ECC 2015 English

SpringerMedizin.at/memo_inoncology SpringerMedizin.at 2/15 /memo_inoncology memo – inOncology SPECIAL ISSUE Congress Report ECC 2015

A GLOBAL CONGRESS DIGEST ON NSCLC

Report from the 18th ECCO- 40th ESMO European Cancer Congress, Vienna 25th–29th September 2015

Editorial Board:

Alex A. Adjei, MD, PhD, FACP, Roswell Park, Cancer Institute, New York, USA Wolfgang Hilbe, MD, Departement of Oncology, Hematology and Palliative Care, Wilhelminenspital, Vienna, Austria Massimo Di Maio, MD, National Institute of Tumor Research and Th erapy, Foundation G. Pascale, Napoli, Italy Barbara Melosky, MD, FRCPC, University of British Columbia and British Columbia Cancer Agency, Vancouver, Canada Robert Pirker, MD, Medical University of Vienna, Vienna, Austria Yu Shyr, PhD, Department of Biostatistics, Biomedical Informatics, Cancer Biology, and Health Policy, Nashville, TN, USA Yi-Long Wu, MD, FACS, Guangdong Lung Cancer Institute, Guangzhou, PR China Riyaz Shah, PhD, FRCP, Kent Oncology Centre, Maidstone Hospital, Maidstone, UK Filippo de Marinis, MD, PhD, Director of the Th oracic Oncology Division at the European Institute of Oncology (IEO), Milan, Italy

Supported by Boehringer Ingelheim in the form of an unrestricted grant

IMPRESSUM/PUBLISHER Medieninhaber und Verleger: Springer-Verlag GmbH, Professional Media, Prinz-Eugen-Straße 8–10, 1040 Wien, Austria, Tel.: 01/330 24 15-0, Fax: 01/330 24 26-260, Internet: www.springer.at, www.SpringerMedizin.at. Eigentümer und Copyright: © 2015 Springer-Verlag/Wien. Springer ist Teil von Springer Science + Business Media, springer.at. Leitung Professional Media: Dr. Alois Sillaber. Fachredaktion Medizin: Dr. Judith Moser. Corporate Publishing: Elise Haidenthaller. Layout: Katharina Bruckner. Erscheinungsort: Wien. Verlagsort: Wien. Herstellungsort: Linz. Druck: Friedrich VDV, Vereinigte Druckereien- und Verlags-GmbH & CO KG, 4020 Linz; Die Herausgeber der memo, magazine of european medical oncology, übernehmen keine Verantwortung für diese Beilage. Lecture Board for this issue: Maximilian Hochmair, MD; Helmut Prosch, MD; Martin Filipits, MD

The Publisher does not assume any legal liability or responsibility for the accuracy, completeness, or usefulness of the information supplied herein, nor for any opinion expressed. The Publisher, its agent, and employees will not be liable for any loss or damage arising directly or indirectly from possession, publication, use of, or reliance on information obtained from this report. It is provided in good faith without express of implied warranty.

Reference to any specific commercial product or service does not imply endorsement or recommendation by the Publisher. All articles are peer-reviewed and protected from any commercial influence. This issue is intended only for healthcare professionals outside the US, the UK, Australia and Canada. ECC2015 special issue

Table of Contents

2 Preface 3 News on targeted agents in the advanced setting 6 Interview: “Liquid biopsy is a revolution” 7 Pivotal results and sub-analyses in the field of immunotherapy 10 Interview: “Immunotherapy has opened up a new avenue of research” 11 Lung cancer screening: diagnosis in the nick of time 12 Genomic testing – becoming part of everyday practice 13 Optimising treatment in local and regional lung cancer 14 Small-cell lung cancer: established and novel

approaches © vladi79 / iStock

other important endpoints, such as Preface quality of life, and define the benefits of new drugs in difficult-to-treat subgroups. Refined molecular testing tech- Dear Colleagues, niques have become available, although their wide-spread implementation in Oncologists are currently witnessing clinical practice has yet to be improved. rapid diagnostic and therapeutic ad- Significant therapeutic advances vances in their field. These advances were also shown for the immune check- require that physicians are up-to-date point inhibitors nivolumab and pem- regarding the ever-changing standards brolizumab, while new representatives of care. With the present publication, of this drug class, such as atezolizumab, we hope to contribute to this goal, by are well on their way. Nivolumab also summarising recent findings in the di- excelled in the treatment of patients agnosis and treatment of lung cancer, with small-cell lung cancer. However, therapy might be improved by use of as presented at the European Cancer the patient selection through predictive the IASL/ATS/ERS classification in the Congress (ECC) that took place in Vi- biomarkers still needs further research future. Finally, sublobar resection was enna, from 25th–29th September, 2015. with regard to these novel immunother- shown to be feasible in stage IA tu- Innovations for patients with ad- apeutics. mours according to HRCT and maxi- vanced non–small-cell lung cancer are Early-stage and locally advanced mum standardized uptake values on of particular interest due to their poor non–small-cell lung cancer deserves at- FDG-PET/CT. prognosis. Targeted agents have al- tention as well, in particular with regard ready been shown to improve survival to improving long-term outcomes. For outcomes in this setting. The latest patients with adenocarcinoma, the se- Robert Pirker, MD, Medical University analyses shed light on their effects on lection of patients for adjuvant chemo- of Vienna, Vienna, Austria

2 2/2015 © Springer-Verlag memo special issue ECC2015

News on targeted agents in the advanced setting

Afatinib in squamous-cell 1,0 carcinoma: update of LUX- Afatinib Erlotinib Lung 8 Median, month 7.9 6.8 0,8 (95 % CI) (7.2–8.7) (5.9–7.8) Squamous-cell carcinoma of the lung HR (95 % CI) 0.81 (0.69–0.95) p value 0.0077 represents approximately 30 % of non– 0,6 small-cell lung cancer (NSCLC) cases. Until 2015, docetaxel and erlotinib were 36.4 % the only approved second-line treat- 0,4 22.0 % ment options in these patients. Typi- Estimated OS probability 28.2 % cally, squamous-cell carcinoma of the 0,2 lung has a high burden of somatic muta- 14.4 % tions and genomic alterations. Overex- 0,0 pression and dysregulation of EGFR, 0 3 6 9 12 15 18 21 24 27 30 FGFR1, PI3K and their downstream pathways are implicated in the patho- Time (months) genesis, providing a rationale for the use Figure 1: Overall survival with afatinib versus erlotinib in LUX-Lung 8 of ErbB inhibitors in this setting of ma- jor medical need. were identified. According to the bio- mean scores over time significantly fa- The global, open-label, randomised, marker analyses, the prevalence of voured afatinib over erlotinib for cough phase III LUX-Lung 8 trial compared the EGFR genomic aberrations was consist- (p = 0.0091), dyspnoea (p = 0.0024), irreversible ErbB family blocker afatinib ent with prior reports in patients with and pain (p = 0.0384). with the reversible EGFR tyrosine ki- squamous-cell carcinoma, and no pre- A diarrhoea substudy (n = 63) ana- nase inhibitor (TKI) erlotinib in a total dictive associations between genetic al- lysed the time course and severity of di- of 795 patients with squamous-cell car- terations and OS or PFS were observed. arrhoea using patient diaries at se- cinoma of the lung after failure of first- Assessment of EGFR immunohisto- lected centres. In this substudy, the line platinum-based chemotherapy. chemistry and blood-based markers is overall incidence of all-grade diarrhoea Compared to erlotinib, afatinib signifi- ongoing, as well as further bioinformat- was similar to that reported in the over- cantly improved progression-free sur- ics analysis of next-generation se- all trial population (86.1 % with afatinib, vival (PFS; median 2.4 vs. 1.9 months; quencing. 51. 8 % with erlotinib). Nineteen per- HR, 0.82, 95 % CI 0.68-1.00, p = 0.0427) cent (7 out of 36) of afatinib-treated pa- and overall survival (OS; median 7.9 vs. Quality of life and other tients reported grade ≥ 3 diarrhoea, 6.8 months; HR, 0.81, 95 % CI 0.69-0.95; outcomes with a mean duration of 3 days. No pa- p = 0.0077; Figure 1) [1]. The OS effect of tient discontinued study treatment due afatinib was consistent across sub- The outcome improvements obtained to this AE. groups. in LUX-Lung 8 were accompanied by Overall, these analyses confirm the At the ECC, the updated PFS results similar changes in patient-reported clinical relevance of the improvements and exploratory genetic analyses using outcomes [3]. Prespecified analyses us- observed for PFS, OS and tumour re- next-generation sequencing of select tu- ing the European Organisation for Re- sponse with afatinib in LUX-Lung 8. The mour samples were reported [2]. The PFS search and Treatment of Cancer (EO- researchers concluded that afatinib results significantly favoured afatinib RTC) core quality-of-life questionnaire should be considered the TKI of choice (2.6 vs. 1.9 months; HR, 0.81; p = 0.0103). (QLQ-C30) and its lung-cancer-specific for second-line treatment of squa- Furthermore, there was a significant im- module (QLQ-LC13) showed signifi- mous-cell carcinoma of the lung. provement in disease control rate (DCR; cantly higher proportions of patients 50.5 % vs. 39.5 %; p = 0.002). More pa- reporting improved global health sta- Assessment of nintedanib in tients in the afatinib group had an objec- tus/ quality of life and cough with squamous-cell carcinoma tive response (5.5 % vs. 2.8 %), and me- afatinib than with erlotinib. For dysp- dian duration of response was longer noea and pain, a non-significant ad- Nintedanib is an oral triple angiokinase than in the erlotinib arm (7.3 vs. 3.7 vantage of afatinib compared with erlo- inhibitor that targets factors of three ma- months). Adverse events (AEs) occurred tinib was observed. Afatinib jor proangiogenic pathways. Based on in both arms at similar rates, which also significantly delayed time to deteriora- the results of the randomised, placebo- applied to grade ≥ 3 AEs. tion (TTD) of dyspnoea compared to controlled, phase III LUME-Lung 1 study No biomarkers for the selection of erlotinib, and there was a trend towards [4], nintedanib has been approved in patients for treatment with afatinib delayed TTD of cough. Changes in combination with docetaxel in the Euro-

memo © Springer-Verlag 2/2015 3 ECC2015 special issue

pean Union and in Russia for the treat- Patients who progressed within 9 months after start of ﬁrst-line therapy

ment of patients with locally advanced, 175 metastatic or locally recurrent NSCLC of adenocarcinoma histology after first-line 150  Placebo + docetaxel  Nintedanib + docetaxel chemotherapy. Investigations in other 125 histological subgroups of NSCLC pa- Slope of curve at t = 0: 6.02 tients are ongoing. As an example, a mul- 100 ticentre, phase I, dose-escalating study Treatment difference at six months: 16.8 mm

of target lesions (mm) of target Slope of curve at t = 0: -5.39 75 analysing nintedanib in combination Nadir: 1.09

with standard doses of gemcitabine and sum of longest diameter Average 50 cisplatin for up to 6 cycles shows promis- 0 2 4 6 8 10 12 ing activity for the first-line treatment of Time since randomisation in LUME-Lung 1 (months) patients with advanced squamous-cell carcinoma [5]. Disease control was Patients with progressive disease as best response to ﬁrst-line therapy achieved in 81.3 %, and the 6-month OS rate was 69 %. 175  Placebo + docetaxel Continuous treatment with nint-  Nintedanib + docetaxel 150 edanib 200 mg twice daily together with cisplatin/ gemcitabine had a managea- 125 Slope of curve at t = 0: 2.07 ble safety profile. Nausea, asthenia, decreased appetite, and constipation were 100 Treatment difference at six months: 19.7 mm Slope of curve at t = 0: -9.33

the most frequent AEs. The pharmacoki- lesions (mm) of target 75 Nadir: 1.51 netic profile of nintedanib and its main Average sum of longest diameter Average metabolites in combination with chemo- 50 0 2 4 6 8 10 12 therapy were comparable to previous nintedanib monotherapy trials. There Time since randomisation in LUME-Lung 1 (months) were no relevant interactions between Figure 2: Tumour growth over time in patients with poor prognosis in LUME-Lung 1 gemcitabine/ cisplatin and nintedanib at the treatment schedule used. Further re- nintedanib and docetaxel significantly mutations with and without T790M [7]. search is warranted to determine decreased tumour burden and deceler- The rationale for this trial was the hy- whether antiangiogenic therapy is an ef- ated tumour growth over time com- pothesis that combined VEGFR/ EGFR fective treatment option in patients with pared to placebo plus docetaxel in all pathway blockade might be beneficial in squamous-cell NSCLC. patients with adenocarcinoma histol- the presence of T790M. Patients with ac- ogy. Improvements in tumour burden tivating EGFR mutations were treated Reductions in tumour burden in were greatest in those with larger base- with erlotinib 150 mg and bevacizumab LUME-Lung 1 line tumour burden. The two groups of 15 mg/kg every 3 weeks until progres- patients with the poorest prognosis, as sion. Pre-treatment T790M mutations An analysis of the LUME-Lung 1 study mentioned above, showed similar re- were identified centrally. Overall, 109 investigated the impact of treatment sults (Figure 2). patients were enrolled. Substudy 1 in- with nintedanib plus docetaxel on tu- cluded patients with T790M (n = 37), mour growth over time [6]. Tumour bur- T790M resistance mutation: whereas those without T790M were as- den has been shown to be associated erlotinib plus bevacizumab sessed in substudy 2 (n = 72). with clinical outcomes in NSCLC; de- The combination of erlotinib and creases in tumour burden and slowing Activating EGFR mutations are found in bevacizumab resulted in an overall of tumour growth is an important out- approximately 15 % of all NSCLC tu- 1-year PFS rate of 56.7 % and median come for patients. Patients with poor mours, which provides the basis for PFS of 13.8 months. In patients with prognosis in LUME-Lung 1 were in- EGFR TKI therapy, either as a first-line documented T790M mutation, the cluded in this analysis, as well as pa- or later-line treatment option after 1-year PFS rate was 72.4 % and the me- tients with adenocarcinoma who had chemotherapy. However, approximately dian PFS was 16.0 months; thus, the pre- progressed within 9 months after start of 60 % of patients who receive EGFR TKI defined endpoint for success was first-line therapy, patients who had pro- treatment develop the acquired resist- reached. Patients without T790M had a gressive disease as best response to first- ance mutation T790M. Identifying strat- 1-year PFS rate of 49.4 % and median line therapy, and all of the patients with egies to overcome this therapeutic ob- PFS of 10.5 months. Those with T790M squamous-cell carcinoma histology. stacle has become an important area of at baseline fared better across sub- Baseline tumour burden was greatest research. groups. With one exception, all patients in adenocarcinoma patients with pro- The open-label, multicentre, phase II experienced tumour shrinkage. No un- gressive disease as best response to first- ETOP 2-11 BELIEF trial investigated the expected toxicities were identified. line therapy, followed by patients who combination of erlotinib and bevaci- Further investigations using multiple progressed within 9 months of starting zumab in patients with advanced non- orthogonal methods including digital first-line therapy. The combination of squamous NSCLC with activating EGFR polymerase chain reaction and multi-

4 2/2015 © Springer-Verlag memo special issue ECC2015

100 hibitory eff ect on insulin-like growth factor 1 receptor (IGF-1R) and insulin re- 80 ceptor (IR) kinases. IGF-1R/ IR might 60 drive resistance to initial EGFR inhibitor therapy. TKI retreatment may not be a 40 ORR 35 % likely explanation, as the majority of pa- 20 tients had a recent history of progression on EGFR TKI therapy. In view of these re- 0 + sults, the clinical profi le of rociletinib in + -20 + T790M-negative NSCLC patients contin- ues to be encouraging. Th e effi cacy of -40 + + +

Change from baseline (%) Change from rociletinib in this population is currently -60  500 mg BID HBr being evaluated in the TIGER-2 and TI- +  625 mg BID HBr GER-3 clinical studies. -80  750 mg BID HBr + + Ongoing -100 Activity of rociletinib against the background of CNS disease Figure 3: Waterfall plot of best RECIST response for target lesions obtained with rociletinib in T790M-negative patients Central nervous system (CNS) metasta- plex next-generation sequencing are progression upon at least two TKIs or ses occur in up to 50 % of advanced ongoing. chemotherapy. Treatment was con- NSCLC cases. In EGFR-mutant patients ducted with rociletinib 500 mg, 625 mg treated with fi rst-generation EGFR TKIs, Rociletinib in T790M-negative or 750 mg, twice daily (BID). the 2-year CNS progression rate is 21 %, patients Th e analysis presented at the ECC fo- and 40 % among those with a prior his- cussed on updated results in centrally tory of CNS disease. Th ere is an unmet medical need for new confi rmed tissue T790M-negative pa- Patients with asymptomatic treated therapies that are active in both T790M- tients [8]. Overall response rate (ORR) CNS metastases were allowed to partici- positive and T790M wild-type NSCLC was 35 % in this population (Figure 3). pate in the TIGER-X study. A T790M-pos- patients who progressed after EGFR TKI Disease control occurred in 65 %. A com- itive biopsy was required at the time of treatment. Rociletinib, a novel, oral, se- parison of available tissue-based testing study entry in phase 2 of the trial. In this lective covalent EGFR TKI, was devel- assays (Th erascreen® and Cobas®) yielded phase, a total of 41 % of patients with a oped to address key activating mutations highly concordant results. Plasma T790M history of CNS disease were treated. Th is together with the T790M mutation. testing revealed an ORR of 45 % and a factor did not appear to aff ect response TIGER-X was a phase I/II study that in- DCR of 83 % in patients with negative rates, as the ORRs among patients with- vestigated rociletinib in previously mutation status. Th e investigators stated out and with a history of CNS metastases treated, EGFR-mutant patients with ad- that plasma tests may be more represent- were 58 % and 45 %, respectively [9]. vanced or recurrent NSCLC and both ative, especially with extra-thoracic DCRs were 92 % and 75 %, respectively. T790M-positive (n = 111) and T790M- spread. However, the greater rate of false Also, the CNS radiation rate on study was negative (n = 482) mutation status. Phase negatives has to be taken into account. assessed on the assumption that CNS ra- 1 of the trial was conducted for dose-es- Th e most common treatment-related AEs diation and post-progression TKI therapy calation, while in phase 2, expansion co- were similar to those observed in the gen- can be used as a surrogate for CNS pro- horts were treated. One cohort consisted eral TIGER-X patient population. gression on rociletinib. Based on these of second-line patients with disease pro- It is possible that the effi cacy of roci- parameters, it was estimated that 15 % of gression upon one immediate prior TKI, letinib in T790M-negative patients is progressing patients might have CNS and the other comprised patients be- driven in part by clonal heterogeneity, as progression on rociletinib, which is lower yond second line who had experienced not all cells express T790M, or by the in- than available historical data on erlotinib.

REFERENCES

1 Soria JC et al., Afatinib versus erlotinib as 4 Reck M et al., Docetaxel plus nintedanib ver- 7 Stahel R et al., A phase II trial of erlotinib (E) second-line treatment of patients with advanced sus docetaxel plus placebo in patients with pre- and bevacizumab (B) in patients with advanced squamous cell carcinoma of the lung (LUX-Lung viously treated non-small-cell lung cancer non-small-cell lung cancer (NSCLC) with activat- 8): an open-label randomised controlled phase 3 (LUME-Lung 1): a phase 3, double-blind, ran- ing epidermale growth factor receptor (EGFR) trial. Lancet Oncol 2015; 16(8): 897-907 domised controlled trial. Lancet Oncol 2014; 15: mutations with and without T790M mutation. 2 Goss GD et al., Phase III trial of afatinib ver- 143-155 The Spanish Lung Cancer Group (SLCG) and sus erlotinib in patients with squamous cell car- 5 Forster M et al., Nintedanib in combination the European Thoracic Oncology Platform cinoma of the lung (LUX-Lung 8): EGFR molecu- with cisplatin/gemcitabine as 1st-line therapy for (ETOP) BELIEF trial. ECC 2015, abstract 3BA lar aberrations and survival outcomes. ECC advanced squamous non-small cell lung cancer. 8 Solomon B et al., Rociletinib treatment and 2015, abstract 3084 ECC 2015, abstract 3112 outcomes in non-small cell lung cancer (NSCLC) 3 Popat S et al., Second-line afatinib versus er- 6 Reck M et al., Tumour growth over time in pa- patients with negative central testing for T790M. lotinib in patients with advanced squamous cell tients with advanced non-small cell lung cancer ECC 2015, abstract 3104 carcinoma of the lung: patient-reported outcome treated with nintedanib + docetaxel or placebo + 9 Varga A et al., Activity of rociletinib in EGFR data from the global LUX-Lung 8 phase II trial. docetaxel: analysis of data from the LUME-Lung mutant NSCLC patients with a history of CNS ECC 2015, abstract 3085 1 study. ECC 2015, abstract 3102 involvement. ECC 2015, abstract 3009 memo © Springer-Verlag 2/2015 5 ECC2015 special issue

Rociletinib might provide ongoing ex- lated AEs. Hyperglycaemia and diarrhoea glucose measurements that exceeded tracranial disease control in patients who were the most frequent toxicities. Hyper- 250 mg/dL at least twice. Interstitial lung received CNS radiation due to progres- glycaemia was the only grade ≥ 3 AE ob- disease did not occur. Additional data on sive disease. served in >10 % of patients; it occurred in the clinical efficacy of rociletinib in -pa The study treatment was generally 17 %. In the 500 mg BID group, only 9.6 % tients without and with a history of CNS well tolerated, with 2.5 % of patients dis- of patients without a history of diabetes metastases continue to be generated in continuing the trial due to treatment-re- or glucose impairment had post-baseline TIGER-X and the other TIGER studies. n

Interview: Filippo de Marinis, MD, PhD, Director of the Thoracic Oncology Division at the European Institute of Oncology (IEO), Milan, Italy

“Liquid biopsy is a revolution”

pill that is taken daily at home. Here, we the results, according to the degree of see large differences compared to symptoms. chemotherapy, also with regard to toxicity. On a scientific level, are there currently any trends that are particularly Can you observe the same benefits in promising? your own patients as shown in the One of the most interesting develop- trials? ments in the diagnostic field is liquid bi- Yes, and these benefits are even im- opsy, which we have started to use at the proved upon. Registration trials on European Institute of Oncology in Mi- EGFR inhibitors use the RECIST criteria, lan. Mutations can be diagnosed based which are radiological criteria. In clini- on blood samples within 2 hours. To my cal practice, however, we use a broader mind, this is a revolution, because pa- evaluation, which is not confined to ra- tients that have not yet benefited from Filippo de Marinis, MD, PhD, Director of the Thoracic Oncology Division at the European diological criteria. We do not consider a modern treatments due to the issues in- Institute of Oncology (IEO), Milan, Italy progression of 2 millimetres, for involved in biopsy assessment can be pre- stance, as an indication for discontinua- scribed targeted therapy thanks to liq- tion of treatment, and we continue to uid biopsy. It is estimated that more What changes in practice have been use local treatment. This way, the bene- than one third of patients would be eli- brought about by the recent advances fits achieved in the registration studies gible for biologicals but are not being in the treatment of lung cancer? are almost doubled in practice. treated with the right drug. To date, In the context of progress obtained in there are two academic centres in Milan the field of precision medicine in the Are new treatments being imple- that perform this kind of test, but I am last 10 years, the assessing of molecular mented in the real-world setting to a confident that this proportion will differences between patients allows for sufficient degree? swiftly increase. Also, the costs of liquid a personalised approach, which means Precision medicine is based on genomic biospy are moderate, which will con- that the efficacy of the treatments is ap- alterations. Up to now, molecular test- tribute to this development. proximately three times that of treating has been exclusively performed on With regard to treatment, immuno- ments without any mutational selec- tissue samples, but it is not possible to therapy is of course promising, but I tion. The anti-EGFR strategies have obtain tissue and receive this informa- think that some additional data is called completely changed the face of treat- tion in all cases. In nearly 40 % of pa- for to select those patients who will par- ment, because these mutations show tients, EGFR mutation or ALK rear- ticularly benefit from the treatment. It is the greatest incidence globally, and rangement testing is impossible at the not certain that immunotherapy works many trials have been conducted in this time of diagnosis of an adenocarcinoma for all patients, which means that we field. A patient with anEGFR -mutated of the lung. Not all hospitals are linked have the same problem as with the tar- tumour who receives anti-EGFR treat- to distinguished molecular laboratories, geted agents. The significance of the ment can survive for more than 30 and the time that elapses until the re- PD-L1 expression levels has been inves- months. On the other hand, for a patient sults come back varies between 6 or 8 tigated, but trials have yielded conflict- with adenocarcinoma without muta- working days in some academic centres, ing results. Different assays for the tion, survival ranges between 8 and 10 and 20 days in the south of Europe. The measurement of PD-L1 levels are being months. Also, the quality of life is very oncologist might decide to start chemo- used by different companies. This is a high with treatment that consists of a therapy treatment without waiting for debated problem. Nivolumab was ap-

6 2/2015 © Springer-Verlag memo special issue ECC2015

proved in the second-line setting in pa- ALK translocation. Second-generation it is possible to obtain survival results tients with squamous histology inde- ALK inhibitors such as ceritinib and similar to those observed in first line pendent of biomarker expression. For alectinib offer better results compared treatment. Therefore, a chemo-free patients with adenocarcinoma, on the to those achieved with the first-genera- schedule is being designed that in- other hand, the CheckMate 057 study tion ALK inhibitor crizotinib. Recently, cludes second-line treatment with a bi- showed that those expressing PD-L1 ex- ceritinib was registered in the US by the ological after a first-line biological. This perienced higher efficacy of nivolumab FDA and in Europe by the EMA for the is of importance for the patients, as than those without PD-L1 expression. treatment of patients with ALK-positive chemotherapy is not very popular with We need more trials to clarify whether advanced NSCLC after failure of crizo- them. PD-L1 is the ideal biomarker. Also, the tinib. The phase III ALEX trial is cur- costs of immunotherapy must be taken rently evaluating alectinib in the first- Will chemotherapy disappear in the into account. Selecting patients by line setting of advanced ALK-positive long run? means of biomarkers is of course cost- NSCLC, in comparison to crizotinib. No. It will be possible to increase the saving. For EGFR, second-generation and percentage of patients treated without third-generation inhibitors are being chemotherapy, but I do not think that Which molecular targets are of par- tested. Rociletinib and AZD9291 have chemotherapy will disappear from the ticular interest? shown positive phase I and phase II re- schedules in the next 10 years. Research At present, the story of molecular target- sults in patients expressing the T790M efforts will focus on combinations of ing is the story of EGFR mutation and mutation resistance. With these agents, chemotherapy with other options. n

Pivotal results and sub-analyses in the field of

immunotherapy

CheckMate 017: favourable 40 quality-of-life outcomes 30 Nivolumab 20 Docetaxel Binding of the inhibitory receptor PD-1 WORSE to its ligands, PD-L1 and PD-L2, inhibits 10 T-cell responses. This pathway can be ex- ploited by tumours to escape T-cell-in- 0 duced anti-tumour activity. Therefore, it -10

is a target for antibodies designed to Baseline Change from -20

block this mechanism, with the aim of Index LCSS Symptom Burden enhancing immune responses. The fully -30 BETTER human anti-PD-1 antibody nivolumab -40 has already been approved in the US and 0 12 24 30 36 42 48 54 60 Europe for use in pre-treated patients Week with advanced squamous NSCLC. In the phase III CheckMate 017 study, Figure 1: Symptom burden on treatment with nivolumab versus docetaxel nivolumab demonstrated superior OS compared with docetaxel in this popula- Index and the EQ-5D visual analogue stable from baseline in patients remain- tion (9.2 vs. 6.0 months; HR, 0.59; scale [2]. Nivolumab was superior to ing on treatment with docetaxel, but im- p = 0.00025) [1]. This also applied to PFS docetaxel according to both scales. On proved meaningfully in those remain- (3.5 vs. 2.8 months; p = 0.0004). treatment, changes for nivolumab indi- ing on nivolumab (Figure 1). One of the predefined secondary cated stable or improved health status, endpoints of CheckMate 017 was im- while changes for docetaxel suggested Eighteen-month update of provement of symptoms. The results of stable or declining health status. In pa- CheckMate 057 this analysis were presented at the ECC, tients treated with docetaxel, their together with those of an exploratory health status deteriorated at a signifi- For patients with advanced non-squa- quality-of-life analysis that included pa- cantly faster rate than for the patients on mous NSCLC, the phase III, randomised tient-reported outcomes using the Eu- nivolumab. Symptom burden according CheckMate 057 trial also demonstrated roQoL-5 Dimensions (EQ-5D) Utility to the Lung Cancer Symptom Scale was the superiority of nivolumab over doc-

memo © Springer-Verlag 2/2015 7 ECC2015 special issue

OS with regard to OS, as they experienced Median, months 6-month rate, % median survival of 15.5 months in the 100 (95 % CI) TPS ≥ 50 % (n = 99) 15.5 (10.0–NR) 71.6 10-mg dose group (Figure 2). The same 90 TPS 1 %–49 % (n = 127) 7.8 (5.8–12.4) 57.3 correlation applied to PFS: at 6 months, 80 TPS < 1 % (n = 68) 8.6 (5.5–12.0) 57.1 49.9 % of those with TPS ≥ 50 % were 70 Total (N = 394) 11.3 (8.8–14.0) 63.0 progression-free, compared to 25.3 % 60 and 23.2 % in the groups with TPS 1 % to 50 49 % and < 1 %, respectively. Overall, OS (%) 40 PD-L1 TPS ≥ 50 % was identified as a 30 marker for patients with the greatest 20 likelihood to derive benefit from pem- 10 brolizumab treatment. Randomised 0 data will be generated in the ongoing 0 4 8 12 16 20 24 28 32 KEYNOTE-010 study that is evaluating Time (months) pembrolizumab 2 mg/kg or 10 mg/kg three-weekly compared to docetaxel. Figure 2: Overall survival according to tumour proportion score in the pembrolizumab 10 mg cohort of KEYNOTE-001 Is PD-L2 expression important? etaxel. In this pre-treated cohort, the tom Burden Index. By week 12, symp- immunotherapeutic agent conveyed tom improvement rates were similar for A laboratory analysis addressed the po- benefits with regard to OS (12.2 vs. 9.4 nivolumab and docetaxel, at 17.8 % and tential relevance of PD-L2, one of the months; HR, 0.73; p = 0.0015) and ORR 19.7 %, respectively. Lung Cancer Symp- two known binding partners of PD-1, (19 % vs. 12 %; p = 0.0246) [3]. OS rates at tom Scale scores remained stable with respect to the efficacy of anti-PD-1 1 year were 51 % and 39 %, respectively. throughout treatment, in both arms. therapies in various cancers, such as The biomarker analysis showed a corre- pembrolizumab [6]. PD-L2 negatively lation between PD-L1 expression and Rapid tumour reduction with regulates T cells in immune responses. OS, as well as PFS. pembrolizumab: KEYNOTE-001 Some tumours show documented PD- The 18-month update continued to L2 expression by tumour cells and/or favour nivolumab treatment, with OS Two doses of the humanised anti-PD-1 infiltrating immune cells. PD-L2 has a rates of 39 % versus 23 % [4]. This differ- antibody pembrolizumab were tested in role in mediating the severity of disease ence translated into a 28 % reduction in the KEYNOTE-001 trial in 449 previ- in murine models of autoimmunity, hy- mortality risk (HR, 0.72), which was ously treated patients who suffered from persensitivity and infection. highly significant (p = 0.0009). Accord- advanced NSCLC of any histology [5]. Archival samples obtained from ing to subgroup analysis, the ORRs The analysis showed similar efficacy pembrolizumab-treated patients with a were superior for nivolumab in all sub- and safety with pembrolizumab 2 mg/ range of tumours, among them NSCLC, sets, with the exception of never smok- kg and 10 mg/kg, supporting 2 mg/kg were evaluated. PD-L2 expression was ers and EGFR-positive patients. As in every three weeks as an effective dose in found in various degrees on tumour the primary analysis, nivolumab dem- NSCLC. The correlation of efficacy with cells, stromal cells, and endothelium. In onstrated clinical benefit in patients PD-L1 expression was assessed on the NSCLC, stromal cell expression out- expressing PD-L1. Depending on the basis of tumour samples that were weighed both tumour cell and endothe- degree of expression, the median OS scored according to the percentage of lial expression. PD-L2 and PD-L1 ex- ranged from 17.7 months to 19.9 tumour cells with membranous PD-L1 pression were generally concurrent, months with nivolumab (vs. 8.0 to 9.0 staining (tumour proportion score; although discordance was observed in months with docetaxel), whereas in TPS). both directions. Notably, some NSCLC non-expressors, survival outcomes did Indeed, tumour shrinkage was more samples showed PD-L1 expression in not differ between the two treatment pronounced in patients showing PD-L1 the absence of PD-L2. However, as for arms. Response rates also favoured TPS ≥ 50 % compared to those with PD- the other tumour types, the agreement nivolumab (31 % to 37 %) over doc- L1 TPS < 50 % (74.2 % vs. 51.7 %). ORR was highly significant. A pilot analysis in etaxel (12 % to 13 %) in the patients ex- was highest in the PD-L1 TPS ≥ 50 % co- patients with squamous-cell carcinoma pressing PD-L1. In PD-L1–negative pa- hort in both dose groups. While tumour of the head and neck suggests that PD- tients, on the other hand, the ORR was size at baseline did not affect ORR, re- L2 status predicts the outcome on pem- slightly higher with docetaxel than sponses were observed less frequently brolizumab treatment after adjusting nivolumab. The median duration of re- in patients with liver metastases (13.6 %) for the impact of PD-L1 expression. sponse was longer for nivolumab in than in those without (21.2 %). Rapid tu- both expressors (16.0 vs. 5.6 months) mour reductions occurred predomi- Primary analysis of POPLAR and non-expressors (18.3 vs. 5.6 nantly in the cohort with TPS ≥ 50 %; months). also, the duration of response was long- By inhibiting PD-L1 instead of PD-1, Patient-reported outcomes were as- est in this subgroup. Correspondingly, additional benefits can be gained, be- sessed according to the Average Symp- patients with TPS ≥ 50 % benefited most cause this approach leaves the PD-L2/

8 2/2015 © Springer-Verlag memo special issue ECC2015

BIRCH: atezolizumab in a Subgroup n (%) 0.49 PD-L1–enriched cohort TC3 or IC3 47 (16 %) 0.54 In contrast to POPLAR, the single-arm, TC2/3 or IC2/3 105 (37 %) phase II BIRCH trial tested atezoli- 0.59 TC1/2/3 or IC1/2/3 198 (68 %) zumab in a PD-L1–selected NSCLC 1.04 population [9]. PD-L1 expression was TC0 and IC0 92 (32 %) tested using immunohistochemistry (IHC); only patients with TC2/3 or IC2/3 0.73 were included in the study. Three co- ITT (N = 287) horts of patients with locally advanced or metastatic tumours received atezoli- 0.2 1 2 zumab as first line (Cohort 1) or as sub- Hazard Ratioa sequent lines (Cohort 2: one prior plati- aUnstratiﬁed HR for subgroups and stratiﬁed HR for ITT. num chemotherapy; Cohort 3: at least In favour of atezolizumab In favour of docetaxel Data cut-off May 8, 2015. two prior chemotherapies, including one platinum-containing regimen). The Figure 3: Overall survival according to PD-L1 expression in POPLAR (atezolizumab vs. docetaxel) primary endpoint was ORR, according to the Independent Review Facility. PD-1 interaction intact, thus poten- The primary analysis presented at BIRCH met its primary endpoint in tially preserving peripheral homeosta- ECC showed significant OS improve- all of the predefined subgroups. ORR sis. The humanised anti-PD-L1 anti- ments in both squamous and non-squa- was highest in patients with maximum body atezolizumab works through mous NSCLC [8]. Median OS in the en- TC or IC expression (TC3, IC3) in all inhibition of the binding of PD-L1 to tire cohort was 12.6 versus 9.7 months lines. The OS data are not yet mature, PD-1 and B7.1. This mechanism can re- with atezolizumab and docetaxel, re- but the 6-month OS rates were shown to store anti-tumour T-cell activity and spectively (HR, 0.73; p = 0.040). Again, be consistent with the POPLAR results enhance T-cell priming. The interim the results were in favour of atezoli- for the second-line and third-line set- analysis of the randomised phase II zumab in patients expressing PD-L1 on ting. In the TC2/3 and IC2/3 cohorts, OS POPLAR study demonstrated promis- TC or IC, with higher expression indi- was 76 % and 71 % at 6 months for sec- ing ORR with atezolizumab monother- cating improved OS (Figure 3). The ond and third line, respectively. In the apy in the second-line and third-line same correlation applied to PFS and TC3 and IC3 cohorts, it was 80 % and treatment of metastatic or locally ad- ORR. Both TC and IC expression were 75 %, respectively. The majority of advanced NSCLC, as compared to doc- shown to be independent predictors of verse events were grades 1 or 2, and no etaxel [7]. This effect correlated with survival improvement with atezoli- unexpected safety signals occurred. n PD-L1 expression on tumour cells (TC) zumab. Duration of response was 14.3 and/or tumour-infiltrating immune versus 7.2 months with atezolizumab cells (IC). Expression was defined ac- and docetaxel, respectively. The safety cording to four cut-off levels (0 to 3 for profile of atezolizumab was consistent both TC and IC), and four cohorts were with previous studies and compared fa- investigated (TC0 and IC0; TC1/2/3 vourably to chemotherapy. Several on- and IC1/2/3; TC2/3 and IC2/3; TC3/ going trials are assessing atezolizumab IC3). in various settings.

References

1 Spigel DR et al., A phase III study (Check- 4 Horn L et al., Phase 3, randomized trial 2L/3L NSCLC (POPLAR). J Clin Oncol 33, 2015 Mate 017) of nivolumab (NIVO; anti-programmed (CheckMate 057) of nivolumab (NIVO) vs doc- (suppl; abstr 8010) death-1 [PD-1] vs docetaxel (DOC) in previously etaxel (DOC) in advanced non-squamous (non- 8 Vansteenkiste J et al., Atezolizumab mono- treated advanced or metastatic squamous (SQ) SQ) non-small cell lung cancer (NSCLC): Sub- therapy vs docetaxel in 2L/3L non-small cell cell non-small cell lung cancer (NSCLC). J Clin group analyses and patient reported outcomes lung cancer: Primary analyses for efficacy, safety Oncol 33; 2015 (suppl; abstr 8009) (PROs). ECC 2015, abstract 3010 and predictive biomarkers from a randomized 2 Reck M et al., Evaluation of overall health sta- 5 Soria J-C et al., Efficacy and Safety of Pem- phase II study (POPLAR). ECC 2015, abstract tus in patients with advanced squamous non- brolizumab (Pembro; MK-3475) for Patients (Pts) 14LBA small cell lung cancer treated with nivolumab or With Previously Treated Advanced Non-Small 9 Besse B et al., Phase II, single-arm trial docetaxel in CheckMate 017. ECC 2015, ab- Cell Lung Cancer (NSCLC) Enrolled in KEY- (BIRCH) of atezolizumab as first-line or subse- stract 3011 NOTE-001. ECC 2015, abstract 33LBA quent therapy for locally advanced or metastatic 3 Paz-Ares L et al., Phase III, randomized trial 6 Yearley JH et al., PD-L1 expression in human PD-L1-selected non-small cell lung cancer (CheckMate 057) of nivolumab (NIVO) versus tumors: relevance to anti-PD-1 therapy in can- (NSCLC). ECC 2015, abstract 16LBA docetaxel (DOC) in advanced non-squamous cer. ECC 2015, abstract 18LBA cell (non-SQ) non-small cell lung cancer 7 Spira A et al., Efficacy, safety and predictive (NSCLC). J Clin Oncol 33; 2015 (suppl; abstr biomarker results from a randomized phase II LBA109) study comparing MPDL3280A vs docetaxel in

memo © Springer-Verlag 2/2015 9 ECC2015 special issue

Interview: Riyaz Shah, PhD, FRCP, Kent Oncology Centre, Maidstone Hospital, Maidstone, UK

“Immunotherapy has opened up a new avenue of research”

combinations of these with CTLA-4 an- Can you observe improved survival in tibodies are being tested. Also, investi- your patients as a result of new treat- gations are ongoing in the adjuvant set- ments? ting. Of course, these drugs are I can definitively answer that as a yes. expensive. I work in the UK, where ac- Junior doctors who come to my lung cess to new drugs is not always straight- cancer clinic almost always comment forward, but my preliminary experience within the first week that they cannot has been very encouraging. New under- believe that all these patients are alive. standing of the side effects is constantly They are patients with stage-IV lung emerging, which is the one concern I cancer, who have druggable mutations have. and who have been alive with a range of One of the other exciting new areas is treatments for 2 or 3 years, or some- our understanding of acquired resist- times even up to 4 or 5 years. We just did Riyaz Shah, PhD, FRCP, Kent Oncology Centre, ance in EGFR-mutated lung cancer. not observe that 5 or 10 years ago. Of Maidstone Hospital, Maidstone, UK Data with the new third-generation in- course we need to appreciate that there hibitors rociletinib and AZD9291 are is a huge drop-off; many patients die being presented. Overall, there are de- very quickly after diagnosis, so a certain velopments in almost every facet. selection bias applies to the survivors, The treatment of lung cancer has ad- but there can be no doubt that things vanced considerably in the last few Are new treatments being imple- have improved considerably. Patients years. Which of these advances would mented in the real-world setting to a with brain metastases, for example, are you deem most important from the sufficient degree? now able to have resections or stereo- clinical point of view? I think the problem with new treatments tactic radiotherapy, and they live for We think of lung cancer as a generic is that there are all sorts of different is- much, much longer periods of time. term, but actually it is a term that en- sues, such as the country you work in. compasses many different diseases. Each country has its own regulatory Which molecular targets deserve the EGFR-mutated lung cancer, squamous process, its own funding pathway, and greatest attention at present? lung cancer, and ALK-positive lung can- its own way of managing health care. To my mind, the degree of benefit dem- cer are completely different diseases That means there is a wide variation in onstrated in lung cancer with immuno- with different biologies and different practice around the world. The main is- therapy means that this is the area behaviours. Within each of the main sue that we have in the UK is the cost of where we really need to try and improve subtypes of lung cancer, huge advances the drugs and the fact that it is a social- upon what we already know. There may are being made. From my point of view, ised health-care system that has a finite well be combinations of drugs that will this year’s most exciting data is the ac- set of resources. It is therefore very diffi- give even greater benefits. However, it is tivity of immune checkpoint inhibition cult to fund some of the latest drugs for a very complex area. There are a multi- in squamous lung cancer that was all cancers. The developments that are tude of similar drugs that are being de- shown in the CheckMate 017 trial pre- going on in lung cancer are also going veloped by different companies with sented at the ASCO Congress. These on in colorectal cancer, in breast cancer different biomarkers looking at different were landmark results that are practice and in all the other malignancies. All of subgroups of patients. changing. Within a few weeks of that these drugs need to be funded. How- data being presented, an expanded ac- ever, the real-world limitation is not just Will new findings change the future of cess programme became available in about money. The ability of oncologists lung cancer prevention and early de- the UK, and I started to prescribe to keep up-to-date is being stretched tection? nivolumab to patients. I have seen some now because of the increasing complex- There is a lot of really interesting emerg- absolutely dramatic responses; the ity. It is very difficult for a busy oncolo- ing data about screening and early de- course of disease was completely gist to even know all of the options that tection of lung cancer. We now have ir- changed with that PD-1 antibody in are available. Also, the treatment has to refutable evidence that screening will some very sick patients. An area with a be delivered, which calls for chemother- identify patients with lung cancers very high unmet need is also small-cell apy units, trained nurses, support staff early. If some sort of national and inter- lung cancer, where immunotherapy and primary care professionals who national screening system is estab- shows promise as well. Immunotherapy know what to do once side-effects oc- lished, I am confident that we will be has opened up a whole new avenue of cur. Overall, it is a huge, complex web able to detect more cases earlier and research in cancer treatment. Many that needs to be developed, and this will give people curative treatment when other drugs are being developed, and be a big challenge for the world. they are able to receive it.

10 2/2015 © Springer-Verlag memo special issue ECC2015

Which patient characteristics must be Some are not that interested in survival. What will happen to chemotherapy in taken into account for treatment de- They are often quite elderly and want the long run? cisions? nature to run its course. Others are will- Chemotherapy is a very, very effective The key aspect about treating patients ing to go to any lengths for even small treatment for lung cancer. It improves sur- with cancer is their performance status. benefits. I think that it is part of the phy- vival, helps the patients maintain their The treatment I prescribe is mostly sician’s job to assess how far your pa- quality of life, and reduces tumour-related chemotherapy, and patients have to be tients want to go, and to give them the symptoms. Even if new drugs replace fit enough for that. Otherwise, things best within their wishes. Someone who chemotherapy as a first-line treatment, it are made worse for them. In addition, does not want treatment should not be will still be there as a second-line or third- the patients’ wishes are important. treated. line treatment. It will always be there. n

Lung cancer screening: diagnosis in the nick of time

500 Lung cancer is the leading cause of cancer population and correct screening inter- Chest radiography mortality worldwide. Only 16 % of pa- vals can be achieved by use of validated 400 tients survive for 5 years, compared to risk models. Also, cost-effectiveness of Low-dose CT 89 % with breast cancer and almost 100 % lung cancer screening has been estab- 300 with prostate cancer. Likewise, only 16 % lished: “These costs are lower than those of patients with lung cancer are diagnosed of breast screening.” 200 before the disease has spread (vs. 60 % with breast cancer and 90 % with prostate Large-scale assessment of early 100 cancer). “Once symptoms develop, it is detection Cumulative number of lung-cancer deaths 0 too late”, emphasised Giulia Veronesi, 1 2 3 4 5 6 7 8 MD, Division of Thoracic Surgery, Euro- A number of cohort studies have investi- Years since randomization pean Institute of Oncology, Milan, Italy. gated the usefulness of screening, includ- In contrast to breast and prostate can- ing the Early Lung Cancer Action Pro- Figure: Lung-cancer-related mortality after radiographic cer, identification of early lung cancer is gram, the Anti-Lung Association Project versus low-dose computed tomography (CT) screening in the National Lung Screening Trial not part of established screening pro- in Tokyo, Japan, the Nagano Population- grammes. As Dr. Veronesi noted, screen- Based Lung Screening Trial, the NELSON ing with low-dose computed tomography Trial, the Italian Lung Cancer CT Screen- screening and should therefore be fully (LDCT) should be urgently implemented ing Trial, the Multicentric Italian Lung integrated into all screening pro- in Europe. LDCT has been shown to be Detection Trial, the German Lung Can- grammes. This implies that optimum superior to X-rays for the detection of cer Screening Intervention Study, the smoking cessation techniques must be NSCLC. “It is a non-invasive tool, and the Danish Lung Cancer Screening Trial, and identified. Also, registries are needed for examination can be performed quickly the United Kingdom Lung Cancer continued improvement and quality as- and at low cost, without the use of contrast Screening Trial. In the US, the National surance. “More nimble methodology for medium.” Lung Screening Trial was the largest ran- assessing new potential screening tests Lung cancer mortality is reduced by domised controlled trial of LDCT screen- is called for”, said Dr. Henschke. Collec- LDCT screening, as surgery then offers ing for lung cancer (n = 53,454) [3]. Peo- tion of biological samples (blood, spu- the prospect of cure in an earlier stage. ple with high risk for lung cancer were tum, urine, buccal cells) for future inte- The 10-year survival rate for resected randomly assigned to undergo three an- gration into screening is important. n stage I cancer is as high as 92 % [1]. “Diag- nual screenings with either LDCT or Source: Special Session: Lung Cancer Screening nostic algorithms allow for a safe screen- chest radiography. The trial achieved its and Prevention, 26th September, 2015 ing process and low numbers of resec- goal of showing that the stated mortality tions for benign disease”, stated Dr. reduction threshold of 20 %, which was References Veronesi. In a study on the distribution of required to provide national screening, lung cancers according to volume dou- was reached with LDCT as compared to 1 International Early Lung Cancer Action Pro- gram Investigators, Survival of patients with bling time, 10 % of screened tumours radiography (Figure). “The results led to stage I lung cancer detected on CT screening. were overdiagnosed, meaning that these the acceptance of screening in the US,” N Engl J Med 2006; 355: 1763-1771 2 Veronesi G et al., Estimating overdiagnosis in tumours grew so slowly that they would noted Claudia Henschke, PhD, MD, Head low-dose computed tomography screening for not have affected the life expectancy of of the Lung and Cardiac Screening Pro- lung cancer: a cohort study. Ann Intern Med 2012; 157: 776-784 the patients, as they showed a volume gram, Mount Sinai Medical Center, USA. 3 The National Lung Screening Trial Research doubling time of more than 600 days [2]. Aggressive smoking cessation pro- Team, Reduced lung-cancer mortality with low- dose computed tomographic screening, Optimal selection of the high-risk target grammes increase the effectiveness of N Engl J Med 2011; 365: 395-40 memo © Springer-Verlag 2/2015 11 ECC2015 special issue

Genomic testing – becoming part of everyday practice

Next-generation sequencing: Non-Squamous NSCLC (n = 4244) Squamous NSCLC (n = 1498)

robust and reliable ROS1 DDR2 BRAF 1 % 1 % 1 % DDR2 NRAS EGFR Other 1 % Other (HER-2, HRAS, 2 % (RET, FGFR1) PIK3CA HER-2 1 % Network Genomic Medicine (NGM), a RET, ALK, NRAS) 1 % 1 % 1 % MET 1 % KRAS large healthcare-provider network that 2 % ALK 2 % involves over 220 lung cancer centres in 2 % BRAF 3 % Germany, was established with the goal PIK3CA of nationwide implementation of per- MET 4 % 4 % sonalised medicine and molecular wild-type 37 % treatments [1]. Over 5,000 comprehen- EGFR 13 % FGFR1 wild-type 19 % sive next-generation sequencing (NGS)- 68 % based lung cancer tests are provided KRAS each year, whereby testing and counsel- 35 % ling is performed centrally, followed by decentralised treatment. A clinical trial platform is attached to NGM. However, on the whole, test rates are still lagging Figure: Gene alterations in non-squamous and squamous NSCLC behind. In 2014, the test rate for EGFR mutations in Germany was low, at ap- of NGS. NGS provides reduction in turn- alterations. Approximately 50 % of spec- proximately 52 %. This corresponds to around time, with the assessment of an imens were obtained at metastatic sites. 3,454 life years that were lost without entire panel (14 genes) taking 12 days, Two thirds of the patients had been di- appropriate treatment. while the assessment of 4 genes with agnosed with adenocarcinoma. Squa- To date, the histopathological data of Sanger sequencing takes 10 days. NGS is mous-cell carcinoma was present in 6,210 lung cancer patients have been as- highly sensitive for co-occupied and 11 %, and small-cell lung cancer (SCLC) sessed. The Figure shows the distribu- rare mutations, and for detection of re- in 6 %. Sixteen percent were classified as tion of genetic alterations in non-squa- sistance. Moreover, its cost is fixed and NSCLC-NOS (not otherwise specified). mous and squamous NSCLC. In transparent, compared to the multipli- Within this population, 4.6 % of pa- squamous-cell carcinoma, 68 % of the cation of single-test costs. tients harboured BRAF mutations, which cases were wild-type, and FGFR1 muta- were found to be enriched in adenocar- tions were found in 19 %. The current Spectrum of BRAF mutations cinoma (6.1 %). More than half of the al- outcome data confirm survival benefits in lung cancer terations in adenocarcinoma belonged gained by the use of targeted treatment. to the non-V600E category. Squamous- For patients with ALK rearrangement or Over the last decade, oncogenic drivers cell carcinoma harbours BRAF altera- EGFR mutation, median OS was 35 and in lung cancer have been identified, but tions in 0.8 %; none of these were 29 months, respectively. In contrast, only a subset is mentioned in consensus BRAFV600E. In patients with NSCLC NOS, those with wild-type tumours had a me- guidelines. One of these is the BRAFV600E BRAF alterations were found in 3.2 %, dian OS of 11 months. In patients with mutation, which suggests potential with 85 % falling into the non-V600E cat- BRAF mutations or HER2-positive tu- benefit from molecularly targeted ther- egory. No BRAF mutations were ob- mours, a median OS of 23 and 25 apy. Non-BRAFV600E alterations are seen served in SCLC. Certain other genomic months was observed, respectively. in lung cancer as well, and are thought alterations, such as TP53, SETD2, and Furthermore, the analysis demonstrates to be involved in oncogenesis. However, STK11, tended to co-segregate with that patients included in clinical trials previous studies did not differentiate BRAF alterations. BRAF fusions, which have a significantly better prognosis between BRAFV600E and other muta- appear to confer susceptibility to MEK than those treated outside of trials. For tions. inhibitor treatment in metastatic mela- instance, EGFR-mutated patients re- A study presented at ECC used a hy- noma, were only rarely observed. n ceiving third-generation EGFR inhibi- brid capture NGS-based comprehen- tors lived for a median of 55 months (vs. sive genomic profiling (CGP) integrated References 22 months in patients outside of trials; assay to identify the nature of BRAF al- 1 Kostenko A et al., Broad implementation of p = 0.002). terations in lung cancer [2]. For this next generation sequencing based lung cancer Cost-covering NGS is now available analysis, 3,300 lung carcinoma cases genotyping in clinical routine within a nationwide health care provider network in Germany. ECC for about 35 % of all German lung can- were tested by CGP in the course of clin- 2015, abstract 3006 cer patients within the NGM. A compar- ical care. The genomic profiles were an- 2 Ali SM et al., Comprehensive genomic profiling characterizes the spectrum of non-V600E ison of NGS with Sanger sequencing alysed by histological type, alterations activating BRAF alterations including BRAF fu- yielded a significant difference in favour within BRAF, and other co-segregating sions in lung cancer. ECC 2015, abstract 3007

Optimising treatment in local and regional lung cancer

Prediction of node negativity 1,0 with a view to sublobar resection 0,8

As patients with node-negative early lung cancer might be ideal candidates 0,6 for sublobar resection, predictors of pathological node-negative disease 0,4 were investigated in a cohort of patients  With platinum-based chemotherapy with clinical stage IA NSCLC [1]. These survival Disease-free  Surgery alone included 502 patients with adenocarci- 0,2 noma and 100 with squamous-cell car- P = 0.011 cinoma from four institutions. The rela- 0,0 tionship between lymph node status 0 20 40 60 80 100 and preoperative factors, such as tu- Follow-up after surgery (months) mour size according to high-resolution computed tomography (HRCT) and the Figure: Improved disease-free survival with platinum-based chemotherapy versus surgery alone in maximum standardised uptake value patients with a micropapillary/solid subtype (SUVmax) on fluorodeoxyglucose posi- tron emission tomography (FDG-PET/ therapy in patients with resected stage vant chemotherapy, neither the micro- CT), was examined. IB lung adenocarcinoma [2]. All of these papillary/solid predominant pattern In the adenocarcinoma cohort, SUV- patients had undergone complete re- nor the lepidic/acinar/papillary pre- max on FDG-PET/CT and tumour size section with mediastinal lymph node dominant pattern were predictive of OS on HRCT may be useful to predict node- dissection or sampling. Adjuvant chem- and DFS. Interestingly, in patients with negative stage IA lung cancer. When otherapy was not given in a randomised the micropapillary/solid predominant solid tumour size was < 0.8 cm or SUV- manner, but was used according to the subtype, adjuvant platinum-based max was < 1.5 (N0 criteria), approxi- physician’s choice. chemotherapy significantly improved mately 50 % of patients with stage cT1 Out of 359 patients, 137 (38.2 %) had DFS (p = 0.011) and tended to improve disease had no affected lymph nodes received adjuvant therapy, which con- OS (p = 0.055) compared to surgery (Table). Sublobar resection was shown sisted of platinum-based doublet chem- alone (Figure). In contrast, patients with to be feasible in stage IA tumours that otherapy in 54 % of cases. Forty-two per- the lepidic/acinar/papillary predomi- meet N0 criteria, as relapse-free survival cent were treated with oral tegafur-uracil, nant subtype did not derive any benefit and overall survival (OS) did not differ and 4.4 % received EGFR tyrosine kinase from adjuvant platinum-based chemo- between patients treated with lobec- inhibitor therapy. The platinum-based therapy. tomy or sublobar resection. doublet chemotherapy regimens con- The researchers concluded that the For patients with squamous-cell car- tained docetaxel, vinorelbine and gem- IASL/ATS/ERS classification may have a cinoma, no independent predictive fac- citabine. In the group of patients who significant predictive value with regard tors for lymph node metastasis were were treated with adjuvant chemother- to potential benefits from adjuvant ther- identified. In particular, tumour size on apy, female gender, tumour size of apy in stage IB lung adenocarcinoma. HRCT and SUVmax on FDG-PET/CT > 3 cm, and a predominantly micropap- However, prospective multi-institu- were not predictive of lymph node sta- illary/solid pattern were found signifi- tional studies and randomised clinical tus in IA carcinoma. cantly more frequently as compared to trials are mandatory to further validate those who only underwent surgery. these results. IASLC/ATS/ERS classification Indeed, tumour size > 3 cm and mi- and benefit from adjuvant cropapillary/solid predominant pattern Mutation patterns across lung therapy were identified as factors that signifi- cancer cantly decreased survival. In patients A retrospective study evaluated whether receiving surgery alone, the lepidic/aci- The prevalence and clinical association subtypes according to the 2011 Interna- nar/papillary predominant pattern was of gene mutations were investigated in tional Association for the Study of Lung associated with a significantly longer OS the ETOP Lungscape Project, in which Cancer (IASLC)/American Thoracic So- (p = 0.027) and disease-free survival 17 centres that are mainly located in Eu- ciety (ATS)/European Respiratory Soci- (DFS; p = 0.001) compared to the micro- rope participated [3]. A total of 2,709 ety (ERS) classification are predictive for papillary/solid predominant pattern. In surgically resected, stage I to III NSCLC benefits derived from adjuvant chemo- contrast, in patients treated with adju- patients constituted the Lungscape Tu-

Table groups of active proteins involved in an- Number of patients without nodal metastasis according to solid tumour giogenesis, including the expression lev- size, SUVmax, and their combination els of VEGF-A, FGFR, and HIF-1α. In this cT1 cT1a cT1b trial, Rh-endostatin was administered by (n = 502) (n = 289) (n = 213) means of intracavitary injection together Solid tumour size < 0.8 cm 187 (37.3 %) 131 (45.3 %) 56 (26.3 %) with cisplatin, while the control group received cisplatin only. SUVmax < 1.5 206 (41.0 %) 138 (47.8 %) 68 (31.9 %) The ORR, which was defined as the Solid tumour size < 0.8 cm or SUVmax < 1.5 255 (50.8 %) 169 (58.5 %) 86 (40.4 %) primary endpoint, was significantly in favour of the combination (76.4 % vs. mour Cohort. In the study presented at (3.3 % and 6.4 %, respectively). EGFR 55.0 %; p < 0.05). This was accompanied the ECC, the prevalence of selected can- mutations were more frequent in never by a significantly greater improvement in cer-related mutations, their interrela- smokers than in current or former Karnofsky performance status (88.0 % vs. tionships, the correlation of the muta- smokers (19.7 % versus 3.3 %). 60.0 %; p < 0.05). With regard to AEs, pa- tion patterns with other molecular KRAS and EGFR mutation preva- tients receiving Rh-endostatin plus cispl- alterations, as well as outcome of the lence was higher in females, patients atin experienced higher rates of neutro- patients were determined. Multiplex with adenocarcinoma, and smaller tu- penia, anaemia, diarrhoea, fatigue and mutation testing was applied in 1,801 mour size. In patients diagnosed with rash, but none of these differences were patients, whose median follow-up after PIK3CA mutation, tumour size tended significant. No grade 3/4 AEs were ob- surgery was 4.7 years. Gene mutation to be larger, and the histology was pre- served. The authors concluded that the testing was conducted using Fluidigm dominantly squamous-cell carcinoma. combination has promising efficacy that technology. The Fluidigm Gene Panel is The well-known mutual exclusivity be- is superior to cisplatin alone. n designed to reveal multiple cancer indi- tween KRAS mutation and EGFR muta- cations, including for lung cancer. The tion was confirmed. MET status showed functionally relevant genes related to an association with KRAS and EGFR lung cancer include EGFR, KRAS, mutations, but not with PIK3CA muta- ERBB2, BRAF (V600E/K), PIK3CA tion. The outcome analysis showed no (L755P) and AKT1 (E17K). The roles of association between relapse-free sur- ERBB2, BRAF, PIK3CA and AKT1 muta- vival or OS and any of the mutations. References tions in anti-cancer therapies remain to be established. 1 Tsutani Y et al., Sublobar resection choice Malignant pleural effusion: based on HRCT and FDG-PET/CT findings for In the entire cohort, KRAS was the Rh-endostatin clinical stage IA non-small cell lung cancer. ECC most frequent mutation (23.1 %), fol- 2015, abstract 3004 2 Jung-Jyh H et al., Predictors of benefits from lowed by MET (6.8 %), EGFR (5.2 %) and Recombinant human endostatin (Rh- adjuvant chemotherapy in stage IB lung adeno- PI3KCA (4.6 %). The other mutations endostatin) combined with chemother- carcinoma. ECC 2015, abstract 3002 3 Kerr K et al., Prevalence and clinical associa- had very low prevalence. According to apy was assessed in Chinese patients suf- tion of gene mutations through Multiplex Muta- the histology, adenocarcinoma is asso- fering from malignant pleural effusion, tion Testing in patients with NSCLC: Results from the ETOP Lungscape Project. ECC 2015, ciated with a much higher prevalence of both as primary treatment and after fail- abstract 3001 KRAS mutations (38.0 %) than squa- ure of previous intra-pleural therapy [4]. 4 Hu Y et al., A Clinical study of recombinant human endostatin combined with chemotherapy mous-cell carcinoma (6.2 %). For Rh-endostatin is a broad-spectrum anti- for malignant pleural effusion. ECC 2015, ab- PIK3CA, the distribution was reversed angiogenesis inhibitor that regulates stract 3005

Small-cell lung cancer: established and novel approaches

Small-cell lung cancer (SCLC) accounts only approved agent in the second-line nivolumab monotherapy and the combi- for 14 % of all lung cancers. It is initially setting. nation of nivolumab and ipilimumab sensitive to chemotherapy and radia- The phase I/II CheckMate 032 trial have anti-tumour activity in patients tion therapy, but resistance tends to de- evaluated nivolumab as monotherapy who have progressed after at least one velop rapidly, which leads to high recur- and in combination in various tumour prior therapy, including a platinum- rence rates. Outcomes with second-line types, including SCLC. The updated re- based regimen as first line [1]. The -pa treatments are poor, with 5-year sur- sults for the SCLC cohort that were pre- tients were unselected in terms of PD-L1 vival rates of only 5 %. Topotecan is the sented at the ECC showed that both expression. Nivolumab monotherapy

was administered at a dose of 3 mg/kg Table very 2 weeks (n = 80). The combination Clinical activity of nivolumab monotherapy and nivolumab plus was applied every three weeks for 4 cy- ipilimumab cles at three different doses (nivolumab 1 Nivolumab 3 mg/kg Nivolumab 1 mg/kg plus mg/kg plus ipilimumab 1 mg/kg [n = 3]; (n = 55)a Ipilimumab 3 mg/kg nivolumab 1 mg/kg plus ipilimumab (n = 45)b 3 mg/kg [n = 47]; nivolumab 3 mg/kg ORR, % 12.7 31.1 plus ipilimumab 1 mg/kg [n = 53]). Ap- Complete response, % 0 2.2 proximately one third of patients was platinum-resistant/ refractory. Partial response, % 12.7 28.9 Stable disease, % 16.4 22.2 Benefits irrespective of platinum Disease control rate, % 29.1 53.3 sensitivity Progressive disease, % 61.8 37.8 Responses were durable and occurred Death prior to first response assessment, % 5.5 4.4 early on. The ORR, which was defined as Other, % 1.8 2.2 the primary outcome, was 12.7 % in the Not reported, % 1.8 2.2 nivolumab monotherapy arm and 31.1 % Median time to objective response, months 1.61 2.15 in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg arm (Table). Objective responses Median duration of response, months Not reached (4.40, NR) 6.90 (1.48, not reached) (95% CI) range 4.4-14.1+ 1.3-9.5+ were observed in second-line patients a 25 patients were not evaluable with both platinum-sensitive and plati- b Two patients were not evaluable num-resistant disease. Median OS were 3.55 months and 7.75 months, with 27.1 % lapsed SCLC, and CheckMate 451 is test- portantly, responses were similar regard- and 47.5 % of patients alive at 1 year. For ing nivolumab alone and in combination less of whether Rova-T was administered PFS, median estimates were 1.38 months with ipilimumab as maintenance ther- as second line or third line. Patients ex- and 3.35 months for the two regimens. The apy after platinum-based first-line ther- periencing stable disease, on the other 9-month PFS rates were 10.2 % and 30.4 %. apy in SCLC. hand, showed variable DLL3 expression. In both treatment arms, tumour responses These responses were durable. At the were observed in patients with < 1 % and Rova-T: single-agent activity of 0.3 mg/kg every 6 weeks dosing sched- ≥ 1 % PD-L1 expression, according to the an antibody drug conjugate ule, patients had an ongoing response for preliminary analysis. 189 days after their confirmatory com- Treatment-related AEs occurred To date, no targeted therapy has shown puted tomography. The survival re- more frequently with the combination proven benefit in patients with SCLC. mained prolonged in these patients. regimen. Grade 3–4 AEs were seen in Encouraging phase I data are now avail- Therefore, the 0.3 mg/kg every 6 weeks 11.3 % of patients in the nivolumab mon- able for rovalpituzumab tesirine (Rova- schedule was chosen as the randomised otherapy arm and 31.9 % of patients in T), a delta-like protein (DLL)3-targeted phase II dose. the nivolumab 1 mg/kg plus ipilimumab antibody drug conjugate [2]. DLL3, Rova-T showed a manageable safety 3 mg/kg arm. Fatigue and diarrhoea con- which is overexpressed in SCLC tumour- profile. Toxicity was comparable be- stituted the most frequent AEs in both initiating cells, is directly targeted by the tween the two dosing cohorts. Fatigue groups. Grade-2 limbic encephalitis oc- humanised monoclonal antibody pre- occurred most frequently, at 28 %, fol- curred in two patients, which resolved sent in Rova-T. lowed by peripheral oedema, rash, with immunosuppressive treatment. One This trial included 73 patients with re- thrombocytopenia, pleural effusion, and patient had grade 4 limbic encephalitis, lapsed and refractory SCLC who had ex- nausea. Also, photosensitivity reactions which did not resolve with immunosup- perienced disease progression after first- occurred in 12 %. Overall, the benefits pressive treatment. The authors there- line or second-line treatment. Escalating achieved with Rova-T are exceptional in fore recommended close monitoring for doses of Rova-T were administered once the second-line and third-line SCLC set- early signs or symptoms of paraneoplas- every 3 weeks. Confirmed responses ting. These results support biomarker- tic syndromes (e. g., limbic encephalitis) were noted at 0.2 mg/kg, 0.3 mg/kg and guided phase II studies, as DLL3 might and autoimmune disease (e. g., myasthe- 0.4 mg/kg. Subsequently, the phase Ib be the first predictive biomarker associ- nia gravis). Pneumonitis was diagnosed expansion cohorts received 0.2 mg/kg ated with drug efficacy in SCLC. n in two patients in the monotherapy arm every 3 weeks or 0.3 mg/kg every 6 weeks. and in one patient in the combination In the group of patients evaluable for arm. The management of toxicity fol- response assessment (n = 53), a total of References lowed established safety guidelines. 23 % achieved ORR, with a clinical bene- 1 Calvo E et al., Nivolumab monotherapy or in Phase III studies in SCLC patients fit rate (CBR) of 68 %. Forty-nine samples combination with ipilimumab for treatment of recurrent small cell lung cancer (SCLC). ECC 2015, with extensive stage disease in the first were obtained for the assessment of abstract 3098 line and second line are presently being DLL3 expression, which was high in ap- 2 Pietanza MC et al., Phase I study of a DLL3-targeted antibody drug conjugate, rovalpituzumab te- initiated; CheckMate 331 is assessing proximately 70 % of patients. In this sirine, in patients with relapsed and refractory small nivolumab versus chemotherapy in re- group, ORR was 44 % and CBR 78 %. Im- cell lung cancer (SCLC). ECC 2015, abstract 7LBA

3/15 SpringerMedizin.at

Springer /memo_inoncology Medizin .at memo – inOncology/memo_inoncology SPECIAL ISSUE Congress Report ESMO 2015

Forthcoming Special Issue A GLOBAL CONGRESS DIGEST ON NSCLC Report from the 18th ECCO- 40th Vienna 25th ESMO European Cancer Congress, This special issue will be offering a synopsis from the ESMO ASIA–29th September 2015 2015 that will be held in Singapore, in December of this year. The report promises to make for stimulating reading, as the ESMO Congress itself draws on the input from a number of partner organizations, representing a multidisciplinary approach to cancer treatment and care. Again, lung cancer will be at the

IMPRESSUM/PUBLISHER heart of this special issue. Medieninhaber und Verleger: Springer-Verlag GmbH, Professional Media, Prinz-Eugen-Straße 8–10, 1040 Wien, Austria, Tel.: 01/330 24 15-0, Fax: 01/330 24 26-260, Internet: www.springer.at, www.SpringerMedizin.at.Springer-Verlag GmbH, Eigentümer Professional und Media, Copyright: Prinz-Eugen-Straße © 2015 Springer-Verlag/Wien. 8–10, 1040 Wien, Springer Austria, istTel.: Teil 01/330 von Springer 24 15-0, Science Fax: 01/330 + Business 24 26-260, Media, springer.at. Leitung Professional Media: Dr. Alois Sillaber. Fachredaktion Medizin: Dr. Judith Moser. Corporate Publishing: Elise Haidenthaller. Layout: Verlagsort: Wien. Herstellungsort:Dr. Alois Sillaber. Eigentümer und Copyright: Wien. Herstellungsort: Fachredaktion Medizin: © 2015 Springer-Verlag/Wien. Springer ist Teil von Springer Science + Business Media, springer.at. Die Herausgeber der memo, magazineLinz. of europeanDruck: medical oncology, übernehmenDr. Judith keineMoser. Verantwortung für diese Beilage. Friedrich VDV, Vereinigte Druckereien- undCorporate Verlags-GmbH Publishing: & CO KG, 4020 Linz; Elise Haidenthaller. The Publisher does not assume any legal liability or responsibility for the accuracy, completeness, or usefulness of the information suppliedLayout: herein, Katharina nor for Bruckner. any opinion Erscheinungsort: expressed. Erscheinungsort: The Publisher, its agent, and employees will not be liable for any loss or damage arising directly or indirectly from possession, publication, use of, or reliance on information obtained Wien. from this report. It is provided in good faith without express of implied warranty.

ESMO ASIA 2015 SINGAPORE, 18–21 DECEMBER 2015

www.springermedizin.at/ memo_inoncology

For additional expert information on oncology topics, why not explore memo inoncology (www.springermedizin.at/memo_inoncology), an educational webpage sponsored by Boehringer Ingelheim. Not only will you always ﬁ nd the latest issue of the memo – inoncology Special Issue series here, you will in future also be able to look up previous issues by congress and year. In addition, this webpage aims to offer a number of further educational materials speciﬁ cally chosen to complement each issue as it is published.