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P. Mack
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MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:S. Lu, P. Waring
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside 204 A+B, Level 2
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MO01.11 - DISCUSSANT (ID 3901)
11:20 - 11:35 | Author(s): P. Mack
- Abstract
- Presentation
Abstract not provided
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MO13 - SCLC I (ID 118)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:C.K. Liam, E.S. Santos
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside 201 - 203, Level 2
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MO13.01 - Disease control rate at 8 weeks predicts subsequent survival in platinum-treated extensive stage small cell lung cancer (ES-SCLC): a patient level analysis of SWOG trials (ID 967)
10:30 - 10:35 | Author(s): P. Mack
- Abstract
- Presentation
Background
Disease control rate (DCR) – the sum of partial (PR) and complete response (CR) plus stable disease (SD) – is a significant predictor of subsequent survival following platinum-based chemotherapy in patients with advanced non-small cell lung cancer (Lara, et al. JCO 2008). We evaluated whether this observation is also relevant in patients with platinum-treated ES-SCLC on investigational systemic therapy.Methods
Updated patient-level data from recent SWOG trials in 2[nd] and/or 3[rd] line ES-SCLC (S0802: topotecan + aflibercept; S0435: sorafenib; and S0327: PS-341) were pooled. Landmark analysis was performed among patients still alive at 8 weeks for overall survival (OS) measured from the 8-week landmark. Association of clinical prognostic factors (including age, sex, platinum sensitivity status, number of prior chemo, weight loss, and LDH, among others) with DCR was assessed using logistic regression. A Cox proportional hazards model was used to assess the associations between DCR at the landmark time and subsequent OS, adjusted for prognostic factors.Results
319 patients were included: median age = 63 years; male sex = 51%; PS 1 = 68%; weight loss > 5% = 29%; > 2 prior chemo = 16%; and elevated LDH = 43%. Only 8 patients had PR by RECIST for an overall response rate of 2.5%. Disease control at 8 weeks was observed in 74 patients (8 PR + 64 SD), for a DCR of 23.2%. Bivariate analysis of OS from the 8-week landmark revealed that only DCR (Hazard Ratio [HR] 0.53, p<0.0001) and elevated LDH (HR 1.69, p=0.001) were significantly associated with OS. Multivariable analysis showed that only DCR remained as an independent predictor of subsequent survival from the 8-week landmark (HR=0.58, p=0.002).Conclusion
In this large 2[nd]- and 3[rd]-line ES-SCLC database, DCR at 8 weeks was found to be the strongest predictor of subsequent survival in patients receiving investigational therapy. Thus, DCR at 8 weeks should be considered for use as a surrogate clinical trial endpoint to screen for drug activity against ES-SCLC. These results have critical implications in the design of future prospective trials in ES-SCLC.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO18 - NSCLC - Targeted Therapies IV (ID 116)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:L. Horn, J. Wolf
- Coordinates: 10/29/2013, 16:15 - 17:45, Bayside Auditorium B, Level 1
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MO18.08 - Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer (SCCA). (ID 1958)
16:55 - 17:00 | Author(s): P. Mack
- Abstract
- Presentation
Background
There are few new effective therapeutic options for patients with advanced, lung SCCA; overall survival for metastatic disease being less than one year. The Cancer Genome Atlas (TCGA) project and similar studies have detected a significant number of somatic gene mutations/amplifications in patients with this disease, some of which are targetable by investigational agents. However, the frequency of these changes is low (5-20%) in these patients, making recruitment and treatment very challenging in the traditional single-agent trial setting. Our approach is to use a common platform (Next Generation DNA Sequencing) to enable a single “umbrella screening protocol” to efficiently find patients with varied, uncommon molecular changes.Methods
Figure 1 This is a prospective, multi-substudy randomized Phase II/III Master Registration Protocol in which patients with advanced stage Lung SCCA (2[nd] line therapy)are randomized to biomarker-driven targeted therapy (TT) or standard of care (SOC) as shown in the schema after undergoing genomic screening. Genomic screening of a large patient resource provided by sites participating in the NCI North American Intergroup will identify molecular targets/biomarkers with an analytically validated diagnostic assay and a new drug match, leading to appropriate drug treatment-arm assignment. Archival FFPE tumor and/or core needle biopsies will be screened by a broad analytically validated next generation sequencing (NGS) platform centrally to establish eligibility within 10-14 days. This platform will be supplemented by individual immune-histochemical (IHC) protein assays performed in a CLIA setting as necessitated by the specific experimental agent used. Patients will be screened with homogeneous eligibility criteria. The overall trial objective is to establish a mechanism to genomically screen large but homogeneous cancer populations and subsequently assign and accrue simultaneously to multiple substudies comparing new TT to SOC therapy based on the identified therapeutic biomarker-drug combination. Each sub-study will function autonomously and will open and close independently of the other sub-studies. Drug combinations in the experimental arm will be allowed in appropriate settings and where appropriate the control arm may consist of FDA approved targeted therapy such as erlotinib. Each sub-study is independently powered for OS with an interim analysis for PFS to determine the “go-no go” decision to proceed from Phase II into Phase III. Each agent, along with the paired biomarker, that is successful at the interim analysis based on PFS will advance to a Phase III randomized registration trial (on behalf of the Master Protocol Steering Committee).Results
NAConclusion
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MO20 - Preclinical Therapeutic Models II (ID 93)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:P. Waring, M. Kohonen-Corish
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Gallery B, Level 1
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MO20.04 - Divergent activity of afatinib (AFAT) and cetuximab (CET) in patient-derived xenograft (PDX) models of acquired erlotinib resistance. (ID 1458)
10:45 - 10:50 | Author(s): P. Mack
- Abstract
- Presentation
Background
The combination of AFAT and CET has demonstrated remarkable clinical activity in patients with acquired resistance to erlotinib. Preclinical modeling in genetically engineered mice and cell lines predicted activity in cases where erlotinib resistance was mediated by the EGFR T790M gatekeeper mutation. However, in the clinic, patients lacking T790M-positive tumors showed equivalent benefit from this combination, suggesting alternative mechanisms of synergy. We explored the individual and combined molecular and growth inhibitory activity of these agents in PDX models derived from NSCLC patient tumors with distinct mechanisms of acquired resistance to erlotinib. These models were developed by the UC Davis - Jackson Laboratories Consortium, which has xenotransplanted over 170 NSCLC models using the nod/scid/IL2Rgamma chain-null (NSG) mouse.Methods
EGFR-mutant PDX models LG0703 (T790M-negative) and LG1049 (T790M-positive) were established from tumor biopsies from patients who progressed following durable responses to erlotinib. Both patients were subsequently treated with AFAT+CET, with the LG0703 donor patient exhibiting a prolonged response and the LG1049 donor patient exhibiting a transient response followed by rapid progression. Excised tumors from passage 1 PDXs were fragmented and implanted into treatment cohorts. When tumors reached 300mm[3], mice were randomized to erlotinib (50 mg/kg qd po), AFAT (20 mg/kg qd po), CET (10 mg/kg twice weekly iv), AFAT-CET, or vehicle control (n per arm = 12) for 3 weeks followed by a 75-day monitoring period. In a parallel cohort, tumor pharmacodynamic changes in signal transduction mediators and RTKs were assessed after 6 and 24h treatment exposures using kinase arrays (R&D systems) and immunoblotting.Results
In LG0703, AFAT, CET and AFAT-CET resulted in complete tumor response (CR) during the 21-day treatment period. After cessation of treatment, mice treated with CET or AFAT-CET remained in complete remission; whereas AFAT-treated mice progressed within 2 weeks. Clinical activity in this model was associated with complete blockade of EGFR and Her2 phosphorylation. Substantial down-regulation of AKT1, AKT2, ERK1, p38a, RSK1 and p70S6K phosphorylation was evident within 6h of treatment. In contrast, the T790M-postive LG1049 model demonstrated only modest clinical benefit from AFAT, with no single-agent CET activity, and no CET-mediated synergy with AFAT. No treatments were able to ablate EGFR phosphorylation or downstream signal transduction, and compensatory induction of EGFR, HER2, ERK1 and p38 were noted after 24h of drug exposure.Conclusion
In these PDX models derived from patients with EGFR-activating mutant cancer with acquired resistance to erlotinib, treatment with AFAT+CET recapitulated the clinical experience of the donor patients receiving this combination. In the LG0703 model, both the AFAT-CET combination as well as single-agent CET resulted in complete tumor regression associated with total ablation of EGFR phosphorylation and subsequent blockade of multiple signal transduction pathways. In the LG1049 model, AFAT prompted limited but statistically significant tumor delay, with no additional benefit from CET. These experiments demonstrate the considerable potential of this PDX resource to assess therapeutic strategies in models representing individual patients. Supported by BJALCF.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MTE11 - How Do PDXs Help Us In the Clinic (ID 55)
- Event: WCLC 2013
- Type: Meet the Expert (ticketed session)
- Track: Biology
- Presentations: 1
- Moderators:N. n/a
- Coordinates: 10/29/2013, 07:00 - 08:00, Bayside 103, Level 1
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MTE11.1 - How Do PDXs Help Us In the Clinic (ID 604)
07:00 - 08:00 | Author(s): P. Mack
- Abstract
- Presentation
Abstract
Patient-derived xenotransplant (PDX) models are generated by engrafting human tumor material directly from surgery or biopsy into an immune-compromised mouse without any intervening in vitro culturing. Previous efforts to accomplish this were hampered by poor tumor “take rates” of all but the highest grade tumors, limiting the spectrum of cancer types available for study. Several technical advances have led to improved model formation, including the advent of the NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mouse by The Jackson Laboratories: a new immunodeficient strain that, in addition to a compromised complement system, have defective dendritic cell and macrophage activity, lack mature T and B cells, and have no functional NK cells. This strain has demonstrated high rates of engraftment of a wide variety of tumor types, with the resulting xenografts retaining the tumor heterogeneity and oncogenic driver activity of the patient’s tumor; thus providing a model system that more closely reflects what is seen in the clinic. The University of California, Davis Comprehensive Cancer Center and The Jackson Laboratory have collaborated to establish over 50 fully functional NSCLC PDX models. Testing to date has demonstrated a high fidelity between the contributing patient tumor and the resultant PDX model (at passages 1 and 2) in terms of driving mutations, histology and treatment response. Models developed from tumors known to harbor alterations in EGFR, KRAS or ALK all retain the exact mutational characteristics of the donor tumor. Additionally, these models clearly recapitulate the tumor histologic characteristics and grade of their donors. Squamous cell carcinoma PDX models in this panel have a high incidence of p53 mutations, with several models harboring PIK3CA or PTEN mutations, amplification of PIK3CA and FGFR1. KRAS-mutant models have a high incidence of KRAS and MYC amplification. EGFR-mutant positive adenocarcinomas include models derived from patient tumors prior to or following acquisition of resistance to erlotinib, and in models tested to date recapitulate the clinical results of the contributing patient when treated with the matching therapy. By the third passage, a large number of matched sister models can be generated, sufficient for multi-armed therapeutic testing with an n of 10 or more per arm. Additionally, short-term molecular effects of targeted agents, particularly kinase inhibitors, can easily be measured. Inhibition of drug target and the resultant downstream effects on kinase pathways have already been documented in ongoing studies (Mack et al, WCLC 2013), granting unique insight into drug activity, resistance and cellular compensatory effects. Such studies provide a rational basis for determining appropriate therapeutic combinations of signal transduction inhibitors and receptor tyrosine kinase inhibitors to achieve complete signaling blockade. Similarly, PDX models should aid in identification of targeted strategies to improve activity of chemotherapy. The use of early passage (or passage 0) PDX models as “avatars” for patient response to therapy is also under investigation, although the parameters in which models can be treated in a time-frame sufficient for patients with advanced NSCLC need to be determined. In summary, the PDX platform, with its high degree of fidelity to patient tumors and minimized culture-induced artifacts, should significantly improve the predictive ability of preclinical modeling in the era of personalized therapy.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O21 - SCLC II (ID 119)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:M. Ahn, P. Lara
- Coordinates: 10/29/2013, 16:15 - 17:45, Parkside Ballroom B, Level 1
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O21.07 - A new prognostic model for relapsed/refractory extensive stage small cell lung cancer (ES-SCLC) derived from prospective SWOG trials: implications for study design (ID 966)
17:20 - 17:30 | Author(s): P. Mack
- Abstract
- Presentation
Background
ES-SCLC patients (pts) with progressive disease (PD) following plat-based chemo have traditionally been categorized as plat-sensitive (PD >/= 90 days from last plat dose) or refractory (PD < 90 days). Plat-sensitivity status has previously been strongly associated with response and survival in the 2[nd]/3[rd] line treatment setting. However, in a recent pooled analysis of SWOG trials in 2[nd]/3[rd] line SCLC pts, plat-sensitivity status was found to no longer be a significant independent variable for survival (Lara, ASCO 2013). We subsequently developed a new SCLC prognostic model for overall survival (OS) for potential clinical trial and bedside application.Methods
Updated data from recent SWOG trials in 2nd and/or 3rd line ES-SCLC (S0802: topotecan + aflibercept: S0435: sorafenib; and S0327: PS-341) were pooled. Accrual goals were specified for sensitive and refractory in each trial. Hazard ratios (HRs) for OS were calculated using Cox Proportional Hazard (PH) models [unadjusted and adjusted]. To investigate a predictive model for OS, recursive partitioning was performed using the likelihood tree model of LeBlanc and Crowley. The minimum node size was set at 20.Results
Of 329 pts, 151 were classified as sensitive, 178 refractory; median age = 63 years; males = 52%; Performance Status (PS) 1 = 67%; weight loss >5% = 28%; > 2 prior chemo = 16%; and elevated LDH = 43%. HRs from unadjusted Cox models for OS for refractory vs. sensitive were 1.0 (95% CI 0.81-1.25, p=0.98) and 1.24 (95% CI 0.99, 1.57; p=0.06). Cox PH models adjusted for baseline prognostic factors showed that plat-sensitivity status was not significantly associated with OS. Elevated LDH was significantly associated with PFS while LDH, PS, weight loss, and male sex were independently associated with OS. Clinically relevant prognostic risk groups (High, Intermediate, and Low) were identified by recursive partitioning analysis, as shown below (MST= median survival time). High Risk (MST = 2 months: Elevated LDH And > 5% Weight Loss Or PS >0) Intermediate Risk (MST = 5 months: Elevated LDH but not High Risk Or Male) Low Risk (MST=8 months: Normal LDH And Female)Conclusion
In this large database analysis, clinically relevant prognostic risk groups were identified, categorized as low, intermediate, and high risk, with differential survival outcomes observed for each group. Validation of these risk groups in an independent SCLC dataset is warranted. If validated, these risk groups will have important implications for individualized patient counseling in clinic and stratification of patients in prospective trials in the second and third line setting.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
