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G. Goss



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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.04 - Biomarker Analysis of NCIC Clinical Trials Group IND.196, a Phase I study of erlotinib plus foretinib in advanced pretreated non-small cell lung cancer patients (ID 3148)

      10:45 - 10:50  |  Author(s): G. Goss

      • Abstract
      • Presentation
      • Slides

      Background
      Upregulation of MET and more recently AXL have been described as potential mechanisms of resistance to EGFR tyrosine kinase inhibitors in NSCLC. We explored the impact of baseline MET and AXL tumour expression and circulating hepatocyte growth factor levels, (HGF), in advanced NSCLC patients receiving erlotinib plus foretinib, an oral multi-targeted kinase inhibitor of MET, RON, AXL, TIE-2 and VEGFR.

      Methods
      Advanced NSCLC patients that previously received one or two lines of chemotherapy were treated in IND.196, a phase I dose-finding trial with an initial two-week run-in of single agent erlotinib (100-150 mg daily). If erlotinib was well tolerated, foretinib was then added (30-45 mg daily). Submission of tumour samples (archival or fresh) was mandatory, and circulating HGF levels were determined at baseline and on treatment. Tumour samples were genotyped using Sequenom MassARRAY analysis. MET and AXL expression were determined by immunohistochemistry. For AXL, the human Axl affinity purified polyclonal goat IgG antibody (R&D systems, AF154, Minneapolis MN) was scored manually. For MET, the anti-total MET (SP-44) rabbit monoclonal antibody (Ventana Medical Systems, Tucson AZ) was scored using the Benchmark XT autostainer. Staining intensity (0-3+) and percent cells stained were used to calculate the H-score; H-scores >100 were deemed positive for AXL, and >200 positive for MET.

      Results
      Of 31 patients enrolled, 28 were evaluable for response to combination therapy, with a recommended phase II dose of erlotinib 150 mg daily for a 2-week run-in and then foretinib 30 mg daily added. The overall response rate in the intent to treat population (RECIST 1.1) was 16.1% (95% CI 5.5-33.7%), with partial responses (PR) seen in 5/31 patients and a median response duration of 17.9 months (range 3.6-17.9). Stable disease was seen in 42% (13/31), with a median duration of 4.8 months (95% CI 2.4-15.4). Tumour samples were submitted for 25 patients; 15 had sufficient tissue for genotyping, 17 for assessment of MET, and 16 for AXL expression. 2/5 responding patients had confirmed EGFR mutations, (1 wildtype, 2 unknown). Another 5 had KRAS mutations, one with >20% reduction in tumour size but SD by RECIST. Of 17 patients with MET IHC results, 71% (12/17) were positive. PR was seen in 3/12 patients with MET-positive tumours, (2 with EGFR mutations, 1 wildtype). No response was seen in those with MET-negative tumours. Of 16 samples with AXL IHC results, 9 were positive (56%). PR was seen in 2/9 with AXL-positive tumours and 2/6 with AXL-negative tumours. AXL expression was not seen in samples with EGFR mutations, but 3/5 KRAS mutant samples were AXL positive. Assessment of circulating HGF levels will be presented at the 2013 WCLC meeting.

      Conclusion
      Baseline MET expression, uncontrolled for EGFR status, may be associated with response to combination erlotinib/foretinib. No correlation between baseline AXL expression and response was seen although the sample size is small. Further study is needed to control for the impact of EGFR mutation status on response, and to assess whether combination erlotinib/foretinib can overcome resistance to EGFR TKI therapy mediated by MET and AXL.

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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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      O03.01 - GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients. (ID 1715)

      10:30 - 10:40  |  Author(s): G. Goss

      • Abstract
      • Presentation
      • Slides

      Background
      Ganetespib (G) is a highly potent 2[nd]-generation Hsp90 inhibitor showing synergistic activity with docetaxel (D) in NSCLC xenografts. G has a favorable clinical safety profile and has shown single-agent clinical activity in NSCLC patients with tumors harboring EML4-ALK translocations and KRAS mutations (mKRAS).

      Methods
      We conducted a randomized, international open-label Phase 2 study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m[2] on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m[2] on Days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutation. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma patients, including 120 eLDH and 80 mKRAS patients. The study was initiated in all NSCLC patients and amended to include only those with adenocarcinoma histology.

      Results
      Enrollment of 252 adenocarcinoma patients completed in November 2012; enrollment of eLDH (total N=112) and mKRAS (total N= 86) patients completed in May 2013. In all adenocarcinoma patients (N=252), baseline characteristics were balanced between the two arms (median age 60 years, males 56%, PS 0 41% and never-smokers 25%). Median numbers of cycles delivered were 6 and 4 for D+G and D, respectively. Grade 3/4 adverse events for the D+G and D alone arms were: neutropenia 37% vs. 38%; fatigue 6% vs. 3%; anemia 8% vs. 2%; diarrhea 3% vs. 0; fever with neutropenia 11% vs. 2%. A pre-specified analysis was conducted in May 2013. PFS HR for eLDH population (N=76) was 0.88 (90% CI: 0.57, 1.36, p=0.310); OS HR was 0.63 (90% CI: 0.40, 0.99, p=0.046). PFS HR for mKRAS population (N=63) was 0.83 (90% CI: 0.51, 1.37, p=0.271); and OS HR was 0.85 (90% CI: 0.48, 1.50, p=0.313). OS HR in the all adenocarcinoma population was 0.82 (90% CI: 0.62, 1.09, p=0.082), and the PFS HR was 0.84 (90% CI: 0.65, 1.07, p=0.038). For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=176), a pre-specified stratification factor, the OS HR was 0.61 (90% CI: 0.43, 0.87, p=0.0093), and the PFS HR was 0.61 (90% CI: 0.45, 0.83, p=0.0041). Final data analysis is expected by end of September 2013. Updated PFS and OS results for all populations will be presented at the meeting.

      Conclusion
      Survival improvement was noted in all adenocarcinoma patients with the addition of ganetespib to docetaxel. The maximal benefit was achieved in patients with eLDH and those diagnosed with advanced NSCLC >6 months prior to study entry.

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    O06 - Cancer Control and Epidemiology I (ID 135)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O06.06 - Factors Associated with Smoking Cessation in Participants of The Pan Canadian Early Lung Cancer Study (ID 1469)

      11:35 - 11:45  |  Author(s): G. Goss

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer screening programs provide unique opportunities to facilitate smoking cessation in smokers who participate in these programs. However, the effects of screening on motivation to quit might be mediated or modified by other variables. Identifying the participants more likely to quit will allow rapid application of smoking cessation resources to these participants, while those least likely to quit can be afforded experimental interventions. The aim of our study was to assess the impact of lung cancer screening on smoking cessation in current smokers at the time of enrollment and to identify factors that were associated with quitting smoking in this screening population.

      Methods
      Using data collected from the Pan-Canadian Study of Early Detection of Lung Cancer, both univariate and multivariable logistic regression analysis was used to identify predictors of smoking cessation among current smokers at enrolment. Smoking cessation was defined as quitting for at least a 6 month period, occurring anytime after enrolment.

      Results
      We analyzed baseline and follow-up questionnaires of 2320 participants, of which 1419 were current smokers. Of these 1419 patients, 392 (27.8%) met the definition of smoking cessation during a median of two annual follow-up visits. In both univariate and multivariable (MV) analysis, greater smoking cessation was associated with four factors: (i) having a diagnosis of lung cancer at any time during the screening process, with a MV Odds ratio (OR) of quitting of 2.4 (95%CI: 1.1-5.0); (ii) lower and medium nicotine addiction as assessed by the Fagerström Nicotine Dependence Scale Score, with MV-ORs of 3.2 (95%CI: 2.2-4.6) and 1.4 (95%CI: 0.9-2.0), respectively; (iii) having higher education, with MV-OR: 1.4 (95%CI: 1.1-1.9); and (iv) having an earlier age of onset of regular alcohol intake, with MV-OR of 1.11 (95%CI: 1.02-1.21) per 5 year decrease in age. Smoking cessation was also associated with (i) previous attempts of quitting [UV-OR 1.8 (95%CI: 1.2-2.7)], willingness to quit smoking within the next month (at baseline screening) [UV-OR 2.2 (95%CI: 1.8-2.9)] or within the next 6 months after baseline screening [UV-OR 1.8 (95%CI: 1.3.-2.4)]. Second-hand smoking exposure, including exposure as a child, or as an adult at work, at home, privately with friends, or in public settings, or a cumulative index of these different exposures, was not associated with smoking cessation. Presence of potential index symptoms for lung disease, including shortness of breath, cough (both dry and productive), hoarseness, audible wheezing or even chest pain, was not associated with an increased chance of smoking cessation.

      Conclusion
      The diagnosis of a new lung cancer had a major positive impact on screening participants quitting smoking, as were factors such as lower nicotine dependence, higher education, earlier starting alcohol drinking age, and willingness to quit. Whether a new lung cancer diagnosis triggered additional efforts by clinicians to help the person quit will be explored further. Individual lung symptoms and secondhand smoke exposure were not associated with smoking cessation. (Geoffrey Liu and Martin Tamemmagi are co-senior authors)

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-042 - Chemotherapy in advanced non-small cell lung cancer patients previously treated with adjuvant chemotherapy (ID 2349)

      09:30 - 09:30  |  Author(s): G. Goss

      • Abstract

      Background
      Adjuvant chemotherapy (CT) improves survival in patients (pts) with completely resected early stage NSCLC. Adjuvant cisplatin/vinorelbine (CV) is considered a standard of care in this population. However many pts relapse and require palliative CT, which may involve platinum doublet CT again. We investigated treatment choices on relapse after prior adjuvant CT, specifically in pts receiving palliative platinum doublet CT, and its impact on response rate (RR) and overall survival (OS).

      Methods
      With ethics approval, we performed a retrospective chart review of all pts with resected NSCLC who received adjuvant CT from January 2002 until December 2008 at our institution. Baseline pt demographics and cancer stage were recorded, along with treatment decisions upon relapse. The primary outcome was the RR to first-line palliative systemic therapy (ST).

      Results
      We identified 176 pts who received adjuvant platinum doublet CT (82% received CV). Patient characteristics were: median age 63 years (range 25-82); 55% female: median follow up 4.2 years: the primary surgical procedures were lobectomy (79%) or pneumonectomy (16%). The pathologic stage at surgery was 1A (2%), 1B (30%), 2A (7%), 2B (40%) and 3A (15%). In total 85 pts relapsed (48%), with a median time to relapse of 18.5 (95%CI 15-21.3) months. The variable most strongly associated with a shorter time to relapse was nodal stage (p=0.03); increasing T stage also demonstrated a trend towards shorter time to relapse (p=0.09). Of the 85 relapsed pts, 43 received palliative CT, and 42 received best supportive care (BSC) alone. Of the 43 pts treated, 25 (58%) were re-challenged with platinum doublet CT, with a RR of 28%, versus 17% (p=0.47) in 18 pts receiving other ST (most commonly docetaxel [n=7, 39%] or erlotinib [n=4, 22%). There was a trend towards increased clinical benefit rate (CR+PR+SD) in patients who were treated with a platinum doublet (67% versus 41% p=0.12). For all pts the median OS after relapse was 11.6 months. In pts receiving any CT (n=43), median OS was 15.3 months, compared to 7.8 months in those receiving BSC alone. Pts in the platinum-treated group had a longer survival after relapse than those pts treated with non-platinum regiments (18.4 versus 9.7 months, p=0.041). See Figure 1.Figure 1

      Conclusion
      In pts previously treated with adjuvant CT, re-treatment with platinum doublet CT upon relapse is feasible and associated with numerically higher response rates and significantly longer survival than those receiving other first-line ST.

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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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      P2.10-009 - Intrinsic and acquired resistance patterns in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy (ID 853)

      09:30 - 09:30  |  Author(s): G. Goss

      • Abstract

      Background
      Platinum-based chemotherapy (PBC) yields clinical benefit in some but not all patients with advanced NSCLC. All patients eventually become resistant to treatment. We assessed degree and timing of onset of tumor regression (TR) and tumor growth (TG) as a surrogate indicator of sensitivity and resistance patterns.

      Methods
      In 130 NSCLC patients on PBC, we assessed percent change in tumor diameter (TG or maximum TR on treatment) compared to pre PBC, and also assessed incremental percent further TR or TG in serial scans compared to the most recent prior scan on treatment.

      Results
      Of the 130 patients, 32 (25%) had intrinsic resistance, with TG at 1[st] repeat scan after 2 cycles of PBC. Only 1 patient with initial TG had later TR on PBC. Among those with TR at 1[st] re-evaluation, pattern of onset of acquired resistance varied: 81 had a 2[nd] repeat scan after 4 cycles of PBC, of whom 20 (25%) had TG. Of 41 patients with earlier TR who then had a 3[rd] repeat scan <4 weeks post PBC cycle 6, 13 (32%) had TG compared to prior scans. In 76% of those with TR, the greatest TR compared to most recent prior scan was seen at the first re-evaluation, with TG or a lower percent TR on later scans. 26 patients had progressive further TR over each of >4 re-evaluation scans, of whom 11 had initial rapid TR at 1[st] re-evaluation, with subsequent more gradual further TR over later scans (a pattern that we designated as “Incremental TR pattern 1”). The other 15 patients with progressive TR over >4 re-evaluation scans had modest initial TR followed by greater TR on a later scan (a pattern that we designated as “Incremental TR pattern 2”). By Spearman coefficients, maximum percent TR from pre PBC (with TG coded as a negative value for TR) correlated with OS (r=0.46, p<0.0001), time to progression (TTP) (r=0.69, p<0.0001) and post-progression survival (PPS) (r=0.30, p=0.001). OS also correlated with TTP (r=0.63, p<0.0001), and PPS correlated with TTP (r=0.44, p<0.0001), and with OS (r=0.95, p<0.0001). Median OS was 11.0 months, and varied with TR pattern (p<0.0001): for patients with first TG at 1[st], 2[nd], 3[rd] and 4[th] repeat scans, median OS was 5.9, 10.8, 10.5 and 15.1 months, respectively. Median OS was 18.2 months in patients with “Incremental TR pattern 1”, and was 30.5 months in patients with “Incremental TR pattern 2”. Median OS with RECIST partial response (23% of patients), minor TR (52%), minor TG (13%) and RECIST progressive disease (13%) was 16.9, 12.4, 9.8 and 4.0 months, respectively (p<0.0001).

      Conclusion
      Intrinsic resistance was noted in 25% of patients. Degree of TR vs TG and patterns of intrinsic and acquired resistance correlated strongly with OS, TTP and PPS, with longest median OS in patients with “Incremental TR pattern 2”. Our observations require confirmation. While numerous biological factors correlate with resistance preclinically, it remains unclear which are most relevant clinically, and it is also unclear what factors may be responsible for the different patterns of clinical resistance observed.