Virtual Library

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Recent advances in molecular biology have revealed that lung cancer is not a single disease and that there are subsets of non-small cell lung cancer (NSCLC) with specific genetic alterations that are critical to the growth and survival of cancer cells. Alterations of the EGFR, ALK and ROS1 gene, which are present in a mutually exclusionary fashion, are representative driver oncogene mutations. Targeted drugs against each driver oncogene usually result in dramatic tumor shrinkage and prolongation of progression free survival (PFS) compared with conventional platinum doublet chemotherapy. However, there is only a weak association between WHO pathologic classification 2015 and type of driver oncogenes. Therefore, it is of utmost importance to identify who are likely to benefit from targeted drugs by performing molecular tests for each lung cancer patient who is a candidate for drug therapy. A list of driver oncogenes is further expanding; BRAF, RET, MET, HER2, NTRK1 are being recognized as new drivers that can be exploited in the clinic. It is getting more practical to screen these molecular alterations by use of next generation sequencing technology, rather than to detect each gene alterations one by one using different platforms. We have also known that not all the tumors with mutations of the same gene behave similarly. For example, while deletional mutation in exon 19 and L858R in exon 21 are two representative mutations that sensitize cancer cells to EGFR-tyrosine kinase inhibitors (TKI), G719X in exon 18 has an intermediate sensitivity and insertional mutation in exon 20 or de novo T790M are known to be resistant. It has been shown that there is a heterogeneity in efficacy of EGF-TKIs depending on the class of mutation. For example, afatinib is active among other EGFR-TKIs for exon 18 mutations. Furthermore, a certain molecular context is known to be associated with primary resistance even within lung cancers with the same EGFR mutations. For example, it is reported that mutations in the PI3K/AKT/mTOR pathway (AKT1, PIK3CA, STK11, PTEN) or TP53 mutations are more frequent in non-responders and are associated with shorter PFS. This context dependence may present in other driver oncogenes, too. Acquired resistance is almost inevitable in the treatment of lung cancer with targeted drug. Mechanisms of this resistance has been extensively studied and now we know there are at least 3 types of mechanisms; i.e., 1) target modification by the secondary mutation that alters the affinity between the drug and the target relative to the affinity between ATP and the target (e.g., T790M in EGFR, L1196M in ALK), 2) accessory pathway activation that bypass the inhibitory effect of the drug(e.g., Met amplification in EGFR), and histologic transformation, such as small cell lung cancer transformation and epithelial-mesenchymal transition. We are now able to use the newer generation of TKIs to treat some of the resistance due to the secondary mutation of the target gene. Osimertinib has recently been shown to prolong PFS of patients who acquired resistance to EGFR-TKI through T790M mutation compared with platinum-pemetrexed in the AURA 3 trial. Therefore, detection of this mutation which accounts for about 50~60 % of the acquired resistance against EGFR-TKI is important. However, re-biopsy is sometimes more challenging compared with that in the first-line setting, and therefore detection of T790M in cell-free DNA in plasma has been rapidly developed and is now approved in regulatory authorities in several countries. There is another issue which should be taken into consideration when treating patients with acquired resistance. When there are multiple metastatic lesions, resistance mechanisms may vary from one tumor to another. Hence, it can happen that while one tumor shrinks but others increase in size. It may be reasonable and thus beneficial for patients when treatment is planned according to most prevalent mechanism of resistance in the plasma as a sum of total resistant mechanism. In this talk, I would like to overview recent advances of molecular diagnosis in targeted therapy of lung cancer and also like to discuss future perspectives in this field.

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ALK positive NSCLC represents 2-7% of advanced NSCLC. Three ALK TKIs have shown positive first line trials against either platinum-doublet chemotherapy (ceritinib and crizotinib) or against crizotinib (alectinib). At least three other first line trials against crizotinib are ongoing (brigatinib, ensartinib and lorlatinib). Activity of different ALK TKIs post crizotinib are characterized by comparable response rates but differing toxicity profiles, durations of benefit and extent of CNS activity. With changes in the first line standard, data post non-crizotinib ALK TKIs continues to emerge with attendant caution re the applicability of both biological and clinical data currently available for clinical decision making. Advances in our understanding of CNS trial endpoints has also helped facilitate cross trial comparisons of CNS activity of these different agents. Chemotherapeutic, radiotherapeutic and immunotherapeutic options other than ALK TKIs have all generated different clinical datasets - defining both some reasonable clinical options and some clearly in need of additional research.

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As a result of recent advances, systematic genomic testing for patients with non-small cell lung cancer (NSCLC) is the new standard of care in clinical decision-making, due to the identification of driver molecular alterations that have triggered the development of new molecules targeting these specific alterations in cancer cells. Several studies have enabled to conclude that both EGFR-mutant and ALK-positive NSCLC constitute two defined subgroups of oncogene-driven tumors with potentially effective targeted therapy. Furthermore, approximately 15-20% of NSCLC diagnosed in Europe and North America bear EGFR mutations or ALK rearrangements, enhancing the significance of the development of drugs capable of interfering with their intracellular effects. Based on these results, the identification of other activating mutations has been pursued in hopes of improving survival in NSCLC by specifically treating these genomic alterations. These potential therapeutic targets include ROS1, BRAF, RET, HER2, MET exon 14 skipping mutations and NTRK, among others. Here, we seek to review the characteristics of emerging targets that enable interaction with molecules that specifically target these receptors in lung adenocarcinomas, as well as the results of preliminary studies that assess the efficacy of these new strategies applied to NSCLC. ROS1 ROS1 rearrangement characterizes a small subset (1%–2%) of NSCLC and is associated with slight/never smoking patients and adenocarcinoma histology. Crizotinib was shown to harbor relevant activity in ROS1-rearranged NSCLC. A number of agents including ceritinib, lorlatinib and entrectinib are now been developed in order to overcome the resistance to crizotinib. At present, ROS1-rearranged patients represents a clearly defined NSCLC molecular subgroup with highly active therapeutic options. BRAF BRAF mutations occur in 2%–4% of patients with NSCLC, with the most common resulting in a glutamate substitution for valine at codon 600 (V600E). Non‐V600E BRAF mutations make up the remaining BRAF mutations and may be either activating (i.e., G469A/V, K601E, L597R) or inactivating (i.e., D594G, G466V). Efforts targeting BRAF‐mutant NSCLC to date have almost exclusively focused on patients with V600E‐mutant disease. Direct inhibition of mutant BRAF and/or the downstream mitogen-activated protein kinase kinase has led to good outcomes survival in patients with BRAF-mutant metastatic NSCLC. Dabrafenib plus trametinib achieved 63·2% response rate (RR) in BRAF(V600E)-mutant NSCLC. RET RET fusions are detected in 1-2% of lung adenocarcinomas and a number of genes, such as KIF5B, CCDC6, NCO4 and TRIMM33, can act as fusion partners. In a global registry of RET positive NSCLC patients, 41 received a RET inhibitor achieving a median progression-free survival of 2.9 months and a median overall survival of 6.8 months. Response rate was 34% for those patients receiving cabozantinib and 27% for those receiving vandetanib. Overall RET inhibitors strategies seem active in a subgroup of patients with RET-rearranged NSCLC. However, RR is lower to that observed in EGFR-mutated/ALK-positive patients. HER2 HER2 mutations are identified in about 2-4% of NSCLC and are critical for lung carcinogenesis. A number of series shows the chemosensitivity of HER2-driven NSCLC, and the potential interest of HER2-targeted agents. In a recent study, NSCLC patients with HER2 mutations were treated with T-DM1 and achieved a 44% RR. MET Approximately 2-3% of NSCLCs harbor activating mutations of the MET proto-oncogene that cause exon 14 skipping (METex14) and accumulation of c-Met lacking a juxtamembrane domain. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated in patients harboring MET exon 14 skipping lung cancer. MET seems a relevant target in NSCLC and a number of clinical trials with MET inhibitors in this population are now ongoing. NTRK TRK rearrangements represent the molecular driver of a subset of solid tumors, including 1-2% of NSCLCs. Preliminary data indicate that molecularly selected NSCLC patients harboring NTRK fusions derive an unprecedented clinical benefit from Trk-directed targeted therapies. There are two different targeted agents, entrectinib and larotrectinib, that are in phase II testing for any patients who have solid tumors with NTRK rearrangement, including NSCLC patients. Both drugs have achieved dramatic responses, regardless of histology in earlier phase I studies. In a study presented at ASCO 2017, larotrectinib has demonstrated consistent and durable antitumor activity in TRK fusion cancers, across a wide range of ages and tumor types. REFERENCES Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS-1 rearranged non-small-cell lung cancer: N Engl J Med. 2014; 371:1963-1971. Planchard D, Besse B, Groen HJ, et al. Dabrafenib plus trametininb in patients with previously treated BRAF (V600E)-mutant metastatic non-small cell lung cancer: an opne-label, multicentre phase 2 trial. Lancet Oncol. 2016;17:984-993. Gautschi O, Milia J, Filleron T, et al. Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry. J Clin Oncol. 2017;35:1403-1410. Mazières J, Barlesi F, Filleron T, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol. 2016;27:281-286. Lu X, Peled N, Greer J, et al. MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma. Cancer Res. 2017 May 18. [Epub ahead of print]. Drilon A, Nagasubramanian R, Blake JF, et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov. 2017 Jun 3. [Epub ahead of print]. Hyman DM, Laetsch TW, Kummar S, et al. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. J Clin Oncol. 2017;35 (suppl; abstr LBA2501). Riely GL. What, When, and How of Biomarker Testing in Non-Small Cell Lung Cancer. J Natl Compr Canc Netw. 2017;15:686-688. Jordan EJ, Kim HR, Arcila ME, et al. Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. Cancer Discov. 2017;7:596-609.

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Clinical development and approval of immune-checkpoint inhibitors have transformed the treatment of many types of tumors. In recent years, three anti-PD-1 or –PD-L1 antibodies have been approved for advanced NSCLC, including nivolumab, pembrolizumab, and atezolizumab. These antibodies have entered into the routine practice of treatment for patients with advanced NSCLC. In addition, all clinical trials, which compared the efficacy of anti-PD-1 or PD-L1 antibodies with chemotherapy, demonstrated that these antibodies are less toxic than chemotherapy (1-4). However, these immunomodulatory antibodies have led to the emergence of unusual autoimmune toxicities, also called immune-related adverse events (IrAEs). IrAEs management is challenging because they may concern many organ systems, including the skin, hepatic, gastrointestinal, endocrine, and pulmonary systems. Furthermore, given the recent success of immunotherapy, the incidence of immunotoxicity will likely continue to rise as these therapies become more widely used not only in advanced diseases but also in early stage diseases (5). Treatment-related toxicities have correlated with better response in some cases, and it is probable that serious adverse events from immune-mediated reaction will increase as immunotherapeutic approaches become more effective (6). Adding more complexity, the natural history of certain irAEs is unpredictable. The onset of clinical disease manifestation can vary from weeks to decades after the appearance of autoantibodies (7). Thus understanding irAEs is critical for early detection and appropriate management of patients. We will discuss the mechanisms that might be related with the induction of anutoimmunity from immunotherapy. References: Lancet. 2016; 387(10027):1540-50. N Engl J Med. 2015;373(2):123-35. N Engl J Med. 2015; 373(17):1627-39. Lancet. 2016;387(10030):1837-46. Eur J Cancer. 2016 ;54:139-48. Blood. 2011;118(3):499-509. Nat Med. 2017 ;23(5):540-547.

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Checkpoint protein inhibition is associated with on- and off-target, cell and metabolic toxic effects that need to be carefully monitored and managed during and after treatment[1]. Despite important clinical benefits, immunotherapy is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs) or, occasionally, adverse events of special interest. IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. Most irAEs remain mild in intensity but approximately 10% of patients treated with immune checkpoint blockade agents will develop severe, sometimes life-threatening, grade 3–4 dysimmune toxicities. Before prescribing immune checkpoint blockade agents to patients, oncologists need to be aware of the toxicity spectrum and must identify potential risk factors that could favor the emergence of irAEs[2]. Patients should be informed that most of these irAEs are mild and reversible if detected early and specifically addressed. Therefore, patients should be educated about signs of organ inflammation that would require prompt referral such as diarrhea, blood or mucus in the stool, severe abdominal pain, fatigue, weight loss, nausea, vomiting, thirst or appetite increase, polyuria, extensive rash, severe pruritus, shortness of breath, coughing, headache, confusion, muscle weakness, numb-ness, arthralgia or swelling joints, myalgia, unexplained fever, hemorrhagic syndrome
and severe loss of vision in one or both eyes. Any new symptom or deterioration of pre-existing symptoms must at least be monitored attentively and if necessary be explored to determine its etiology and rule out any dysimmune cause that could be worsened by immunotherapy continuation. Although early recognition and treatment improves symptoms and severity, a broad differential diagnosis should be entertained. It is recommended that all patients receiving these agents routinely have thyroid function studies, complete blood counts, and liver function and metabolic panels at each treatment and at intervals of 6 to 12 weeks for the first 6 months after finishing treatment. Adrenocorticotropic hormone, cortisol, and in men, testosterone should also be checked in patients who develop fatigue and nonspecific symptoms. Follow-up testing may need to increase in frequency based on individual response and adverse events that occur[3]. It is challenging to differentiate between infection, early pulmonary edema, alveolar hemorrhage, immune-mediated pneumonitis, immune-related tumor inflammation, and tumor progression (figure 1). Infections, thromboembolism, congestive heart failure, and COPD are among the many diagnoses to consider before committing patients to a long course of steroid therapy with additional consideration of prophylaxis for opportunistic (i.e., pneumocystis with or without fungal) infections. Pulmonary specialty consultation and consideration of bronchoscopic evaluation with lavage to assess for infections alongside biopsies of lung tissue can help narrow the diagnosis. IrAEs can develop at any time: at the beginning, under treatment and after immunotherapy termination. As shown with nivolumab, the majority of irAEs occur within the first 4 months[4]. On the basis of this median time to onset, irAEs could be classified as early (median time to onset <2 months) and late toxicities (median time to onset >2 months). Early toxicities include skin (5 weeks), gastrointestinal (7.3 weeks) and hepatic (7.7 weeks), whereas late toxicities include pulmonary (8.9 weeks), endocrine (10.4 weeks) and renal (15.1 weeks). However, clinicians should keep in mind that all toxicities can develop at any time since confidence interval may vary widely among organs: 0.1–57 weeks for skin; 0.1–37.6 weeks for gastrointestinal. Rarely, other irAEs may occur after week 24 with any checkpoint-blocking antibodies. In trials including maintenance ipilimumab, colitis has been seen 47 months from initiation of treatment[5]. Patients with prior autoimmune diseases or a history of viral hepatitis have been excluded from receiving ipilimumab on trials, but recent data suggest that the drug can be given safely to those patients. Nonetheless, extreme caution should be taken in treating patients with recent or ongoing autoimmune conditions, particularly any type of inflammatory bowel disease[6]. Management algorithms have been established for patients treated with immunotherapy, which may be useful in helping to manage irAEs but they are based upon clinical experience, since no prospective trials have been conducted to guide the treatment of irAEs. Resolution of irAEs usually follows a temporal pattern: 2 weeks for gastrointestinal, 4 weeks for hepatic, 6 weeks for skin, and 20 weeks for endocrine irAEs[7]. The key to successful management of checkpoint protein antibody toxicities is early diagnosis, high suspicion, excellent patient-provider communication, and rapid and aggressive use of corticosteroids and other immune suppressants for irAEs. Effective biomarkers to predict toxicity could be valuable in the development of these agents. Figure 1 FIGURE 1: CT scan of a patient with non-small cell lung cancer presenting with cough, dyspnea, and hypoxia on an immunotherapy drug. References: Fecher LA, et al: Ipilimumab and its toxicities: A multidisciplinary approach. Oncologist 18:733-743, 2013 Champiat S. et al., Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper Annals of Oncology Volume 27, No. 4, 559-74, 2016 Weber JS et. al. Toxicities of Immunotherapy for the Practitioner, J of Clin Oncol., volume 33, No 18, 2092-2099, 2015 Weber JS et al. Safety profile of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL): a pooled analysis. J Clin Oncol 2015; 33 (suppl): abstr 9018 Sarnaik AA et al: Extended dose ipilimumab with a peptide vaccine: Immune corre- lates associated with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma. Clin Cancer Res 17:896-906, 2011 Hodi FS, et al: Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial. JAMA 312:1744-1753, 2014 Weber JS, et al. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-2697

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Checkpoint inhibitors have changed the outcome of patients with metastatic non-small cell lung cancer (NSCLC). Radiotherapy has consistently been shown to activate key elements of the immune system that are responsible for resistance for immune therapy. Radiation upregulates MHC-class I molecules that many cancer cells lack or only poorly express, tumor-associated antigens, provokes immunogenic cell death, activates dendritic cells, decreases regulatory T-cells (Tregs) in the tumor, broadens the T-cell repertoire and increases T-cell trafficking, amongst many other effects. Radiation may convert a completely or partly poorly or non-immunogenic tumor immunogenic. Radiotherapy in combination with different forms of immune therapy such as anti-PD-(L)1, anti-CTLA4,immunocytokines, dendritic cell vaccination and Toll-like receptor agonists improved consistently local tumor control and very interestingly, lead to better systemic tumor control (the “abscopal” effect) and the induction of specific anti-cancer immunity with a memory effect. At the time of writing, the most compelling data in human studies come from Shaverdian et al. (Lancet Oncol 2017). In 97 patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial it was shown that patients having received prior radiotherapy, the six-month PFS rate was 54.3% vs. 21.4% among never irradiated patients. The median OS was 11.6 months and the six-month OS estimate was 75.3% among patients who previously received extra-cranial radiation therapy vs. a median OS of 5.3 months and a six-month OS estimate of 45.3% among patients who did not receive extra-cranial radiation therapy. Patients with prior thoracic radiotherapy had more overall pulmonary toxicity compared to never irradiated patients: 12.5% vs. 1.4%. Unfortunately, no dose-volume parameters such as the mean lung dose are available of these patients. The biggest concern of combining radiotherapy and immune treatment is indeed a higher incidence of pneumonitis. Many studies are investigating the combination of radiotherapy, chemotherapy and immune therapy in lung cancer, including the PACIFIC, the STIMULI and the NICOLAS studies. The results of these studies have not been reported at the time of writing, but none of the trials have been closed prematurely. Moreover, as radiotherapy is used to stimulate the immune system, classical concept in dose and volume will have to be investigated again. Less dose in a few fractions may suffice, and margins may be reduced, which in turn will lead to less side effects. When studied meticulously, radiotherapy and immune therapy may well turn out to be efficacious and with few side effects and additional costs.

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The Holy Grail of precision medicine is the comprehensive integration of patient genotypic with phenotypic data to develop personalized disease prevention and treatment strategies. Single cell sequencing, single cell mass cytometry (CyTOF), microbiome, and other types of high-throughput assays have exploded in popularity in recent years. The ability to generate big data brings us one step closer to the realization of precision medicine; nevertheless, across the life cycle of such data, from experimental design to data capture, management, analysis, and utilization, many challenges remain. In this session, I will discuss the artificial intelligence in cancer research, common statistical and bioinformatic mistakes for designing, analyzing, and interpreting the Omics based biomarker research. I will also discuss potential pathways for the seamless integration of cellular and molecular data with clinical, behavioral, and environmental parameters – a critical next step in advancing the goals of precision medicine.

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Lung cancer is the leading cause of cancer-related deaths in other Western countries, with more than 1.8 million new cases and 1.5 million deaths worldwide in 2012 (Globocan, 2012). Recent advances in the management of NSCLC have included use of therapies targeting oncogenes (EGFR, BRAF or HER2 mutations, ALK or ROS1 rearrangements) but molecular alteration is currently detected in only the half of the patients with non-squamous NSCLC (Barlesi et al., 2016). Immune check point inhibitors (ICI), the first of which targeted the lymphocyte cell surface inhibitory receptor PD-1 or its ligand PD-L1, have recently become available and have been shown to provide an overall survival advantage over standard second-line chemotherapy (Borghaei et al., 2015; Brahmer et al., 2015; Herbst R et al, Lancet 2016; Rittmeyer et al, 2016), and more recently over first-line standard chemotherapy in monotherapy for a small subgroup driven by PD-L1 expression (Reck et al., 2016) or in combination regardless of PD-L1 expression (Langer et al, Lancet Oncol 2016), for both squamous and non-squamous NSCLC. Unfortunately, the long-term overall survival benefit is driven by only about 20-25% of the patients. PD-L1 tumor expression has been proposed to guide the patients’ selection but remains controversial (Kerr K, 2016). However, PD-L1 tumor expression of more than 1% and 50% is mandatory for the use of pembrolizumab monotherapy in second and first-line, respectively. Therefore, how to choose the best way to use ICIs for advanced NSCLC patients? Many aspects may be considered and will be discussed during the session including the PD-L1 expression and other potential predictive biomarkers (as tumor mutational burden), the current contra-indications to ICIs, the potential suspected factors predicting a higher risk of rapid progression on ICIs, the potential synergy for the concomitant combination of ICIs with chemotherapy or conversely a sequential use, the side effects for monotherapies and combinations, and the recent data on ICIs combinations versus standard chemotherapy. In summary, the attendees will have the arguments to globally assess the risk/benefit balance in using ICIs first or at resistance to chemotherapy and discuss the chosen strategies with their patients.

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Combination of chemotherapy with immune-check point inhibitor is considered to be one of the most promising strategy to improve efficacy of immune-check point inhibitors. Several clinical trials of chemotherapy with immune-check point inhibitor are conducted and the results have been reported. KEYNOTE-021 cohort G is a randomised, open-label, phase 2 cohort of a multicohort study assessed whether the addition of pembrolizumab to carboplatin and pemetrexed improves efficacy in patients with advanced non-squamous NSCLC. Thirty-three (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (p=0·0016). Progression-free survival (PFS) was significantly longer with pembrolizumab plus chemotherapy compared with chemotherapy alone (HR 0·53 [95% CI 0·31–0·91]; p=0·010). Median PFS was 13·0 months for pembrolizumab plus chemotherapy and 8·9 months for chemotherapy alone. The FDA has granted an accelerated approval to pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced non-squamous NSCLC, regardless of PD-L1 expression. Antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab that are currently approved for use in the treatment of NSCLC. Bevacizumab, in addition to platinum-based chemotherapy is widely used for the first-line treatment of advanced, metastatic, or recurrent NSCLC, excluding squamous cell carcinoma. VEGF influences lymphocyte trafficking across endothelia to the tumor by inhibiting lymphocyte adhesion and VEGF has a systemic effect on immune-regulatory cell function through multiple mechanisms, such as Tregulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs); suppression of dendritic cell maturation; and inhibition of T-cell development from hematopoietic progenitor cells. Thus, combination of antiangiogenic monoclonal antibody and immune-check point inhibitor is potentially synergistic. National Cancer Center Hospital conducted a single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced NSCLC. In this trial, nivolumab with gemcitabine/cisplatin, pemetrexed/cisplatin, paclitaxel/carboplatin/bevacizumab, or docetaxel were evaluated for six patients each arm. Combination of nivolumab and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Although small number of patients, nivolumab with paclitaxel/carboplatin/bevacizumab seems to be most promising with higher response rate and longer PFS. Based on these data, phase III study of paclitaxel/carboplatin/bevacizumab with/without nivolumab for advanced non-squamous NSCLC is ongoing.

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The development of metastases from a primary tumor is the ultimate cause of death in most of patients with cancer. In a non-small cell lung cancer (NSCLC) series of 236 patients with advanced disease, brain metastasis appeared to be the second leading site of metastasis after bone (1). In fact, 31.8% of the patients presented brain metastasis at onset and a total of 42.8% of all patients included developed brain metastasis at any time point (1). Despite recent advances in the treatment of patients with NSCLC, CNS infiltration remains a frequent complication leading to impaired quality of life and shortened survival among NSCLC patients. In the era of personalized medicine for patients harboring oncogenic driver mutations, CNS infiltration has become an especially relevant clinical issue. In fact, an apparent higher incidence of brain metastasis at onset, among patients with molecular alterations, in particular for ALK + tumors has been reported (2). In addition, a higher cumulative incidence of CNS involvement overtime during treatment with targeted agents has been shown and CNS may be the only site of progression to first or second-line tailored therapies. Unfortunately however, most patients with advanced NSCLC present tumors lacking druggable oncogenic driver aberrations. In 2011, the tumors’ capacity of avoiding immune destruction was recognized as a new emerging hallmark of cancer. More recently, the constellation of interactions between tumor cells and the immune environment around them has definitely emerged as a potential and valuable source of innumerable novel anti-cancer targets. From the clinical perspective, treatment with immune checkpoint inhibitors targeting programmed-cell death 1 (PD-1) and its ligand (PDL-1) represent the best treatment option for many patients with advanced NSCLC in first-line (3) and most of them in second-line (4-6) due to an improved quality of life and a significant survival benefit. Unfortunately, most phase II randomized/phase III clinical trials assessing the efficacy of monoclonal antibodies against PD-1 (3,4,6) and PDL-1 (5) immune checkpoints in second or first-line settings excluded patients with active or untreated brain metastasis. Additionally, no data on the evolution of previously locally treated CNS lesions during immunotherapy have been provided, nor information revealing the sites of distant progression in patients on the study arm experiencing progression disease to the treatment. The only available results in this regard are reflected in KEYNOTE-024 trial in which the subgroup analysis showed a statistically significant benefit in terms of progression-free survival for patients without baseline brain metastasis on pembrolizumab compared to non-significant differences among patients with brain involvement receiving the PD-1 blocker (3). More interestingly, Goldberg et al. reported the only direct evidence on the potential activity of an immune checkpoint inhibitor against brain metastasis from NSCLC in a non-randomized, open label, phase II clinical trial (7). The study enrolled 36 patients with untreated brain metastases from melanoma (18 patients) or NSCLC (18 patients) receiving pembrolizumab monotherapy. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression and the primary endpoint was brain metastasis response assessed in all treated patients. In the preliminary results reported, a brain metastasis response was achieved in four (22%; 95% CI 7–48) of 18 patients with melanoma and six (33%; 14–59) of 18 patients with NSCLC. Despite the low number of patients included, this remarkable activity shown by pembrolizumab among brain metastases in patients with NSCLC warrants further investigation in larger series and prompt the analysis of the anatomic, molecular and immune factors involved in those responses. Other studies have focused their attention in the immune microenvironment of the brain in an attempt to unravel the theoretical activity of an immune-directed therapeutic approach. Berghoff at al. investigated tumor-infiltrating lymphocytes (TIL) subsets and their prognostic impact in 116 brain metastases (BM) from different tumor type’s specimens using immunohistochemistry for CD3, CD8, CD45RO, FOXP3, PD1 and PD-L1 (8). Interestingly enough, they found TIL infiltration in 115/116 (99.1%) BM specimens. PD-L1 expression was evident in 19/67 (28.4%) BM specimens and showed no correlation with TIL density (p > 0.05). High infiltration was most frequently observed for CD3+ TILs (95/116; 81.9%) and least frequently for PD1+ TILs (18/116; 15.5%; p < 0.001). Highest TIL density was observed in melanoma, followed by renal cell cancer and lung cancer BM (p < 0.001). More importantly, the density of CD3+, CD8+, and CD45RO+ TILs showed a positive and significant correlation with favorable median overall survival (OS) times. The same group has found TIL infiltration and PD-L1 expression as a common feature in Small-cell Lung Cancer (SCLC) BM. In addition, the presence of CD45RO+ memory T-cells and PD-L1+ TILs in SCLC BM seemed to be associated with favorable survival times suggesting an active immune microenvironment in SCLC BM (9). Takamori et al., evaluated the discordance in PD-L1 expression between primary and metastatic lesions and analyzed the association between the discordance and other clinical factors in 21 NSCLC patients (10). Remarkably, among the 16 patients with brain metastases, in three of them there was a good correlation in PDL-1 expression between the primary tumor and the brain metastasis. In other two patients however, positive PDL-1 primary lesions produced PDL-1 brain metastases. Interestingly enough, in two patients with PDL-1 negative NSCLC undergoing radiation therapy for brain metastases followed by surgical resection of BM, irradiated lesions turned to be positive for PDL-1 expression suggesting a potential capacity of radiotherapy to induce PDL-1 expression in BM (10). In fact, these observations along with several preclinical findings have paved the way for the design of clinical trials combining radiation therapy and immune checkpoint inhibitors against brain metastases. In summary, here we present and discuss the most relevant evidences about the particular immune microenvironment of the brain, the clinical activity of immune checkpoint inhibitors against NSCLC brain metastasis as well as their potential combination with local radiation therapy and the hypothetical use of TIL infiltrates and PDL-1 expression as predictive biomarkers for response of brain metastases to immunotherapy. Several clinical cases illustrating these evidences will be also presented and discussed. References 1. Castanon E, Rolfo C, Vinal D, Lopez I, Fusco JP, Santisteban M, et al. Impact of epidermal growth factor receptor (EGFR) activating mutations and their targeted treatment in the prognosis of stage IV non-small cell lung cancer (NSCLC) patients harboring liver metastasis. J Transl Med. 2015;13:257. 2. Kang HJ, Lim HJ, Park JS, Cho YJ, Yoon HI, Chung JH, et al. Comparison of clinical characteristics between patients with ALK-positive and EGFR-positive lung adenocarcinoma. Respir Med. 2014;108(2):388-94. 3. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-33. 4. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627-39. 5. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837-46. 6. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-50. 7. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17(7):976-83. 8. Berghoff AS, Fuchs E, Ricken G, Mlecnik B, Bindea G, Spanberger T, et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology. 2016;5(1):e1057388. 9. Berghoff AS, Ricken G, Wilhelm D, Rajky O, Widhalm G, Dieckmann K, et al. Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J Neurooncol. 2016;130(1):19-29. 10. Takamori S, Toyokawa G, Okamoto I, Takada K, Kozuma Y, Matsubara T, et al. Discrepancy in Programmed Cell Death-Ligand 1 Between Primary and Metastatic Non-small Cell Lung Cancer. Anticancer Res. 2017;37(8):4223-8.

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Abstract:
The significant activity of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) checkpoint inhibitors in heavily pre-treated patients with advanced non–small-cell lung cancer (NSCLC) marked the beginning of a new era of immunotherapy. Recently published randomised clinical trials’ data have led to the approval of 3 PD-1/PD-L1 inhibitors—nivolumab (Opdivo; Bristol-Myers Squibb Company), pembrolizumab (Keytruda; Merck Sharp & Dohme Corp), and atezolizumab (Tecentriq, Genentech/Roche)—for the treatment of advanced NSCLC after first-line therapy. Furthermore, pembrolizumab was recently approved by the FDA as a first-line therapy for patients with advanced NSCLC. However, the overall response rates to these agents in an unselected population are reportedly low, thus emphasising the need for predictive biomarkers that identify beneficial candidates. The recently approved tests for anti-PD-1/PD-L1 therapy in NSCLC include the assessment of PD-L1 expression using immunohistochemistry (IHC) as a companion diagnostic test (22C3 for pembrolizumab) and 2 complementary diagnostic tests (28-8 for nivolumab and SP142 for atezolizumab). Another PD-L1 assay is being currently tested in clinical trials (e.g. SP263). In addition to commercial assays, laboratories and research institutions may establish their own laboratory-developed tests (LDTs) using various antibodies available, most notably the E1L3N clone. Hence, the PD-L1 expression status, as well as its predictive and prognostic value, differ considerably based on the antibody clones, platforms, and interpretation criteria used. However, the current assays evaluating the predictive role of tumour PD-L1 expression remain without harmonization in terms of the staining analysis and scoring system. The intratumoural heterogeneity in PD-L1 expression is another important issue. At present, PD-L1 testing is mainly conducted on biopsy specimens, which may not represent the tumour as a whole, and it may lead to false results, particularly in cases where testing is conducted using small tissue specimens, such as bronchial or transthoracic biopsy specimens. The resulting false-negative results could lead to the under-treatment of patients. In this presentation, I’d like to introduce 1) the results of comparison study between 4 different PD-L1 IHC and scoring systems in the surgically resected early stage lung cancer specimen 2) the correlation of PD-L1 expression between TMA specimens and the corresponding resected specimen to better understand the intratumoral heterogeneity.

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