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A.J. Wozniak



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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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      O03.06 - First-In-Human Evaluation of CO-1686, an Irreversible, Highly, Selective Tyrosine Kinase Inhibitor of Mutations of EGFR (Activating and T790M) (ID 1354)

      11:25 - 11:35  |  Author(s): A.J. Wozniak

      • Abstract
      • Presentation
      • Slides

      Background
      Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition. CO-1686 is an oral, covalent TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest greatest efficacy when plasma concentrations exceed 200ng/ml for >16hrs/day.

      Methods
      This is an ongoing first-in-human dose finding study (3+3) of oral CO-1686 administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. All patients must undergo tumor tissue biopsy within 28 days before study drug dosing for central EGFR genotyping. Endpoints include safety, pharmacokinetics (PK), and efficacy.

      Results
      As of 12 June 2013, 45 patients have been treated with CO-1686. 31/42 (74%) were T790M+; data for three patients is pending. The median age is 58 years, 82% are female, 75% are white, and 73% ECOG 1. The median number of previous therapies was 4 (range: 1- 6), with a median of 1 (range: 1- 4) previous EGFR TKI therapies. Dosing started at 150mg QD and escalated to 900mg QD, 900mg BID and 400mg TID, with a maximum tolerated dose not yet reached. Treatment-related AEs (all grades) occurring in > 5% patients were: fatigue (19%), diarrhea (15%), nausea (14%), anemia (10%), arthralgia (7%), muscle spasms (10%), myalgia (7%), headache (7%). The majority of events were mild or moderate. Unlike other EGFR inhibitors, rash and diarrhea were not commonly seen. This AE profile is consistent with the expected lack of wild type EGFR inhibition with CO-1686. The PFS for T790M+ patients with CO-1686 plasma concentrations > 200ng/mL for > 16 hours was 194 days compared with 72.5 days for those that achieved these concentrations for < 16 hours (Figure 1). At the highest evaluated dose, 900mg BID, four T790M+ patients were evaluable for response; 3 of the 4 achieved PRs, one achieved SD. One patient at a lower dose cohort also achieved a PR. Further safety and efficacy data will be presented at the meeting. Figure 1

      Conclusion
      CO-1686 has demonstrated good tolerability and efficacy against proven T790M+ EGFR mutant NSCLC with a strong suggestion of a dose-response relationship. Additional evaluation of the optimal dose and formulation of CO-1686 are underway to further explore its potential for improved activity and better tolerability over other existing EGFR TKIs.

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    O24 - Cancer Control and Epidemiology III (ID 134)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O24.04 - Risk of second primary lung cancer (SPLC) in patients (pts) with previously treated lung cancer: Analysis of the Surveillance, Epidemiology and End Results (SEER) data (ID 2204)

      16:45 - 16:55  |  Author(s): A.J. Wozniak

      • Abstract
      • Presentation
      • Slides

      Background
      BACKGROUND: Second primary lung cancer (SPLC) in patients who have been treated for a prior lung cancer is a recognized phenomenon. There has been an improvement in the staging and treatment of lung cancer in the last several decades resulting in longer survival for pts and affording an opportunity for the development of SPLCs. The objective of this study was to establish the frequency of SPLCs and to characterize the demographics, histology and stage at presentation, time interval between diagnoses, and cumulative risks of developing a SPLC in this pt population.

      Methods
      METHODS: The pts were identified from population-based SEER-9 Registries Data Base. All pts with a primary lung cancer between 1973 and 2004 were included with follow-up to 2009. The histology and stage of the SPLCs were evaluated in comparison to the initial primary lung cancer (IPLC). The incidence of SPLCs was compared to the expected incidence by calculating multiple primary-standardized incidence ratios (MP-SIRs) using the SEER Stat program. Selected cohorts were stratified by sex, race, age at diagnosis, and date of diagnosis. Sex-specific cumulative risks of developing SPLCs were calculated using the Kaplan-Meier method.

      Results
      RESULTS: 208,486 pts had an IPLC diagnosed from 1973-2004. No smoking history was available. Patient Characteristics at time of IPLC: 60.4% male; 84.3% white; 8.5% (20-49 yr), 55.9% (50-69 yr), 35.6% (≥ 70 yr); 84% non-small cell lung cancer (NSCLC); 33.8% distant disease, 23.5% regional, 29.9% local. 5,302 pts developed SPLC. The majority were male (56.6%), white (84.9%), and in the 50-69 yr age group (68%). Females had the highest SIR values across all ethnicities and age groups particularly in the youngest cohort (20-49 yr) where the SIR was 8.58. The SIR values were ≥ 2 for all cohorts expect for males ≥ 70 yr (SIR=1.65). The predominant histologic types for IPLCs were adenocarcinoma (ADC) and squamous cell cancer and the associated SPLCs were usually of the same histology. IPLC ADC and BAC pts were most likely to develop a SPLC. Most SPLCs (50%) presented with regional or distant disease, while only 37% were localized at diagnosis. The median time to development of SPLCs was 68 mo for males and 74 mo for females. The risk of developing a SPLC continually increased as a function of time for both sexes.

      Conclusion
      CONCLUSION: Patients with a history of IPLC are at high risk for developing SPLC and this risk increases over time. This is especially true of females who are diagnosed at an early age with their initial lung cancer. The majority of SPLCs present late and at a more advanced stage. These findings could have major implications with regard to the length and type of surveillance in pts who survive their initial lung cancer diagnosis.

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    P1.08 - Poster Session 1 - Radiotherapy (ID 195)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P1.08-011 - Dosimetric Predictors of Esophageal Toxicity in Patients with Non-small Cell Lung Cancer Receiving Chemotherapy and Radiotherapy (ID 1507)

      09:30 - 09:30  |  Author(s): A.J. Wozniak

      • Abstract

      Background
      Esophageal toxicity can be a dose-limiting event in patients with non-small cell lung cancer receiving chemotherapy and radiotherapy necessitating treatment breaks with potential to cause adverse treatment related factors. The objective of this study was to investigate those factors, both clinical and dosimetric, which predict for esophageal toxicity.

      Methods
      Patients (pts) with non-small cell lung cancer prospectively enrolled into an IRB approved database were retrospectively reviewed. Pts with biopsy-proven non-small cell lung cancer treated with radiotherapy alone, sequential or concurrent chemoradiotherapy had maximal esophageal toxicity scored per CTCAE 4.0 criteria. V5, V10, V20, V30, V40, V50, V60, V70, esophageal hot spot, and dose per fraction were the dosimetric variables and age, sex, race, chemotherapy, and stage were the clinical variables investigated. Data were analyzed using SAS (SAS INC, Cary, NC) Version 9.2 software package. Ordinal maximum reported esophageal toxicity was evaluated using logistic regression. A multivariable regression model was fit using important univariate predictors along with a backwards elimination stepwise regression. Probability of esophageal toxicity as a function of absorbed dose in a partial volume was modeled by the method of Lyman, by converting the dose volume histograms into an equivalent fractional volume receiving the maximum dose in the DVH, using the effective volume method of Kutcher and Burman. The parameters in this model (D50, slope m and volume exponent n) were determined by maximum likelihood estimation.

      Results
      A total of 100 pts were enrolled between 7/10 and 12/12 into a prospective database and eligible for analysis. Pts were excluded without a complete dose volume histogram data or were stage I disease leaving 71 eligible for analysis, 43 females and 28 males with a median age of 61 (range: 39-85). 14 pts were treated with radiotherapy alone while 23 received sequential treatment and 34 concurrent treatment. The median delivered dose was 66.6 Gy (range: 27.5-66.6) in a median of 1.8 Gy (range: 1.8-3.0) per fraction. Maximal esophageal toxicity was rated as 0: 12pts, 1: 21 pts, 2: 33 pts, and 3: 5pts. Univariate predictors of > grade 2 esophageal toxicity included, V5-V60 and use of concurrent chemotherapy. The maximum likelihood fit of the Lyman model parameters to patients with ≥ 2 esophageal symptoms were n=0.26 m=0.32, TD50=39.1 Gy when the α/β ratio was assumed to be 10 Gy. The maximal likelihood fit of the Lyman model parameters to patients when the α/β ratio was not set were n=0.26, m=0.32 and TD50 39.3 with the α/β calculated at 7.6 Gy. Patients not having chemotherapy had a higher TD50, 46.4 Gy as compared to patients having chemotherapy, TD50=37.1 Gy, p=0.09.

      Conclusion
      We have shown the TD50 for > grade 2 esophageal toxicity is lower for patients receiving chemotherapy and radiotherapy compared to patients receiving radiotherapy alone. This is first report to show the α/β ratio for esophageal toxicity may be lower than 10. Confirmations of these data are needed in an independent data set.

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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P1.18-007 - Multiplex testing of driver mutations in Non-Small Cell Lung Cancer (NSCLCs) of African-American (AA) patients (ID 1312)

      09:30 - 09:30  |  Author(s): A.J. Wozniak

      • Abstract

      Background
      Recently driver genetic alterations have been identified in NSCLC that can be targeted for therapeutic interventions. Previous reports have suggested that rates of certain mutations may vary according to ethnic background. We conducted multiplex testing of NSCLCs of AA and white patients to assess variability in the mutation rates by race.

      Methods
      We identified tumor tissues of 139 AA and 340 white NSCLC patients collected as part of three different institutional review board approved studies. Using the Sequenom MassArray system and a multiplexed panel, we analyzed tumor DNA for 214 oncogenic mutations in 26 genes previously identified in NSCLC. Estimated risk (Odds Ratios (OR)) of any mutation and specific gene mutations among AA patients compared to white patients were calculated after adjusting for age, sex, smoking status and histology (adenocarcinoma versus non-adenocarcinoma). Information on smoking status was unavailable on 45 patients and was not included in calculations of ORs for some genes (OR[b]).

      Results
      The median age at diagnosis was 60 vs 66 years in AA vs white patients; 42% of AA patients and 65% of white patients were males; 67% of AA patients and 49% of white patients had adenocarcinoma; 67% of AA patients and 85% of white patients had stage I/II NSCLC and 10% of AA patients and 6% of white patients were never smokers. 43% of the AA patients and 46% of white patients had at least one mutation detected (OR=0.8; 0.5-1.2). 19% of AA patients and 8% of white patients had more than 1 mutation detected (OR 2.1; 1.1-4.1) (Table 1). AA patients were more likely to harbor mutations in STK11 (LKB1) (OR=7.5; 3.1-18.2) and NOTCH1 (OR[b]=8.4; 2.2-31.7), and they were less likely to have MET mutations (OR[b]=0.2; 0.1-1.1) then white patients. While not statistically significant, AA had lower prevalence of Kras mutations (OR[b]=0.5, 0.2-1.0) and p53 mutations (OR= 0.7; 0.4-1.4). Table 1

      Outcome OR for African American Race 95% CI P
      Any driver mutation[a] 0.8 0.5-1.2 0.203
      >1 driver mutation[a] 2.1 1.1-4.1 0.036
      STK11 Mutation[a] 7.5 3.1-18.2 <.001
      P53 Mutation[a] 0.7 0.4-1.4 0.359
      Kras Mutation[b] 0.5 0.2-1.0 0.041
      NOTCH1 Mutation[b] 8.4 2.2-31.7 0.002
      MET mutation[b] 0.2 0.1-1.1 0.065
      [a]Adjusted for age, sex, ever/never smoking and adeno/non-adeno
      [b]Adjusted for age, sex, and adeno/non-adeno

      Conclusion
      Our analysis of NSCLCs shows that AAs were more likely to have multiple genetic mutations than whites and the mutation profile differs by race.