Virtual Library

Abstract:
Smoking Cessation - What will it look like in the near future Perspective of the smoking epidemic by global map of smoking prevalence: Figure 1 What is ‘smoking cessation’ and what does it get us? Why should we care what is happening to the tobacco products that people are smoking? California led the tobacco control efforts in the USA and within 3-5 years saw a drop in lung cancer deaths. The tobacco control efforts in California began in the late 1980’s and the drop in lung cancer quickly was evident from people stopping smoking. (Barnoya & Glantz. Cancer Causes Control 2004;15(7): 689-95) With better tobacco control, with resultant smoking cessation, many other countries have similarly seen a decline in the deaths from lung cancer, mostly in western, high income countries. Most people who smoke want to quit, and wish they had never started and most people started smoking before they were 18 years of age. Smoking cigarettes, with its pulmonary delivery, is a very good delivery system for nicotine. It is the nicotine that addicts people and creates one of the most difficult to quit drugs in our societies. So, it is known that smoking cigarettes is addicitve, that most people who smoke want to quit and smoking them causes the number one cause of cancer death in the world - lung cancer. And, it is well-established that quitting smoking decreases the incidence and mortality from lung cancer. There are three major transnational tobacco companies in the world: Phillip Morris International (PMI), based in Laussane, Switzerland; British American Tobacco (BAT) based in London, UK; and Japan Tobacco International (JTI)based in Tokyo, Japan. The largest tobacco company, is the Chinese National Tobacco Corporation - and they are not quite yet international in their marketing scope. There are rumors of a financial bonus if PMI mergers with Altria in the USA - following their split in 2008; BAT has purchased Reynold Tobacco - the second-largest tobacco company in the USA. Thus, selling the product that causes a third of all cancers, including the number one, lung cancer, is an outcome of successful marketing by 4 major companies: PMI, BAT, JTI and China (largely overseen by the government). Marlboro cigarettes are one of the largest brand in the world - sold by PMI and Altria. Why does all of this matter to us? Because, where Marlboro goes, so goes the market. PMI has started to market its replacement of the Marlboro cigarette and they call i iQOS - or, ‘I quit ordinary smoking’. It is a ‘heat-not-burn’ product that they claim does not combust the tobacco and therefore is a less deadly product. At the time of this writing, PMI is in 30 countries and will be expanding globally in the near future. They have an application for the ability to claim a ‘reduced-harm’ product in the USA. (https://www.fda.gov/downloads/TobaccoProducts/Labeling/MarketingandAdvertising/UCM560044.pdf). Japan was one of the early markets for iQOS and it has taken the country by storm. One must make a reservation to purchase the product, as their specially designed stores are not able to keep them in stock. The iQOS product is steadily gaining prevalence in Japan - to the dismay for JTI who previously overwhelming had the largest market share. PMI has launched in South Korea, in hopes to capture the same success as they have found in Japan. As was stated earlier, most people want to quit smoking cigarettes - both for their health and the impact of secondhand smoke on others. iQOS claims to provide them with the nicotine that will continue to support their addiction, but removes the ‘harm’ from smoking. Of course, this is not known if this is true until changes are seen in the incidence of tobacco induced diseases, including of lung cancer. BUT - if there is a dramatic change from what people have smoked in the past and what they change to smoke in the future - there may be dramatic differences in lung cancer incidences and probably, of the type of lung cancer. Electronic cigarettes have also significantly impacted the marketplace and also claim to cause significantly less tobacco related disease. Uptake of electronic cigarettes has been variable around the world due to differences in regulatory environments and availbility of marketing acumen. However, none of electronic cigarettes have the marketing strength of the largest trans-national tobacco company, PMI, and their heat-not-burn product. The CEO of PMI Andre Calantzopoulos has stated: “if you extrapolate the figures, then logically we could reach the tipping point in five years. That is when we could start talking to governments about phasing out combustible cigarettes entirely.” {in interview with Nikkei Asian Review} Of course, he only means for the countries that can afford their heat-not-burn product - for the rest of the world, they can still have their combusted cigarettes. For us in IALSC, we can hope that electronic cigaretes and heat-not-burn products do cause less lung cancer - as people who smoke cigarettes quit - even if they transition to heat-not-burn cigarettes or electronic cigarettes. What is unknown is whether people who use either a heat-not-burn or electronic cigarettes - who quit smoking cigarettes - will have fewer lung cancers - in the very near future.

Abstract:
Advances in CT scanners. CT screening was first introduced when helical CT scanners became available in the early 1990’s (1-4). Since then, there have been remarkable advances in CT scanner technology with concurrent increase in the number of CT examinations per year by approximately 10% annually. More powerful hardware and image reconstruction algorithms have allowed faster scanning at lower radiation doses in today’s multidetector CT (MDCT) scanners. Ultra low-dose techniques are gaining acceptance. With respect to lung cancer screening, thinner collimation now possible has led to the detection of many more small pulmonary nodules. Also, there have been evolutions in diagnostic techniques such as percutaneous biopsies, navigational bronchoscopy, and PET scans and these advances have been integrated into the regimen of screening with a resulting decrease in the frequency of surgical resection of benign nodules (5). Definition of Positive Results. Updates in the definition of positive results have continued to be developed that allow for improvements in the efficiency of workups. One of the major changes has been to update the size thresholds for positive results from 4 to 6 mm and also to avoid rounding errors (6, 7). The NELSON trial introduced the concept that a positive result should be based on the initial CT scan and a follow-up CT scan for small nodules, rather than solely on the initial CT scan and this has been adopted by I-ELCAP (6). The I-ELCAP and NLST databases have been used to provide follow-up strategies for nonsolid and part-solid nodules (6). Considerations as to screening frequency may substantially reduce costs for lower risk individuals. There is increasing recognition that different approaches are needed for baseline and repeat scans where even when nodules might have the same characteristics as they should be managed differently. The management of both nonsolid and part-solid nodules has dramatically changed. For the first time, imaging as a biomarker for aggressiveness has been used to monitor whether a cancer is progressing. Growing nonsolid nodules can be followed on an annual basis and only the emergence of a solid component triggers more aggressive intervention. For the part-solid nodule it has now been recognized that the important component from a prognostic perspective is the solid portion not the overall size. Quantitative assessments. Quantitative assessment of many findings on chest CT scans have been developed (6). In particular, assessment of nodule size and growth as to the probability of malignancy and lung cancer aggressiveness has progressed. Most guideline organizations have moved from a single measurement of length to an average diameter (average of length and width) (6) and to three measurements of volume (7). The errors involved in any of these measurements are influenced by multiple factors including the intrinsic properties of the nodule and the software used to make the measurement (8, 9). Additionally, they are impacted by the variability of CT scanners and their adjustable scan parameters. Advances in incorporating measurement errors into growth assessment by RSNA’s Quantitative Imaging Biomarkers Alliance (QIBA) has led to a web-based calculator. The American College of Radiology (ACR) specifies that growth for a nodule of any size requires “an increase of 1.5 mm or more.” Both approaches allow for large measurement errors for the wide range of CT scanners and the protocols. The I-ELCAP guidelines for solid and the solid component of part-solid nodules is given explicitly in I-ELCAP protocol (6). Each of these approaches has specific technical requirements as measurement error is influenced by both the scanner itself, the choice of various adjustable parameters on the scanner (slice thickness, slice spacing, dose, FOV, pitch, recon kernel etc.) as well as characteristics of the nodule itself. Additional considerations for computer-assisted volume change assessment requires: 1) inspecting the computer scans and the segmentation for image quality (e.g. motion artifacts) and for the quality of the segmentation; 2) the radiologist visually inspecting both nodule image sets side-by-side to verify the quality of the computer segmentation for each image that contains a portion of the nodule; 3) examination of the segmentations for errors such as when a vessel is segmented as part of a nodule in one scan but not in the other; 4) that the scan slice thickness for the purpose of volumetric analysis should be 1.25 mm or less. When using any computer-assisted software, the radiologist must be satisfied with the CT image quality and the computer segmentation results, further substantiating the notion that the decision of whether growth has occurred is ultimately based on clinical judgment. Innovations in use of imaging and genetic information. Radiomics is an emerging field of study on the quantitative processing and analysis of radiologic images and metadata to extract information on tumor behavior and patient survival (10). The hypothesis is that data analysis through automated or semi-automated software can provide more information than that of a physician. Its use has shown improved diagnostic accuracy in discriminating lung cancer from benign nodules. It has been used successfully in breast imaging, with 2017 FDA approval of a computer-aided diagnosis tool which utilizes advanced machine learning analytics. Furthermore, radiomics has been linked with the field of genomics, inferring that imaging features are closely linked to gene signatures such as EGFR expression, a known therapeutic target. In the future, as larger data sets emerge and inter-institutional sharing of images becomes more commonplace, radiomics will become more tightly integrated with lung cancer diagnosis, treatment planning, and patient survival prognostication. References 1. Henschke C, McCauley D, Yankelevitz D, Naidich D, McGuinness G, Miettinen O, Libby D, Pasmantier M, Koizumi J, Altorki N, and Smith J. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999; 354:99-105. 2. The International Early Lung Cancer Action Program Investigators. Survival of Patients with Stage I lung cancer detected on CT screening. NEJM 2006; 355:1763-71 3. Kaneko M, Eguchi K, Ohmatsu H, Kakinuma R, Naruke T, Suemasu K, and Moriyama N. Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology 1996; 201: 798-802. 4. Sone S, Nakayama T, Honda T, Tsushima K, Li F, Haniuda M, et al. Long-term follow-up study of a population-based 1996-1998 mass screening programme for lung cancer using mobile low-dose spiral computed tomography. Lung Cancer. 2007; 58:329-41. 5. Linek HC, Flores RM, Yip R, Hu M, Yankelevitz DF, Powell CA. Non-malignant resection rate is lower in patients who undergo pre-operative fine needle aspiration for diagnosis of suspected early-stage lung cancer. Am J Respir and Crit Care Med 2015; 191: A3561 6. International Early Lung Cancer Action Program protocol. http://www.ielcap.org/sites/default/files/I-ELCAP%20protocol-v21-3-1-14.pdf Accessed March 27, 2015 7. Van Klaveren RJ et al. Management of Lung Nodules Detected by Volume CT Scanning. N Engl J of Medicine 2009; 361: 2221-9 8. Henschke CI, Yankelevitz DF, Yip R, Archer V, Zahlmann G, Krishnan K, Helba B, Avila R. Tumor volume measurement error using computed tomography (CT) imaging in a Phase II clinical trial in lung cancer. Journal of Medical Imaging 2016; 3:035505 9. Avila RS, Jirapatnakul A, Subramaniam R, Yankelevitz D. A new method for predicting CT lung nodule volume measurement performance. SPIE Medical Imaging 2017: 101343Y 10. Lee G, Lee HY, Park H, et al. Radiomics and its emerging role in lung cancer research, imaging biomarkers and clinical management: State of the art. Eur J Radiol. 2017; 86:297-307.

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Abstract:
Introduction With the recent development of the CT scanner, the number of CT screen-detected early-stage lung cancer showing ground-grass opacity (GGO) is rising. Therefore a new optimal therapeutic strategy for pulmonary resection for screen-detected lung cancer has been required. History of standard surgical procedure for lung cancer Cahan (1960) reported the first 48 cases that successfully underwent lobectomy with regional lymph node dissection, which was called “radical lobectomy.” Since then, this procedure was universally accepted and has remained a standard surgery for lung cancer. As for sublobar resection, segmentectomy was initially used for the resection of localized bronchiectasis as reported by Churchill and Belsey (1939). Jensik (1973) reported their 15-year successful experience of segmentectomy for lung cancer patients. However, the use of sublobar resection as definitive management of NSCLC has been a controversial issue. Lung Cancer Study Group (LCSG) (1995) conducted the only randomized trial comparing sublobar resection with lobectomy for stage IA NSCLC patients. They observed a 75% increase in recurrence and a 50% increase in cancer death in the patients undergoing sublobar resection, compared to those in the patients undergoing lobectomy. This is the reason why lobectomy has remained a standard lung cancer surgery for a half century since Cahn’s successful report in 1960. Controversies in sublobar resection for patients with small-sized NSCLC Sublobar resection is a lung parenchyma-preserving surgery with limited nodal dissection. However, even small-sized lung cancer less than 2 cm in size shows hilar and mediastinal nodal disease with an incidence of more than 20%. Although PET is considered to be the most sensitive and accurate investigation for screening of lymph node involvement, with a sensitivity of 79 to 85% and specificity of 90 to 91% in a meta-analysis, the assessment of nodal status by PET is not reliable in patients with microscopic nodal metastasis. Riquet (1989) reported that lung cancer metastasizes so easily to the mediastinum that selection of the patients for limited surgery should be discussed carefully. Furthermore, lung cancer has a phenomenon termed “skip metastasis” consisting of N2 disease without N1 involvement with the incidence of 20-38% in N2 patients. Therefore, lobectomy with hilar and mediastinal lymph node dissection is considered to be a basic standard procedure for lung cancer. Differences in survival between sublobar resection and lobectomy Proposals of sublobar resection for clinical stage IA small-sized lung cancer less than 2 cm have been undertaken in some previous reports. Although these were non-randomized study, Okada (2001) and Koike (2003) conducted the comparative study between intentional sublobar resection and standard lobectomy in patients with tumors 20 mm or less in diameter. They showed no significant difference in survival between two groups and suggested that sublobar resection was acceptable operation for small-sized lung cancer. The significance and role of sublobar resection for subsolid tumor have become important so far. Clinical trials regarding sublobar resection vs. lobectomy Japan Clinical Oncology Group (JCOG) has conducted a cohort study (JCOG0201) evaluating correlation between radiological and pathological findings in stage I adenocarcinomas. With pathologic non-invasive adenocarcinoma defined as those with no lymph node metastasis or vessel invasion, radiological non-invasive lung adenocarcinoma was defined as those with a consolidated maximum tumor diameter to tumor diameter ratio (C/T ratio) of less than 0.5 (9). Currently, a prospective, randomized, multi-institutional phase III trial for small-sized (<=2 cm) lung cancer patients is being conducted by Cancer and Leukemia Group B (CALGB140503) to determine the effectiveness of an intentional sublobar resection for small-sized peripheral tumors. Similar phase III study (JCOG0802) is also being conducted, comparing lobectomy vs. segmentectomy for small-sized tumor with more than 0.5 C/T ratio. JCOG has already accumulated planned number of patients and now following the patients. JCOG is also conducting other two prospective multi-institutional phase II trials regarding the sublobar resection for GGO-dominant type tumors. One is JCOG0804, wide wedge resection for non-solid GGO lesion less than 2cm, and the other is JCOG1211, segmentectomy for part-solid GGO lesion with less than 0.5 C/T ratio and 2.1-3.0 cm in tumor diameter. Sublobar resection: anatomic or non-anatomic? No large-scale randomized trial comparing AS with non-anatomic WR, which is technically much easier than AS, for small-sized NSCLC has been conducted so far. Despite the fact that patients undergoing AS were more likely to have nodal sampling/dissection, and more LNs retrieved than patients undergoing WR in the present study, Altoki (2017) suggested that it did not lead to an improvement in survival. This is consistent with the results of the ACOSOG Z0030 trial comparing lymph node sampling with systematic nodal dissection in patients with T1-2 N0-1 NSCLC with no difference in survival between the two groups. These findings are of interest since data from the LCSG randomized trial showed that locoregional recurrence after WR was two-fold higher than that after AS. The results that AS should be the preferred option for SR were supported by recent large population-based studies suggesting. Smith (2013) reported the results of evaluating a large population Surveillance, Epidemiology and End Result-Medicare registry (SEER) database. They found that WR were associated with inferior survival compared to AS. However, advantage of AS over WR in the SEER database is probably due to different patient selection criteria as well as inadequate wedge resections with sub-optimal resection margins and insufficient or no nodal assessment. Whether WR and AS were comparable oncologic procedures for cT1N0M0 NSCLC patients or not has been still controversial issue so far. Conclusions Since the clear evidence regarding the survival benefit of sublobar resection for lung cancer patient is lacking so far, lobectomy should be an appropriate therapy for medically operable lung cancer patient at the moment. Abovementioned randomized trials will clearly define the role of sublobar resection in patients with stage I patients. As the number of early-stage peripheral lung cancers is increasing, and a certain number of patients are with multifocal small lesion, the choice of surgical procedure, that is, lobectomy, AS or WR, should be tailored to each case in the future.

Background:
Durvalumab, an engineered human IgG1 anti-PD-L1 mAb, demonstrated an improvement in PFS vs placebo and favorable benefit/risk profile in the Phase 3 PACIFIC study in locally advanced, unresectable NSCLC. Here we summarize patient-reported outcomes from PACIFIC.

Method:
In the randomized, double-blind, Phase 3 PACIFIC study (NCT02125461), patients who had previously received ≥2 cycles of platinum-based concurrent chemotherapy with definitive dose radiation without disease progression were randomized (2:1) to durvalumab 10 mg/kg i.v. q2w or placebo for up to 12 months. Secondary endpoints included evaluation of symptoms, function and global health status/QoL using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 v3 questionnaire and its lung cancer module, QLQ-LC13. Patients completed the questionnaires at baseline, Week 4, Week 8, q8w until Week 48, then q12w until disease progression. Changes from baseline for key symptoms were analyzed using a mixed model for repeated measures (MMRM). Time to deterioration (TTD) and odds of improvement were analyzed. Deterioration or improvement was defined as a change in score from baseline ≥10. Hazard ratios (HR) were calculated using a stratified log-rank test and odds ratios (OR) using logistic regression.

Result:
Compliance with completing the questionnaires was high in both durvalumab (n=476) and placebo (n=237) groups (>80% up to Week 48). There were no differences between groups at baseline in symptoms, function or global health status/QoL. MMRM analysis showed no statistically significant differences between treatment groups in adjusted mean changes from baseline (average over 12 months) in the prespecified symptoms of dyspnea, cough, chest pain, fatigue and appetite loss, and for global health status/QoL and physical functioning. Clinically relevant improvements from baseline were observed throughout the study in both durvalumab and placebo groups for dysphagia (mean [SD] change at Week 48, −14.2 [26.1] and −14.8 [25.3], respectively) and alopecia (−22.1 [33.0] and −21.4 [29.5]). There were no differences in median TTD between groups except ‘other pain’ (9.2 months with durvalumab vs 5.6 months with placebo [HR 0.72; 95%CI 0.58, 0.89]). The only difference in improvement rates between groups was for appetite loss (26.1% improvement rate with durvalumab vs 24.9% with placebo [OR 1.72; 95%CI 1.04, 2.85]). Other symptoms, function and health-related QoL remained stable throughout with no between-group differences in TTD or improvement rates.

Conclusion:
Durvalumab treatment did not worsen symptoms, function or health-related QoL. Clinically relevant improvement in alopecia and dysphagia with durvalumab and placebo was likely due to resolution of toxicities related to prior chemoradiation.

Abstract not provided

Background:
Postop platinum-based CT is considered standard of care in resected NSCLC with lymph node involvement. BRCA1 and BRCA2 are important DNA repair factors primarily involved in the repair of double strand DNA breaks. BRCA-1 functions may act as a differential regulator of response to cisplatin (Cis) and antimicrotubule agents. BRCA1 defficiency enhances Cis resistance and loss of BRCA1 function is associated to sensitivity to DNA-damaging CT and may also be associated with resistance to spindle poisons.

Method:
SCAT randomized phase III multicenter trial tests individualized optimal CT based on expression of BRCA1. After surgery patients (p) with St II and Iii NCSLC were random 1:3 to control arm (3 cycles Cis-Docetaxel) or to experimental arm with treatment assigned according BRCA1 expression levels (low levels: Cis-Gemcitabine; intermediate levels: Cis-Doc; high levels: Docetaxel alone). Stratification factors: N1 vs N2; age < or > 65 y; non-Squamous vs Squamous (Sq) histology; lobectomy vs pneumonectomy). Planned PORT in N2. Primary end-point OS. Secondary end-points DFS, toxicity profile (CTCAE v 3.0) /compliance, recurrence pattern. Statistical hypothesis: 5y survival rate control group (45%) could be increase 20% in experimental arm.

Result:
From June/2007 to May/2013, a total of 591 p were screened and 500 of them were randomized in the study, 108 in control arm, 392 in experimental arm. In experimental arm 110 p received Cis-Gem, 127 Cis-Doc and 110 Doc alone. There were no significant differences between arm for known prognostic factors: Median age 64 y; 79% males, 21% females; 43% Sq, 49% Adenoca, 8% others; 57% former smokers, 32% current smokers, 11% never smokers; pneumonectomy 26%; N1 58%, N2 48%. Median tumor size 4.4 cm (0.8-15.5 cm). Median mRNA BRCA1 levels 15.78 (0.73-132). Mean BRCA1 levels 6.95 in Adenoca vs 20.29 in Sq (p<0.001). Compliance of CT was better in experimental arm with less dose-reductions and without differences according extent of surgery. CT compliance was lower in patients older 70 y. Median PFS: 38.7 m (control), 32.2 m Cis-Gem, 34.3 m Cis-Doc and 41 m Doc. At 5 years, event-free rate is 54% in control arm and 56% in experimental arm and median OS 73.3 m (control) vs 77.5 m (exp) (p=0.75). In experimental arm: Docetaxel alone 80.2 m, Cis-Doc 80.5 m and Cis-Gem 74 m.

Conclusion:
Higher survival than expected in patients with lymph node involvement. No significant difference in survival achieved with the experimental arm. In case of high levels BRCA CT treatment without cisplatin is not detrimental. (Eudract:2007-000067-15; NCTgov: 00478699)

Abstract not provided

Background:
The residual tumor (R) classification describes the tumor status after treatment. It reflects the effectiveness of treatment, has prognostic impact and may affect further treatment. We analyzed existing and potential R status criteria, including the proposed IASLC definition for “uncertain” resection margin status (2005), from data collected for the IASLC Lung Cancer Staging Project.

Method:
This analysis is based on 14,712 patients undergoing NCSLC surgery, for whom full R status and survival data were available. R status criteria and the following data were evaluated: number of N2 stations explored; lobe-specific systematic lymph node dissection (SLND); extra-capsular extension (ECE); status of the highest station; bronchial carcinoma in situ (cis) at bronchial resection margin (BRM); pleural lavage cytology (PLC). Revised categories of R0, R(un), R1 and R2 were designated and tested for survival impact.

Result:
There were 14,293 R0, 263 R1 and 156 R2 cases, with median survival not reached, 33 and 29 months (p<0.0001). R status correlated with T and N stages (p<0.0001). Greater or equal to 3 N2 stations were explored for 9,290 cases (63%) and lobe-specific SLND in 6,619 (45%), with positive associations for increasing pN2 stage (p<0.0001). ECE was recorded in 61 (20%) of 304 N+ cases evaluated. The highest station was positive in 942 (6.4%) cases. PLC was positive in 59 (3.6%) of 1,646 cases and there was BRM cis in 13 cases. After reassignment according to the IASLC proposed definition, there were 6,103 R0 cases, 8,203 R(un), 250 R1 and 156 R2. Figure 1



Conclusion:
These data confirm the proposed criteria for Uncertain R status, R(un), with a prognosis stratifying between R0 and R1. Further detailed prospective data collection is required to characterize fully the prognostic impact of these criteria. Detailed evaluation of R status is of particular importance in the design and analyses of clinical trials of adjuvant therapies.

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Abstract not provided

Abstract:
Summary of the Lecture “Serendipities of acquired immunity” In 1992, we started working on PD-1 and found that this acts as a brake in the immune system. Then, in 2002, we discovered that PD-1 inhibition could be effective in treating cancer in animal models. After 22 years of study, this idea has borne fruit in a new, breakthrough immunotherapy that is being hailed as a 'penicillin moment' in cancer treatment. I believe that, just as a number of antibiotics developed in the wake of the discovery of penicillin now protect humans against threats of infectious diseases, this discovery will play a leading role in advancement of cancer immunotherapy so that in the future the fear of dying from cancer will cease to exist. Through evolution, vertebrate animals have developed immunity against infection by microorganisms. In the process, they incidentally acquired a sophisticated system for diversifying genomic information by combining gene fragments. It was doubly fortunate that the success in cancer treatment via PD-1 inhibition brought the realization that immunity, a “weapon” against infectious diseases, could also serve as a “shield” against cancer. It has been said that, whereas humankind’s greatest enemies in the 20th century were infectious diseases, cancer is the major foe in the 21st century. It is a pleasant surprise to discover that the acquired immunity system holds the keys to overcoming both of these difficult medical challenges.

Abstract not provided

Abstract:
PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each having been developed as a predictive biomarker for specific anti-PD-1/PD-L1 immunotherapies.[1] The Blueprint phase 1 was conducted as a feasibility study to assess the staining (analytical) comparability of four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263) that were developed for their respective immune checkpoint inhibitor therapies.[2] Without correlation with treatment outcome, the study also assessed the putative diagnostic performance of these assays through comparisons of PD-L1 status classification above and below selected expression cutoffs associated with the clinical use of various assays. Serial sections from paraffin blocks of 39 resected non-small cell lung cancers (NSCLC) were stained using assays that were used in the clinical trials, and three experts in interpreting the four respective assays independently assessed the percentages of tumor and immune cells staining positive at any intensity. The results demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells, while the SP-142 PD-L1 assay appeared to stain less tumor cells compared to the other assays.[2] In contrast, all assays stained tumor infiltrating immune cells, but with poor concordance between assays. The phase 1 study had several limitations: (1) samples were obtained from a commercial source and did not necessarily reflect the real-world samples tested clinically, and (2) the number of pathologists involved in the scoring was small. In addition, a fifth PD-L1 assay (73-10) has since been developed as a potential biomarker for avelumab (EMD Serono/Merck KGaA/Pfizer). The goals of Blueprint phase 2 are: (1) to validate the assay comparability results obtained in Blueprint phase 1 study using real world clinical lung cancer samples and all five clinically used PD-L1 assays (28-8, 22C3, SP142, SP263, and 73-10), (2) to assess the comparability and heterogeneity of PD-L1 assay results in surgical tumor resection, core needle and FNA samples prepared from same tumor, and (3) to assess the concordance of PD-L1 scoring by pathologists from around the world using standard light microscopy vs. digital images accessed by a web-based system. In blueprint phase 2A, 18 participating pathologists, with respective institutional research ethics board approval, contributed unstained serial sections from altogether 81 lung cancer cases that came through routine clinical practice. These included 40 adenocarcinomas, 25 squamous cell carcinomas, 5 poorly differentiated non-small cell carcinoma and 11 small cell carcinomas. The cases included resected tumor (n=20), core/bronchial biopsies (n=20), tumor positive lymph node biopsy/resection (n=20) and cytology cell block (n=21) samples. In blueprint phase 2B, 9 pathologists prepared from 30 freshly resected NSCLC specimens, paraffin blocks of matched resection, core needle and fine needle aspiration samples. Each slide set of 81 cases from phase 2A were stained with the FDA-cleared (28-8, 22C3, SP142) or clinical trial (SP263 and 73-10) PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. The slides were scored by 24 experienced pulmonary pathologists (IASLC Pathology committee Blueprint phase 2 members),[4] all having received group training on scoring the PD-L1 IHC on tumor and immune cells. PD-L1 stained tumor cells were scored as continuous number (0% to 100%), and placed into 1 of 7 categories (<1%, 1-4%, 5-9%, 10-24%, 25-49%, 50-79%, 80-100%). These categories represent cut-offs that have been used in various immune checkpoint inhibitor trials. All assays were also scored for immune cell PD-L1 staining based on the scoring system developed for the SP-142 assay. As only one set of glass slides is available for each assay, each pathologist was randomly assigned to conduct the scoring using microscope (2 glass assays) or by web-based digital images (3 digital assays). The inter-assay concordance of PD-L1 staining on tumor cells and tumor infiltrating immune cells will be assessed using the mean scores from all pathologists. The large sample size scores should provide more reliable data on their analytical comparability. Inter-pathologist concordance results should provide evidence on reliability of scoring with different cut-points. Importantly, the above concordance results across different sample types should also provide insights on potential variability and feasibility in PD-L1 scoring across different sample types, especially cytology samples. This may then allow for a broad implementation strategy on PD-L1 testing in clinical practice. The results of phase 2A will be presented at the meeting.IASLC Pathology Committee Blueprint phase 2 members: Mary-Beth Beasley, Alain Borczuk, Johan Botling, Lukas Bubendorf, Gang Chen, Lucian Chirieac, Teh-Ying Chou, Jin-Haeng Chung, Sanja Dacic, Fred R. Hirsch, Keith M. Kerr, Mari Mino-Kenudson, Sylvie Lantuejoul, Andre Moreira, Andrew Nicholson, Masayuki Noguchi, Guiseppe Pelosi, Claudia Poleri, Prudence Russell, Jennifer Sauter, Erik Thunnissen, William D. Travis, Ming S. Tsao, Ignacio Wistuba, Murry Wynes, Yasushi Yatabe, Hui Yu. References: IASLC ATLAS of PD-L1 Immunohistochemistry Testing in Lung Cancer. M.S.Tsao, K.M. Kerr, Y. Yatabe, S. Dacic, F.R. Hirsch (Editors), International Association for Study of Lung Cancer (IASLC) Press, 2017 Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the "Blueprint PD-L1 IHC Assay Comparison Project". J Thorac Oncol. 2017 Feb;12(2):208-222. Feng Z, Schlichting M, Helwig C, et al. Comparative study of two PD-L1 expression assays in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 35, 2017 (suppl; abstr e20581)

Abstract:
The therapeutic approach to overcome Tumor-induced suppression of specific T-cell activation by using specific antibodies, which are interacting with regulating pathways, the immune check-points has substantially changed treatment of patients with advanced NSCLC. In particular the development of antibodies inhibiting cytotoxic T-lymphocyte-associated antigen 4 (anti CTL4), programmed death receptor 1 (anti PD-1) or programmed death receptor ligand 1 (anti PDL-1) have shown efficacy in NSCLC. In five randomized trials anti PD-1/anti PD-L1 antibodies have shown significant improvement in overall survival (OS) compared to chemotherapy and an improved safety profile. Efficacy was correlated to PD-L1 expression on tumor cells. However confirmed activity has also been documented in patients with PD-L1 negative tumors. Besides harmonization of different existing tests for assessment of PD-L1 expression identification of novel markers like tumor mutational burden (TMB) might help to identify best benefitting patients. In selected patients with high PD-L1 expression on tumor cells (TPS =/> 50%) monotherapy with the anti PD1 antibody pembrolizumab has demonstrated superiority in response, progression free survival and OS compared to platinum based chemotherapy in first-line treatment. Current randomized trials evaluate the activity of combinations of chemotherapy with checkpoint inhibitors or of immunotherapy combinations compared to chemotherapy and will provide important information about the next steps in the development of immunotherapy in lung cancer. For the future the development of novel immunotherapeutic agents either as monotherapy or in combination with checkpoint inhibitors as well as the understanding of resistance mechanisms and strategies to overcome resistance will be of paramount importance.