Virtual Library

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Abstract:
Medical therapy in advanced NSCLC in 2016 is characterized by personalization, individualization, and therapy precision. Not only clinical factors are used for treatment differentiation but also the histological type (squamous versus non-squamous) and the molecular profile (mutant versus wild type). In addition, the complexity of the treatment algorithm has gradually increased over time by the incorporation of a number of approved molecules for 1[st], 2[nd] -, subsequent line therapy (Peters, 2012; Masters, 2015; NCCN, 2016). NSCLC – 1[st]-line-therapy - wild-type: For patients with wild-type non-squamous NSCLC it is generally accepted that upfront platinum based doublet chemotherapy (DCT) remains the backbone for individuals with good performance and that this approach should be modified according to feasibility and tolerability, co-morbidity, and age over 70 years. Progress has been made through pemetrexed, which is recommended as the favorite partner of platinum-based components (Scagliotti; 2008/2011). In addition, it has lately been demonstrated that the extension of induction chemotherapy by single agent pemetrexed until progression - in case of non-progression under four cycles of DCT not containing pemetrexed (switch maintenance) (Ciuleanu, 2009) or containing pemetrexed (continuation maintenance) (Paz-Ares, 2012/2013) - prolongs survival. In this case survival may also be prolonged by erlotinib, when used in the switch maintenance setting, but erlotinib’s benefit seem to be restricted to patients, which have experienced disease stabilization to induction chemotherapy (Cappuzzo, 2010; Coudert, 2012). Bevacizumab, when added to platinum-based to DCT, significantly improves response rate, progression free survival, as well as overall survival in eligible patients (Sandler, 2006/2010; Reck, 2009/2010). In wild-type squamous NSCLC platinum based DCT (no pemetrexed, no bevacizumab) remains standard. Nonetheless, necitumumab has recently shown to improve survival when combined with cisplatin/gemcitabine (Thatcher, 2015). Maintenance therapy in squamous tumors with docetaxel or erlotinib (switch) or gemcitabine (continuation) may be justified in some patients even so study evidence is weaker than for non-squamous tumors (Fidas, 2009; Perol, 2012). NSCLC – 1[st]-line-therapy - mutant: For patients with advanced NSCLC expressing specific molecular features – mainly non-squamous tumors – 1[st]- line treatment with targeted agents has been established. In tumors with EGFR mutations gefitinib, erlotinib, and afatinib have shown to prolong progression free survival over standard chemotherapy (Mok, 2009; Rosell, 2012; Sequist, 2013). In tumors bearing ALK-/ROS1-gene-rearrangements crizotinib has also shown to prolong progression free survival when compared to platinum/pemetrexed. (Solomon, 2014). Therefore, erlotinib, gefitinib or afatinib should be prescribed for patients with tumors bearing EGFR-mutations. For patients with tumors bearing ALK-/ROS1 crizotinib should be prescribed. However, for these patients molecular testing is critical and should be used to select patients for EGFR/ALK/ROS1 targeted therapy. Patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics (ethnicity, gender, smoking status) (Lindeman, 2013). NSCLC - 2[nd] /subsequent-line therapy - wild-type: In patients with disease progression during or after completion of 1[st ] -line chemotherapy, 2[nd] -, subsequent-line therapy is indicated when the patient remains in good clinical condition. Approved older treatment options include docetaxel, pemetrexed and erlotinib. Two anti-angiogenic agents and two immune-checkpoint inhibitors have recently been added. These include nintedanib and ramucirumab (Reck, 2014; Thatcher, 2015), as well as nivolumab and pembrolizumab (Brahmer, 2015; Borghaei, 2015; Herbst, 2016). Nintedanib/docetaxel increases significantly survival in patients with adenocarcinoma who specifically progressed within 9 months after the start of 1[st]-line therapy, who have experienced disease progression as best response to 1[st]-line therapy and decreases tumor burden and decelerates tumor growth. Nintedanib/docetaxel has been approved in the EU for the treatment of patients with adenocarcinoma. Ramucirumab/docetaxel has also been approved in the US and EU for patients with disease progression on or after DCT for wild-type non-squamous and squamous NSCLC. This approval has been based on phase III study evidence indicating survival advantage in non-squamous NSCLC (statistically significant) and squamous NSCLC (numerically longer). Comparing head-to head nivolumab and docetaxel in patients with squamous and non-squamous NSCLC after failure of DCT has demonstrated superior overall survival in patients receiving nivolumab. Nivolumab has received US and EU approval for advanced NSCLC with progression on or after DCT. Nivolumab appears to be most effective in patients with more than 6 months from completion of the latest treatment regimen to randomization in comparison to patients with less than 3 months to randomization. Pembrolizumab has received approval in the US and EU for patients with advanced NSCLC who’s tumors expressed PD-L1 and who have disease progression on or after chemotherapy. Approval has been based on head-to-head comparison of pembrolizumab and docetaxel in patients with previously treated PD-L1 positive squamous and non-squamous NSCLC, which has demonstrated a significant survival benefit for pembrolizumab. NSCLC-2[nd]/subsequent-line therapy - mutant: Resistance to first and second generation EGFR-TKIs is a multifactorial process with a variety of clinically patterns. Its management requires different, case adapted approaches. Several strategies are currently under investigation, but some have already find its way into todays practice although study evidence is still rather weak. In case of oligoprogression the EGFR-TKI therapy may continue but local therapies (radiation, surgery) should be added. In case of diffuse progression EGFR-TKI therapy may continue, but in combination with chemotherapy; EGFR-TKI therapy may be switched to chemotherapy, but at the moment of chemotherapy resistance patients may be re-exposed to EGFR-TKI therapy; admission to clinical trials offering investigational agents may be a valid option for some patient. Osimertinib has just been approved and is recommended for tumors expressing P790M (Jänne, 2015). In tumors bearing ALK-/ROS-gene-rearrangements ceritinib is approved and recommended in case of crizotinib resistance (Shaw, 2014). Conclusion: During the past ten years the complexity of the treatment algorithm of advanced NSCLC has gradually increased by the incorporation of several approved molecules. Novel immunotherapies have recently changed the management of advanced wild-type NSCLC. Treatment by histo-type and geno-type has been established and it can be assumed by the given speed of growth of molecular information that the process of treatment differentiation will fast continue. Identification of new prognostic and predictive factors undoubtedly will accelerate this process.

Abstract:
Several trials have evaluated the appropriate initial duration of platinum based chemotherapy: 3 versus 6 cycles, 4 versus continuous cycles, or 2 versus 4 cycles after non-progression to the initial 2 treatments. In all situations there was no benefit to longer duration of chemotherapy and both ASCO and NCCN recommend no more than 6 cycles of initial treatment. Continuation of lower intensity therapy (typically with a single agent from the initial doublet) was also tested. Studies of weekly paclitaxel after carboplatin-paclitaxel (Belani et al) or gemcitabine after cisplatin-gemcitabine (Brodowicz et al) showed no OS difference, but a possible benefit in PFS. Studies evaluated the introduction of a non-cross resistant agent (early second line) in patients without progression after initial chemotherapy. Westeel et al. randomized patients after MIC x 3 to either observation versus vinorelbine; Fidias et al. evaluated immediate versus delayed docetaxel after carboplatin-gemcitabine x 4 and JMEN study looked into pemetrexed versus placebo after four cycles of platinum doublet. For the latter two studies, about 50% of patients completed 6 maintenance cycles and 50-60% of patients in the observation arm received second line therapy; this is consistent with rates of second line therapy in multiple studies of NSCLC. Results showed a 2-3 month difference in PFS favoring immediate therapy. In terms of overall survival, there was no difference with vinorelbine, and a 2.6-2.8 month difference with either docetaxel or pemetrexed (significant only with pemetrexed). QoL was not affected by continuous chemotherapy and tumor related symptoms improved with pemetrexed. Erlotinib has been evaluated in 3 randomized trials against placebo (SATURN), observation (IFCT-GFPC 0502) or in combination with bevacizumab against placebo-bevacizumab (ATLAS). In all studies there was a PFS benefit (HR 0.71-0.82), but OS was only significant in the SATURN trial (HR 0.81). PFS benefit was limited to non-squamous histology for pemetrexed, as opposed to the docetaxel and erlotinib trials. Despite the initial negative trials, continuation pemetrexed following platinum-pemetrexed doublet has emerged as a standard option for non-squamous NSCLC. PARAMOUNT randomized between pemetrexed and placebo following four cycles of cisplatin pemetrexed. It showed a PFS benefit (HR 0.64) and also an OS benefit (2.9 month difference, HR 0.78) in favor of continuation maintenance. AVAPERL used a similar design, however with the addition of bevacizumab throughout therapy, i.e. initial cisplatin-pemetrexed-bevacizumab followed by pemetrexed-bevacizumab versus bevacizumab. PFS significantly favored pemetrexed (10.2 versus 6.6 months), and although OS was also superior (19.8 versus 15.9 months) it was not statistically significant. The IFCT-GFPC 0502 trial also evaluated continuation gemcitabine and demonstrated a PFS advantage, but no OS benefit in an underpowered study. Bevacizumab continuation is an accepted approach based on the design of E4599, although its contribution has never been established in a randomized trial. However, a direct comparison between E4599 (carboplatin-paclitaxel-bevacizumab followed by bevacizumab) and carboplatin-pemetrexed-bevacizumab followed by pemetrexed-bevacizumab was undertaken in the POINTBREAK study. It showed no OS differences (numerically favored E4599: 13.4 versus 12.6 months), although in pre-specified analysis of patients going through maintenance (as opposed to ITT) there was a 2-month difference favoring the combination of pemetrexed-bevacizumab. E5508 [ClinicalTrials.gov identifier:NCT01107626] is attempting to answer this question by directly randomizing patients to either bevacizumab, pemetrexed or the combination after carboplatin-paclitaxel-bevacizumab. Subset data from the SATURN trial strongly supports switch maintenance with erlotinib for EGFR mutant patients, who had an impressive three fold higher median PFS (44 vs 14 weeks; HR: 0.10; 95% CI: 0.04–0.25). INFORM included 296 asian patients, who were randomized between gefitinib and placebo. PFS favoured gefitinib maintenance (4.8 vs 2.6 months, HR=0.42; 95% CI: 0.33–0.55; p <0.0001). No overall survival benefit has been found for squamous cell patients. However, a PFS benefit was seen in IFCT-GFPC 0502 for continuation maintenance with gemcitabine and in SATURN for sequential erlotinib. The ABOUND study with carboplatin/ nab-paclitaxel is exploring the nab-paclitaxel maintenance in squamous-cell and results are awaited. The SQUIRE trial evaluated the anti-EGFR monoclonal antibody necitumumab in combination with cisplatin-gemcitabine followed by maintenance necitumumab. It modestly improved overall survival and PFS over chemotherapy alone (median OS 11.5 vs 9.9 months, HR 0.84, p=0.012; PFS HR 0.85, p=0.02). The contribution of bevacizumab maintenance phase was not prospectively been established. However, a retrospective landmark analysis of E4599 evaluated the patients who were alive without progression for at least 3 weeks after completion of 6 cycles of chemotherapy. The PFS favored bevacizumab maintenance (4.4 vs 2.8 months; HR 0.64). OS was also longer (median 12.8 vs 11.4 months). ECOG 5508 is an important ongoing study, as mentioned previously Another ongoing study (MO 22097) is evaluating the role of continuing bevacizumab in combination with a second line chemotherapy, beyond progression to maintenance bevacizumab. In a phase III placebo-controlled study, carboplatin and paclitaxel were given with or without concurrent and maintenance sorafenib, but no improvement in overall survival was shown and the results were detrimental in patients with squamous cell histology. CALGB 30607 of maintenance sunitinib versus placebo met its primary endpoint of improving PFS (4.3 versus 2.8 mos), including squamous histology. There was no effect on OS. EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis. A phase III trial of carboplatin, paclitaxel with or without concomitant and maintenance ipilimumab (an anti-CTLA4 agent) is ongoing, and was initiated taking into account the positive results obtained adding maintenance ipilimumab to the platinum doublet in a previous phase II study. Vaccine therapy has also been studied as maintenance treatment in NSCLC. Belagenpumatucel-L (Lucanix) is an allogeneic cancer vaccine, obtained from TGF-beta2 antisense gene modified whole NSCLC cell lines. There was no difference in overall survival between arms (median survival 20.3 versus 17.8 months with belagenpumatucel-L versus placebo, respectively. Tecemotide (L-BLP-25) is a vaccine against MUC1 antigen. START trial randomized patients with stage III NSCLC who completed chemoradiotherapy between tecemotide injections or placebo. No significant difference in overall survival with the administration of tecemotide after chemoradiotherapy was found - median OS was 25.6 months with tecemotide versus 22,3 months with placebo. References 1. Cost-utility analysis of maintenance therapy with gemcitabine or erlotinib vs observation with predefined second-line treatment after cisplatin–gemcitabine induction chemotherapy for advanced NSCLC: IFCT-GFPC 0502-Eco phase III study. I Borget, M Pérol, D Pérol, A Lavolé, L Greillier, P Dô, V Westeel, J Crequit, H Léna, I Monnet, H Le Caer, P Fournel, L Falchero, M Poudenx, F Vaylet, S Chabaud, A Vergnenegre, G Zalcman, C Chouaïd. BMC Cancer2014,14:953 DOI: 10.1186/1471-2407-14-953) 2. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Tudor Ciuleanu, Thomas Brodowicz, Christoph Zielinski, Joo Hang Kim, Maciej Krzakowski, Eckart Laack, Yi-Long Wu, Isabel Bover, Stephen Begbie, Valentina Tzekova, Branka Cucevic, Jose Rodrigues Pereira, Sung Hyun Yang, Jayaprakash Madhavan, Katherine P Sugarman, Patrick Peterson, William J John, Kurt Krejcy, Chandra P Belani. Lancet Vol 374: 1432, 2009 3. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT):a double-blind, phase 3, randomised controlled trial. Luis Paz-Ares, Filippo de Marinis, Mircea Dediu, Michael Thomas, Jean-Louis Pujol, Paolo Bidoli, Olivier Molinier, Tarini Prasad Sahoo, Eckart Laack, Martin Reck, Jesús Corral, Symantha Melemed, William John, Nadia Chouaki, Annamaria H Zimmermann, Carla Visseren-Grul, Cesare Gridelli. Lancet Vol 13: 247, 2012 4. PointBreak: A Randomized Phase III Study of Pemetrexed Plus Carboplatin and Bevacizumab Followed by Maintenance Pemetrexed and Bevacizumab Versus Paclitaxel Plus Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB or IV Nonsquamous Non–Small-Cell Lung Cancer. Jyoti D. Patel, Mark A. Socinski, Edward B. Garon, Craig H. Reynolds, David R. Spigel, Mark R. Olsen, Robert C. Hermann, Robert M. Jotte, Thaddeus Beck, Donald A. Richards, Susan C. Guba, Jingyi Liu, Bente Frimodt-Moller, William J. John, Coleman K. Obasaju, Eduardo J. Pennella, Philip Bonomi, and Ramaswamy Govindan. JCO 31:4349, 2013

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Small cell lung cancer is the prototype of a smokers cancer and therefore with changing smoking patterns and decreasing prevalence of smoking this is a tumour that happily we are seeing less frequently. However the nature of the disease, the morbidity and suffering it causes, and the tantalising chemo and radiotherapy sensitivity of this tumour make it of great medical and academic interest to us. More attention is now given to the morphology of small cell lung cancer and the blurred boundary with large cell neuroendocrine tumours and non small cell lung cancer with neuroendocrine features. At the end of the EGFR mutation driven lung cancer natural history, small cell lung cancer appears once resistant has developed to EGFR mutation therapies. If we start from the early stage disease and look at radical approaches and how these have changed in the last 20 years we see that the gains made by systemic treatment have been stable while outcomes have been improved by intensive local and focused treatments in the form of prophylactic cranial irradiation and consolidation radiotherapy to the mediastinum. Small gains have also been made by the timing of radiotherapy both quickly after last chemotherapy or when given in a concurrent fashion. The Convert study has now given us a faster twice a day delivery with equal effectiveness and toxicity to a higher dose once daily schedule. Surgery has never really taken off as a widely used treatment for SCLC. For all the anecdotal cases who have been cured with combined treatment involving surgery, we will also remember those patients who have failed to recover or have delayed recovery from surgery and lost the window of opportunity for systemic treatment in a disease that can rapidly change from asymptomatic to very symptomatic. Despite little change in systemic therapies, it is important that what we have, we use well and to this end patients with SCLC should be carefully monitored during treatment for treatment induced neutropenia as this is readily treated and prevented by the use of GCSF which has become cheap and readily available in most countries. In addition SCLC was also one of the solid tumours that benefited from denosumab in the trials of patients with bone metastases and thus denosumab or zometa should be added to patients with SCLC who have bone metastases to decrease bone morbidity. Extensive stage small cell lung cancer is still a challenge and currently a graveyard for drugs development. The drugs that are looking promising are the PD-L1 inhibitors, although PD-L1 in itself does not appear to be a biomarker. Anti- PD1 and PD-L1 antibodies, while active in some cases of SCLC are not as broadly active as in NSCLC. Indeed it does not appear that PD-L1 expression on tumour cells is not a predictors of response. On could argue that the patients with SCLC who have a response to anti PD1 therapies may have heterogeneous disease and have areas of NSCLC which drive the response. It has always been thought that SCLC must be a problem of proliferation of abnormalities at the stem cell level. Indeed now it is no surprise that an anti DDL3 antibody (rovalpituzumab tesirine) is showing activity in relapsed disease – a situation where responses are few but results of trials are rapid. It also appears that DDL3 expression is a biomarker to predict response. Once again this biological pathway like the PD1 pathway, is unpatentable and thus we can expect a florry of antibodies targeting in and around these receptors on stem cells. The PARP inhibitors are again a group of drugs that held much promise but as yet have failed to deliver a treatment option at any point in the SCLC pathway. Further trials are ongoing. Positive benefits from radiotherapy in extensive stage as in limited SCLC, tells us that any treatment that can control a site of disease and can improve outcome, and suggests that removal of clones is important as either a form of debulking treatment or indeed these clones are a future source of resistance. Thus research on the treatment of oligometastatic sites either at presentation, residual after treatment or on relapse, as in the ongoing work in NSCLC (e.g the Saron study) may lead to future gains in survival. The biology of SCLC should be approached in the same way as NSCLC i.e. when disease relapses, rebiopsies should become the norm with as large a piece of tissue as possible. SCLC also sheds tumour cells into the circulation, which are a source of material for interrogation. Despite the negative trials, it is still rewarding to treat SCLC patients – for the rapid improvement in symptoms with treatment and the small but real group who get long term responses, in addition the rapid results makes this still an area for many more years of research.

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Monitoring of treatment efficacy and treatment-related toxicity –both in the real-world and the clinical trial setting- is a crucial, complex and constantly evolving aspect in the field of modern personalized oncology. The expansion of our lung cancer armamentarium, due to continuous implementation of novel (and costly) targeted and immunotherapeutic agents, along with their companion diagnostics, has inevitably led not only to substantial improvements in clinical outcomes, but also to increasing demands for a more accurate prediction and prevention of toxicities and more robust evaluation of cost-effectiveness. Furthermore, transition to targeted therapies displaying modes of action and biologic behavior vastly distinct to those of traditional cytotoxic agents, has necessitated the need to revisit our concept of what constitutes “tumor response” in lung cancer treatment (and solid tumors in general). Vital issues that need to be urgently -albeit concertedly- addressed include –but are not limited to- the need to adapt response evaluation criteria, monitoring tools and techniques to this rapidly changing landscape of lung cancer treatment and to increase our focus towards a patient-centered standard of care. Monitoring of treatment efficacy using imaging modalities Monitoring of tumor size changes -as evidenced on quantitative imaging modalities such as CT and MRI scans and typically assessed by the unidimensional RECIST criteria- remains the cornerstone of treatment response evaluation and decision-making in oncology practice and a strong surrogate endpoint for overall survival in clinical trials. Limitations of this approach are, nevertheless, significant and increasingly recognized. First, measurement inaccuracies and considerable inter-observer variability should be pointed out. Second, considerable time and cycles of cytotoxic drugs are needed prior to the appearance of any clinically meaningful tumor size changes on standard imaging studies, meaning that a reduction of tumor volume alone may not represent an early indicator of treatment response. Third, antitumor activity of targeted agents, which may not necessarily result in significant tumor size modification, cannot be accurately assessed or predicted with the use of these conventional strategies; multiparametric imaging –evaluating both anatomical and functional parameters of tumors-is thus required for optimal assessment of tumor behavior (stability, progression or regression). Within this context, functional imaging modalities (i.e. dynamic contrast-enhanced MRI, diffusion weighted imaging or FDG-PET and FLT-PET ) with the potential to visualize physiologic changes in the molecular level, have been investigated for their ability to influence decision-making by predicting or monitoring response to molecularly targeted agents or their value as surrogate outcome measures in the trial setting. Notably, FDG-PET is increasingly used for the evaluation of treatment response (mainly with PET response criteria /PERCIST) in lung cancer, while it is generally acknowledged that combined use of both RESIST and PERSIST criteria might lead to increased accuracy of prediction of treatment response in the earlier treatment stages. Evidently, earlier recognition of tolerance to treatment is vital for reduction of unnecessary toxicity and increase of cost-effectiveness. The barriers of complexity, high cost and limited availability, with regard to the above functional imaging techniques, should nevertheless also be emphasized. Evaluation of response to immune checkpoint inhibitors represents an emerging challenge in the field of immuno-oncology; since the specific patterns of tumor response to these agents cannot be accurately described using conventional imaging criteria, immune-related response criteria (irRC) were first defined in 2009, so as to provide a “common language”, enabling the application of a unified assessment of response to immunotherapy. Controversy with regard to the use of bidimensional measurements (according to the WHO criteria) in the irRC nevertheless ensued; immune-related RECIST 1.1 criteria are now increasingly used in clinical studies. Immune-related response evaluation remains to be implemented in routine practice and seems to represent an emerging endpoint in clinical trials. Monitoring of treatment efficacy using non-imaging modalities Monitoring of response to biomarker-driven therapies targeting specific molecular alterations in the lung cancer genome remains a major challenge in the field of personalized oncology, mainly due to shortage of tissue for the performance of genetic profiling of tumors. Liquid biopsies –detecting circulating tumor cells/CTCs and fragments of cell-free circulating tumor DNA/ctDNA- carry much promise for becoming an excellent and non-invasive alternative to tissue-based testing for the identification of genetic mutations with prognostic or therapeutic relevance. As a blood-based biomarker, ctDNA analysis offers the potential of serial investigations at any time point during the course of treatment, and thus of real-time dynamic monitoring of treatment response and early identification of acquired resistance to treatment or even early detection of recurrence (ideally prior to visible tumor size changes on imaging). The first liquid biopsy test approved by the FDA as a companion diagnostic, cobas[®] EGFR Mutation Test v2, is now increasingly used in routine practice for EGFR mutation testing in patients with advanced non-small cell lung cancer, expanding the access of this population to potential disease-modifying treatments. Comprehensive molecular profiling of tumors using next-generation sequencing (NGS) analysis of ctDNA is another major advancement in personalized lung cancer oncology, with tremendous potential for monitoring of dynamic tumor behavior in response to targeted therapy. Other simple and innovative tools for monitoring of treatment response are also being explored. For example, recent data showed that breath analysis using nanoarray technology may represent a quick and patient-friendly monitoring tool for earlier recognition of treatment failure and thus potentially serve as a surrogate marker for response to lung cancer therapy. Monitoring of treatment-related toxicity Subjective toxicity -which cannot be assessed by current toxicity scales- is frequently under-reported in clinical trials, with important negative implications on drug safety evaluations and patient care in general. Recent data highlight the need to improve the current system of toxicity assessment in the trial setting, mainly via implementation of patient-reported outcomes (PROs). Self-reported (and, ideally, real-time) monitoring of toxicity is increasingly investigated in the setting of routine oncology practice as well. As of yet it remains to be firmly established whether this system may significantly contribute to earlier identification and better management of adverse events, improved patient-physician communication and higher quality of life. Suggested reading 1.Nishino M, Hatabu H, Johnson BE, McLoud TC. State of the art: response assessment in lung cancer in the era of genomic medicine. Radiology 2014; 271: 6-27. 2.Bennett CW, Berchem G, Kim YJ, El-Khoury V. Cell-free DNA and next-generation sequencing in the service of personalized medicine for lung cancer. Oncotarget 2016; doi: 10.18632/oncotarget.11717. 3.Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res 2013; 19: 3936-43. 4.Di Maio M, Basch E, Bryce J, Perrone F. Patient-reported outcomes in the evaluation of toxicity of anticancer treatments. Nat Rev Clin Oncol 2016; 13: 319-25.

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Introduction At the time of the 17[th] World Conference on Lung Cancer, the 8[th] edition of the tumor, node and metastasis (TNM) classification of lung cancer will have been published by the Union for International Cancer Control, the American Joint Committee on Cancer and the International Association for the Study of Lung Cancer (IASLC) in their respective staging manuals. The innovations introduced, based on the analyses of the new IASLC database that includes 70,967 evaluable patients with non-small cell lung cancer and 6,189 with small cell lung cancer are described in the table. (1-9) These innovations will lead to some changes in clinical practice that are worth reflecting on. Table. Innovations introduced in the 8[th] edition of the TNM classification of lung cancer.

Descriptor	8[th] edition
T component
>/= 1cm	T1a
>1 – 2cm	T1b
>2 – 3cm	T1c
>3 – 4cm	T2a
>4 – 5cm	T2b
>5 – 7cm	T3
>7cm	T4
Brochus <2cm from carina	T2
Total atelectasis/pneumonitis	T2
Diaphragm inasion	T4
Mediastinal pleura invasion	-
M component
Metastases in thoracic cavity	M1a
Single extrathoracic metastasis	M1b
Multiple extrathoracic metastases	M1c
Other innovations in classification
Second primaries	One TNM for each
Separate tumor nodules	T3, T4 and M1a
Multifocal adenocarcinomas with ground glass opacity/lepidic features	Highest T (#/m) and global N and M
Pneumonic type adenocarcinoma	T3, T4 and M1a

The T component Tumor size is a much more relevant prognostic factor than in previous editions and is now a descriptor in all T categories. Therefore, tumor size measurement should be carefully performed because small changes in size mean important changes in prognosis. (2) In part-solid tumors, only the solid/invasive part counts to measure tumor size. (7) The fact that adenocarcinoma in situ –Tis(AIS) – and minimally invasive adenocarcinoma –T1mi– have their own coding in the TNM classification will increase their awareness. (7) These, together with the smallest coded solid tumors, those of one cm or less in largest dimension –T1a– can become the base from which to study therapeutic options, such as sublobar resections, stereotactic radiotherapy, radiofrequency ablation; tumor biology, including tumor growth, tumor density and intensity of the standardized uptake value, as well as molecular profile and genetic signatures. Visceral pleural invasion and its two categories (PL1: invasion beyond its elastic layer; and PL2: invasion of the pleural surface) have been confirmed as important prognostic factors. (2) This means that pathologists should intensively investigate the identification of visceral pleural invasion, and, if it is not evident by the standard hematoxylin and eosine stains, elastic stains should be used, as recommended in the 7[th] edition of the TNM classification. (10) The N component Although there will be no changes in the N categories, the analyses for the 8[th] edition have shown that quantification of nodal disease has prognostic implications. This had already been evident in the 7[th] edition, when it was found that the number of involved nodal zones was prognostic. The analyses for the 8[th] edition have considered the number of involved nodal stations and have found that the more nodal stations involved, the worse the prognosis; and that the prognosis of tumors with involvement of multiple N1 stations was similar to that of tumors with single station N2 without concomitant N1 disease (skip metastases). (3) The findings of the 7[th] edition already raised the issue of indicating upfront resection in patients with tumors with single N2 zone involvement, because their prognosis was the same as that of tumors with multiple N1 zones. The question will be raised again in the light of the results of the 8[th] edition. However, in both occasions, the quantification of nodal disease derived from pathological staging of those tumors that had been resected and the resection had been accompanied by a properly performed systematic nodal dissection. This is difficult to replicate at clinical staging, the moment at which therapeutic decisions are made, unless a transcervical mediastinoscopic lymphadenectomy is performed. This lymphadenectomy has been found to be equivalent to that performed at the time of resection, either by thoracoscopic or open surgery, and is the only pre-resection test that can define single station or single zone N2 disease reliably. The M component There is no change in the metastasis within the thoracic cavity (M1a), but single extrathoracic metastases have better prognosis than multiple extrathoracic metastasis in one or in several organs, and different categories have been defined for them: M1b for single and M1c for multiple extrathoracic metastases. (4) The fact that single extrathoracic metastasis have their own category will facilitate the redefinition of oligometastatic and oligoprogressive disease, the establishment of therapeutic protocols with radical intention, and the investigation of all therapeutic modalities to eliminate the advance disease. However, clinical staging will have to be precise and will have to determine the number and the organ location of the metastatic deposits. The stages Some TNM subsets have moved from one stage to another and new stages and sub-stages have been created to accommodate groups of tumors with similar prognosis. (5) As it occurred with the 7[th] edition, the question of how to treat patients whose tumors have changed stage will be raised at multidisciplinary team meetings. Taxonomic changes do not necessarily mean an automatic change in therapy if the clinical trials performed to test therapeutic options did not include the tumors that are now included in the selected stages for study. Therefore, in the absence of results from clinical trials, clinical judgment will have to determine what the best options are for a given patient with a given tumor. Lung cancer with multiple lesions The 8[th] edition will provide a set of rules with the intention to classify lung cancers with multiple lesions in a homogeneous way. (8) It is our responsibility to follow the rules to collect prospective data uniformly and validate the given recommendations with international data. Conclusion The 8[th] edition will help us refine prognosis both at clinical and pathologic staging and stratify tumors in future clinical trials, but will require more attention from us at measuring tumor size, at determining nodal disease, at searching for metastases, and at using clinical judgment to indicate treatment. References 1. Rami-Porta R, Bolejack V, Giroux DJ et al. The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer. J Thorac Oncol 2014; 9: 1618-1624. 2. Rami-Porta R, Bolejack V, Crowley J et al. The IASLC lung cancer staging project: proposals for the revisions of the T descriptors in the forthcoming 8[th] edition of the TNM classification for lung cancer. J Thorac Oncol 2015; 10: 990-1003. 3. Asamura H, Chansky K, Crowley J et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the N descriptors in the forthcoming 8[th] edition of the TNM classification for lung cancer. J Thorac Oncol 2015; 10: 1675-1684. 4. Eberhardt WEE, Mitchell A, Crowley J et al. The IASLC lung cancer staging project: proposals for the revisions of the M descriptors in the forthcoming 8[th] edition of the TNM classification for lung cancer. J Thorac Oncol 2015; 10: 1515-1522. 5. Goldstraw P, Chansky K, Crowley J et al. The IASLC lung cancer staging project: proposals for the revision of the stage grouping in the forthcoming (8th) edition of the TNM classification of lung cancer. J Thorac Oncol 2016; 11: 39-51. 6. Nicholson AG, Chansky K, Crowley J et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the clinical and pathologic staging of small cell lung cancer in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol 2016; 11: 300-311. 7. Travis WD, Asamura H, Bankier A et al. The IASLC Lung Cancer Staging Project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol 2016; 11: 1204-1223. 8. Detterbeck FC, Nicholson AG, Franklin WA et al. The IASLC Lung Cancer Staging Project: summary of proposals for revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol 2016; 11: 539-650. 9. Detterbeck FC, Chansky K, Groome P et al. The IASLC Lung Cancer Staging Project: methodology and validation used in the development of proposals for revision of the stage classification of NSCLC in the forthcoming (eighth) edition of the TNM classification of lung cancer. J Thorac Oncol 2016; 11: 1433-1446. 10. Travis WD, Brambilla E, Rami-Porta R et al. Visceral pleural invasion: pathologic criteria and use of elastic stains. Proposal for the 7[th] edition of the TNM classification for lung cancer. J Thorac Oncol 2008; 3: 1384-1390.

Background:
Osimertinib is a potent, irreversible, CNS active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for sensitising (EGFRm) and T790M resistance mutations. Osimertinib is indicated for the treatment of patients with locally advanced or metastatic EGFR T790M-positive NSCLC. AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib versus platinum-based chemotherapy plus pemetrexed in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on first-line EGFR-TKI therapy.

Methods:
Eligible patients were ≥18 years with documented EGFRm, radiological disease progression following first-line EGFR-TKI and centrally confirmed T790M-positive (by cobas® EGFR Mutation Test) from a tissue biopsy after disease progression. Asymptomatic, stable CNS metastases were allowed. Patients were randomised 2:1 to osimertinib 80 mg orally, once daily or platinum-pemetrexed (pemetrexed 500 mg/m[2] plus either cisplatin 75 mg/m[2] or carboplatin AUC5) every three weeks for up to six cycles; pemetrexed could be continued as maintenance treatment. Primary endpoint was progression-free survival (PFS) by investigator assessment according to RECIST v1.1; sensitivity analysis was by blinded independent central review (BICR).

Results:
A total of 419 patients were randomised to treatment (osimertinib, n=279; platinum-pemetrexed, n=140). Baseline characteristics were generally balanced across treatment groups: female 64%, Asian 65%, never smoker 68%, CNS metastases 34%, EGFR exon 19 deletion 66%. Osimertinib significantly improved PFS compared with platinum-pemetrexed: hazard ratio [HR] 0.30; 95% CI: 0.23, 0.41; p<0.001 (median 10.1 months vs 4.4 months). The result was consistent with PFS analysis by BICR: HR 0.28; 95% CI: 0.20, 0.38; p<0.001 (11.0 months vs 4.2 months). Objective response rate was significantly improved with osimertinib (71%) vs platinum-pemetrexed (31%); odds ratio 5.39 (95% CI: 3.47, 8.48; p<0.001). Median duration of response was 9.7 months (95% CI 8.3, 11.6) with osimertinib and 4.1 months (95% CI 3.0, 5.6) with platinum-pemetrexed. Grade ≥3 causally-related adverse events (AEs) as assessed by the investigator were reported in 6% of patients (n=16) treated with osimertinib and 34% (n=46) treated with platinum-pemetrexed. Most common causally-related AEs in the osimertinib group: diarrhoea (29% [grade ≥3, 1%]), rash (28% [<1%]); in the platinum-pemetrexed group: nausea (47% [3%]), decreased appetite (32% [3%]).

Conclusion:
In patients with EGFR T790M-positive advanced NSCLC following progression on EGFR-TKI treatment, osimertinib demonstrated a superior clinically-meaningful efficacy over platinum-pemetrexed, with a 70% reduction in the risk of disease progression, and well-characterised safety profile, establishing the new standard of care for these patients.

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Background:
Non-small cell lung cancer (NSCLC) with brain metastases （M） had a poor prognosis. Whole brain irradiation (WBI) is a standard of care for this critical medical condition. The median survival is only 4-6 months. Small molecule inhibitors of epidermal growth factor receptor (EGFR) including icotinib achieved very successful results in advanced NSCLC with EGFR mutations. There were no prospective randomized clinical trials to explore the efficacy of EGFR tyrosine kinase inhibitors (TKIs) on brain M.

Methods:
Advanced NSCLC with EGFR sensitive mutations and brain M were randomized to WBI plus chemotherapy (chemo) or icotinib. Patients in WBI arm received radiotherapy with 30Gy/3Gy/10 fractions plus concurrent or sequential doublet chemo of 4-6 cycles. Patients in EGFR TKI arm received icotinib 125mg orally tid until disease progression. Icotinib could be continued beyond progression if clinical benefit was observed by the investigator. Crossover to icotinib from WBI could be permitted. Key inclusion criteria were EGFR mutations and radiologically confirmed brain M with at least 3 lesions. The primary endpoint was intracranial progression-free survival (iPFS) by investigator assessments according to RECIST v1.1. The secondary endpoints included objective response rate (ORR), PFS and overall survival (OS). Safety and tolerability were assessed by measuring adverse events （AEs） (CTCAE v4).

Results:
From Dec. 2012 to June 2015, 176 patients from 17 sites were randomized to WBI+Chemo arm (N=91) or icotinib arm (N=85). The baseline clinicopathologic factors were balanced between the two groups. Median age was 58, PS 1 was 87.2%, non-smoker 70.9%, adenocarcinoma 96.8%, symptomatic brain M were 16.5%. Icotinib significantly improved median iPFS compared with WBI+chemo: hazard ratio [HR] 0.56; 95% CI: 0.36-0.90; p=0.014 (10.0 vs 4.8 months). Median PFS was 6.8 vs 3.4 months, (HR 0.44, 95% CI 0.31-0.63, P<0.001). Median OS had no significant difference between the arms (18.0 vs 20.5 months, HR 0.93, 95%CI 0.60-1.44, P=0.734). Intracranial ORR was significantly improved with icotinib than WBI+Chemo (67.1% vs 40.9%; p<0.001); Overall ORR was 55.0% vs 11.1% (P<0.001). Grade ≥3 AEs assessed by the investigators were reported in 8.2% (N=7) of patients treated with icotinib and 26.2% (N=28) treated with WBI+Chemo. Most common causally related AEs in the icotinib arm were increased liver transaminase & rash; in the WBI+Chemo arm were hematologic toxicity.

Conclusion:
Icotinib demonstrated superior iPFS, PFS and ORR over WBI+Chemo in EGFR mutant advanced NSCLC with brain M, and well-tolerated safety profile. Icotinib would be a treatment option for EGFR mutant patients with brain M (NCT01724801).

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Background:
Here, we report results of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.

Methods:
Untreated ALK+ (IHC confirmed), advanced, nonsquamous NSCLC patients (N=376; median age, 54 years) were randomized (1:1) to ceritinib 750 mg/day (n=189 [59 with brain metastases (BM)]) or chemotherapy (n=187 [62 with BM]; [pemetrexed 500 mg/m[2] plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed), stratified by WHO PS (0 vs 1-2), BM at screening, and prior neo-/adjuvant chemotherapy. Crossover from chemotherapy to ceritinib was allowed at progression (n=80 crossed-over).

Results:
Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. Median follow-up duration was 19.7 months (randomization to cut-off date). The study met its primary objective, with ceritinib demonstrating statistically significant improvement in BIRC PFS (RECIST 1.1; median, 16.6 [12.6, 27.2] vs 8.1 months [5.8, 11.1], HR=0.55, P<0.001) versus chemotherapy. OS was immature (HR, 0.73 [0.50, 1.08]; P=0.056) with 42.3% of required events at interim analysis. ORR (BIRC, 72.5% vs 26.7%) and DOR (BIRC, median, 23.9 vs 11.1 months) were also higher with ceritinib versus chemotherapy. Among patients with measurable baseline BM and ≥1 postbaseline assessment, intracranial ORR (BIRC neuroradiologist; modified RECIST v1.1) was higher with ceritinib (72.7% [49.8, 89.3] vs 27.3% [10.7, 50.2]) versus chemotherapy (Table). Most common AEs (>50%) with ceritinib were diarrhea (84.7%), nausea (68.8%), vomiting (66.1%), ALT increase (60.3%), and AST increase (52.9%). Overall, 5.3% ceritinib- and 11.4% chemotherapy-treated patients discontinued due to AEs suspected to be drug-related. Figure 1



Conclusion:
First-line ceritinib achieved statistically significant and clinically meaningful improvement in median PFS with an estimated 45% risk reduction in advanced ALK+ NSCLC versus chemotherapy including maintenance. Moreover, ceritinib achieved high and durable systemic responses and high OIRR in patients with measurable BM. Safety profile of ceritinib is consistent with previously reported.

Abstract not provided

Background:
Heat shock protein 90 functions as a chaperone to stabilize oncoproteins. Ganetespib (G), a highly potent Hsp90 inhibitor, has demonstrated efficacy in combination with docetaxel (D) over D alone in the second-line therapy of patients with advanced adenocarcinoma of the lung in a phase 2 study.

Methods:
GALAXY-2 is a randomized (1:1), international, open-label study of D with or without G. Patients with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) of adenocarcinoma histology, EGFR and ALK wild-type, diagnosed ≥ 6 months prior to study entry, one prior systemic therapy and ECOG PS 0-1 were eligible. D was given at 75 mg/m[2] on day 1 of three-week cycle; D was given on day 1 with G at 150 mg/m[2 ]on Days 1 and 15 of each cycle. Patients were stratified by performance status (PS), LDH, and geographic region. Primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS) and OS in elevated LDH (eLDH) patients. We report the results of a planned interim analysis at 336 events, which occurred on October 5, 2015, with type I error level set at 0.01 (2 sided stratified log-rank test).

Results:
677 patients were randomized with 335 patients in G+D arm and 337 patients in D arm. Baseline characteristics: females 60%, age < 65 68%; never-smoker 18%; PS 0 36%; eLDH 29%; North America/Western Europe 39%. The median number of cycles delivered was 5 in G+D and 4 in D arm. There was no difference in median OS (mOS) for the two arms: 10.9 months with G+D versus 10.5 months with D alone. The hazard ratio for OS was 1.111 (95% CI 0.899-1.372), which met the early stopping criteria for futility. Median PFS was similar in the two arms: 4.2 versus 4.3 months, G+D and D, respectively (HR 1.161, 95% CI 0.961-1.403). There was no improvement with the addition of G for any secondary endpoint, including survival in the eLDH and EGFR and ALK negative populations, response rate, or progression due to new metastatic lesions. The most common grade 3/4 treatment-emergent adverse event in both arms was neutropenia (31.1% versus 24.3%, G+D and D, respectively).

Conclusion:
The addition of ganetespib to docetaxel did not result in improved efficacy for salvage therapy of patients with advanced stage lung adenocarcinoma.

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