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C. Ho



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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): C. Ho

      • 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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    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O15.01 - Evaluation of a "watch and wait" approach for patients with newly diagnosed advanced non-small cell lung cancer in a diverse community population (ID 2384)

      10:30 - 10:40  |  Author(s): C. Ho

      • Abstract
      • Presentation
      • Slides

      Background
      The current treatment paradigm for metastatic non-small cell lung cancer (NSCLC) includes systemic therapy, radiotherapy or both. A “watch and wait” approach (WW) is commonly used in clinical practice. Whether this approach would have any effect on survival outcomes has not previously been evaluated.

      Methods
      The British Columbia Cancer Agency (BCCA) provides comprehensive cancer care to a population of 4.5 million across 944735 sq kms. A retrospective review was conducted of all referred patients diagnosed with stage IIIb/IV NSCLC from January to December 2009 in BC who saw a medical oncologist (MO). Patient characteristics, treatment recommendations, and outcomes were abstracted. WW-treated is defined as initial observation with chemotherapy > 8 weeks from MO consult. WW-missed are patients who were on a WW strategy that did not receive chemo. Kaplan-Meier survival analysis was compared using log rank test. Cox proportional hazards modeling was used to evaluate prognostic factors and control for potential confounders.

      Results
      710 patients were seen by a MO. Median age 66 years (29-90), ECOG 0-1 51%, male 52%, non squamous/squamous/NOS 40%/19%/41%, rural/urban 19%/81%. 327 received upfront chemo, 171 WW and 209 deemed chemo ineligible due to poor ECOG, and comorbidities. Of the 171 patients on a WW approach 44% missed an opportunity for chemotherapy (Figure 1). Reasons for WW-missed included poor ECOG (50%), death (47%), asymptomatic (1%), and illness (1%). Median OS was highest in the WW-treated 16.5 months (CI 12.7-20.3), followed by 13.9 months (CI 12.0-15.8) in the upfront chemo and lowest in the WW-missed 5.9 months (CI 4.4-7.4), p<0.0001. On multivariate analysis, factors predicting a poorer OS included ECOG >2, squamous histology, and a shorter the time from diagnosis to referral and referral to MO consult. When controlled for confounding factors (age, sex, ECOG) OS was similar between the upfront chemo and WW-treated (HR 1.16, CI 0.849-1.58, p=0.353), while those who were in the WW-missed had a significantly lower OS (HR 5.54, CI 3.00-10.24, P<0.0001). Figure 1

      Conclusion
      Our study demonstrates that a “watch and wait” strategy is potentially detrimental to patients because a significant proportion never receives chemotherapy. A decline in ECOG status accounts for 50% of the “missed” chemotherapy. Frequent follow up should be employed for patients who are on a WW approach to ensure the window of opportunity for chemotherapy is not lost.

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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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      P2.10-015 - Less toxic chemotherapy improves uptake of all lines of chemotherapy in advanced non small cell lung cancer, particularly in the elderly: A ten year retrospective population-based review (ID 1066)

      09:30 - 09:30  |  Author(s): C. Ho

      • Abstract

      Background
      The platinum doublet is standard first-line therapy in advanced NSCLC. Over the past decade, well tolerated second-line therapies have been approved including erlotinib and pemetrexed. We hypothesize that the introduction of less toxic chemotherapy has increased treatment of advanced NSCLC resulting in improved survival.

      Methods
      The BC Cancer Agency provides cancer care to a population of 4.5 million. A retrospective review was conducted of all referred Stage IIIB/IV patients in four 1 yr time cohorts; C1 baseline (1998) and 6 months after the provincial approval of C2 docetaxel (2001), C3 erlotinib (2006) and C4 pemetrexed (2007).

      Results
      2, 623 patients were referred and 720 had systemic therapy. Characteristics: M/F 55%/45%, median age 67 (33-101), ECOG <=1/>=2/unknown 33%/56%/11%, never/former/current/unknown smoker 9%/35%/36%/20%, squam/nonsquam/NOS 18%/41%/41%. More patients received first line chemotherapy over time; 16%, 23%, 34%, 33% C1-4 respectively. In C1 to C4 uptake of second line (21%, 27%, 38%, 55%) and third line (10%, 10% 14%, 18%) increased. In C1 the most common first line doublet was cis/vino (70%) and in C4, cis/gem (45%). Second line doce was frequently used in C2 (51%) but usage decreased in C4 to 7% vs. erlo 50% and pem 26%. In the >=70 group (n=1118), 1[st] line usage increased from C1 9% to C4 19% and 2[nd]line in the C2 (doce) 4% to C4 (erlo+pem avail) 56%. The increased use of systemic therapy was associated with improved survival in all patients: C1 4.56 m vs C4 4.98 m (p=0.004) and treated patients; C1 9.48 m vs C4 12.07 m (p=0.014) and the >= 70 group; C1 9.7 m vs C4 12.5 m (p=0.07).

      Conclusion
      This population-based data set represents the trend of treatments over time in a large geographical area, including community and tertiary care cancer treatment sites. The introduction of less toxic systemic therapy for advanced NSCLC resulted in an increased proportion of patients treated with first-line chemotherapy and an even greater increase in 2nd/3rd line treatment. This trend was particularly evident in the elderly. Associated with this was a significant improvement in overall survival for all subsets.

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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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      P3.10-048 - Referral patterns in advanced non small lung cancer: Impact on delivery of treatment and survival in British Columbia (ID 2931)

      09:30 - 09:30  |  Author(s): C. Ho

      • Abstract

      Background
      Chemotherapy improves overall survival in advanced non-small cell lung cancer (NSCLC). We sought to evaluate clinical effectiveness of chemotherapy in the general population by looking at referral patterns, and outcomes.

      Methods
      The British Columbia (BC) Cancer Agency is a publicly funded system that serves a population of over 4.5 million. All referred cases of stage IIIb/IV non-small cell lung cancer were identified using the BC Outcomes and Surveillance Integrated System and retrospectively reviewed. Patient demographics, tumour characteristics and treatments were extracted. Overall survival (OS) was estimated using the method of Kaplan-Meier. Cox Proportional Hazards (CPH) modeling was used to control for possible confounders. Multiple logistic regression (MLR) was used to compare characteristics between patients who were referred and not referred to a medical oncologist (MO).

      Results
      1384 patients were diagnosed with Stage IIIb/IV NSCLC between January 1 to December 31, 2009. Median age 70 years (29-96), male 53%, ECOG 0-1 38%, rural/urban 17%/83%, non-squamous/squamous/NOS 34%/21%/46%. 710 (51%) patients were assessed by a MO and of these, 382 (54%) received chemotherapy. 1225 (89%) were assessed by a radiation oncologist (RO), and 1025 (84%) received radiation. MLR showed that patients referred to MO were more likely to be younger, from an urban area, and have a better ECOG. Median OS for the entire cohort was 9.6 months (CI 8.5-10.7). There was a statistically significant improvement in OS in patients who received chemotherapy at 14.2 months (CI 12.5-15.9) in comparison to 7.6 months (CI 6.6-8.6) who did not receive chemotherapy (p<0.0001). This remained statistically significant in the CPH model, controlling for ECOG, sex, age, histology (HR 0.80, CI 0.65-0.92). In comparison, OS was 8.6 months (CI 7.4-9.8) for patients who received only radiotherapy, and 5 months (CI 3.1-6.8) for those treated with best supportive care.

      Conclusion
      Only half of the referred patients were assessed by a medical oncologist and only 54% of them received chemotherapy. This is despite the awareness that chemotherapy significantly improves OS. Strategies to improve upon this 51% referral rate should be evaluated, such that patients do not miss out on life-prolonging therapy.