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S. Gadgeel



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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): S. Gadgeel

      • 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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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O16.07 - Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer (NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761, NCT01588028). (ID 1668)

      11:35 - 11:45  |  Author(s): S. Gadgeel

      • Abstract
      • Presentation
      • Slides

      Background
      Disease progression in brain occurs in ~50% ALK-rearranged NSCLC patients treated with crizotinib. This is likely due in part to low penetration of crizotinib into CNS. CH5424802 is a new ALK inhibitor that is effective in patients who have ALK re-arrangement. Preclinical studies in CNS implantation models suggest a promising anti-tumor activity of CH5424802 against CNS lesions. This report describes CNS activity observed in an ongoing phase I/II clinical trial.

      Methods
      A phase I dose escalation study of CH5424802 was performed in ALK-rearranged NSCLC who have failed crizotinib. Patients received oral CH5424802 doses ranging from 300 to 900 mg BID. All patients had head CT/MRI and body CT scans at baseline, and every 6 weeks after initiation of treatment if baseline scans are positive for brain metastasis. Brain lesions without prior radiation were used to assess CNS response based on modified RECIST criteria. Simultaneous collection of cerebrospinal fluid (CSF) and plasma PK samples in selective patients is ongoing to evaluate CSF/plasma CH5424802 ratios to correlate with clinical activity in brain metastasis.

      Results
      As of June 6, 2013, 37 patients were enrolled in the phase I study, and 31 of them were evaluable for efficacy. Preliminary overall response rate (ORR) is ~48% (15/31) in evaluable patients. 16 had brain metastases at baseline, and 2 had no prior brain irradiation but all had documented CNS progression prior to study treatment. These 16 patients received CH5424802 at 300mg (n=2), 460mg (n=2), 600mg (n=5), 760mg (n=3), and 900mg (n=4) BID. The median duration of follow-up of these 16 patients was 130+ days, with the longest being 347+ days. Activity against CNS lesions was observed as early as the first scan (3[rd] week). The preliminary CNS response is highly promising as shown in the representative scans below. Enrollment is still ongoing and CNS progression-free survival (PFS) will be presented. Currently 2 patients had simultaneous CSF and plasma levels of CH5424802, and the CSF/plasma ratios will be reported to evaluate any correlation between CSF/plasma ratios and the observed clinical activity of CH5424802 in brain metastasis.Figure 1

      Conclusion
      CH5424802 demonstrates consistent and rapid clinical activity in brain metastases in ALK+ NSCLC patients who progressed on crizitinib. Within 3-6 weeks of treatment, CH5424802 dramatically shrinks brain lesions that progressed on crizotinib. CH5424802 could potentially replace or delay the need of brain radiation in ALK-positive NSCLC patients.

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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): S. Gadgeel

      • 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): S. Gadgeel

      • 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): S. Gadgeel

      • 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.

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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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      P2.11-032 - Patient Report of Dacomitinib (PF-00299804)-Associated Symptom and HRQoL Benefit in Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2293)

      09:30 - 09:30  |  Author(s): S. Gadgeel

      • Abstract

      Background
      Decreasing tumor burden may reduce/delay cancer-related symptoms experienced by patients with NSCLC and favorably impact global health-related quality of life (HRQoL). Dacomitinib is an irreversible small-molecule inhibitor of all catalytically active members of the human epidermal growth factor receptor (HER) family of tyrosine kinases (EGFR/HER1, HER2, and HER4), and has shown anticancer activity and manageable toxicity in NSCLC clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012; Mok et al 2012]. Qualitative assessment of the adverse event (AE) burden from the patient’s perspective helps to provide a greater understanding of the overall impact of treatment-related AEs than grading of AEs alone. Here we report the impact of dacomitinib on core lung cancer symptoms in patients with previously treated, advanced NSCLC in three phase II clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012].

      Methods
      Dacomitinib was evaluated in advanced NSCLC, in patients who had received prior chemotherapy and erlotinib (study 1002; n=66) [Janne et al 2009], in Korean patients who had received prior chemotherapy and erlotinib or gefitinib (study 1003; n=43 in phase II) [Park et al 2010], and in comparison with erlotinib in patients who had received prior chemotherapy (study 1028; n=188) [Ramalingam et al 2012]. In each of the trials, HRQoL was evaluated using validated patient-reported outcome (PRO) measures. Disease/treatment‑related symptoms were recorded using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core module (EORTC QLQ-C30) and its lung cancer module (LC13). Scores were summarized using the mean (and 95% CI) for each group and plotted over time. Mean changes from baseline were also reported.

      Results
      On-study questionnaire mean completion rates were high (>90% of patients answered at least 1 question across treatment cycles) in each of the studies. Across the three trials, patients reported a rapid onset (typically ≤3 weeks of starting therapy) of improvement in key lung cancer symptoms (e.g. cough, pain in chest, and pain in arm/shoulder) relative to baseline scores, with symptomatic improvements remaining durable over the course of therapy. Diarrhea and sore mouth were the most commonly reported class-related AEs (for dacomitinib in studies 1002 and 1003, and for both dacomitinib and erlotinib in study 1028). These AEs peaked at weeks 3–6, were manageable, and remained stable or improved over time with intervention. Compared with erlotinib in study 1028, clinically meaningful improvements from baseline (>10 points difference on a 0–100-point scale) in key NSCLC symptoms (cough, dyspnea, pain in chest, pain in arm/shoulder, fatigue, and physical function) were reported by patients receiving dacomitinib. The difference in mean change from baseline was more favorable with dacomitinib at most time-points.

      Conclusion
      Dacomitinib demonstrated consistent improvements in common NSCLC symptoms across three clinical trials in pretreated patients with advanced NSCLC. PROs such as cough and pain improved within 3 weeks of initiating treatment, with benefits sustained throughout the course of therapy. Dacomitinib also demonstrated greater improvements in key NSCLC symptoms than erlotinib.