therapy or trial in 275 (28%). Among 938 patients with follow-up, the median survivals were 3.5 years for the 264 with an oncogenic driver treated with genotype-directed therapy, 2.4 years for the 318 with an oncogenic driver with no genotype-directed therapy, and 2.1 years for the 360 with no driver identified (p<0.0001).

      Conclusion
      Individuals with lung cancers with oncogenic drivers receiving a corresponding targeted agent lived longer than similar patients who did not. An actionable driver was detected in 64% of tumors from patients with lung adenocarcinomas; more than one was present in 3%. Multiplexed testing aided physicians in choosing therapies and targeted trials in 28% of patients. This paradigm for care and research will expand as genotyping becomes more efficient with Next-Gen platforms, additional drivers are identified (i.e.ROS1 and RET), and more targeted drugs become available in the pharmacy and through clinical trials. Supported by HSS NIH NCI 1RC2CA148394-01. Trial Registered with Clinicaltrials.gov: NCT01014286.

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