Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

S. Thongprasert

Moderator of

  • +

    PC 02 - Pro vs Con: Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? / Pro vs Con: Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) (ID 48)

    • Event: WCLC 2015
    • Type: Pro Con
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 4
    • +

      PC02.01 - Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? - Pro (ID 2030)

      14:20 - 14:40  |  Author(s): S.A. Laurie

      • Abstract
      • Presentation

      Abstract:
      With the dramatic clinical benefit that can be observed using tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) harbouring activating mutations in EGFR, there has understandably been a focus on the use of these agents in this subset of NSCLC. However, EGFR mutation positive NSCLC represents only approximately 10 – 15 % of all non-squamous NSCLC in non-East Asian patients, and a substantial proportion of East Asian patients do not harbour this mutation. Thus, world-wide, the vast majority of those with NSCLC are so-called “wild-type” for EGFR. For these patients, it is clear from randomized clinical trials that the treatment of choice in the first-line metastatic setting is platinum-doublet chemotherapy. Increasing data suggest that chemotherapy may be preferred in the second-line setting. Is there any role for the use of EGFR TKIs in the wild-type population? Randomized data in which an EGFR TKI is compared to placebo in both the maintenance and refractory settings suggest that there may be. NCIC Clinical Trials Group study BR21 [1] which randomized 731 unselected patients to either erlotinib or matching placebo, was designed and conducted prior to the discovery of activating mutations. Patients had received 1 (50 %) or > 2 (50 %) lines of prior therapy; > 90 % had received a platinum-doublet. An improvement in median survival (6.7 versus 4.7 months [HR 0.70, p < 0.001]) was also associated with a quality of life benefit. This benefit was consistent across subgroups, including in the 50 % of patients with non-adenocarcinoma histology. In a separate analysis of ever-smokers with squamous histology, patients highly unlikely to harbour an EGFR mutation, the magnitude of survival benefit was the same as in the overall study population (median 5.6 versus 3.5 months [HR 0.66, p=0.009])[2]. The SATURN trial [3] randomized 889 patients who had not progressed after 4 cycles of platinum-doublet chemotherapy to either erlotinib or placebo. While of debatable clinical relevance, there was a statistically significant one month prolongation of median survival with the use of erlotinib (HR 0.81, p=0.009). A similar effect was observed in the 44 % of patients with known EGFR wild-type status (HR 0.77, p=0.02). In a pre-planned subgroup analysis [4], a greater magnitude of benefit was observed in those patients whose best response to induction chemotherapy was stable disease (median overall survival 11.9 versus 9.6 months [HR 0.72, p=0.002]), with a similar effect noted in those patients with squamous histology (HR 0.67, p=0.01), and those known to be EGFR wild-type (HR 0.65, p=0.004). Maintenance erlotinib has been shown to not negatively impact quality of life [5], and when used in those with stable disease, to be cost effective [6]. Meta-analyses of placebo-controlled trials of EGFR TKIs in the maintenance setting have confirmed a modest progression-free survival benefit in squamous [7] and known wild-type [8] patients. Multiple trials have compared an EGFR TKI to either docetaxel or pemetrexed in the second-line setting. The TAILOR trial [9], the only trial to prospectively determine and enrol only wild-type patients, showed a clear PFS advantage to docetaxel, and a trend towards improved overall survival. However several other trials that enrolled patients who were unselected with regard to EGFR status had a substantial number of wild type patients, and none of these trials demonstrated a difference in overall survival in wild-type patients between an EGFR TKI and chemotherapy. While these were retrospective analyses on only a subset of enrolled patients with available tissue, wild-type patient numbers in many trials approached (and in one exceeded) the number of patients enrolled to TAILOR. Further, unlike other trials, TAILOR prohibited crossover, which may have impacted survival results, particularly for patients with squamous carcinoma in the erlotinib arm. Taken together these trials suggest that a treatment strategy that includes both chemotherapy and an EGFR TKI sequentially, irrespective of order, will lead to a similar length of survival provided patients receive both lines of therapy. In platinum-pretreated patients who are fit it is likely preferred to use chemotherapy and then at progression move on to an EGFR TKI, as the chance of patients receiving both treatments is higher. Additional data to suggest that EGFR TKIs may have activity in wild-type patients comes from several small, randomized phase II trials comparing second-line chemotherapy with the same chemotherapy with intercalated EGFR TKIs. These studies have shown prolonged PFS in patients treated with the combination. What these trials demonstrate is that EGFR TKIs appear to have a modest treatment effect in EGFR wild-type patients. In these days of targeted therapies leading to substantial treatment effects in a variety of tumours with oncogenic drivers, is this magnitude of benefit sufficient? In lung cancer, many other treatments have been adopted for a similar magnitude of benefit. Although objective response rates to EGFR TKIs are low in wild-type patients, they are also low to standard cytotoxic chemotherapies beyond first-line, and it seems possible that there is a larger proportion of patients with stabilization of disease and / or slowing of progression that is clinically relevant. Not all oncologists or patients will feel that a trial is warranted, but an EGFR TKI is a reasonable choice as last-line therapy when the option is no further treatment, or as maintenance treatment in patients with squamous histology following a best response of stable disease to induction platinum-based chemotherapy. EGFR “wild-type” is a heterogeneous, not homogeneous, population, and as with any therapy, only a subgroup of patients will benefit from treatment. However a consistent reproducible biomarker for benefit in the wild-type subgroup has not yet been discovered. EGFR protein expression, gene copy number, Kras status and serum proteomics have all been evaluated with at times conflicting results, due to limited samples and the retrospective nature of the analyses. The development of rash may be a pharmacodynamic predictor of greater efficacy [10]. Additional work is required to determine which wild-type patients may derive benefit from an EGFR TKI, to avoid needless toxicity and improve cost-effectiveness. References 1. Shepherd et al. N Engl J Med 353: 123-132, 2005 2. Clark et al. Clin Lung Cancer 7:389-394, 2006 3. Cappuzzo et al. Lancet Oncol 11:521-529, 2010 4. Coudert et al. Ann Oncol 23:388-394, 2012 5. Juhasz et al. Eur J Cancer 49:1205-1215, 2013 6. Walleser et al. Clinicoeconomics Outcomes Res 4:269-275, 2012 7. Ameratunga et al. Asia-Pacific J Clin Oncol. 10:273-278, 2014 8. Vale et al. Clin Lung Cancer 16:173-182, 2015 9. Garassino et al. Lancet Oncol 14:981-988, 2013 10. Ding et al. Contemp Clin Trials 29:527-536, 2008

      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.

    • +

      PC02.02 - Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? - Con (ID 2031)

      14:40 - 15:00  |  Author(s): L.V. Sequist

      • Abstract
      • Presentation

      Abstract not provided

      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.

    • +

      PC02.03 - Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) - Pro (ID 2032)

      15:00 - 15:20  |  Author(s): I.I. Wistuba

      • Abstract
      • Presentation

      Abstract not provided

      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.

    • +

      PC02.04 - Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) - Con (ID 2033)

      15:20 - 15:40  |  Author(s): Y. Yatabe

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Great advantages of next generation sequencing have been published so far, and many new genetic alterations were found with whole genome sequencing. Targeted sequencing using next generation sequencing technique can analyze FFPE small biopsy specimens, but may be equivalent or less than the current selected testing, such as EGFR and ALK testing. Although the targeted sequencing can actually analyze multiple genes, most diagnostic panels include the genes that are frequently altered in cancer generally, thus practically useful genes are limited in terms of lung cancer, such as EGFR, ALK, ROS1, and RET. In contrast, whole exome sequencing is potentially useful, as it can comprehensively examine mRNA expression on tumor cells. In general, mRNA in clinical samples well represents tumor genetic status even with significant dilution with the normal cells, which are less active in transcription. However, it is difficult to perserve high quality RNA with clinical samples, and it is unclear that the whole exome sequencing is constantly clinically applicable for small biopsy specimens. Furthremore, there are some cases that show discrepant results between DNA and RNA based assays. As EGFR transcript is suppressed in SCLC, EGFR mutation cannot be detected with the exome sequencing in SCLC transformed as a resistant mechanism to EGFR-TKI treatment. On the other hand, current selected testing for EGFR and ALK has been confirmed with clinical trials and are adjusted to clinical demands, e.g., short turnaround time and high sensitivity.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.



Author of

  • +

    ORAL 34 - Quality/Survival/Prognosis in Localized Lung Cancer (ID 153)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
    • +

      ORAL34.03 - Prognostic Factors in Early Stage NSCLC: Analysis of the Placebo Group in the MAGRIT Study (ID 24)

      17:07 - 17:18  |  Author(s): S. Thongprasert

      • Abstract
      • Presentation
      • Slides

      Background:
      The MAGRIT study was a worldwide, multicenter, phase-3 double-blind, randomized trial evaluating efficacy of the MAGE-A3 Cancer Immunotherapeutic in resected non-small cell lung cancer (NSCLC) (www.clinicaltrials.gov NCT00480025). We examined baseline patient and disease characteristics associated with overall survival (OS) and disease-free survival (DFS) among patients assigned to placebo.

      Methods:
      Study participants were ≥18 years, with histologically proven, MAGE-A3-positive stage IB, II or IIIA NSCLC (AJCC 6.0). Participants had undergone complete anatomical resection of the tumor (lobectomy or pneumectomy) with mediastinal lymph node (LN) dissection or sampling according to standard of care. Up to four cycles of platinum-based adjuvant chemotherapy were allowed. Cox regression models were used to explore characteristics that could predict DFS and OS. Factors statistically significant in univariate analysis (p<0.05) were included in multivariate models using a stepwise approach (p<0.05 to enter/remain in the model).

      Results:
      There were 757 placebo patients in the total treated population; median age 63 years, 76% male, 53% with squamous cell carcinoma (SCC), 34% with adenocarcinoma, 98% with performance status 0-1, 52% had received adjuvant chemotherapy.In univariate analyses, SCC, lower N-category and earlier disease stage were associated with improved DFS. Lower N-category, earlier stage and smaller tumor size were associated with improved OS. In multivariate analysis, N-category (HR 1.34, 95%CI [1.16-1.55]) and histological type (HR for SCC vs non-SCC 0.64, 95%CI [0.51-0.81]) remained significant for DFS. N-category (HR 1.47, 95%CI [1.21-1.79]) and tumor size (HR by unit increase 1.08, 95%CI [1.01-1.15]) did so for OS. No association was found between DFS or OS and age, gender, race, region, baseline performance status, quantitative MAGE-A3 expression, chemotherapy administration or type of chemotherapy, smoking status or type of LN sampling (minimal/systematic). Among patients with SCC, univariate analysis identified increased number of chemotherapy cycles and operative technique (pneumectomy) as associated with improved DFS (p<0.05). Only operative technique remained in the multivariate model. When including N-category (p<0.10 in univariate analysis) in the multivariate model, N-category and number of chemotherapy cycles were also selected. Lower N-category and smaller tumor size were significantly associated with improved OS, in univariate and multivariate analyses. Among patients with non-SCC, univariate analysis identified younger age, being female, lower N-category and earlier disease stage with improved DFS, and lower N-category, earlier disease stage and region (East Asia) with improved OS. N-category and gender, and N-category and region remained significant in the multivariate analysis for DFS and OS, respectively.

      Conclusion:
      This is the first prognostic factor analysis in resected NSCLC performed on data from a large, prospective randomized study. It highlighted that in terms of DFS, SCC patients have a better prognosis than non-SCC patients. N-category plays a major role in determining prognosis. Operative technique (pneumectomy), number of chemotherapy cycles (SCC) and gender (non-SCC) are also associated with outcome. Variables predictive for OS are N-category and tumor size (all) and region (non-SCC). These results confirm retrospective studies done within the context of TNM classification, but add that histopathology subtype is a strong determinant for DFS in resected NSCLC.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

  • +

    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
    • +

      P2.04-034 - The Study of EGFR Mutation Specific-Antibody for Detection of EGFR Status in Non-Small Cell Lung Cancer (ID 750)

      09:30 - 09:30  |  Author(s): S. Thongprasert

      • Abstract
      • Slides

      Background:
      Specific somatic mutations of the epidermal growth factor receptor (EGFR) associate with increasing response to EGFR tyrosine kinase inhibitors (TKIs) treatment in NSCLC. Assessment of EGFR mutation status by gene-based assay remains expensive and is not routinely reimbursed in Thailand. The objective of this study is to test a simple immunohistochemical (IHC) method using EGFR mutation-specific antibodies for detection of EGFR status.

      Methods:
      Specimen from 76 NSCLC patients whose EGFR mutation status had been detected by DNA direct sequencing were collected from January 2010 to July 2014 as the reference standard. We performed IHC analyses using 2 EGFR mutation-specific antibodies to E746-A750 del in exon 19 and the other to L858R in axon 21 for all samples. IHC staining were score as 0 (no, or faint staining intensity in <10% tumor cells), 1+ (faint, staining >10%), 2+ (moderate) and 3+ (strong).

      Results:
      The reference DNA sequencing showed exon 21 L858R EGFR mutations in 17 (22.4%) patients, exon 19 deletions in 12 (15.8%) patients, G719X mutation in 1 (1.3%) patients, exon 20 insertion in 1 (1.3%) patients, multiple sites mutation in 1 (1.3%) patients and no mutation detected in 46 (52.9%) patients. With the DNA sequencing results were set as the reference standard, the prevalence of mutation detected by IHC-based analyses was 25.8% (8/31), 44.4% (8/18), 100% (7/7) and 66.7% (8/12) respectively, for samples with scores 0, 1+, 2+ and 3+. At IHC cut point value 2+, sensitivity and specificity for antibodies L858R were 52.9% wand 98.3 respectively. Likewise for antibodies E746-A750, cut point value 2+ showed sensitivity and specificity as 50.0% and 95.3% E746-A750 respectively. Additional, indicate similar cut point as score 2 ,PPV and NPV were 66.7% and 91.0% for antibodies E746-A750 and 90.0% and 88% for L858R antibodies.

      Conclusion:
      A simple IHC-based analysis using EGFR mutation-specific antibodies in this study have good correlation with gene-based for EGFR mutation analysis. In Thailand, these simple IHC cost less for five times, have shorter turn around time than gene-based for EGFR mutation analysis and could be useful where molecular-based assay is not readily accessible.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

  • +

    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
    • +

      P3.01-088 - Phase IV Study of Afatinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (ID 1562)

      09:30 - 09:30  |  Author(s): S. Thongprasert

      • Abstract

      Background:
      First-line afatinib, an oral, irreversible ErbB family blocker, improved progression-free survival (PFS), objective response rate and symptom control in patients with epidermal growth factor receptor (EGFR) mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), when compared with standard platinum-doublet chemotherapy. Afatinib also significantly prolonged overall survival in patients with Del19 mutations. Some EGFR mutation-positive patients still receive first-line chemotherapy and there are limited data regarding the effect of afatinib in chemotherapy pre-treated EGFR mutation-positive patients. This study was designed to evaluate the efficacy and safety of 40 mg/day afatinib in the second-line setting.

      Methods:
      Across centers in Europe, Asia and North Africa, 60 patients with locally advanced or metastatic NSCLC (stage IIIB/IV) harboring common EGFR mutations (Del19 and/or L858R) who have failed first-line platinum-based chemotherapy will be recruited to this ongoing, single-arm, open-label, Phase IV trial. Patients will be treated with oral afatinib 40 mg/day until the development of progressive disease or study discontinuation due to intolerable adverse events (AEs). Inclusion criteria include age ≥18 years, ECOG PS 0 or 1, documented EGFR Del19 and/or L858R mutation with no other known EGFR mutation, and adequate organ function with a life expectancy of ≥3 months. Patients are excluded from enrolling if they have received >1 line of prior therapy for disease (radiotherapy and radiosensitizers and/or intrapleural administration of anti-cancer agents is not counted as a line of therapy), or received <3 cycles of platinum-based chemotherapy due to toxicity and/or intolerance of treatment, or received previous treatment with an EGFR-targeted tyrosine kinase inhibitor or antibody. The primary endpoint is objective tumor response (complete response [CR], partial response [PR]) according to RECIST v1.1. Secondary endpoints include PFS, disease control (CR, PR, stable disease) and assessment of safety. All patients who received at least one dose of afatinib will be included in the analysis of safety, with AEs graded according to CTCAE v3.0. Efficacy and safety will be evaluated in a descriptive manner; there are no formal statistical hypotheses. This trial was initiated in October 2014 and is open for accrual. Study locations include 22 trial sites in 7 countries. Trial sites are currently open to enrollment in Egypt, Romania, and Serbia. Enrollment will soon be open in Malaysia, the Philippines, Poland, and Thailand. The estimated completion date for the primary outcome is December 2016; further details are available at ClinicalTrials.gov (NCT02208843).

      Results:
      Not applicable.

      Conclusion:
      Not applicable.