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S. Kamel-Reid



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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)

      10:30 - 12:00  |  Author(s): S. Kamel-Reid

      • 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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    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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      P3.11-044 - Clinical impact of EGFR mutation fraction and tumour cellularity in EGFR mutation positive NSCLC (ID 2982)

      09:30 - 16:30  |  Author(s): S. Kamel-Reid

      • Abstract

      Background
      We investigated the impact of mutation fraction, tumour sample cellularity, and diagnostic specimen type on EGFR TKI response, time to treatment failure (TTF) and overall survival (OS), as well as patterns of treatment in a population-based cohort of advanced EGFR mutation positive NSCLC patients.

      Methods
      From March 2010 to May 2012, EGFR testing in the province of Ontario (Canada) was conducted at a single centre, using fragment analysis for exon 19 deletion and Sau961 restriction enzyme digest for exon 21 mutations. Patients with EGFR mutation positive samples were identified and tumour sample cellularity, mutation fraction (percent of tumour cells mutated), demographic, treatment and outcome data were collected. Regression analysis was undertaken to assess the association between demographic variables, mutation fraction, tumour sample cellularity and sample type on clinical outcomes.

      Results
      Among 293 patients identified with EGFR mutation positive NSCLC, 253 received EGFR TKIs and are included in this analysis. Most are female (72%), never smokers (59%), have exon 19 deletions (53%; 47% exon21 L858R), and median age 65 years (range 26 to 96). Tumour specimens tested include resection (32%), cytology (30%), and core biopsies (38%). Median EGFR mutation fraction is 30% (range 0.4% to 96%); 24% had a low (≤10%) mutation fraction, and 13% had a mutation fraction ≤5%. Responses (any tumour reduction) were seen in 62%, mixed response or stable disease in 25%, and progression as the best response in 13%. Median TTF from the start of EGFR TKI therapy is 13.2 months (range 0-43.7 months). Median OS from TKI start is 22.3 months (95% CI: 19.5-28.2 months), with 1-, 2- and 3-year survival rates of 72%, 49% and 37%. In multivariable analysis, factors associated with TTF included female sex (HR 0.69, p=0.03) and sample type (resection HR 0.56, cytology HR 0.82, core biopsy as reference, p=0.01). Age at metastatic diagnosis (p=0.01), sample cellularity (p=0.01) and sample type were significantly associated with OS, (resection HR 0.51, cytology HR 0.70, core biopsy as reference, p=0.04). Proportional odds logistic regression identified that mutation frequency and age at metastatic diagnosis were significantly associated with the odds of response, (p=0.047, p=0.04 respectively). Responses were seen even in those with lower EGFR mutation fraction, 48% (24/50) at a mutation frequency of ≤10% and 33% (9/27) at a mutation frequency of ≤5%. The average cellularity in the high (>10%) mutation fraction group was 53% (95%CI 50– 56%), and 36% (95%CI 29 – 43%) in those with a low mutation fraction (p<.0001).

      Conclusion
      Pathologic features may be relevant to clinical outcomes in EGFR mutation positive NSCLC, including mutation fraction, sample cellularity, and specimen tested. The clinical relevance of sample tumour cellularity and sample type tested remains unclear. In particular, initial stage and prognosis may be confounders in the association between resected specimens and favourable outcomes. Given that those with mutation fractions ≤5% may have significant response from EGFR TKI therapy, treatment should not be withheld on the basis of mutation frequency alone.

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    P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.12-015 - Surgery for Early Non-Small Cell Lung Cancer with Preoperative Erlotinib (SELECT): A Correlative Biomarker Study (ID 2529)

      09:30 - 16:30  |  Author(s): S. Kamel-Reid

      • Abstract

      Background
      Erlotinib has demonstrated major activity in EGFR mutation positive NSCLC, but may also benefit those with wild type tumours. We conducted a single-arm trial of pre-operative erlotinib in early stage NSCLC to assess radiologic and functional response as well as correlation with known and investigational biomarkers.

      Methods
      Patients with clinical stage IA-IIB NSCLC received erlotinib 150 mg daily for 4 weeks followed by surgical resection. Tumor response was assessed using pre- and post-treatment CT and PET imaging. Tumor genotype was established using Sequenom MassARRAY analysis. EGFR, PTEN, cMET and AXL expression levels were determined by immunohistochemistry. Pre- and post-treatment circulating markers/ligands for EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR ECD) were measured by ELISA. Tumor MET copy number by FISH and VeriStrat® analysis of pre-treatment serum samples is ongoing. Secondary endpoints included pathological response, toxicity and progression-free survival.

      Results
      Twenty-five patients were enrolled; 22 received erlotinib treatment with a median follow up of 4.4 years (range 2.2 to 6.4 years). Histology was predominantly adenocarcinoma (15) with smaller numbers of squamous cell carcinoma (7). PET response (25% SUV reduction) was observed in 2 patients (9%), both with confirmed squamous carcinoma histology. All patients met criteria for stable disease by RECIST and several experienced minor radiographic regression with histologic findings of fibrosis/necrosis, including 2 with squamous histology. The presence of an EGFR activating mutation was detected in two adenocarcinoma cases; one patient experienced minor radiographic response to treatment (exon 19 deletion) and the other stable disease (L858R). High pre-treatment serum levels of TGF- α correlated with tumor growth or primary resistance to erlotinib therapy (p=0.04), whereas high post-treatment soluble EGFR levels correlated with tumor response (p=0.02). Expression of EGFR, PTEN, cMET and AXL did not correlate significantly with tumor response.

      Conclusion
      Erlotinib appears to demonstrate some activity in EGFR wild-type tumors including those with squamous histology. These findings support that certain EGFR wild-type patients may respond to EGFR TKIs. Further research is needed to characterize these patients and elucidate the predictive ability of potential biomarkers such as TGF- α, EGFR copy number and others.