News of the year: impact on clinical practice Istituto Toscano Tumori Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy Slide di presentazione modificata per stile Istituto Toscano Tumori –Livorno, Italy

LACE Meta-analysis: Survival Curves Titolo : Modificato da calibri 25 a calibri 30 Istituto Toscano Tumori –Livorno, Italy

Massuti B, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy Randomized phase III trial of customized adjuvant chemotherapy (CT) according BRCA-1 expression levels in patients with node positive resected Non-Small Cell Lung Cancer (NSCLC)<br /> SCAT :A Spanish Lung Cancer Group trial <br /> Massuti B, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy

Massuti B, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy Slide 5 Massuti B, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy

Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT) Massuti B, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy

Results/1 (cut-off March 15th 2015): Overall survival Massuti B, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy

ITACA Adjuvant Trial Pharmacogenomic Taxanes High Profile 4 Control TS Pem High Profile 3 Low Control Cis/Gem ERCC1 High Profile 2 Low Control TS Cis/Pem Low Profile 1 Control Control = Investigators’ choice; Primary end-point =overall survival; Sample size =700 patients Istituto Toscano Tumori –Livorno, Italy

Phase III trial of carbo-paclitaxel +/- bevacizumab in metastatic NSCLC: OS 12 mo. 24 mo. 1.0 0.8 0.6 0.4 0.2 bevacizumab + CP CP 52% 22% 44% 17% HR: 0.77 (0.65, 0.93) Probability p= 0.007 Medians: 10.2, 12.5 0 6 12 18 24 30 36 Months Sandler A, NEJM 2006 Istituto Toscano Tumori –Livorno, Italy

Overall Survival Disease Free Survival Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non-small cell lung cancer (NSCLC): Results of E1505 Overall Survival Disease Free Survival OS hazard ratio (B:A): 0.99 95% CI: (0.81-1.21) p=0.93 DFS hazard ratio (B:A): 0.98 95% CI: (0.84-1.14) p=0.75 . Wakelee H, et al WCLC 2015 Istituto Toscano Tumori – Livorno, Italy

RADIANT trial design Tumor samples EGFR IHC+ and/or EGFR FISH+ (n=623) Erlotinib 150mg/day No adjuvant chemotherapy Stage IB–IIIA NSCLC Complete surgical resection (N=973) Randomization stratified by: histology, stage, prior adjuvant chemo, EGFR FISH status, smoking status, country 90 d 2:1 2-yr treatment period Up to 4 cycles of platinum-based doublet (n=350) Placebo 180 d Radiology assessment: every 3 months on treatment and yearly during long-term follow up Primary endpoint: DFS Secondary endpoints: Overall survival (OS); DFS and OS in patients with del19/L858R (EGFR M+) Kelly K, JCO 2015 Istituto Toscano Tumori – Livorno, Italy

RADIANT: DFS and OS in the whole study population Placebo Erlotinib Erlotinib Placebo Kelly K, JCO 2015 Istituto Toscano Tumori – Livorno, Italy

RADIANT: DFS and OS in EGFR mut+ Placebo Erlotinib Erlotinib Placebo Stage Ib-IIa: 59.8% versus 39% in erlotinib arm versus placebo arm Kelly K, JCO 2015 Istituto Toscano Tumori – Livorno, Italy

Take home message degli studi di terapia adiuvante La chemioterapia basata sul platino rimane lo standard terapeutico adiuvante nei pazienti con carcinoma polmonare resecato La farmacogenomica non aiuta ad ottimizzare I risultati della terapia adiuvante (in attesa dello studio ITACA) L’aggiunta del bevacizumab alla chemioterapia adiuvante non migliora la sopravvivenza dei pazienti Nessun farmaco biologico è attualmente indicato come terapia precauzionale neppure in pazienti selezionati (esempio EGFR-TKIs nei pazienti con mutazione di EGFR) Istituto Toscano Tumori –Livorno, Italy

Locally advanced (stage III) NSCLC: a heterogeneous group “surgical multimodality” “non-surgical multimodality” unresectable some IIIA-N2 some T4-N0/1 bulky IIIA-N2 most IIIB Induction chemo  surgery Induction CTRT potentially resectable Radiotherapy Systemic therapy Vansteenkiste ERS 2008 Istituto Toscano Tumori –Livorno, Italy

Concurrent versus sequential chemoradiation: metaanalysis of survival Auperin et al J Clin Oncol 2010; 28:2181 Istituto Toscano Tumori –Livorno, Italy

Senan S, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy Final overall survival results of the phase III PROCLAIM trial: Pemetrexed, cisplatin or etoposide, cisplatin plus thoracic radiation therapy followed by consolidation cytotoxic chemotherapy in locally advanced nonsquamous non-small cell lung cancer Senan S, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy

PROCLAIM: Study Design Senan S, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy

Senan S, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy Slide 11 Senan S, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy

Senan S, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy Slide 17 Senan S, et al. ASCO 2015 Istituto Toscano Tumori –Livorno, Italy

OS with CDDP-VP16 versus CBDCA-Paclitaxel concomitant with RT Santana-Davila et al. JCO 2014 Istituto Toscano Tumori –Livorno, Italy

Take home message degli studi sul trattamento della malattia localmente avanzata La chemioradioterapia concomitante è lo standard terapeutico per la malattia localmente avanzata non resecabile La chemioterapia con platino-Vepesid rimane una valida opzione in concomitanza con la radioterapia La tossicità può essere ridotta utilizzando platino- pemetrexed ma Solo nei non squamosi Con aumento dei costi Carbo-taxolo valida alternativa low-cost Istituto Toscano Tumori –Livorno, Italy

Istituto Toscano Tumori – Livorno, Italy Pembrolizumab (MK-3475) in Patients With Extensive-Stage Small Cell Lung Cancer: Preliminary Safety and Efficacy <br />Results from KEYNOTE-028 Istituto Toscano Tumori – Livorno, Italy

Ott P, et al. ASCO 2015 Istituto Toscano Tumori – Livorno, Italy Change From Baseline in Tumor Size <br />(RECIST v1.1, Investigator Review) Ott P, et al. ASCO 2015 Istituto Toscano Tumori – Livorno, Italy

Presented By Scott Antonia at 2015 ASCO Annual Meeting Phase I/II Study (CheckMate 032) of Nivolumab<br />With or Without Ipilimumab for Treatment of Recurrent Small Cell Lung Cancer (SCLC) Presented By Scott Antonia at 2015 ASCO Annual Meeting

CheckMate 032 Study Design Scott A, et al. ASCO 2015 Istituto Toscano Tumori – Livorno, Italy

Summary of Clinical Activity Scott A, et al. ASCO 2015 Istituto Toscano Tumori – Livorno, Italy

Tumor Responses (PD-L1 expression) Scott A, et al. ASCO 2015 Istituto Toscano Tumori – Livorno, Italy

Scott A, et al. ASCO 2015 Istituto Toscano Tumori – Livorno, Italy Overall Survival Scott A, et al. ASCO 2015 Istituto Toscano Tumori – Livorno, Italy

Phase I Study of a delta-like protein 3 (DLL3)-Targeted Antibody Drug Conjugate Rovalpituzumab in SCLC DLL3, is a protein encoded by the DLL3 gene This gene encodes a member of the delta protein ligand family. This family functions as Notch ligands DLL3 is higly expressed in 70% of SCLC Rova-T is an antibody drug conjugate (ADC) consisting of : An antibody A linker A chemotherapy

Rova-T: Best Response Data in Evaluable SCLC Patients 0 Rova-T: Best Response Data in Evaluable SCLC Patients 0.2 mg/kg q3w and 0.3 mg/kg q6w cohorts (n=53) Expression H-Score SCLC % High 180+ 70% Intermediate 90-180 11% Low 0-90 19% Unknown NA DLL3 tested in 48 cases, with 33 cases with high levels of expression with 34% RR and 31% SD All patients received the drug as second or third-line Pietanza C, et al. ECC 2015 Istituto Toscano Tumori – Livorno, Italy

Take home message sul microcitoma polmonare L’immunoterapia rappresenta una potenziale nuova opzione terapeutica per il microcitoma polmonare con promettenti dati preliminari In monoterapia In combinazione con altri immunoterapici Rovalpituzumab ha mostrato di indurre remissione di malattia in pazienti pretrattati e selezionati per espressione di DLL3 Istituto Toscano Tumori –Livorno, Italy

IFCT MAPS: study design Scherpereel, et al. WCLC 2015 Istituto Toscano Tumori –Livorno, Italy

IFCT MAPS: OS 1.0 0.8 0.6 0.4 0.2 OS estimate 10 30 40 50 20 60 HR 0.76 (0.61–0.94) p=0.0127 Pemetrexed + cisplatin (n=225) 225 7 No. at risk 223 166 171 77 91 36 45 8 16 Time (months) 18.82 16.07 Pemetrexed + cisplatin + bevacizumab (n=223) Scherpereel, et al. WCLC 2015 Istituto Toscano Tumori –Livorno, Italy

IFCT MAPS: OS by subgroup All (n=448) Male (n=338) Female (n=110) Age <65.7 years (n=224) Age ≥65.7 years (n=224) PS 0/1 (n=433) PS 2 (n=15) Epithelioid (n=361) Sarcomatoid (n=42) Mixed (n=45) Smokers (n=254) Never smokers (n=194) Platelet <400x109/L (n=336) Platelet ≥400x109/L (n=111) Haemoglobin ≤14g/L (n=309) Haemoglobin >14g/L (n=139) Leucocytes ≥8.3x109/L (n=191) Leucocytes <8.3x109/L (n=256) EORTC good prognosis (n=320) EORTC poor prognosis (n=128) 0.5 1.0 1.5 2 Favours triplet Scherpereel, et al. WCLC 2015 Favours doublet Istituto Toscano Tumori –Livorno, Italy

Take home message sul mesotelioma L’aggiunta di bevacizumab all’attuale standard terapeutico di platino-pemetrexed aumenta la sopravvivenza dei pazienti con mesotelioma pleurico La riduzione del rischio di morte è rilevante (24%) Il vantaggio in sopravvivenza è presente in tutti i sottogruppi Nuovo standard terapeutico se bevacizumab verrà registrato con questa indicazione Istituto Toscano Tumori –Livorno, Italy