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B.C. Cho
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ED 07 - How to Treat Advanced Squamous Carcinoma of the Lung (ID 7)
- Event: WCLC 2015
- Type: Education Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
- Moderators:B.C. Cho, P. Lara Jr.
- Coordinates: 9/08/2015, 14:15 - 15:45, Four Seasons Ballroom F1+F2
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ED07.01 - Overview of the Histology and Potential Driver Mutations (ID 1798)
14:15 - 15:45 | Author(s): P. Hammerman
- Abstract
- Presentation
Abstract:
While genomic studies of lung adenocarcinomas over the past decade have enabled substantial improvements in treatment and patient outcomes, advances in squamous cell carcinomas of the lung have been far more modest. At present there are no targeted agents approved for the treatment of squamous cell lung cancers and there has been limited success in the use of targeted kinase inhibition in this disease. Here, I will review the results of genomic studies of squamous cell carcinomas and highlight the molecular features which drive these cancers and make them distinct from lung adenocarcinomas. I will discuss specific subtypes of squamous cancers, animal models of the disease and associations among genomic features and patient outcomes. I will discuss therapeutically relevant genetic alterations and efforts aimed at exploring these targets both pre-clinically and clinically with an emphasis on FGFR pathway genes. I will discuss heterogeneity and adaptive responses to therapy in squamous cell carcinomas as potential challenges to the treatment paradigms which have been successful in adenocarcinomas and these concepts in the context of the recent introduction of immunotherapeutic approaches.
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- Abstract
- Presentation
Abstract:
Squamous cell carcinoma of the lung accounts for 20-30% of all non-small cell lung cancer (NSCLC). Until recently, treatment options for advanced squamous NSCLC (sqNSCLC) were limited. Compared to non-squamous NSCLC, standard care of sqNSCLC was restricted to first-line platinum-based doublet chemotherapy and second-line docetaxel or the epidermal-growth factor receptor (EGFR) inhibitor, erlotinib, and did not include pemetrexed because of inferior efficacy[1], bevacizumab because of increased risk of pulmonary hemorrhage[2] or agents active against known oncogenic driver mutations. Prompted by the high levels of EGFR overexpression in sqNSCLC and encouraging activity of EGFR-targeted therapies in patients with squamous histology [3,4] EGFR-inhibition trials limited to patients with sqNSCLC were initiated, the results of which are redefining the treatment of sqNSCLC. In the first-line setting, the addition of the second-generation recombinant human IgG1 EGFR monoclonal antibody (Mab), necitumumab, to gemcitabine and cisplatin has been shown to improve overall survival (OS) 11.5m vs 9.9 m (HR: 0.84, 95%CI: 0.74-0.96) in the phase III open-label SQUIRE trial, with comparable adverse events (AE) leading to treatment discontinuation in both treatment arms.[5] The better tolerability of necitumumab over the first-generation chimeric EGFR Mab, cetuximab, is supported by the similar OS efficacy in patients with good (PS: 0-1) (HR: 0.85, 95%CI: 0.74-0.98) and poor performance status (PS=2) (HR: 0.78, 95%CI: 0.51-1.21), in the absence of additional safety risk.[6] In fact, in SQUIRE, necitumumab was notably more effective at higher levels of baseline symptom severity[7] , which is contrary to the belief that patients with sqNSCLC deteriorate too quickly to benefit from combination approaches. In the second-line setting, the newer second-generation EGFR small molecule inhibitor, afatinib, has also been shown to improve OS. Most recently, the results of the phase III LUX-Lung 8 trial of afatinib vs erlotinib in patients with sqNSCLC progressing after four cycles of platinum-based chemotherapy have been published, demonstrating improved OS with afatinib 7.9m vs 6.8m (HR: 0.81, 95%CI: 0.69-0.95), with similar adverse events profiles noted between groups.[8 ]Based on these results, afatinib is clearly a treatment option for patients in the second-line management of sqNSCLC. Together, the recent results of these small molecule and MAb anti-EGFR studies support the continued relevance of EGFR as a target in the treatment of sqNSCLC and are shaping management strategies. Despite being a hallmark of cancer, the inhibition of angiogenesis has historically proven challenging in the treatment of patients with sqNSCLC due to the central location of these tumors and their close proximity to large blood vessels in the chest wall, and has been associated with an increased risk of bleeding. Findings from newer second-generation angiogenesis inhibitors, however, show comparable levels of gastrointestinal and respiratory tract bleeding events across all NSCLC histologies. [9 ] Compared to placebo, the anti-VEGFR-2 IgG MAb, ramucirumab, has recently been shown to improve progression-free survival (PFS) 4.5m vs 3.0 m (HR: 0.76, 95%CI: 0.68-0.86) and OS 10.5m vs 9.1m (HR: 0.86, 95%CI:0.75-0.98) in patients with advanced NSCLC progressing after first-line platinum-based chemotherapy, with significant improvements in patients with squamous histology in terms of overall objective response (ORR) (26.8% vs 10.5%, p=0.001), disease control rate (59.9% vs 45%, p=0.015) and PFS 4.2m vs 2.7m (HR 0.78, 95%CI0.61-0.96) and a numerically superior OS benefit 9.5m vs 8.2m (HR: 0.88, 95%CI: 0.69-1.13). [9 ] In Dec 2014, ramucirumab received FDA approval for use with docetaxel in the second-line management of advanced NSCLC, including patients with squamous histology. Finally, the inhibition of T-cell activation through programmed death (PD-1) receptor interaction with the tumor expressing PD-L1 ligand (immune checkpoint) is a noted mechanism of tumor immune surveillance escape in NSCLC. From early clinical trials immune checkpoint blockade is an attractive therapeutic strategy in NSCLC, given its ability to activate the immune system and produce long-term response. In the management of sqNSCLC, the fully human IgG4 anti-PD-1 monoclonal antibody, nivolumab, has recently replaced docetaxel as the preferred second-line therapy based on the results of CHECKMATE 017 [10], a phase III study of nivolumab versus docetaxel. Findings in CHECKMATE 017 demonstrated improved median OS 9.2m vs 6.0m (HR: 0.59, 95%CI: 0.44-0.79) and improved 1-year survival over docetaxel (42% vs 24%), with a more favorable safety profile and fewer treatment related grade 3/4 AE (7% vs 55%).[10] With the recent FDA approval of nivolumab in the second-line setting in March 2015, docetaxel will likely be relegated to third-line therapy in the management of sqNSCLC. However, additional studies are required to confirm the results of CHECKMATE 017 given the lower than expected median survival observed in the docetaxel arm, to identify biomarkers of response, and to better define the unique toxicities associated with these immune-modulating agents. The last year has seen an unprecedented evolution in the management of sqNSCLC, with survival gains noted in both the first and second-line setting in randomized clinical trials. Unfortunately, to date the identification of oncogenic driver mutations in sqNSCLC have yet to yield the significant improvements seen in non-squamous histology, however it is likely that the relevant biomarkers of efficacy will soon be identified. Regardless, with the current regulatory approvals and the numerous novel agents in development, improved outcomes in patients with squamous cell carcinoma of the lung are anticipated. The immediate task, with the expanded treatment options now available for sqNSCLC, is the interrogation of new combinations and the sequencing of available therapies to maximize the benefit for this historically underserved subgroup of patients with NSCLC. References 1. Scagliotti G, Brodowicz T, Shepherd FA et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in non-squamous non-small cell lung cancer. J Thorac Oncol 2011; 6: 64-70. 2. Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 2004; 22: 2184-91. 3. Pujol JL, Pirker R, Lynch TJ et al. Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer 2014; 83: 211-218. 4. Kim JH, Grossi F, De Marinis F et al. Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy : interim subset analysis from a phase III trial. Proc Am Soc Clin Oncol 2012; 30 (suppl 15): abstr 7558. 5. Thatcher N, Hirsch F, Luft A et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomized, controlled phase 3 trial. Lancet Oncol 2015; 16(7): 763-774. 6. Socinski M, Luft A, Szczesna A et al. Subgroup analyses by performance status (PS) in the phase III SQUIRE study: First-line necitumumab (N) plus gemcitabine-cisplatin (GC) vs. GC in squamous non-small cell lung cancer (NSCLC). J Clin Oncol 2015; 33:suppl; abstr e19023. 7. Reck M, Gralla RJ, Bonomi P et al. Maximum severity score (MSS) of baseline patient-reported Lung Cancer Symptom Scale (LCSS) as a prognostic and predictive factor for overall survival (OS) in the Phase III SQUIRE study. ASCO Meeting 2015 abst; 33: 8099. 8. Soria J-C, Felip E, Cobo M et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; dx.doi.org/10.1016/s1470-2045(15)00006-6. 9. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomized phase 3 trial. Lancet 2014; 384: 665-73. 10. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in advanced squamous-cell non small cell lung cancer. NEJM 2015; doi: 10.1056/NEJMoa1504627.
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ED07.03 - Lung Master Protocol in Squamous Cell Lung Cancer (Lung-MAP, S1400) (ID 1800)
14:15 - 15:45 | Author(s): D.R. Gandara, M. Redman, R. Herbst, J. Abrams, S. Malik, E. Sigal, F.R. Hirsch, P.C. Mack, V. Papadimitrakopoulou
- Abstract
- Presentation
Abstract:
In recent years, our understanding of non-small cell lung cancer (NSCLC) has evolved from thinking of this malignancy as a single disease, or a small number of histologic subtypes, to now a multitude of genomically-defined subsets, both in adenocarcinoma and squamous lung cancer. In development of new targeted therapies against these abnormalities, so-called Master Protocols offer a number of advantages over traditional single study designs for drug-biomarker approval, including a common infrastructure, homogeneous patient populations with consistent eligibility across multiple independent sub-studies, and the ability to screen large numbers of patients in rapid fashion. Thus, the Lung-MAP project was designed to facilitate approval of targeted therapy-predictive biomarker combinations in squamous lung cancer, a recognized area of unmet need. Lung-MAP is constructed as a unique public-private partnership engaging the National Cancer Institute (NCI) and its Thoracic Malignancies Steering Committee (TMSC), the Foundation of the NIH (FNIH), the pharmaceutical industry and advocacy groups such as Friends of Cancer Research (FOCR), along with an advisory role by the Federal Drug Administration (FDA). The design is multiple simultaneously running Phase II/III trials, each capable of independently opening and/or closing without affecting the other sub-studies, in which patients eligible for 2[nd] line therapy for lung SCC have their cancers genomically screened through a next generation sequencing (NGS) platform (Foundation Medicine). Patients are then randomized into one of several sub-studies, each comparing an experimental targeted therapy with standard of care therapy, based on identification of candidate predictive biomarkers associated with each sub-study. At launch, drug targets under study consisted of “match sub-studies” for PI3K, FGFR, CDK 4/6 and HGF, and a non-match sub-study testing PD-L1-directed therapy, as described below. Rapid turn-around time of NGS screening results, within 2 weeks, allows real time assignment into the appropriate sub-study. For those patients with cancers that do not “match” into a biomarker-driven sub-study, there is a ‘non-match” sub-study, in which a predictive biomarker is not yet of sufficient validation to utilize it in a drug-biomarker registration strategy. Due to changes in the therapeutic landscape since the launch of Lung-MAP, a number of amendments and modifications have been implemented, which will be discussed during this presentation.
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ED07.04 - Targeting Gene Amplification in Squamous Cancer (ID 1801)
14:15 - 15:45 | Author(s): P. Paik
- Abstract
- Presentation
Abstract:
Copy number alterations are common events in squamous cell lung cancers. A number of these play defined roles in tumorigenesis. Some are known to be oncogenic drivers in a subset of cases. Broad high-level amplification of the 3q26-28 cytoband occurs in about 30% of squamous cell lung cancers and was one of the first recurrent alterations characterized in this disease.(1) More focal amplification of 8p11 occurs between 10-20% of tumors.(2, 3) Specific genes in 3q26 that are recurrently amplified include SOX2, PIK3CA, and PRKCI. Other genes commonly amplified in 3q27-28 include BCL6, TP63, and EPHB3. Genes that are amplified at lower frequencies include EGFR, MYC, MCL1, RICTOR, CCND1, and CDK6. The table below summarizes these alterations.
Pharmacologic targeting of gene amplification events in squamous cell lung cancers has centered largely on 4 genes- FGFR1, PIK3CA, CCND1, and CDK6. The pre-clinical data and clinical trial work defining FGFR1 amplification as an oncogenic driver and drug target, respectively, are the most mature. Three abstracts summarizing the preliminary efficacy of the pan-FGFR inhibitors AZD4547, BGJ398, and JNJ42756493 were presented in 2014.(4-6) The overall response rates were low, ranging from 8-15%. Some of these have continued on as phase 2 trials (NCT02154490, AD4547). Other studies using less-specific FGFR inhibitors are also ongoing (NCT01935336, ponatinib; NCT02109016, lucitanib). Upstream PI3K pathway alterations have been the therapeutic targets for a number of trials of PI3K inhibitors, though only a subset have included PIK3CA amplification as a biomarker of interest. These include two phase 1 trials of PI3K-α or PI3K/mTOR inhibitors that have added expansion arms for PIK3CA amplified squamous cell lung cancers (NCT01296555, GDC0032; NCT01655225, LY3023414). Data for these studies have not yet been presented. Finally, G1/S checkpoint inhibitors, whose efficacy has been best defined in breast cancer, are now being tested for CCDN1 and CDK4/6 amplified squamous cell lung cancers. Drugs include palbociclib (S1400, NCT02154490) and abemaciclib (NCT02450539). It is worth noting, however, that the pre-clinical rationale for targeting the G1/S checkpoint alone is substantially weaker than for other pathways. The clinical experience derived from targeting FGFR1 amplification in squamous cell lung cancers can serve as a framework to understand, in general, which targeted therapy strategies are likely to fail both now and in the future. Comprehensive genomic analyses of squamous cell lung cancers have shown that these tumors are complex, with overlapping alterations in more than one oncogene and/or tumor suppressor occurring in most cases. This is particularly problematic for gene amplification targets, which are also plagued by questions of functional relevance apropos degree of amplification and association with protein expression. As borne out in the phase 1 trials of the pan-FGFR inhibitors, single-target inhibition is unlikely to generate the breadth and depth of responses seen with other drugs targeting other oncogenes. Issues surrounding pharmacodynamic efficacy and target inhibition may also play a role in limiting responses. Data from ongoing work will be presented identifying potential genomic and non-genomic modifiers of response to FGFR1 inhibition. References 1. Björkqvist A-M, Husgafvel-Pursiainen K, Anttila S, Karjalainen A, Tammilehto L, Mattson K, et al. DNA gains in 3q occur frequently in squamous cell carcinoma of the lung, but not in adenocarcinoma. Genes, Chromosomes and Cancer. 1998;22:79-82. 2. Paik PK, Shen R, Won H, Rekhtman N, Wang L, Sima CS, et al. Next generation sequencing of stage IV squamous cell lung cancers reveals an association of PI3K aberrations and evidence of clonal heterogeneity in patients with brain metastases. Cancer Discovery. 2015. 3. TCGA. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519-25. 4. Paik P, Shen R, Ferry D, Soria J-C, Mathewson A, Kilgour E, et al. A phase 1b open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers: Preliminary antitumor activity and pharmacodynamic data. J Clin Oncol. 2014;32:suppl; abstr 8035. 5. Nogova L, Sequist L, Cassier P, Hidalgo M, Delord J-P, Schuler M, et al. Targeting FGFR1-amplified lung squamous cell carcinoma with the selective pan-FGFR inhibitor BGJ398. J Clin Oncol. 2014;32:suppl; abstr 8034. 6. Bahleda R, Dienstemann R, Adamo B, Gazzah A, Infante J, Zhong B. Phase 1 study of JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2014;32:abstr 2501.Gene Chromosome Frequency SOX2 3q26 35% PIK3CA 3q26 30% BCL6 3q27 20% PRKCI 3q26 25% TP63 3q28 21% FGFR1 8p11 12% MYC 8q24 8% MCL1 1q21 6% RICTOR 5p13 6% EGFR 7p12 5% CCND1 11q13 10% CDK6 7q21-22 3%
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ORAL 34 - Quality/Survival/Prognosis in Localized Lung Cancer (ID 153)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 8
- Moderators:B.C. Cho, R.L. Keith
- Coordinates: 9/09/2015, 16:45 - 18:15, 201+203
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ORAL34.01 - Compliance with Follow-Up Programs After Surgery for Non-Small Cell Lung Cancer in the Phase III IFCT-0302 Trial (ID 2148)
16:45 - 18:15 | Author(s): V. Westeel, F. Barlesi, P. Foucher, J. Lafitte, J. Domas, P. Girard, J. Trédaniel, M. Wislez, P. Dumont, E. Quoix, O. Raffy, D. Braun, M. Derollez, F. Goupil, J. Hermann, E. Devin, M.P. Lebitasy, F. Morin, G. Zalcman
- Abstract
- Presentation
Background:
In patients operated on for non-small cell lung cancer, several guidelines recommend a follow-up based on regular clinic visits and chest CT-scans. However, evidence to support these recommendations is poor, in the absence of randomized data. The IFCT-0302 trial is a randomized multicenter trial which compared 2 follow-up programs after complete resection for a clinical stage I, II, IIIA and T4 (pulmonary nodules in the same lobe) N0-2 NSCLC (TNM 6[th] edition). We present the results of compliance with the follow-up programs for the first 2 years after randomization.
Methods:
In the CXR arm, follow-up consisted of clinic visit and chest X-rays. In the CCT arm, patients underwent clinic visit, chest X-rays, thoraco-abdominal CT scan plus fiberoptic bronchoscopy (only mandatory for squamous cell and large cell carcinomas). In both arms, procedures were repeated every 6 months after randomization during the first 2 years, and yearly until 5 years, in the absence of recurrence or second primary cancer. Supplementary procedures were allowed in case of symptoms. Primary endpoint was overall survival.
Results:
Between January 2005 and November 2012, 1775 patients were randomized (CXR: 888; CCT: 887). Patient characteristics were well balanced between the two arms : males 76.3%, median age 62 years (range: 33-87), adenocarcinomas 56.7%, stage I-II 82.1%, lobectomy or bilobectomy 86,8%, pre- and/or post-operative radiotherapy 8.7%, and pre- and/or post-operative chemotherapy 45%. Surveillance was performed in 97% of patients at 6 months, in 94% at 12 months, in 90% at 18 months and in 84% at 24 months, and did not differ between the 2 arms. Intervals between randomization and visits were respected with no difference between arms (mean +/-SD in months from randomization: 5.93 +/- 0.84; 11.95 +/- 0.98; 18.05 +/- 0.99; 24.18 +/-1.30, respectively). In the 757 patients of the CXR arm, who had a follow-up visit at 6 months and no recurrence, 754 (99.6%) had a clinic visit and 730 (96.4%) a chest X-ray. In the 706 patients of the CCT arm who had a follow-up visit at 6 months and no recurrence, 702 (99.4%) had a clinic visit, 478 (67.7%) a chest X-ray, 678 (96%) a chest CT-scan, and 342 (48.4%) a bronchoscopy. Comparable compliance results were observed at 12, 18 and 24 months. In the CXR arm, supplementary thoracic CT-scans were done in 119 patients (15.7 %) at 6 months, in 96 (14.4 %) at 12 months, in 78 (13.2%) at 18 months and in 58 (11.4%) at 24 months. Other supplementary procedures were more frequent in the CCT arm than in the CXR arm, consisting mostly of brain imaging (at 6 months, in 93 (13.2%) and 39 (5.2%) patients, respectively, p<.001).
Conclusion:
Compliance with the follow-up programs was excellent in terms of timing. Chest X-ray was often omitted in the CCT arm. In the CXR arm, supplementary CT-scans that did not lead to a diagnosis of recurrence or second primary cancer were performed in 10 to 15% of patients. In the CCT arm, the most frequently performed supplementary procedure was brain imaging.
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ORAL34.02 - Impact of Attainment of National Comprehensive Cancer Network (NCCN) Quality Parameters on Patient Survival after Resection of Lung Cancer (ID 2190)
16:45 - 18:15 | Author(s): N. Faris, X. Yu, R. Eke, M.P. Smeltzer, G. Relyea, F.E. Rugless, C. Fehnel, N. Chakraborty, C. Houston-Harris, F. Lu, E.T. Robbins, R.S. Signore, L. McHugh, B. Wolf, C. Mutrie, L. Deese, P. Levy, E. Crocker, L. Wiggins, R.U. Osarogiagbon
- Abstract
- Presentation
Background:
The NCCN surgical resection guidelines for non-small cell lung cancer (NSCLC) recommend lobectomy or greater extent of resection, negative margins, and examination of lymph nodes from the hilum, and 3 or more mediastinal stations. We sought to determine the impact of these guidelines on patients’ long-term survival.
Methods:
We conducted a retrospective review of patient-level data from all curative-intent NSCLC resections at 11 institutions in 5 Dartmouth Hospital Referral Regions in Eastern Arkansas, North Mississippi, and Western Tennessee from 2004 to 2013. Following a descriptive analysis of the cohort, we used a Cox proportional hazard model to assess the overall survival impact of attaining the NCCN guidelines. All models were adjusted for patient age and pathologic stage.
Results:
Of the 2,410 eligible resections, 314 (13.1%) were sub-lobar, 86.9% were lobectomy or greater; 90.2% had negative margins, 5.8% had positive margins, 4% unknown margin status; 73.2% had hilar nodes sampled; but only 25.9% of surgeries had three or more mediastinal nodal stations sampled. Overall, although only 18% of surgeries met all four criteria, there was a significant increasing trend from 4% in 2004 and 12% in 2009, to 39% in 2013 (p<0.001). Patients whose surgery met all four criteria had a 23% survival benefit compared with those who did not (Hazard Ratio [HR]: 0.77, 95%CI: 0.64-0.94, p=0.009). Patients with negative margins had 15% survival benefit compared to those with positive margins (HR: 0.85, 95%CI: 0.66-1.08, p=0.18); those with lobectomy or greater resection had a 14% survival benefit over those with sub-lobar resection (HR: 0.86, 95%CI: 0.70-1.04, p=0.12); those with hilar node sampling had a 3% survival benefit (HR: 0.97, 95%CI: 0.83-1.13, p=0.68); and those with three or more mediastinal stations examined had a 17% survival benefit over those without (HR: 0.84, 95%CI: 0.71-0.98, p=0.03). Figure 1
Conclusion:
Although only 18% of NSCLC resections in this cohort from a high lung cancer mortality region of the US met all four NCCN good-quality surgical resection criteria, the rate of quality attainment has significantly increased during the past decade. Patients whose resections met NCCN quality criteria had a substantially survival benefit, which is particularly driven by the recommendation for sampling of ≥3 mediastinal nodal stations. Intraoperative mediastinal lymph node retrieval should be a focus of quality improvement for NSCLC resections.
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ORAL34.03 - Prognostic Factors in Early Stage NSCLC: Analysis of the Placebo Group in the MAGRIT Study (ID 24)
16:45 - 18:15 | Author(s): B.C. Cho, T. De Pas, H. Kalofonos, Q. Wang, M. Holzer, R. Ramlau, S. Thongprasert, Y. Cheng, H. Asamura, F. Vitiello, Q. Zhou, W. Mao, A. Prokop-Staszecka, T. Laisaar, A. Nusch, C. Hu, S.I. Park, E. Vallieres, B. Kubisa, S. Orlov, K. Park, T. Ohira, M. Debois, C. Debruyne, K. Langfeld, P. Therasse, J. Vansteenkiste
- Abstract
- Presentation
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.
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ORAL34.04 - Discussant for ORAL34.01, ORAL34.02, ORAL34.03 (ID 3373)
16:45 - 18:15 | Author(s): R.U. Osarogiagbon
- Abstract
- Presentation
Abstract not provided
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ORAL34.05 - Survival Implications of Variation in the Lymph Node (LN) Count in ACOSOG Z0030 (Alliance) (ID 654)
16:45 - 18:15 | Author(s): R.U. Osarogiagbon, P.A. Decker, K. Ballman, D. Wigle, M. Allen, G. Darling
- Abstract
- Presentation
Background:
Variation in the thoroughness and accuracy of pathologic lymph node (LN) staging may contribute to within-stage variation in survival after curative-intent resection of non-small-cell lung cancer. Accurate staging mandates effective collaboration between surgeons and pathologists. ACOSOG Z0030 tightly controlled surgeon practice, but not pathology practice. We tested the impact of the thoroughness of pathologic examination (using the number of examined LNs as a surrogate) on detection of LN metastasis and survival.
Methods:
We reanalyzed the mediastinal LN dissection arm of ACOSOG Z0030, using linear regression to examine the clinical and demographic factors associated with LN count, Cox proportional hazards models to determine the association between the number of LNs examined and survival of patients with pN0 and pN1 disease, and logistic regression to determine association of number of LN examined and the discovery of unexpected N2 LN metastasis. Overall (OS) and recurrence-free survival (RFS), were analyzed without and with adjustment for T-category.
Results:
The 524 patients, had a mean age of 66.8 years, and were 52% male. Forty-four percent had adenocarcinoma, 27% squamous, 4% large cell, and 25% ‘other’ histology; 96% had T1/2 disease. Four hundred and thirty-nine (84%) were pN0, 63 (12%) pN1, and 21 (4%) pN2. In patients with pN0, pN1, and pN2 respectively, the mean number of mediastinal LNs examined was 13.5, 12.9, and 17.4; station 10 LNs were 2.4, 2.7, and 2.5; station 11-14 LNs were 4.6, 6.2, and 6.2; total LNs (from all stations) were 19.7, 21.3, 25. Tumor histology and pN-category were the only factors associated with the number of LNs examined: patients with squamous histology tended to have the most number of non-hilar N1 LNs examined (p<0.001); patients with pN1/N2 had more non-hilar N1 nodes than those with pN0 (p=0.005); those with pN2 had more N2 nodes examined than those with pN0 or pN1 (p=0.085). There was a consistent association between the number of LNs examined and survival. Patients with pN0 had better OS (HR 0.96; p=0.12) and RFS (HR 0.97; p=0.2) with examination of more non-hilar nodes; patients with pN1, had better OS and RFS with increased examination of LNs from N2 (OS HR=0.96, p=0.059; RFS HR=0.95, p=0.03) and all stations (OS HR=0.97, p=0.048; RFS HR=0.96, p==0.012). Adjustment for T-category strengthened these relationships between the number of LNs, pN-stage and survival. The likelihood of discovering N2 disease was associated with increased examination of LNs from mediastinal (odds ratio=1.04; p=0.035) and all stations (OR=1.03; p=0.035).
Conclusion:
Despite uniformly thorough surgical hilar/mediastinal LN harvesting, the number of LNs examined was associated with the likelihood of detecting nodal metastasis, and survival. Patients with more LNs examined were more likely to have LN metastasis, examination of more LNs was associated with better survival in patients within the same pN-category. This may indicate an effect of variable thoroughness in pathologic examination processes on the accuracy and prognostic value of the pathology nodal staging system. Heterogeneity in the cancer immune response may be an alternative hypothesis to explain these findings.
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ORAL34.06 - Impact of Surgeons' Attainment of Quality Resection Parameters on Non-Small-Cell Lung Cancer (NSCLC) Patients' Survival (ID 2189)
16:45 - 18:15 | Author(s): R.U. Osarogiagbon, G. Relyea, N. Faris, X. Yu, R. Eke, M.P. Smeltzer, F.E. Rugless, C. Fehnel, N. Chakraborty, C. Houston-Harris, F. Lu, R.S. Signore, L. McHugh, L. Deese, P. Levy, E. Crocker, L. Wiggins, C. Mutrie, B. Wolf, E.T. Robbins
- Abstract
- Presentation
Background:
The 60,000 patients who annually undergo curative-intent resection for lung cancer in the US constitute the vast majority of long-term NSCLC survivors. However, >50% of patients die within 5 years after curative-intent resection. We sought to directly measure the effect of variability in surgeon practice on patients’ survival.
Methods:
We collected patient-level data from all NSCLC resections performed in 8 mid-south hospitals from 2009 to 2013. Recipients of preoperative adjuvant therapy were ineligible. We grouped surgeons by their resection proportions for pneumonectomy and wedge resection, resections with positive margins, and resections without mediastinal lymph nodes. We assigned scores of 1 = <5%, 2 = 5-15%, and 3 = ≥ 15% for pneumonectomy and wedge resection rates; 1 = <5%, 2 = 5-10%, and 3 = ≥ 10% for resections with positive margins; 1 = < 10%, 2 = 10-50%, and 3 = ≥ 50% for resections without mediastinal lymph node examination. The individual scores were then combined for an aggregate surgeon score. Surgeons were then grouped into three tiers: 1 =≤6, 2 = 7-8, and 3 = ≥9. A survival analysis was conducted for patients aggregated by surgeon score tier, adjusted for patient race, gender, and age at surgery, pathologic stage, and surgeon’s case-volume.
Results:
1,339 resections were performed by 39 surgeons: 17 surgeons (43.6%) in tier 1(aggregate score ≤ 6) operated on 623 patients (44.5%); 14 surgeons (35.9%) in tier 2 operated on 669 patients (47.8%); and 8 surgeons (25.5%) in tier 3 operated on 107 patients (7.65%). Figure 1 plots the Kaplan – Meier survival curve for patients in each surgeon tier. Tiers 2 and 3 patients had significantly higher hazard rates than tier 1 patients, with Hazard Ratio (HR)=1.76, 95%CI: 1.17, 2.64, p=.007 and HR=1.39, 95%CI: 1.11, 1.75, p=.004, respectively. Hazard rates between patients in surgeon tiers 3 and 2 were not significantly different, HR=1.26, 95%CI: 0.87, 1.82, p=.221. Figure 1
Conclusion:
We have developed a simple method of measuring the effect of variability in surgeon practice on patient outcomes. Patients who had resection by surgeons with lower rates of pneumonectomy and wedge resections, positive margins, and non-examination of mediastinal lymph nodes show improved survival over patients operated by surgeons with higher rates. Deficiency in attaining these quality parameters can be corrected at the individual surgeon level. Surgeon-level corrective interventions are warranted.
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ORAL34.07 - Prevalence, Prognostic Implications and Survival Modulators of Incompletely Resected Non-Small Cell Lung Cancer (NSCLC) in the US (ID 650)
16:45 - 18:15 | Author(s): R.U. Osarogiagbon, C.C. Lin, M.P. Smeltzer, A. Jemal
- Abstract
- Presentation
Background:
The survival impact of incomplete resection of NSCLC has never been systematically quantified, nor has the value of postoperative adjuvant therapy in this situation. Current clinical practice guidelines are based on single-institutional retrospective studies with few patients. The studies have contradictory findings about the survival impact of non-R0 resection and the benefit of adjuvant therapy.
Methods:
We analyzed pathologic stage I-IIIA NSCLC resections in the National Cancer Data Base from 2004 to 2011 to determine clinical, socio-demographic and institutional factors associated with margin involvement using multivariate logistic regression models. We compared the survival of patients with and without positive margins and evaluated the impact of postoperative adjuvant therapy, using proportional hazards models.
Results:
Of 112,998 resections over 8 years, 5335 (4.72%) had positive margins. This population represents >4-fold the sum of all previous English-language publications on margin-positive resections. The annual incomplete resection rate was stable over the 8-year time-span, ranging between 4.38% and 5.23% (trend-test p=0.07). Patient demographic and clinical factors associated with increased adjusted odds ratio (aOR) of incomplete resection included black race (p=0.006), age-based Medicare insurance (p=0.006), urban residence (p=0.01), squamous histology, high tumor grade, tumor overlapping more than 1 lobe, tumor location in the main bronchus, and advanced pathologic stage (p < .001 for all clinical factors). Surgery performed at Community Cancer Programs (p=0.002), institutions with high proportions of underinsured patients (p=0.01), and institutions with lower cancer resection volumes (p=0.006), also had increased aOR. The crude 5-year survival rate of patients with complete v incomplete resection was 58.5% v 33.8% (p < 0.001). The survival difference persisted when patients were stratified by tumor size, T-category and aggregate American Joint Committee on Cancer stage. The survival curve of patients with margin-positive stage I disease overlapped that of patients with completely resected stage II. Patients with incompletely resected stage II disease had worse survival than those with completely resected stage III disease. The survival detriment was consistent at 1, 3, and 5 years. After incomplete resection, adjuvant chemotherapy was associated with improved 5-year survival across all stages (p<0.01); radiotherapy was associated with worse survival in stage I patients (p<0.001), and had no significant impact in patients with stage II and III disease; chemo-radiation therapy had no significant impact in patients with stage I, but was associated with improved survival in patients with stage II and III disease (p<0.001).
Conclusion:
Margin involvement significantly impaired survival after NSCLC resection, irrespective of stage. Causative institutional and provider practices should be identified, to minimize this adverse outcome. Postoperative adjuvant chemotherapy mitigated the mortality risk independently of stage, whilst postoperative radiotherapy exacerbated the risk in patients with stage I disease, and chemoradiation therapy was associated with improved survival in patients with stage II and III disease. These findings need validation in prospective clinical trials.
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ORAL34.08 - Discussant for ORAL34.05, ORAL34.06, ORAL34.07 (ID 3408)
16:45 - 18:15 | Author(s): M. Krasnik
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 09 - Drug Resistance (ID 107)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Villaruz, J. Minna
- Coordinates: 9/07/2015, 16:45 - 18:15, 205+207
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MINI09.07 - Activation of the MET Kinase Confers Acquired Resistance to FGFR-Targeted Therapy in FGFR-Dependent Squamous Cell Carcinoma of the Lung (ID 1212)
16:45 - 18:15 | Author(s): B.C. Cho
- Abstract
- Presentation
Background:
Fibroblast growth factor receptor (FGFR) tyrosine kinase plays a crucial role in cancer cell growth, survival, and resistance to chemotherapy. FGFR1 amplification occurs at a frequency of 10-20% and is a novel druggable target in squamous cell carcinoma of the lung (SCCL). A number of FGFR-targeted agents are currently being developed in SCCL harboring FGFR alterations. The aim of the study is to evaluate the activity of selective FGFR inhibitors (AZD4547, BAY116387) and the mechanisms of intrinsic and acquired resistance to these agents in SCCL.
Methods:
The antitumor activity of AZD4547 and BAY116387 was screened in a panel of 12 SCCL cell lines, among which 4 cell lines harbored FGFR1 amplification. To investigate mechanisms of acquired resistance, FGFR1-amplified H1581 cells which were exquisitely sensitive to FGFR inhibitors, were exposed to AZD4547 or BAY116387 to generate polyclonal resistant clones (H1581-AR, H1581-BR). Characterization of these resistant clones was performed using receptor tyrosine kinase (RTK) array, immunoblotting and microarray. Migration and invasion assays were also performed.
Results:
Among 12 SCCL cell lines, two FGFR1-amplified cells, H1581 and DMS114, were sensitive to FGFR inhibitors (IC~50~<250 nmol/L). Compared with resistant cells, sensitive cells showed increased phosphorylation of FRS2 and PLC-γ, but decreased phosphorylation of STAT3. There was no noticeable difference in FGFR1-3 protein expression level between sensitive and resistant cells. Importantly, phosphorylation of ERK1/2 was significantly suppressed upon treatment of FGFR inhibitors only in sensitive cells, suggesting phospho-ERK1/2 as a pharmacodynamic marker of downstream FGFR signaling. RTK array and immunoblots demonstrated strong overexpression and activation of MET in H1581-AR and H1581-BR, in comparison to almost nil expression in parental cells. Four different SCCL cells with intrinsic resistance to FGFR inhibitors also showed intermediate to high MET expression, suggesting that MET may be involved in both intrinsic and acquired resistance to FGFR inhibitors. Gene-set enrichment analysis against KEGG database showed that cytokine-cytokine receptor interaction pathway was significantly enriched, with MET contributing significantly to the core enrichment, in H1581-AR and H1581-BR, as compared with parental cells. Stimulation with HGF strongly activated downstream FGFR signaling or enhanced cell survival in the presence of FGFR inhibitors in both acquired and intrinsic resistant cells. Quantitative PCR on genomic DNA and fluorescent in situ hybridization revealed MET amplification in H1581-AR, but not in H1581-BR. MET amplification led to acquired resistance to AZD4547 in H1581-AR by activating ERBB3. The combination of FGFR inhibitors with ALK/MET inhibitor, crizotinib, or small interfering RNA targeting MET synergistically inhibited cell proliferation in both H1581-AR and H1581-BR, whereas it resulted in additive effects in SCCL cells with intrinsic resistance to FGFR inhibitors. Acquisition of resistance to FGFR inhibitors not only led to a morphologic change, but also promoted migration and invasion of resistant clones via inducing epithelial to mesenchymal transition phenotype, as documented by a decrease in E-cadherin and an increase in N-cadherin and vimentin.
Conclusion:
MET activation is sufficient to bypass dependency on FGFR signaling and concurrent inhibition of these two pathways may be desirable when targeting FGFR-dependent SCCL.
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.11 - Efficacy and Safety of Dovitinib in Advanced Squamous Cell Lung Cancer with FGFR1 Amplification: A Single-Arm, Phase II Study (ID 666)
18:30 - 20:00 | Author(s): B.C. Cho
- Abstract
- Presentation
Background:
FGFR1 amplification is one of the most common potential driving oncogenes in squamous cell carcinoma (SCC), which accounts for 20% of non-small cell lung cancer (NSCLC) squamous cell carcinoma. This phase II study evaluated the efficacy and toxicity profile of dovitinib, an orally active FGFR (fibroblast growth factor receptor) inhibitor, in advanced SCC patients.
Methods:
Patients with histological confirmed advanced squamous cell NSCLC and previously treated with at least one cytotoxic chemotherapy were enrolled from April 2013 to December 2014. All patients had FGFR1 gene amplification more than 5 copies by fluorescent in situ hybridization (FISH). Each 7-day treatment cycle consisted of dovitinib 500mg orally administration on days 1 to 5 and 2 days off. Primary endpoint was overall response rate and secondary endpoints included PFS, OS and toxicity.
Results:
All 26 patients were male with the median age of 68 years (range, 52 – 80). Most patients were ever smokers (96%) and had good ECOG (0-1) performance status (85%). The median number of dovitinib treatment cycles administered was 2.5 (range, 1-12). The overall response rate (ORR) was 11.5% (95% CI, 0.8 – 23.8) and disease control rate (DCR) was 50% (95% CI, 30.8 – 69.2). There were three partial responses (PR) and ten stable diseases (SD). Duration of response in 3 patients who achieved PR was 4.5+, 5.1+ and 6.1months. After the median follow-up duration of 15.7 months (range, 5.8 – 25.6 ), the median overall survival (OS) was 5.0 months (95% Confidential Interval, 3.61 – 6.39) and progression-free survival (PFS) was 2.9 months (95% CI, 1.54 – 4.26). Grade 1/2 fatigue (69%) and anorexia (85%) were most commonly reported adverse events and 12 patients (46%) required dose reduction of dovitinib.
Conclusion:
Dovitinib treatment a showed modest efficacy in advanced squamous cell lung cancer patients with FGFR1 amplification. Further studies to evaluate other biomarkers correlated with the efficacy of dovitinib in SCC should be warranted.
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ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:G. De Lima Lopes, V. Miller
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL06.02 - Targeted Deep Sequencing of EGFR/KRAS/ALK-Negative Lung Adenocarcinoma Reveals Potential Therapeutic Targets (ID 622)
10:45 - 12:15 | Author(s): B.C. Cho
- Abstract
- Presentation
Background:
Identification of clinically relevant molecular drivers in patient tumors is essential in selecting appropriate targeted therapy. Using next-generation sequencing (NGS) -based clinical cancer gene test, we performed genomic profiling of lung adenocarcinoma tumors.
Methods:
We collected formalin-fixed paraffin-embedded tumors from 41 lung adenocarcinoma patients whose tumors previously tested negative for EGFR/KRAS/ALK by conventional methods in an ongoing trial (NCT01964157). We performed hybridization capture of 4,557 exons from 287 cancer-related genes and 47 introns from 19 genes frequently rearranged in cancer (FoundationOne). Illumina HiSeq2000 platform was used to sequence to high uniform depth.
Results:
Figure 1Tumors were sequenced to a median coverage of 529x. Overall, we identified a total of 170 known and 492 unknown individual genomic alterations. The number of known alterations per sample was average of 3.8 alterations (range 0-10). Cancer genomes are characterized by 45% (77/170) non-synonymous base substitutions, 17% (29/170) insertions or deletions, 2% (4/170) splice site mutations, 20% (34/170) gene amplifications, 5% (8/170) homozygous loss and 5% (8/170) gene fusions. TP53 was the most commonly mutated gene (13%, n=10/77) among non-synonymous base substitutions, followed by KRAS (10%, n=8/77) and PIK3CA (8%, 6/77). Insertions or deletions commonly occurred TP53 (17%, 5/29) and ERBB2 (14%, 4/29), and splice site mutations occurred in TP53, INPP4B, ATR, and MAP2K4 (n=1 each). Among gene amplification, MDM2 amplification was the most frequent (12%, 4/34), followed by ERBB2 (8%, 3/34) and CDK4 (8%, 3/34) amplification. All 8 cases of homozygous loss were observed with CDKN2A and CDKN2B. Fusion genes were most commonly observed with RET (50%, n=4/8). Based on NCCN guidelines, actionable genomic alterations with a targeted agent were identified in 16 patients (39%) (BRAF mutation [n=1], EGFR mutation [n=7], ERBB2 mutation [n=4], MET amplification [n=1], KIF5B-RET rearrangement [n=2], CCDC6-RET rearrangement [n=1], and CD74-ROS1 rearrangement [n=1]). Nine out of all patients (22%) showed discordance in targetable alterations when compared between NGS and conventional non-NGS methods.
Conclusion:
Thirty-nine percent of lung adenocarcinoma wild type for EGFR/KRAS/ALK may harbor a genomic alteration revealed by NGS approach. These results highlight the importance of profiling lung adenocarcinomas using NGS in the clinic.
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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
- Moderators:B.C. Cho, R.L. Keith
- Coordinates: 9/09/2015, 16:45 - 18:15, 201+203
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ORAL34.03 - Prognostic Factors in Early Stage NSCLC: Analysis of the Placebo Group in the MAGRIT Study (ID 24)
16:45 - 18:15 | Author(s): B.C. Cho
- Abstract
- Presentation
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.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-003 - Co-Expression of Programmed Death Ligand-1 (PD-L1) and CD3 in Patients with EGFR Mutant NSCLC Treated with EGFR Tyrosine Kinase Inhibitors (TKI) (ID 1163)
09:30 - 17:00 | Author(s): B.C. Cho
- Abstract
Background:
Recent reports have suggested an association between non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) gene mutations. Other studies have indicated that EGFR signaling can activate PD-L1 expression and immune escape in mutant EGFR driven NSCLC. Furthermore PD-L1 expression is down-regulated by EGFR TKI. In this study, we aim to determine the association between tumoral and immune cell PDL1 expression and clinical characteristics and outcome in EGFR mutant NSCLC patients treated with first line EGFR TKI.
Methods:
Tumors from 90 patients with advanced stage NSCLC with EGFR mutations and treated with first line EGFR TKI were analyzed. Double staining for CD3 and PDL1 was performed by immunohistochemistry. PDL1 expression in tumour membrane, and PDL1 and CD3 expression in tumor and stromal immune cells were segmented and quantified using the Vectra slide imaging system (Perkin Elmer, Waltham, MA).
Results:
The median age of patients was 62 (range 34-88) years, 64 (71%) were female, 69 (77%) were never smokers, and 43 (48%) harbored EGFR exon 19 deletion. Most immune cells were CD3-ve and PDL1-ve in the tumor (median 99%) and stroma (median 86%). PDL1 tumor membrane expression was associated with PDL1 expression in CD3+ve immune in the tumor and stroma. There was no association between PDL1 or CD3 expression with response rate or time to progression.
Conclusion:
This is the first study to characterize PDL1 expression in immune cells in advanced stage NSCLC harboring EGFR mutations. PDL1+ve immune cells are rare in this patient population. PDL1 expression in tumor membrane and immune cells may not be associated with outcome in NSCLC patients harboring EGFR mutations and treated with EGFR TKIs.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-101 - Utility of Patient-Derived Cell Line Models Using Conditional Reprogramming for in Vitro Pharmacogenomics Platform (ID 963)
09:30 - 17:00 | Author(s): B.C. Cho
- Abstract
Background:
To evaluate the potential of conditional reprogrammed cells (CRCs) established from biopsy or effusion samples of advanced non-small cell lung cancer (NSCLC) for in vitro pharmacologic screen and identification of drug resistance mechanisms.
Methods:
A total of 48 tumor specimens obtained from 46 patients with NSCLC were cultured with irradiated fibroblast feeder cells and Rho kinase inhibitor (Y-27632) to induce tumor cells to proliferate indefinitely. The cell lines established from patients harboring EGFR mutation or other druggable oncogenes were subjected to genetic analyses and pharmacologic screen. Corresponding tumor cells were injected into nude mice to test for tumorigenicity and efficacy of targeted agents in vivo.
Results:
Twenty one male patients and twenty five female patients were assessed for establishment of CRC. Adenocarcinoma was the most frequent histologic type (84.7%). There were 21 patients (46%) who harbored an active EGFR mutation. There were four patients with ALK fusion and five with ROS1 fusion. Twenty-six patients experienced disease progressed while on treatment with EGFR (20), ALK (2) or ROS1 (4) tyrosine kinase inhibitors. Tumor cells came from primary or distant metastases in 48% and 52%, respectively. Thirty one (65%) samples were obtained by tumor biopsy and 17 from malignant pleural effusion. Nine CRC model were successfully established (18.7%, 9/48). The successful growth was not dependent on the clinicopathologic characteristics. Both cells from pleural effusion (4 of 17) and biopsy (5 of 31) and adenocarcinoma (8 of 41) and squamous cell carcinoma (1 of 3) were successfully cultured. For biopsy samples, the success rate of cells obtained from primary lung lesion was 21.7% (5 of 23) and cells from metastatic site outside lung was 0% (0 of 8) (P = 0.3). For effusion samples, volume of effusion required for CRC was not significant factors for establishment (success vs. failure cases: mean volume 500 ml vs. 267 ml). The genetic characteristics of patients with non-squamous cell carcinoma did not affect the success rate of CRC (EGFR mutation, 4 of 21; ALK translocation, 0 of 4; ROS1 translocation, 2 of 5; wild or unknown, 2 of 15). Two xenograft models with CRC were successfully established and passaged to maintain tumor in vivo.
Conclusion:
The CRC models derived from NSCLC patients provide useful in vitro platforms of preclinical studies evaluating novel targeted therapies and uncovering the drug resistance mechanisms.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-068 - PD-L1 Expression in Tumor Infiltrating Immune Cells Determined by Digital Imaging Is Associated with Poor Survival in NSCLC Patients (ID 1138)
09:30 - 17:00 | Author(s): B.C. Cho
- Abstract
Background:
Programmed Death-Ligand 1 (PD-L1) has emerged as a potential prognostic marker and as an effective target for therapeutic inhibition in cancer. Using digital slide imaging, we evaluated the clinical, molecular and survival associations of PD-L1 expression in non-small cell lung cancer (NSCLC) according to cell type (tumor and immune cell) and tissue localization (tumor and stroma).
Methods:
Tumor samples from 199 NSCLC patients were stained for PD-L1 by immunohistochemistry (IHC) and quantitatively assessed using the Vectra slide imaging system for PD-L1 tumor membrane expression (TME), PD-L1 positive (+) tumor immune cell density (TICD) and PD-L1+ stroma immune cell density (SICD). Assessment of gene mutation and anaplastic lymphoma kinase rearrangement were performed using the AmpliSeq Cancer Hotspot V2 assay and IHC, respectively.
Results:
High PD-L1 TME correlated with larger tumor size, squamous cell histology and poor differentiation. PD-L1+ TICD was associated with male gender and wild-type EGFR. Univariate analysis revealed that stage (p=0.001), PD-L1 TME (p=0.007) and PD-L1+ TICD (p=0.006) were associated with worse survival. Iterative p-value analysis indicated the optimal thresholds for PD-L1 TME were 30 (p=0.003, 73% of cases) or 160 (p<0.001, 7%), while for PD-L1+ TICD they were 6.9% (p=0.022, 33%) or 20% (p=0.001, 5%). In multivariate analysis, stage (p=0.018), PD-L1 TME≥160 (p=0.040) and PD-L1+ TICD≥6.9% (p=0.015) were independently associated with survival.
Conclusion:
PD-L1 Tumor Membrane Expression (TME) and PD-L1+ Tumor Immune Cell Density (TICD) expression determined by digital analysis have prognostic value in NSCLC.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-077 - A Randomized, Phase II Study of Nimotuzumab Plus Gefitinib vs Gefitinib in Advanced Non-Small Cell Lung Cancer After Platinum- Based Chemotherapy (ID 1176)
09:30 - 17:00 | Author(s): B.C. Cho
- Abstract
Background:
Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody. We aim to evaluate the efficacy of dual inhibition of EGFR with nimotuzumab plus gefitinib in advanced non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.
Methods:
An open label, randomized, phase II trial was conducted in 6 centers; 160 patients were randomized (1:1) to either nimotuzumab (200mg, IV weekly) plus gefitinib (250mg p.o. daily) or gefitinib alone until disease progression or intolerable toxicities. The primary endpoint was progression free survival (PFS) rate at 3 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR) and safety.
Results:
A total of 155 patients (78 in nimotuzumab plus gefitinib, 77 in gefitinib) were evaluable for efficacy and toxicity. Patient characteristics were well balanced in both groups. Majority of patients had adenocarcinoma histology (65.2%) and ECOG performance status 0 to 1 (83.5%). Among 102 patients with EGFR mutation results available, activating EGFR mutation was documented in 27 patients (12/50 in nimotuzumab plus gefitinib, 15/52 in gefitinib). With a median follow-up of 12.1 months, PFS rate at 3 months was 37.2% in nimotuzumab plus gefitinib and 48.1% in gefitinib [HR 1.03; 95% CI, 0.71–1.40; P=0.98]. Median PFS and OS were 2.0 months and 14.0 months in nimotuzumab plus gefitinib and 2.8 months and 13.2 months in gefitinib [HR 1.03, 95% CI 0.71-1.41, P=0.98 for PFS; HR 0.86, 95% CI 0.57–1.30, P=0.47 for OS]. The ORRs were 14.1% in nimotuzumab plus gefitinib and 22.1% in gefitinib, which was not statistically significant (P=0.76). As expected, patients with EGFR mutation showed significantly longer survival than those with wild-type EGFR or unknown EGFR mutation status (10.3 vs. 1.2 vs. 2.7 months, P < 0.001 for PFS; 23.5 vs. 13.5 vs. 10.5 months, P= 0.001 for OS). Combined treatment of nimotuzumab plus gefitinib did not show superior PFS compared to gefitinib alone in patients with EGFR mutation (13.5 vs. 10.2 months in gefitinib alone, P=0.30) and patients with wild-type EGFR (0.9 vs. 2.0 months in gefitinib alone, P=0.90). The median PFS was not significantly different between two treatment arms according to histology (2.8 vs. 2.9 months in gefitinib alone for adenocarcinoma, P=0.64; 1.2 vs. 2.8 months in gefitinib alone for non-adenocarcinoma, P=0.35). Adverse events (AEs) in both treatment arms were mostly grade 1 to 2 and easily manageable. Importantly, combined EGFR inhibition with nimotuzumab and gefitinib did not increase EGFR inhibition-related AEs, such as acneiform rash (32.4 vs. 30.3% in gefitinib alone, P=0.38), diarrhea (30.7 vs. 35.7% in gefitinib alone, P=0.32), and stomatitis (11.5 vs. 13.4% in gefitinib alone, P=0.19). There was no treatment-related death.
Conclusion:
The dual inhibition of EGFR with nimotuzumab plus gefitinib did not show superiority over gefitinib alone for second-line treatment of advanced NSCLC (NCT01498562).
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P3.01-090 - Phase 3, Double-Blind, Placebo-Controlled Study of MEDI4736 after Chemoradiation in Stage III, Locally Advanced, Unresectable NSCLC (PACIFIC) (ID 1263)
09:30 - 17:00 | Author(s): B.C. Cho
- Abstract
Background:
Non-small cell lung cancer (NSCLC) accounts for 85–90% of all lung cancer cases. Approximately 35% of patients with NSCLC have Stage III disease at the time of diagnosis. Platinum-based, concurrent chemoradiation therapy is the standard treatment for patients with locally advanced, unresectable NSCLC. However, most patients progress despite treatment, and 5-year overall survival (OS) is only ~15%. Therefore, there is a significant unmet need for novel, effective therapeutic approaches to prolong survival. Immunotherapies that block checkpoints used by tumor cells to dampen immune responses are a promising new treatment option. Encouraging clinical activity against several tumor types has been seen for anti-PD-L1/PD-1 monoclonal antibodies (mAbs). MEDI4736 is a human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1 and CD-80 with high affinity and selectivity, preventing PD-L1-mediated inhibition of T-cell activation. It has been engineered to harbor a triple mutation in the fragment crystallizable domain, which removes antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Evidence of clinical activity for MEDI4736 in NSCLC has been observed in a Phase 1 study (Study 1108, NCT01693562), with initial data indicating that PD-L1 expression is associated with a higher objective response rate (ORR). Chemotherapy and radiotherapy upregulate the expression of tumor PD-L1, which could increase sensitivity to PD-L1-directed therapy. Based on this rationale, the PACIFIC study (NCT02125461) will evaluate the efficacy and safety of MEDI4736 in patients with locally advanced, unresectable NSCLC (Stage III) whose disease has not progressed following platinum-based, concurrent chemoradiation therapy.
Methods:
In this Phase 3, randomized, double-blind, multicenter, international study, ~700 patients will be randomized 2:1 to receive MEDI4736 (10 mg/kg IV) or placebo every 2 weeks for up to 12 months. Eligible patients must have previously received ≥2 cycles of platinum-based concurrent chemoradiation with no subsequent disease progression, have received a total dose of radiation of ≥60 Gy, and have archival tissue available. Patients treated with sequential chemoradiation therapy for locally advanced disease and those with metastatic disease are excluded. Randomization must occur within 42 days of radiation. Co-primary endpoints are OS and progression-free survival (PFS) (RECIST v1.1). Secondary endpoints include OS at 24 months, proportion of patients alive and progression-free at 12 and 18 months, time to second progression, objective response rate, duration of response, health-related quality of life, safety/tolerability, pharmacokinetics and immunogenicity of MEDI4736. Patients who achieve and maintain disease control up to 12 months will enter follow-up. Patients will be recruited at approximately 300 sites across Australia, Asia, Europe, North and South America and South Africa. Recruitment is ongoing.
Results:
Not applicable
Conclusion:
Not applicable
