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G.R. Oxnard



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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.06 - A prospective internet-based study of patients with lung cancer harboring baseline EGFR T790M to identify germline carriers and characterize familial risk (ID 1667)

      16:40 - 16:45  |  Author(s): G.R. Oxnard

      • Abstract
      • Presentation
      • Slides

      Background
      The EGFR T790M mutation, commonly seen with acquired resistance to EGFR kinase inhibitors, has also been described rarely as a germline mutation in association with familial lung cancer. In a prior study (Oxnard et al, JTO, 2012), the presence of EGFR T790M at diagnosis was associated with a 50% chance of carrying an underlying germline T790M mutation. This suggests that by studying patients whose cancer was shown to carry T790M at diagnosis, it is possible to efficiently screen for a germline allele that otherwise is rare among patients with non-small cell lung cancer. We therefore initiated a prospective trial to identify patients and families carrying germline EGFR mutations in order to characterize phenotype and cancer risk.

      Methods
      Subjects are eligible if they (1) have a cancer harboring EGFR T790M (excluding acquired T790M), (2) are a relative of a known germline carrier, or (3) are already known to carry a germline EGFR mutation on prior testing. Subjects may present at a participating cancer center or may enroll remotely using a study website (www.dana-farber.org/T790Mstudy/). Eligible subjects receive genetic counseling in person or over the phone, and then submit a saliva and/or blood specimen for central testing in a CLIA lab. Results are disclosed to the subject if they wish but do not enter the medical record. Those subjects carrying germline EGFR mutations are given the option of inviting relatives to participate. Chest CT scans are collected from germline carriers and analyzed centrally to study nodule prevalence and characteristics. Available tumor specimens are collected for central pathology review and advanced genomic analysis.

      Results
      The trial was registered to clinicaltrials.gov (NCT01754025) and began accrual in December 2012. To date, 7 subjects have been enrolled and 5 are actively being screened, including 4 kindreds. More than half of the subjects have participated remotely via the study website. Of 4 probands with lung cancer and germline T790M, 3 have a family history of lung cancer, 2 of whom have children with CT scans showing multiple sub-centimeter ground-glass nodules. The fourth proband has no family history of lung cancer, suggesting variable penetrance or a de novo germline event. All cancers in germline T790M carriers have also harbored secondary EGFR kinase domain mutations.

      Conclusion
      Using a novel trial design, including remote accrual, genetic counseling by phone, and germline testing by mail, we have begun collecting a sizeable cohort of families affected by germline EGFR mutations. By leveraging referrals from commercial laboratories and contributing academic centers, we aim to study 100 patients over a three year period in order to better understand the natural history and risk associated with this unique familial cancer syndrome. Supported by grants from the Conquer Cancer Foundation of ASCO, the Bonnie J. Addario Lung Cancer Foundation, and the National Cancer Institute.

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    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO16.06 - Clinical, structural and biochemical characterization of EGFR exon 20 insertion mutations in lung cancer (ID 745)

      16:50 - 16:55  |  Author(s): G.R. Oxnard

      • Abstract
      • Presentation
      • Slides

      Background
      Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for ~10% of EGFR-mutated non-small-cell lung cancer (NSCLC), for the most part occur at the N-lobe of EGFR after its C-helix (after amino-acid M766) and have unsolved patterns of response to ATP-mimetic EGFR tyrosine kinase inhibitors (TKIs).

      Methods
      To understand the patterns of resistance or response to EGFR TKIs of EGFR exon 20 insertion mutations, we decided to study representative mutations using in vitro systems, structural models and also NSCLCs with these specific EGFR mutations.

      Results
      We selected three mutations located within the C-helix (A763_Y764insFQEA [identical to D761_E762insEAFQ], Y764_V765insHH and M766_A767insAI) and four mutations following the C-helix (A767_V769dupASV [identical to V769_D770insASV], D770_N771insNPG, D770_N771insSVD [identical to S768_D770dupSVD] and H773_V774insH [identical to P772_H773insH]) mutations. Our data indicates almost all EGFR exon 20 insertions are resistant to submicromolar concentrations of gefitinib or erlotinib; data that mirrors the lack of clinical response of NSCLCs with these mutations. The crystal structural and enzyme kinetic studies of a prototypical post C-helix EGFR TKI-resistant insertion, between residues D770_N771 (D770_N771insNPG), highlight that these mutations favor the active conformation (i.e., are activating), don’t alter EGFR’s ATP-binding pocket and are less sensitive than TKI-sensitive mutations. D770_N771insNPG is predicted to be 7.66 fold less sensitive than the TKI-sensitive EGFR-L858R. Unexpectedly, we identified the atypical EGFR-A763_Y764insFQEA as the only EGFR exon 20 insertion hypersensitive to EGFR TKIs using enzyme kinetic and cell line models. In patients with EGFR exon 20 mutated NSCLCs, the response rates to gefitinib or erlotinib were significantly higher for A763_Y764insFQEA (2/3; 66.6%) when compared to all other mutations within or following the C-helix (0/17, 0%; p=0.0158). The unorthodox homology model of A763_Y764insFQEA suggests a mechanism of activation (by shifting the register of the C-helix N-terminal) related to TKI-sensitive mutations (such as L858R or L861Q).

      Conclusion
      Our findings not only explain the intricate interplay between different EGFR mutations and their response to EGFR TKIs, but also have clinical implications for the treatment of EGFR exon 20 insertion mutated NSCLCs. Therefore, based on our data and previously published reports the aforementioned mutations affecting amino acids V765 to V774 should be classified as non-sensitizing to the reversible EGFR TKIs gefitinib and erlotinib. Our models may usher the development of EGFR TKIs specific for EGFR exon 20 insertion mutations.

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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.11 - DISCUSSANT (ID 3918)

      11:35 - 11:50  |  Author(s): G.R. Oxnard

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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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      P2.11-011 - A Phase Ib study of high-dose intermittent (HDI) afatinib in EGFR T790M mutation-positive non-small cell lung cancer patients with acquired resistance to reversible EGFR TKIs (ID 1127)

      09:30 - 09:30  |  Author(s): G.R. Oxnard

      • Abstract

      Background
      Afatinib, an irreversible ErbB Family Blocker, displayed nanomolar inhibitory activity in proliferation assays using lung adenocarcinoma cell lines expressing mutant EGFR[L858R/T790M] (NCI-H1975 EC~50~ 92 nM).[1] In NSCLC patients with prior erlotinib/gefitinib failure and one/two previous lines of chemotherapy, 50mg afatinib once daily produced confirmed objective responses in 7% of patients and a median PFS of 3.3 months.[2] Preclinical models suggested that administering afatinib using a high-dose intermittent (HDI) schedule, leading to higher maximal plasma concentrations, may provide an alternative means to block T790M-harbouring cells effectively. It may also potentially reduce wild-type EGFR-mediated adverse events noted with continuous dosing of EGFR TKIs. In this ongoing open-label study, the maximum tolerated dose (MTD), safety and pharmacokinetics (PKs) of HDI afatinib are being assessed in Part A in patients with advanced solid tumours. The MTD of HDI afatinib will be evaluated in Part B in patients with T790M-mutated advanced NSCLC following prior EGFR TKI therapy. Preliminary results from Part A are presented.

      Methods
      In Part A, patients with metastatic/unresectable solid tumours and adequate organ function were administered 90–200mg afatinib on Days 1–3 every 14 days in each 28-day cycle using a 3+3 dose-escalation design. Doses are escalated until MTD (primary endpoint), defined as the dose at which less than two of up to six patients develop dose-limiting toxicities (DLTs) in Cycle 1. PK sampling was conducted on Days 1–3, 8, 15–17, 29, 43 and 57, with C~max~ of afatinib on Day 3 of Cycle 1 being the secondary endpoint. In Part B, the MTD cohort will be expanded to specifically include EGFR TKI-pretreated advanced NSCLC patients with T790M mutations. Exploration of baseline and on-therapy plasma levels of detectable T790M is planned.

      Results
      To date, 16 patients have been recruited in Part A (90mg n=6; 120mg n=3; 150mg n=4; 200mg n=3; male/female n=8/8; median age 65 years; never smokers/ex-smokers n=10/6; primary tumour site lung n=9; known T790M mutation n=7). The most common drug-related adverse events (DRAEs) were diarrhoea, rash, dermatitis acneiform and nausea. DRAEs of Grade ≥3 were seen in one patient at 90mg (Grade 3 worsening cellulitis [Cycle 1; DLT] and urosepsis [Cycle 2]) and one patient at 150mg (Grade 3 dehydration, hypokalaemia, hypophosphataemia, diarrhoea [Cycle 2]). Preliminary response data on evaluable T790M-mutated NSCLC patients will be presented as available. Preliminary PK analyses suggest 150mg afatinib once daily for 3 days is sufficient to achieve total plasma C~max~ concentrations at or above the predicted IC~50~ value for T790M. Afatinib trough plasma concentrations will also be presented.

      Conclusion
      HDI afatinib elicited a manageable safety profile up to 200mg on Days 1–3 every 14 days. Total plasma C~max~ concentrations at or above the predicted efficacious threshold for T790M inhibition were already achieved in the 150mg cohort. Treatment in the 200mg cohort is ongoing. Additional cohorts may be included to explore shorter drug-free dosing periods. 1. Solca F, et al. JPET 2012;343:342–50. 2. Miller V, et al. Lancet Oncol 2012;13:528–38.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-054 - Development of a clinical-grade quantitative assay for non-invasive measurement of tumor genotype in cell-free plasma DNA (cfDNA) using next-generation quantitative genotyping (ID 741)

      09:30 - 09:30  |  Author(s): G.R. Oxnard

      • Abstract

      Background
      Non-invasive genotyping of cfDNA has been shown to be feasible using highly sensitive assays. However, for detection of uncommon genomic events, specificity must approach 100% or false positive results impair clinical utility. Digital droplet PCR (ddPCR) is a quantitative genotyping technology that emulsifies input DNA into ~20,000 droplets which are PCR amplified, fluorescently labeled, and read as mutant or wildtype in a droplet flow cytometer. Using this quantitative technology, we aimed to develop a clinical-grade assay for non-invasive plasma genotyping and serial disease monitoring.

      Methods
      Patients with advanced NSCLC known to harbor EGFR or KRAS mutations were studied in an IRB-approved fashion. Plasma was collected in 10cc EDTA-tubes. Extracted DNA was quantified with a PCR for LINE1 and genotyped using ddPCR. Specificity of EGFR genotyping was determined using patients with KRAS-mutant lung cancer as gold standard negative cases. Serial assessment was piloted on EGFR-mutant cases receiving first-line erlotinib.

      Results
      To minimize risk of false positive results, we identified the “normal range” for EGFR L858R and exon 19 deletions in specimens from KRAS-mutant lung cancers as 0-1 and 0-8 copies/mL of plasma, respectively. Using this threshold for positive, ddPCR for EGFR sensitizing mutations had 67% sensitivity and 100% positive predictive value (Figure 1). Sensitivity was 100% with LINE-1 levels between 60-60000 pg/mcL but was poor with higher or lower cfDNA concentrations. Serial assessment on erlotinib (Figure 2) demonstrated pretreatment detection of EGFR mutations with ddPCR, complete plasma response on erlotinib, and subsequent reemergence of plasma EGFR up to 16 weeks prior to objective progression. Figure 1 Figure 2

      Conclusion
      Plasma genotyping of cfDNA using ddPCR has 100% specificity when using a rigorously defined threshold for a positive result. Sensitivity is highest in specimens with optimal cfDNA concentration. Clinical development is underway to use this non-invasive assay to guide genotype-directed therapy.

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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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      P3.12-004 - A practice-based analysis to gauge the feasibility of genotype-directed induction therapy for stage III non-small cell lung cancer (NSCLC) (ID 1343)

      09:30 - 09:30  |  Author(s): G.R. Oxnard

      • Abstract

      Background
      Genotype-directed therapies are transforming the care of patients with advanced NSCLC, but these have not yet been incorporated into curative therapy for early stage disease. Because trials are in development which will study genotype-directed induction therapy for stage III NSCLC, we retrospectively examined practice patterns to identify strategies for maximizing the feasibility of this approach.

      Methods
      Patients with stage IIIA NSCLC who were treated at our institution with upfront concurrent chemoradiotherapy between 1/2004 and 5/2012 were identified from an institutional database. Management prior to start of definitive therapy was reviewed. For this analysis, biopsies were considered adequate for genotyping while cytology specimens were considered inadequate. To gauge the feasibility of genotyping, we compared the intervals between biopsy and treatment and between first oncologist appointment and treatment with a range of hypothetical turnaround times for genotyping (i.e. time between when test is ordered and when results are available).

      Results
      150 patients were identified in an initial query. 57 were excluded from the analysis: 46 due to treatment at an outside hospital, 5 due to upfront surgery, and 6 due to sequential chemotherapy and radiation. 89 patients were included in the study population with the following characteristics: median age at diagnosis 61 (range 33-86), 45% adenocarcinoma, 25% squamous, 2% neuroendocrine, and 28% NSCLC NOS. Clinical stage: 17% T1N2M0, 42% T2N2M0, 3% T3N1M0, 24% T3N2M0, 9% T4N0M0, 6% T4N1M0. Staging evaluation: 86% underwent bronchoscopy, 86% underwent mediastinoscopy; 100% underwent PET-CT, 100% underwent brain imaging. Best biopsy for genotyping: 51% surgical biopsy, 20% endobronchial biopsy, 7% CT-guided core biopsy, 22% cytology. The median time between best biopsy and treatment initiation was 34 days (IQR: 23-45). The median time between first oncologist appointment and treatment initiation was 18.5 days (IQR: 14-25). Simulating reflex genotyping versus oncologist-ordered genotyping for a range of hypothetical turnaround times (Figure), reflex genotyping may increase the number of patients genotyped in time for start of therapy when turnaround time exceeds 8 days. Figure 1

      Conclusion
      In this practice-based analysis of patients with stage IIIA NSCLC receiving definitive chemoradiotherapy, 78% of patients had a biopsy expected to be adequate for genotyping. To maximize the feasibility of genotype-directed induction therapy for NSCLC, reflex genotyping of staging biopsies may be needed, particularly when genotyping turnaround time exceeds 8 days.