Virtual Library

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Background:
Clinical studies with anti-EGFR agents demonstrate that EGFR TKIs play critical roles in the treatment of non-small cell lung cancer, especially in patients with positive EGFR mutation. Icotinib is an oral, selective EGFR TKIs. Phase 3 study showed that icotinib is non-inferior to gefitinib in treating unselected or EGFR-mutated advanced NSCLC patients as second-line therapy but better safety profile, which provide a rationale to examine icotinib in first-line setting. The objective of this study is to evaluate progression-free survival (PFS), overall survival (OS) and safety of icotinib in chemotherapy naïve NSCLC patients with EGFR mutation.

Methods:
In this phase 3, open-label, randomized study (CONVINCE, NCT01719536), 285 patients (pathologically confirmed NSCLC, positive 19/21 EGFR mutation, treatment naive) will be 1:1 randomized to receive oral icotinib (125 mg, three times daily) or cisplatine (intravenous [IV], 75 mg/m2, day 1) plus pemetrexed (IV, 500 mg/m2, day 1), patients achieving disease control after 4-cycle chemotherapy continue to receive single pemetrexed (IV, 500 mg/m2, day 1) as maintenance therapy until progression. Randomization will be stratified by performance status (0-1/2), smoking status (smoker/non-smoker), disease stage (IIIB/IV), and mutation type (19/21). A total of 228 events would provide 90% power to detect an HR for PFS of 1 at 2-sided significance level of 0.05. Response will be reviewed by both investigator and independent data monitoring committee. Patient enrollment was completed in June 2014, and the results are expected in June, 2015.

Results:
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Background:
Epidermal growth factor receptor (EGFR) exon 20 T790M mutation may have a predictive role before EGFR-tyrosine kinase inhibitors (TKIs) treatment and it also might have a prognostic role after acquired resistance to EGFR-TKIs. However, its role in EGFR-TKI rechallenge after failure of initial EGFR-TKIs in EGFR-mutant advanced non-small cell lung cancer (NSCLC) remains unknown.

Methods:
We retrospectively evaluated the clinical course of 515 EGFR-mutant advanced NSCLC patients who received first generation EGFR-TKIs (gefitinib or erlotinib) from December 2009 to November 2014 at Guangdong General Hospital. Of these 515 patients, 65 patients recieved same EGFR-TKI rechallenge, including 51 patients who underwent rebiopsy and secondary EGFR mutation detection after failure of initial EGFR-TKIs. EGFR detection was performed by Sanger sequencing or Amplification Refractory Mutation System (ARMS) methods. Progression-free survival (PFS) and overall survival (OS) were both calculated from commencement of EGFR-TKI rechallenge. Survival data were analyzed using the Kaplan-Meier method and log-rank test.

Results:
EGFR activating mutations still existed in all the 51 patients who received rebiopsy and 18 patients were with T790M mutation while 33 patients were without T790M. The median PFS for the T790M+ and T790M- groups were 1.8 months (95%CI 1.180~2.420) and 2.0 months (95%CI 1.100~2.900), respectively (P=0.261). The median OS for the two groups were 7.7 months (95%CI 6.548~8.852) and 6.8 months (95%CI 4.730~8.870), respectively (P=0.565). No statistical difference was found in PFS or OS between two groups(Figure 1). Fig 1. Kaplan-Meier curves of patients in two groups. (A)Progression-free survival. (B) Overall survival.

Conclusion:
EGFR T790M mutation is neither a predictive nor a prognostic factor for first generation EGFR-TKI rechallenge in EGFR-mutant advanced NSCLC patients, indicating that whether T790M occurs or not, same EGFR-TKI rechallenge could not be recommended as a good strategy to overcome the resistance to first generation EGFR-TKIs.

Background:
Targeted therapies have considerably improved the prognosis of patients with non-small cell lung cancer (NSCLC).Although not precision enough, RESIST criteria was still the most often used response assessment method to reflecting the clinical benefits. We propose a non-invasive, folate receptor (FR)–based circulating tumor cell (CTC) detection approach to interpret treatment response of targeted therapy between baseline and follow-up CTC values in EGFR mutation/ALK translocation advanced NSCLC.

Methods:
One hundred and thirty eight patients were enrolled in our study. Peripheral blood was analyzed for CTCs enumeration on negative enrichment by immunomagnetic beads. Changes of CTCs levels were correlated with radiological response. Sequential analyses were conducted to monitor CTC signals during therapy and correlate radiological effects with treatment outcome.

Results:
CTCs were detected (≥8.7CTC) in 84.8% of patients. Pretreatment and pro-treatment blood samples from all 118 EGFR-mutant (19deltion:56, L858R:57, G719x:3, L861Q:1, 19 deletion + L858R:1), 14 ALK translocation lung cancer patients and 6 EGFR wild type patients were collected. Of 89 eligible and evaluable patients, baseline CTC counts were not associated with response to treatment by RECIST (P=0.353). There is no difference between exon 19 deletion and L858R of baseline CTC values. (19deletion:19.4 CTCs, L858R:20.9 CTCs,P=0.222) The change of CTCs values increased correlation with radiological response (P=0.042) after treatment of targeted therapy. There is no significant difference between exon 19 deletion and L858R of CTCs values pre and pro EGFR-TKI treatment.(3.32 vs.12.1, P=0.783)

Conclusion:
This study confirms the predictive significance of CTCs in patients with EGFR mutation/ALK translocation NSCLC receiving targeted therapy. The change of CTCs value correlated significantly with radiological response. This strategy may enable non-invasive, specific biomarker assessment method for using CTC decreases as an early indication of response to targeted therapy and monitoring in patients undergoing targeted cancer therapies.

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Abstract:
The traditional obstacles to approval of oncologic therapeutic agents, especially targeted therapies that address a rare-biomarker defined group of patients are the long processes from initial drug discovery to clinical implementation, the difficulties in recruitment for these clinical trials and high number of screen failures and the overall low rate of enrollment in clinical trials. The Lung Master Protocol (Lung-MAP, S1400) is a precedent-setting clinical trial designed to advance the efficient development of targeted therapies for squamous cell cancer of the lung (SCCA). There are few new effective therapeutic options for patients with advanced lung SCCA. Immunotherapies, including nivolumab, have already shown clear benefit for patients with SCCA in 2015 leading to approval by the FDA which has been an unprecedented step forward for the treatment of patients, however we are still lacking predictive markers for these therapies that are reliably selecting patients more likely to benefit. Lung-MAP (S1400) is aiming to identify biomarker-drug pairs that will lead to successful therapeutic outcomes and registration of new agents. It is a registration-intent master protocol that includes a screening component and clinical trial component; the clinical trial component includes multiple sub-studies which independently evaluate investigational therapies. The clinical trial component is designed to be modular such that new sub-studies can be added either as other sub-studies close or as new biomarker-drug pairs are identified for testing in this patient population. Lung-MAP is utlilizing a broad NGS screening platform capitalizing on the expanding application of genomic sequencing in oncology that has through the Cancer Genome Atlas and other sequencing initiatives revealed targetable genetic aberrations including gene mutations, rearrangements, amplifications, and deletions, and creating an immense opportunity to implement personalized therapy with a high potential to improve patients outcomes. Immunotherapy has been integrated in the design of Lung-MAP from its launch in June of 2014. The original study design and structure is shown in the figure. Figure 1 The modular design of the study has allowed for the flexibility to adapt to the approval of nivolumab and the hault in further development of AMG102 (rilotumumab) with discontinuation of the corresponding sub-study by implementing timely modifications which include the following:1)Eligibility has changed from exclusively second line therapy to second-or more line therapy 2)Pre-screening, while patient receive first line therapy has been added to boost accrual 3)the unmatched arm has been changed to a single (not randomized) arm study with the anti-PD-L1 agent MEDI-4736. Theses changes are reflected in the figure. Each independently conducted and analyzed sub-study specifies investigator-assessed progression-free survival (IA-PFS) and overall survival (OS) as the co-primary endpoints for the phase 3 primary objectives. The primary objectives for the phase 3 are to determine if there is a statistically significant difference in OS and to determine if there is both a clinically meaningful and statistically significant difference in IA-PFS. The conduct of Lung-MAP relies on close collaboration (a public-private partnership) among the NCI and NCTN (spearheaded by SWOG), the pharmaceutical industry, the Foundation for the NIH (FNIH), Friends of Cancer Research, advocates, and FDA. This Master Protocol will improve genomic screening of SCC patients for clinical trial entry, and improve time lines for drug-biomarker testing, allowing for inclusion of the maximum numbers of otherwise eligible patients. The clinical trial continues to be updated following science and alterations in the therapeutic landscape, with adaptations in design and incorporation of new agents against matched targets and the implementation of novel immunotherapy approaches for the unmatched arm. Figure 2

Abstract:
Lung-MAP, a “multi-drug, multi-study bio-marker driven squamous cell lung cancer clinical trial” [i] is, as the song says – a new day . . . a new life . . . and the old world is a new world.[ii] It represents an exciting and radical new paradigm for lung cancer research and with that a potential for new, life-saving treatment protocols for lung cancer. Lung-Map was borne of a National Cancer Institute (NCI) sponsored two-day workshop with the NCI Thoracic Steering Committee and the Federal Drug Administration (FDA) “to bring together leading academicians, clinicians, industry and government representatives to identify challenges and potential solutions in the clinical development of novel targeted therapies for lung cancer.”[iii] The objectives of the “workshop were to achieve initial consensus on a high priority biomarker-driven clinical trial designed to rapidly assess the activity of targeted agents and molecularly defined lung cancer subsets and to facilitate generations of data leading to approval of these new therapies.”[iv] The result of this workshop led to the development of an unprecedented public-private collaboration called the Lung-MAP Master protocol. Lung-MAP is a unique research model in several respects. First, it will study five different experimental drugs at the same time for squamous cell lung cancer.[v] The approach stands in stark contrast to the long entrenched research approach whereby only one drug is tested and with that only those patients that might benefit from the treatment are involved in the trial. Second, Lung-MAP researchers will examine the DNA from each participating volunteer patient’s lung tumor to identify the genetic alterations or mutations that are causing the tumor to grow. They will match these results with sub-studies testing related investigative treatments. [vi] Figure 1 Third, while not entirely unique but nonetheless significant, is Lung-MAP’s broad collaborative approach. Those participating in Lung-MAP include NCI, public and private research and advocacy organizations together with five pharmaceutical companies.[vii] The importance of this new paradigm for lung cancer research is graphically illustrated by the treatment and research options that have traditionally been offered to lung cancer patients. In 2000, the only treatments offered and/or available to lung cancer patients were the same platinum chemotherapies, radiation and surgery which had been used to treat lung cancer patients for the prior 30 years. Neither the course of time, nor repeated use of these treatment therapies, offered much hope for survival to lung cancer patients as evidenced by a stagnant 13% five-year survival rate, which has only recently increased to 17% five-year survival rate. The underpinning of Lung-MAP has its genesis, in part, in the completion in 2003 of the Human Genome Project (HGP) which led to The Cancer Genome Atlas (TCGA) in 2005. The completion of the HGP and the TCGA resulted in refreshing and hopefully effective new ways of looking at lung cancer. Before the advent of the HGP and the TCGA, lung cancer tumors were viewed as homogeneous. Now they are viewed as unique biological entities – more like snowflakes, with no two tumors alike. Following the TCGA, the first treatable genomic mutation –EGFR – was identified in 2003. The mutation is found in 10% of non-small cell lung cancer (NSCLC) patients. It was quickly followed by FDA approved treatments gefitinib and erlotinib. In 2007, EML4-ALK fusion was identified. It too was quickly followed by an FDA approved treatment – crizotinib. Following in this vein, Lung-MAP portends the identification of additional genomic mutations and with it, a chance for faster research results and more effective treatment of lung cancer. There are now at least 15 significant identified and hopefully targetable lung cancer genomic mutations. Three of these, EGFR, EML4-ALK and ROS1 have received FDA approved treatments. There are more in clinical trials. In 2015, the first immuno-oncologic therapy received FDA approval for squamous cell lung cancer with many more immuno-oncologic therapies in the clinical trial pipeline that are expected to be approved for not only NCSLC but also small cell lung cancer (SCLC). The core of Lung-MAP is “rapid assessment.” This fast pace of discovery will hopefully render archaic established models requiring 10 to 15 years for development in clinical trials before receiving FDA approval. New approaches to clinical trial protocols such as Lung-MAP, are critical to keeping up with rapidly changing discoveries and changing the old order of research and development. Shortening the timeframe for translational research, from bench to bedside, in order to provide patients with the quickest and most effective benefit from these new therapies is critical and will save lives – especially for lung cancer patients. In order to continue to take advantage of this exciting period in the convergence of research and technology, it is equally imperative that we come together in a collaborative and open-sharing model that will deliver exciting, safe new therapies to patients as fast as possible and with that lead to a long overdue, exponential increase in the survival rate for lung cancer patients. [i] Consensus Report of a Joint NCI Thoracic Malignancies Steering Committee: FDA Workshop on Strategies for Integrating Biomarkers in to Clinical Development of New Therapies for Lung Cancer Leading to the Inception of “Master Protocols” in Lung cancer. Shakun M. Malik, MD, Richard Pazdur, MD, Jeffrey S. Abrams, MD, Mark A. Socinski, MD, William T. Sause, MD, David H. Harpole Jr., MD, John J. Welch, MD, PhD, Edward L. Korn, PhD, Claudio Dansky Ullmann, MD, and Fred R. Hirsch, MD PhD Journal of Thoracic Oncology, Vol. 9, Number 10, October 2014, p. 1443. [ii] Feeling Good, Michael Bublé, 2005 [iii] Consensus Report of a Joint NCI Thoracic Malignancies Steering Committee at p. 1443. [iv] Id. [v] Id. at 1443-1444 and www.lung-map.org/about - lung-map [vi] Id. [vii] Id.

Abstract:
In recent years, we have seen a new practical distinction made in terms of management recommendations for the histologic subtypes of non-small cell lung cancer (NSCLC). There is now a growing recognition of the biological relevance of the differences between major histologic subtypes, as clinical trials and distinct management algorithms emerge for the advanced squamous (SQ) NSCLC population. Though differences in the clinical behavior of SQ vs. non-squamous (NSQ) NSCLC have been recognized for decades (1), the first functional distinction emerged with the recognition of different results for SQ and NSQ populations in multiple trials of pemetrexed that together demonstrated that the efficacy of this agent was limited to patients with NSQ histology (2), ultimately leading to a change in the label of pemetrexed, previously approved for all NSCLC patients as second line therapy, to being indicated for NSQ patients only (3). Development of the anti-angiogenic agent bevacizumab was also limited to patients with NSQ histology after a post-hoc analysis of results in a phase II trial of carboplatin/paclitaxel with either of two dose levels of bevacizumab or placebo demonstrated a high risk of life-threatening or fatal pulmonary hemorrhage among patients with SQ histology (4). Subsequent development and clinical use of bevaicizumab in advanced NSCLC has been limited to NSQ histology. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are another class of anticancer therapy that are more effective in NSQ than SQ NSCLC (5). Though patients with SQ NSCLC were included in early, pivotal trials in molecularly unselected populations that revealed a modest overall survival (OS) benefit with erlotinib, molecular selection of patients with an activating EGFR mutation has shown that high response rates (RR) and prolonged benefit with EGFR TKIs is overwhelmingly in patients with an activating EGFR mutation, so rare in SQ NSCLC that routine testing for it is not recommended. ALK and ROS-1 rearrangements are similarly rare in SQ NSCLC, with routine for these markers in SQ NSCLC not recommended. Patients with SQ NSCLC remain candidates for erlotinib in the maintenance or salvage setting, in which its value is so modest as to be debatable. SQ NSCLC patients are presumed to be ALK and ROS-1 wild type and rarely candidates for therapies against these targets. Until very recently, therefore, SQ NSCLC has been characterized by the NSCLC treatments that are considered ineffective, prohibitively toxic, or of relatively marginal benefit. Several new management options, however, have emerged that are more directed to the SQ NSCLC population. Though the randomized phase III trial that let to approval of nab-paclitaxel in advanced NSCLC (6) was not specifically directed to patients with SQ NSCLC, the trial of carboplatin with either paclitaxel or nab-paclitaxel demonstrated a higher response rate in the nab-paclitaxel arm of 41% vs. 24% in favor of nab-paclitaxel. In the absence of other therapies that have shown enhanced efficacy in SQ NSCLC, nab-paclitaxel has an arguable role as first line therapy for SQ NSCLC, though there are no confirmatory trials or biomarker correlates to corroborate a special utility for nab-paclitaxel here. Another chemotherapy-based approach directed to SQ NSCLC is nedaplatin, a second generation platinum compound tested in a Japanese trial of 350 patients with chemotherapy-naïve advanced SQ NSCLC in which subjects were randomized to cisplatin/docetaxel or nedaplatin/docetaxel (docetaxel on each arm administered at the standard Japanese dose of 60 mg/m2 d1 every 21 days) (7). Median OS was >2 months longer with nedaplatin (13.6 vs. 11.4 months, HR 0.81, p = 0.037), and toxicity was relatively comparable between the two arms. Nedaplatin/docetaxel combination may now be considered a new standard treatment for advanced SQ NSCLC in Japan, but the non-standard dosing of docetaxel for global populations and the recognition of potential differences in efficacy of regimens among different racial populations will likely limit broader use of nedaplatin until studies outside of Japan confirm superior efficacy. The SQUIRE trial of the monoclonal antibody against EGFR necitumumab trial in 1093 first line SQ NSCLC patients showed a modest OS benefit when this agent was added to cisplatin/gemcitabine, compared with chemotherapy alone (8). In absolute terms, however, the median OS benefit of only 1.6 months (11.5 vs. 9.9 months), counterbalanced by greater toxicities and costs with the addition of necitumumab, has led to little enthusiasm for favoring the broader incorporation of this agent. Afatinib has been studied in the LUX-Lung-8 trial as an alternative to erlotinib in previously treated patients with SQ NSCLC (9). While the 1.1 month OS benefit and HR 0.81 with afatanib reflect only marginal superiority to erlotinib, afatanib is now arguably the EGFR TKI of choice in this setting, pending FDA approval. However, with the value of erlotinib for SQ NSCLC considered so debatable in this setting, this may be interpreted as damning with faint praise. By far the greatest excitement for patients with advanced SQ NSCLC stemps from immune checkpoint inhibitor therapy, starting with the programmed cell death protein 1 (PD-1) inhibitor nivolumab, which was compared in the randomized Checkmate 017 trial to docetaxel as second line therapy in 272 chemotherapy-pretreated patients with advanced SQ NSCLC (10). Demonstrating a far superior median OS of 9.2 vs. 6.0 months, HR 0.59 (p = 000025), a median duration of response not yet reached, and a far more favorable tolerability than docetaxel, nivolumab is now the clear, FDA-approved second line standard of care for SQ NSCLC. This trial also demonstrated no correlation of efficacy with nivolumab as a function of tumor expression of programmed death protein ligand-1 (PD-L1), supporting its use in an unselected SQ NSCLC population. As genomic testing becomes more readily available and incorporated into clinical practice, molecular markers relevant for patients with SQ NSCLC are likely to provide new targeted therapy opportunities to accompany those of immunotherapies and conventional chemotherapy for this large population still greatly needing new advances. References 1) Hirsch, JTO 2008 2) Scagliotti, JTO 2011 3) Cohen, Oncologist 2010 4) Johnson, JCO 2004 5) Shepherd, NEJM 2005 6) Socinski, JCO 2012 7) Shukuya, Proc ASCO 2015, A#8004 8) Thatcher, Lancet Oncol 2015 9) Soria, Proc ASCO 2015, A#8002 10) Brahmer, NEJM 2015

Abstract:
Recent advances in personalized medicine and associated companion diagnostic therapeutics have led to an increased utilization of genetic markers in oncology therapy selection. The rapid acceleration of biomarker driven therapy has been widely accepted into clinical guidelines based upon proven clinical utility and unprecedented patient outcomes. Despite these advances, utilization of molecular testing in community oncology practice has been more limited than in academic settings. The Levine Cancer Institute and Carolinas HealthCare System serve a wide variety of oncology patients in both academic and community settings using a multidisciplinary approach. During this session, a discussion of processes used for tissue acquisition and processing, pre-analytics, biomarker testing, and result reporting will be presented. Strategies that have been used in our system to eliminate common roadblocks in the testing process such as tissue stewardship will be discussed. A special emphasis will be given to the discussing the power and pitfalls of common biomarker testing techniques such as real-time PCR companion diagnostic testing, immunohistochemistry, FISH, and next-generation sequencing panels. During the presentation, a significant amount of time will be dedicated to a question and answer session so audience members can address community testing challenges from their local settings. Working to solve these challenges in the community setting will improve the oncology patient journey by increasing access to high quality biomarker testing.

Abstract:
Bronchoscopy dates back to the late 18th century where rigid illuminating tubes were used to examine the tracheobronchial tree. With the introduction of the fiberoptic bronchoscope, bronchoscopy has revolutionized the practice of pulmonary medicine. In lung cancer, due to advances in real-time imaging and catheter based techniques, bronchoscopy remains pivotal not only in diagnosis and staging, it also allows therapeutic intervention for airway restoration in patients with central airway obstruction, and treatment of early detected central airway cancers. For peripheral lung nodules that are beyond the visibility of the bronchoscope, computed tomography (CT) guided, navigational methods, and endobronchial ultrasonography (EBUS) facilitate accurate targeting. Since bronchoscopy allows access to the lung, it enables researchers to better understand lung carcinogenesis, discover biomarkers for early detection and prognostication as well as assess tumor response to targeted therapy by in-vivo microdynamic imaging. Pleuroscopy provides the physician a window to the pleural space by enabling biopsy of the parietal pleura under direct visual guidance in the evaluation of effusions of unknown etiology, guided chest tube placement, and talc pleurodesis as palliation of malignant pleural effusions. Cancer related pleural effusions occur as a result of direct tumor invasion, tumor emboli to the visceral pleura with secondary seeding of the parietal pleura, hematogenous spread, or via lymphatic involvement. Elastin staining and careful examination for invasion beyond the elastic layer of the visceral pleura should be carried out for lung cancer resections, as visceral pleural invasion is regarded as an important stage-defining feature in the absence of nodal involvement. Metastatic spread of lung cancer to the pleura adversely affects survival, and in the recent TNM staging of lung cancer, presence of pleural metastasis is defined as M1a (from T4), representing a corresponding change from stage IIIB to stage IV. It is rare to find resectable lung cancer in the setting of an exudative pleural effusion, despite negative cytologic examination. Thus, pleuroscopy can establish operative eligibility by determining if the pleural effusion is paramalignant or due to metastases. If pleural metastases are found, and therefore confirming inoperable disease, talc poudrage can be performed at the same setting. This has been shown to be more effective in preventing recurrence than intrapleural instillation of a sclerosant.