Virtual Library

Abstract:
Implementation of Precision Medicine in Routine Practice: The Latin American Experience – Part 2 Technology for molecular testing in lung cancer is a highly demanding aspect to tackle in the LATAM countries. Molecular testing requires incorporation of new technologies usually involving expensive equipment, reagents and supplies. Moreover, these items are commonly imported from other countries and are subjected to custom regulation and heavy taxes. Therefore, LATAM labs commonly face unpredictable delays in the legal processing of purchase orders, are constantly adjusting to changes in regulations and in the country’s financial status, and suffer from slow and sometimes poor support from companies that do not see them as preferred clients. As an example of consequences of some of this points, in Argentina the agents Nivolumab and Pembrolizumab were approved by government agencies for immunotherapy for NSCLC before the molecular testing laboratories had conditions to purchase the DAKO platform and the CDx antibodies for appropriate IHC testing. Some technical devices such as automated IHC platforms are more widely available. They were initially integrated onto large pathology labs in the main cities of several countries but smaller automated platforms are currently available in a number of other cities. There are laboratories equipped for fluorescence in situ hybridization (FISH) and for DNA sequencing in most countries. Sanger sequencing is still commonly used, but the main laboratories already incorporated newer technologies such as RT-PCR allele-specific technology (usually Cobas platform) and tailored panels of next generation sequencing (NGS) or have them in the short list for implementation. Additionally to the challenges in the laboratories organization, two other main issues obstruct the implementation of lung cancer molecular testing in the LATAM countries: the lack of a stable logistic infra-structure necessary to ship biological samples to the molecular laboratories in a cheap, reliable and rapid way, and the hurdle of cost reimbursement for the tests. In the past 10 years, expenses and logistics for transfer of biological specimens and reimbursement for molecular test costs, in most countries such as Mexico, Brazil and Argentina, were sponsored by pharmaceutical companies. Companies such as AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer have acted through clinical trials or special access programs. In a smaller scale, molecular tests have been supported by governmental health agencies or covered by private health care insurance companies. A restricted number of patients are paying the tests out of the pocket, mostly sending to US laboratories. Least but not least, the implementation of lung cancer molecular testing relies in the adequate quantity and, most importantly, in the good quality of the available biological sample. Subsequent to the intense interdisciplinary work by the laboratory personnel, significant progress has been detected in the last years in the amount of tumor cells present in the testing specimens. However, proper quality is only achieved in a fraction of specimens. Most LATAM countries do not have local regulations for quality control (QC) of pathology laboratories, and a limited number of those laboratories are taken external QC certification. Moreover, there is no financial support for the adequate validation of the assays at their implementation and for the competency checking periodically thereafter. In consequence, the risk of having laboratories testing in substandard quality conditions is high. Institutions that are well-structured administratively, technically and scientifically and that handle large volumes of clinical specimens usually participate in external QC for molecular tests. They engage in accredited proficiency testing activities or, at least, send material to reference laboratories for investigation of reproducibility of results. Unfortunately, this does not occur in the majority of the LATAM laboratories. Therefore, it is critical to reach potential sponsors to assist the LATAM molecular testing laboratories in overcoming these challenges and rapidly jump to the future. Efforts leading to improve tissue quality, to facilitate local optimization of assays and to ensure assay validation by international standards are needed. A group of regional laboratories have been trying to organize a collaborative project to face these issues and also to come up with an affordable strategy to ensure good quality in pathology and molecular laboratories. Multiple barriers are making it difficult to succeed in this effort. The patient advocate groups have proved effective in sensitizing governments and regulatory agencies in the USA, but those groups are still very under-represented in LATAM. Professional institutions such as the IASLC are specially tailored to help. IASLC congregates internationally conscious personnel and lung cancer experts and would excel, for instance, in matching experts with laboratories requesting specific assistance and in coordinating a regional consortium of laboratories interested in rounds of specimen exchange for proficiency testing and in validated sets of control specimens for implementation of new tests. Data from at least 15 of the highest populated LATAM countries regarding their lung cancer test menu, the technical platforms used, and efforts for investigation of the assay performance characteristics have been surveyed and results will be discussed.

Abstract:
Implementation of Precision Medicine in Routine Practice: The Latin American Experience – Part 1 Marileila Varella-Garcia, PhD The increasing application of the concept of precision medicine (PM) in the last decade has revolutionized health care. Under this concept, the approach to disease treatment and prevention takes into account individual variability in genes, environment, and lifestyle to more accurately predict treatment and prevention strategies for a particular disease in specific patient subsets. PM has been progressing faster among infectious diseases and neoplasia, with emphasis in non-small cell lung cancer (NSCLC) among the solid tumors. However, we are still far away from a stable scenario to which we should adjust. The field is in continuous evolution with constant new discoveries and proposals. The implementation of PM for lung cancer has dramatically impacted several medical areas mainly in two basic aspects: the molecular diagnosis and the therapy regimen. The first involves questions such as how to collect and process specimen for testing, which tests to apply and in which level, how to define scoring criteria and cut-offs for variables with continuous distribution in the population, how to interpret and validate clinical assays, and how to properly communicate with the multidisciplinary team. The second involves questions pertinent to understanding the molecular diagnostic, access to and cost of new and old drugs, evaluation of side effects, selection of combination or sequential regimens, definition of clinical progression and resistance, and proper communication with the multidisciplinary team. Our discussion will primarily address molecular testing in lung cancer in Latin America countries (LATAM). One of the medical areas most largely affected by the changes accompanying PM is Pathology. The new specialty of Molecular Pathology has emerged to focus on the sub-microscopic aspects of disease by examination of molecules within tissues and bodily fluids. Molecular Pathology encompasses aspects of anatomic and clinical pathology as well as molecular biology, biochemistry, genetics, and bioinformatics. Molecular lung cancer testing in LATAM is centralized in the main cities of several countries and usually performed in laboratories of few large, private or public hospitals, mostly belonging to academic institutions. Examples of those laboratories are located in the Hospital Italiano and Hospital Roffo in Buenos Aires, Argentina; in the Instituto Nacional do Cancer in Rio de Janeiro and Instituto AC Camargo in Sao Paulo, Brazil; in the Universidad Catolica de Chile; in the Fundacion Santa Fe de Bogota and Fundacion Valle de Lili in Colombia, and in the Instituto Nacional de Cancerologia in Mexico City. There are also few commercial laboratories that offer standard tests under good laboratory practices. Examples are the laboratories Hermes Pardini and Consultoria em Patologia in Brazil, Argenomics and Biomarkers in Argentina, and ROE in Peru. The implementation of molecular testing poses important challenges to pathology practices in commercial and academic institutions, and efforts to overcome them have been extensively discussed. It is well recognized that changes in two organizational levels are required, one related to personnel and another related to equipment and technology. In terms of personnel, there is a need to increase multi-disciplinary communication affecting all areas including oncologists or surgeons requesting the tests, professionals (surgeons, pulmonologists, interventionists) collecting the specimens, technologists processing and handling the specimens, pathologists performing histology diagnosis and molecular testing interpretation, lab scientists (biologists, biotechnologists, biochemists) executing assays and interpreting the results, and bioinformaticians handling computer-generated data. The interdisciplinary work in the anatomic and clinical pathology laboratory must be intensified and personnel with distinct expertise and no clinical experience must be added and integrated to the team. The role of the pathologist in the communication and integration among team members (clinical/medical and laboratory group) is crucial. Interestingly, the work environment in a complex molecular testing laboratory has changed to demand personnel not only with excellent hard technical skills but also with soft skills such as active listening, coordination, adaptability, punctuality, problem solving, and friendly personality. The lab success relies in that each team member clearly understands his/her role and the value of efficient communication among team members, which is mainly modulated by the pathologists. Most of the LATAM laboratories already performing molecular testing have increased and strengthened this interdisciplinary work using biologists and biotechnologists originally trained in research fields. Nevertheless, the continuous update with the evolving field required from the pathologists, the scarceness of trained bioinformaticians for data sequencing analysis, and the vigorous integration of the entire professional team are still challenging personnel issues to be addressed. Data from at least 15 of the highest populated LATAM countries regarding their efforts in initiating and expanding molecular testing for lung cancer and the strengths and challenges faced have been surveyed and results will be discussed.

Abstract:
Background More than 30 years have passed since industrialized countries started to strictly regulate the use of asbestos, including, in several of them, introducing a total ban on import of raw material and of asbestos-containing products. The use of the International Classification of Diseases (ICD) to classify deaths from mesothelioma has been a source of concern in the past because, before the 10[th] version of ICD (ICD-10), no specific code existed for this type of neoplasm, and analyses based on entities such as ‘pleural cancer’ were subject to misclassification. Since the late 1990s ICD-10 has been used for death certification in many developed countries. Methods We analyzed age-specific mesothelioma mortality rates (all sites), calculated on the basis of the data of the WHO Mortality Database, among men from Canada (2000-2011), USA (1999-2013), Japan (1995-2008), France (2000-2011), Germany (1998-2013), Italy (2003-2012), the Netherlands (1996-2013), Poland (1999-2013), United Kingdom (2001-2013) and Australia (1998-2011), based on ICD-10, to identify temporal patterns following reduction of asbestos exposure. Results Mortality in the age groups 35-54 and 55-64 decreased throughout the study period in all countries (median decrease, 7.9% per year and 4.1% per year, respectively) except in Poland and (up to 2007) in Japan, two countries which started from lower rates. In the age group 65-74, mortality decreased in the USA and, since 2009, in the Netherlands, was stable in Australia, and increased in other countries (median increase, 3.0% per year). In the age group above age 74, a decrease was apparent only in the USA after 2003 (median increase in the other countries, 3.5% per year). Conclusions Our analysis, based on consistent mortality data for mesothelioma, provide strong evidence for a decrease in mortality in the young age groups in most high-income countries: these birth cohorts experienced reduced opportunity for exposure to asbestos during their occupational life. In the case of older age groups, whose members had greater opportunity of exposure, in particular to amphiboles, the evidence of a decrease in mortality is present only in a few countries. Overall, these results stress the importance of early-life exposure circumstances to determine mesothelioma risk throughout life.

Abstract:
Epidemiology: MPM, representing around 90% of all mesothelioma cases diagnosed, is an aggressive tumour with a poor prognosis, and relatively few treatment options. The association of mesothelioma with asbestos exposure is well established. The latency period, the interval between first asbestos exposure to the diagnosis is long (around 40 years), and explains why in many instances the effect of banning asbestos from the workplace has yet to be seen. At the same time there is evidence accumulating that non-occupational asbestos exposure may significantly contribute to mesothelioma incidence [1] and it is most worrying that unrestricted use of this carcinogen is allowed in Russia and most Asian, African and South American countries. Unfortunately the multilateral treaty to promote shared responsibilities in relation hazardous chemicals (Rotterdam convention) has become paralyzed by the veto of asbestos producers and considering the rapid surge of asbestos consumption in developing countries the end of the mesothelioma epidemic is not in sight [2]. Molecular biology: Major efforts have been undertaken to explore the genomic alterations responsible for the development of malignant pleural mesothelioma. Recent next-generation sequencing efforts have confirmed the frequent loss of tumour suppressor genes identified in earlier studies. Deletion and loss of function mutation of CDKN2A, NF2 and BAP1 are common molecular events in MPM, but the overall mutational load tends to be lower in MPM than in lung cancer. Mutation, aberrant splicing, and gene fusions occur in additional genes such as SF3B1, TRAF7 and SETD2, but at lower frequency [3]. Expression analyses suggest that there are subgroups of tumours both within and between the traditional histopathological subtypes of MPM [3, 4], and this has potential implication for prognosis. Although still to be published, the results from a TCGA mesothelioma study paint a similar picture of the mutational and transcriptional landscape. Investigation of microRNA expression reveals a general downregulation of microRNAs with tumour suppressor activities. In addition to miR-31, frequently co-deleted with CDKN2A, the miR-15/16 family is consistently downregulated in MPM tumours. This family controls expression of targets such Bcl-2, CCND1 and VEGF, and thus plays a role in the regulation of proliferation, apoptosis and angiogenesis. Recent data suggest that these microRNAs also play role in controlling the levels of PD-L1 expression in MPM cells [5], targeted by immune checkpoint inhibitors. Treatment Options: MPM is notoriously refractory to localized and systemic treatment. Meta-analyses (multivariate analyses) of large series of patients confirm that the prognosis of the select group of patients able to undergo radical surgery is significantly better than without surgery [6]The debate about the extent of radical surgery has for some time been governed by the significant risks associated with radical surgery as noted in the MARS trial. Therefore, when radical multimodality treatment approaches are considered, it seems prudent to involve an experienced team at a high volume centre. While the important palliative role of radiotherapy in MPM has been accepted by the oncological community, consolidation radiotherapy after radical surgery [7] has not been shown to provide major benefits in terms of local control. To define the role of (intensity modulated) accelerated radiotherapy in MPM comparative studies are needed. The impressive data (median overall survival of 51 months) from the SMART study [8] combining pre-operative intensity modulated radiation therapy (IMRT) immediately followed by extra-pleural pneumonectomy in 62 patients MPM patients with epithelial histology suggests that such an approach may have the potential to become an alternative for induction chemotherapy followed by radical surgery. Almost every chemotherapy agent has been tested in MPM. Cisplatin, methotrexate, pemetrexed and the anthracyclines doxorubicin and daunorubiucin were most active, but single agent activity seldomly exceeded a 20% response rate. A systematic review of the chemotherapy literature carried out in the early 2000s concluded that combination therapy was likely to be more effective than single agent therapy [9]and shortly thereafter Vogelzang’s randomized comparison between cisplatin and cisplatin/pemetrexed confirmed cisplatin/pemetrexed as the new therapy standard. Thirteen years later this standard has been augmented by a large comparative French intergroup study revealing that the addition of bevacizumab to the cisplatin/pemetrexed standard is associated with a 2.7 months advantage in median overall survival [10]. However, it important to note that a not insignificant number of negative phase II and III studies with a range of inhibitors of growth factors including EGFR, VEGF and PDGF had preceded this positive result. Other targeted agents investigated in phase II and III studies including bortezomib, vorinostat, everolimus, and defactinib, the inhibitor of the NF2/mTOR/FAK pathway, have also failed to show notable activity in pre-treated MPM patients [11]. It has become clear that MPM is an immunogenic tumour type and the preliminary data showing responses after immune checkpoint (PD-L1) inhibition [12] seem to indicate that reversing the immunosuppression induced by advancing disease is likely to represent a major step forward. However, monotherapy with Tremelimumab, inhibitor of CTLA-4 and considered active in phase II studies, failed to produce a survival benefit over placebo in 2[nd] and 3[rd] line, underlining the importance of comparative studies [13]. Independent research groups have reported ‘spontaneous’ regression of MPM, revealed a relation between infiltrating lymphocytes and plasma cells and prognosis and presented promising early clinical results with mesothelin-targeting antibodies [11]. Most recently dendritic cell vaccination combined with pulsed (metronomic) cyclophosphamide to deplete regulatory T cells resulted in prolonged tumour control in a limited group of MPM patients [14]. It is not excluded that targeting multiple compartments involved in immune surveillance will lead to increased efficacy. Early signs of efficacy of experimental treatment with tumour suppressive microRNAs packaged in minicells [15, 16] and the interaction between the microRNA 15/16 family and PD-L1 expression point to the complexity of immune checkpoint regulation and underlines the need for additional translational studies to unravel the resilient drug resistance mechanisms operable in MPM. 1. Marinaccio, A., et al., Malignant mesothelioma due to non-occupational asbestos exposure from the Italian national surveillance system (ReNaM): epidemiology and public health issues. Occup Environ Med, 2015. 72(9): p. 648-55. 2. Takahashi, K., P.J. Landrigan, and R. Collegium, The Global Health Dimensions of Asbestos and Asbestos-Related Diseases. Ann Glob Health, 2016. 82(1): p. 209-13. 3. Bueno, R., et al., Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet, 2016. 48(4): p. 407-16. 4. de Reynies, A., et al., Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition. Clin Cancer Res, 2014. 20(5): p. 1323-34. 5. Williams, M., et al., Tumour suppressor microRNAs regulate PD-L1 expression in malignant pleural mesothelioma., in International Mesothelioma Interest Group (iMig) 2016. 2016: Birmingham 6. Linton, A., et al., Factors associated with survival in a large series of patients with malignant pleural mesothelioma in New South Wales. Br J Cancer, 2014. 111(9): p. 1860-9. 7. Stahel, R.A., et al., Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol, 2015. 16(16): p. 1651-8. 8. de Perrot, M., et al., Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg, 2016. 151(2): p. 468-73. 9. Berghmans, T., et al., Activity of chemotherapy and immunotherapy on malignant mesothelioma: a systematic review of the literature with meta-analysis. Lung Cancer, 2002. 38(2): p. 111-121. 10. Zalcman, G., et al., Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet, 2016. 387(10026): p. 1405-14. 11. Schunselaar, L.M., et al., A catalogue of treatment and technologies for malignant pleural mesothelioma. Expert Rev Anticancer Ther, 2016. 16(4): p. 455-63. 12. Alley, E.W., et al., Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028. Cancer Research, 2015. 76(18): p. CT 103. 13. Kindler, H.L., et al., Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma (MM): Results from the global, double-blind, placebo-controlled DETERMINE study. Journal of Clinical Oncology, 2016. 34(15 (May Suppl)): p. #8502. 14. Cornelissen, R., et al., Extended Tumor Control after Dendritic Cell Vaccination with Low-Dose Cyclophosphamide as Adjuvant Treatment in Patients with Malignant Pleural Mesothelioma. Am J Respir Crit Care Med, 2016. 193(9): p. 1023-31. 15. Reid, G., et al., Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer. Epigenomics, 2016. 8(8): p. 1079-85. 16. Kao, S.C., et al., A Significant Metabolic and Radiological Response after a Novel Targeted MicroRNA-based Treatment Approach in Malignant Pleural Mesothelioma. Am J Respir Crit Care Med, 2015. 191(12): p. 1467-9.

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Background:
In KEYNOTE-024 (NCT02142738), pembrolizumab provided superior progression-free survival (PFS) over platinum-based chemotherapy as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) with PD-L1 expression on ≥50% of tumor cells (ie, PD-L1 tumor proportion score [TPS] ≥50%) and no sensitizing EGFR or ALK aberrations (HR 0.50, P < 0.001). Despite a 44% crossover rate from chemotherapy to pembrolizumab, pembrolizumab also significantly improved overall survival (OS) (HR 0.60, P = 0.005). Any-grade (73% vs 90%) and grade 3-5 (27% vs 53%) treatment-related adverse events were less frequent with pembrolizumab. Health-related quality of life (HRQoL) is an important consideration for anticancer therapy, particularly in the first-line setting. We present data from the prespecified exploratory patient-reported outcomes (PRO) analysis of KEYNOTE-024.

Methods:
305 patients were randomized to pembrolizumab 200 mg Q3W or investigator-choice platinum-doublet chemotherapy plus optional pemetrexed maintenance therapy for nonsquamous disease. The EORTC QLQ-C30 and QLQ-LC13 were administered at cycles 1-3 and every 9 weeks thereafter. The key PRO end points were change from baseline to week 15 in the QLQ-C30 global health status/QoL score and time to deterioration in the QLQ-LC13 composite of cough, chest pain, and dyspnea. PROs were analyzed for all patients who received study treatment and completed ≥1 PRO instrument (n = 299).

Results:
Across treatment arms, PRO compliance was >90% at baseline and ~80% at week 15. Least squares (LS) mean (95% CI) change from baseline to week 15 in QLQ-C30 global health status/QoL score was 6.95 (3.29 to10.58) for pembrolizumab (n = 151) and –0.88 (–4.78 to 3.02) for chemotherapy (n = 148). The difference in LS means was 7.82 (95% CI 2.85-12.79; nominal 2-sided P = 0.002). The proportion of improved global health status/QoL score at week 15 was 40.0% for pembrolizumab and 26.5% for chemotherapy. Fewer patients in the pembrolizumab arm had deterioration in the QLQ-LC13 composite of cough, dyspnea, and chest pain (30% vs 39%), and time to deterioration was also prolonged with pembrolizumab (HR 0.66, 95% CI 0.44-0.97; nominal 2-sided P = 0.029).

Conclusion:
Pembrolizumab was associated with a clinically meaningful improvement in HRQoL compared with platinum-based chemotherapy. Combined with the superior PFS and OS and manageable safety profile, these data suggest pembrolizumab may be a new standard of care for first-line treatment of PD-L1–expressing advanced NSCLC.

Background:
Atezolizumab inhibits PD-L1 binding to its receptors PD-1 and B7.1, thereby restoring tumor-specific T-cell immunity. Primary analysis of the Phase III OAK study in previously-treated NSCLC revealed superior survival for atezolizumab vs docetaxel in the ITT population (mOS, 13.8 vs 9.6 months; HR, 0.73) and in patients expressing ≥1% PD-L1 on TC or IC (TC1/2/3 or IC1/2/3; mOS, 15.7 vs 10.3; HR, 0.74). Here we present further subgroup analyses.

Methods:
OAK evaluated atezolizumab vs docetaxel in an unselected NSCLC population who had failed prior platinum-containing chemotherapy. Patients were stratified by PD-L1 expression, prior chemotherapy regimens and histology, and randomized 1:1 to atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. PD-L1 expression by IHC and mRNA was centrally evaluated by VENTANA SP142 IHC assay and Fluidigm, respectively. Data cutoff, July 7, 2016.

Results:
For the first 850 of 1225 randomized patients (primary study population), OS was improved with atezolizumab vs docetaxel regardless of histology and this benefit was observed across PD-L1 subgroups within each histology (Table). PD-L1 gene expression showed a similar association with OS as PD-L1 IHC. In nonsquamous patients ORR was 14.4% vs 15.2%; in squamous patients ORR was 11.6% vs 8.2% (atezolizumab vs docetaxel). OS benefit vs docetaxel was seen across subgroups including patients with treated baseline brain metastases (n=85; mOS 20.1 vs 11.9 mo; HR 0.54, 95% CI 0.63-0.89) and never smokers (n=156; mOS 16.3 vs 12.6 mo, HR 0.71, 95% CI 0.47-1.08). Further secondary endpoints and exploratory biomarker analyses for these subgroups and by age and EGFR/KRAS status will be presented.

Conclusion:
OAK demonstrated clinically relevant improvements with atezolizumab in the ITT population, including in both histology subgroups regardless of PD-L1 expression (measured by IHC or tumor gene expression), and among other subgroups including never smokers and in patients with baseline brain metastases.

	OS
	Atezolizumab		Docetaxel		HR[a]95% CI
	n	Median, mo	n	Median, mo
Nonsquamous
TC3 or IC3	49	22.5	47	8.7	0.35(0.21-0.61)
TC2/3 or IC2/3	89	18.7	99	11.3	0.61(0.42-0.88)
TC1/2/3 or IC1/2/3	171	17.6	162	11.3	0.72(0.55-0.95)
TC0 and IC0	140	14.0	150	11.2	0.75(0.57-1.00)
All	313	15.6	315	11.2	0.73(0.60-0.89)
Squamous
TC3 or IC3	23	17.5	18	11.6	0.57(0.27-1.20)
TC2/3 or IC2/3	40	10.4	37	9.7	0.76(0.45-1.29)
TC1/2/3 or IC1/2/3	70	9.9	60	8.7	0.71(0.48-1.06)
TC0 and IC0	40	7.6	49	7.1	0.82(0.51-1.32)
All	112	8.9	110	7.7	0.73(0.54-0.98)
[a]Unstratified HRs. TC=tumor cell, IC=tumor-infiltrating immune cell

Background:
Treatment with anti-PD-1/PD-L1 antibodies has demonstrated meaningful clinical benefit in patients with advanced NSCLC. Patients that progress after 2 lines of chemotherapy have few treatment options and poor outcomes. Durvalumab is an engineered human IgG1 mAb targeting programmed cell death ligand-1 (PD-L1).

Methods:
ATLANTIC (NCT02087423) is a Phase 2, open-label, single-arm trial in patients with locally advanced or metastatic Stage IIIB–IV NSCLC (WHO PS 0 or 1; ≥2 prior systemic treatment regimens, including one platinum-based). There was no maximum number of prior treatments. The study initially enrolled all-comers and then was restricted to patients with PD-L1 high tumours (≥25% of tumour cells with membrane staining). The study includes three cohorts; here we report final results in Cohorts 2 and 3 that had EGFR/ALK wild-type or unknown status. Patients enrolled in Cohort 3 had ≥90% of tumour cells with PD-L1 staining. The primary endpoint is ORR (RECIST v1.1), based on independent central review. Secondary endpoints include DCR, DoR, PFS, OS, and safety (CTCAE v4.03).

Results:
As of 3 June 2016, in Cohorts 2/3, 265/68 patients (median age 62/61 years, 67/72% PS 1, 21/29% squamous histology; mean of 3.2/2.6 prior therapies) had received durvalumab (10 mg/kg i.v. q2w). Responses were durable; in Cohort 2, patients with PD-L1 ≥25%, the ORR was similar in patients with squamous and non-squamous histology.

	Cohort 2		Cohort 3
	PD-L1 high (≥25%)	PD-L1 low/negative (<25%)	PD-L1 ≥90%
	n=146	n=93	n=68
ORR,* %(95%CI)	16.4(10.8-23.5)	7.5(3.1-14.9)	30.9(20.2-43.3)
DCR, %(95%CI)	28.8(21.6-36.8)	20.4(12.8-30.1)	38.2(26.7-50.8)
mDoR, months(25[th], 75[th] percentile)	12.3(7.5-NR)	NR(7.2-NR)	NR; 18/21 responders progression free at DCO
	n=149	n=94	n=67
mPFS, months(95%CI)	3.3(1.9-3.7)	1.9(1.8-1.9)	2.4(1.8-5.5)
mOS, months(95%CI)	10.9(8.6-13.6)	9.3(5.9-10.8)	NR(5.9-NC)
1-year OS, %(95%CI)	47.7(39.3-55.5)	34.5(25.0-44.1)	50.8(36.9-63.2)
mFollow-up for OS, months	9.4	9.3	7.0
*Confirmed response per independent central review. DCO=data cutoff; DCR=disease control rate (complete response, partial response or stable disease ≥24 weeks); DoR=duration of response; m=median; NC=not calculated; NR=not reached; ORR=objective response rate; OS=overall survival; PFS=progression-free survival

Most AEs were low grade and resolved with treatment delay and/or immunosuppressive interventions. Overall, 10.2% of patients had Grade ≥3 treatment-related AEs and 2.7% had treatment-related AEs leading to discontinuation.

Conclusion:
Durvalumab was active and led to durable responses in a heavily pretreated metastatic NSCLC population; activity was numerically greater for patients whose tumours exceeded the 25% PD-L1 cutoff. The tolerability profile was manageable. Results are consistent with other anti-PD-1/PD-L1 therapies in metastatic, relapsed NSCLC and support further development of durvalumab.

Background:
PD-L1 immunohistochemistry (IHC) is considered as a predictive biomarker for most anti PD-1/PDL-1 therapies in non-small cell lung cancer, but different assays were used in clinical trials. Several studies have compared 4 assays (22C3, 28-8, SP142, SP263) performed in central laboratories on dedicated platforms. In order to harmonise and make PD-L1 testing widely available on most IHC platforms and centers, we compared PD-L1 Dako (22C3, 28-8) and Ventana (SP263) assays and laboratory-developed tests (LDT).

Methods:
IHC with five anti-PD-L1 clones (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers. The IHC platforms used were Ventana BenchMark Ultra (2 centers), Leica Bond (2 centers) or Dako Autostainer Link 48 (3 centers). For each matching platform, 22C3, 28.8 and SP263 assays were performed. For non-matching platforms and other antibodies, LDT were developed in each center and harmonised based on tonsil tissue staining. A total of 35 stainings were performed across different platforms and antibodies for each case. Seven thoracic pathologists trained to PD-L1 scoring in expert courses participated. Each pathologist analysed 6 cases and compared the stainings obtained with the 5 antibodies on all platforms. Tumor cell and immune cell D-L1 stainings were scored semi-quantitatively as recommended in PD-L1 Dako and Ventana assays. For statistical analysis, 1, 5, 25, 50% and 1, 5, 10% thresholds were used for tumor cells and immune cells, respectively.

Results:
28-8, 22C3 and SP263 assays were highly concordant for tumor cell and immune cell stainings across the 5 Dako or Ventana platforms (R2=0.886 to 0.953). LDT demonstrated various levels of concordance as compared to those 3 assays. Notably, LDT using SP263 clone were the most concordant across all platforms for both immune cell and tumor cell stainings, whereas some selected LDT with clones 28-8, 22C3 and E1L3N, but not SP142, showed a good correlation with the 3 assays regarding tumor cells only.

Conclusion:
28-8, 22C3 and SP263 assays gave comparable results across dedicated platforms for tumor cells staining, as well as some selected LDT protocols using 28-8, 22C3, SP263 and E1L3N clones. These results will be further validated at the national level in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.

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