Algoritmo de tratamiento del CNMP escamoso. Jesús Corral, MD Thoracic Oncology Unit HUVR-Oncoavanze, Sevilla

Algoritmo de tratamiento del CNMP escamoso Jesús Corral, MD Thoracic Oncology Unit HUVR-Oncoavanze, Sevilla

Agenda CNMP escamoso vs no escamoso: diferencias? Opciones de tratamiento 1L Opciones de tratamiento 2L Futuro Conclusiones

Squamous vs Non-Squamous Adenocarcinoma 1,2 Squamous 1-3 H-E stain X150 H-E stain X150 Presence of glands and papillary structures Neoplastic cells with round to oval nuclei, prominent nucleoli, and moderate amounts of cytoplasm Stain for mucin, TTF-1, cytokeratin 7 Flattened appearance with keratinization Intercellular bridges Stain for p63, p40, cytokeratin 5/6 Rosado-de-Christenson ML et al. Radiographics 1994 Oliver TG et al. Am J Clin Oncol 2015 Bishop JA et al. Mod Pathol 2012

Squamous vs Non-Squamous Parameter Adenocarcinoma Squamous cell carcinoma Patient demographics Over twice as common as any other lung cancer histology in women; most common histology in nonsmokers; patients tend to be younger More prevalent in men; stronger association with smoking; patients tend to be slightly older Tumor location Peripheral hemorrhages from blood vessel Central (higher incidence of invasion and bronchial obstruction) Cavitation Not typical Typical Disease stage at baseline Metastatic disease often presents before symptom development More likely to be detected at localized stage due to earlier onset of symptoms Metastasis Brain metastases are more common Brain metastases are less common Hirsch FR et al. J Thorac Oncol 2008 Mujoomdar A et al. Radiology 2007

Squamous vs Non-Squamous Socinski M, et al. JTO 2016 Janssen-Heijnen ML et al. Lung Cancer 1998

Non-squamous vs Squamous Socinski M, et al. JTO 2016

Non-squamous vs Squamous Lawrence et al. Nature 2013

Median OS, months Squamous vs Non-Squamous 14 12 10 8 6 4 2 ~30% 0 Squamous Non-squamous Wilson DO et al. Am J Respir Crit Care Med 2012 Veronesi G et al. Ann Intern Med 2012 Sandler A et al. N Engl J Med 2006; Socinski MA et al. J Clin Oncol 2012 Paz-Ares LG et al. J Clin Oncol 2013; Scagliotti GV et al. J Clin Oncol 2008

Agenda CNMP escamoso vs no escamoso: diferencias? Opciones de tratamiento 1L Opciones de tratamiento 2L Futuro Conclusiones

CT= standard of care Schiller et al. N Engl J Med 2002

Rela=ve expre. levels Gemcitabine is better than CT = Histology approach Pemetrexed in SCC of the Lung Adenocarcinoma Squamous Scaglio( GV et al. J. Clin. Oncol 2008; 26:3543 Ceppi P. et al. Cancer 2006 Scagliotti GV et al. J Clin Oncol 2008; Ceppi P, et al. Cancer 2006

CT = Maintenance therapy Non -SCC Non -SCC SCC SCC Cai H, et al. Clin Lung Cancer 14:333-41, 2013 Cai H, et al. Clin Lung Cancer 2013

Abraxane based CT Nab-Paclitaxel in SCC Efficacy endpoint Nab-P + C (n=521) CP (n=531) RRR (95% CI) p value ORR, % 33 25 ORR (squamous), % 41 24 1.313 (1.082, 1.593) 1.680 (1.271, 2.221) 0.005 <0.00 1 ORR (nonsquamous), % 26 25 1.034 (0.788, 1.358) 0.81 Socinski M et al. J Clin Oncol 2012;30:2055 62 Socinski M, et al. J Clin Oncol 2012

Abraxane based CT Socinski M, et al. Ann Oncol 2013

CT + NECITUMUMAB (SQUIRE) Thatcher N, et al. Lancet Oncol 2015

CT + NECITUMUMAB (SQUIRE) EGFR IHC (+) >1% EGFR FISH (+) 95% 17% 1 Paz-Ares L, et al. Ann Oncol 2016 6

CT + NECITUMUMAB (SQUIRE) 1 7 Thatcher N, et al. ASCO 2014

CT + NECITUMUMAB (SQUIRE) Thatcher N, et al. Lancet Oncol 2015

E Study tian Schumann, 10 Jacqueline Brown, 11 Victoria Soldatenkova, 12 Nadia Chouaki, 13 Nick Thatcher CT + NECITUMUMAB (SQUIRE) tology/oncology UPMC, Pittsburgh, PA, United States; 3 Leningrad Regional Clinical Hospital, St. Petersburg, Russia; 4 Mazowieckie Centrum Leczenia gary; 8 Centre Hospitalier Le Mans, Le Mans, France; 9 Clinic for Pulmonology, Thoracic Oncology, Sleep- and Respiratory Critical Care, Hospitals of HRQL LCSS: Lung Cancer Symptoms LCSS: Global Items Figure 3. Forest Plot of Hazard Ratios and 95% CI for Time to Deterioration for LCSS and ECOG PS Loss of Appetite Fatigue Cough Dyspnea Hemoptysis Pain ASB Index Overall Symptoms Interference Quality of Life GTIC Index LCSS Total Score N Events Gem-Cis + Neci 545 545 545 545 545 545 545 545 545 545 545 545 263 264 205 219 68 183 160 225 270 243 218 165 N Events Gem-Cis 548 548 548 548 548 548 548 548 548 548 548 548 232 241 158 199 65 172 135 189 225 218 189 132 HR (95% CI) 1.011 (0.846, 1.207) 1.014 (0.851, 1.209) 1.143 (0.927, 1.409) 0.929 (0.765, 1.127) 0.842 (0.598, 1.188) 0.881 (0.714, 1.087) 0.995 (0.790, 1.253) 1.064 (0.876, 1.292) 1.138 (0.952, 1.359) 0.994 (0.827, 1.196) 1.047 (0.861, 1.274) 1.087 (0.864, 1.368) ECOG PS 545 224 548 185 0.902 (0.736, 1.107) HRQL Summary 88% of patients in both arms had a baseline and at least one completed post-baseline LCSS assessment None of the 95% confidence intervals for time to deterioration for LCSS and ECOG PS excluded a hazard ratio of 1.0 0.5 1 1.5 Favors Gem-Cis + Neci Favors Gem-Cis Supportive Care Resource Utilization Table 5. Supportive Care Resource Utilization Chemotherapy Phase Monotherapy CONCLUSIONS Phase Long-term use Reck of necitumumab M, et al. was J well Thorac tolerated Oncol 2016

1L PD-L1+ NSCLC (both histologies) Reck M, et al. NEJM 2016

1L PD-L1+ NSCLC (both histologies) 10,3 vs 6 months Reck M, et al. NEJM 2016

1L PD-L1+ NSCLC (both histologies) NR both arms 70% vs 54% 1y Reck M, et al. NEJM 2016

1L PD-L1+ NSCLC (both histologies) Reck M, et al. NEJM 2016

Approximate frequency, % Targeted therapies Potential oncogenic drivers for guiding treatment in squamous NSCLC 1 45 40 Data from recent genomic studies of squamous cell lung cancers 1 41% 35 30 25 20 15 10 5 12% 5% 10% 4% 10% 4% 10% 4% 0 FGFR1 amplification FGFR2 / FGFR3 mutation PIK3CA mutation DDR2 mutation PDGFRA amplification BRAF mutation EGFR ErbB2 amplification amplification Unknown Most agents under evaluation for squamous NSCLC are directed Vincent MD. Front Oncol 2014

Agenda CNMP escamoso vs no escamoso: diferencias? Opciones de tratamiento 1L Opciones de tratamiento 2L Futuro Conclusiones

2L Sq-NSCLC scenario Afatinib Taxol+Beva Atezolizumab Soria JC, et al. ASCO 2016

Afatinib 2L Sq-NSCLC LUX LUNG 8: Afa=nib Efficacy OS OS Forest plot PFS PFS Forest plot PFS PFS SC10.04: Second-Line Therapy and Beyond in Squamous Cell NSCLC - Silvia Novello Soria JC, et al. Lancet Oncol 2015 Vansteenkiste J. et Soria al., atezolizumab JC et al, Lancet in NSCLC Oncol (POPLAR) 2015

Ramucirumab 2L Sq-NSCLC Garon EB, et al. Lancet 2014

Nivolumab 2L Sq-NSCLC Brahmer J, et al. NEJM 2015

Pembro 2L NSCLC 12,7 (HR=0,61) vs 10,4 (HR=0,71) vs 8,5 m 17,3 (HR=0,50) vs 14,9 (HR=0,54) vs 8,2 m Herbst ES, et al. Lancet 2016

Pembro 2L NSCLC Herbst ES, et al. Lancet 2016

Atezolizumab 2L NSCLC 13,8 vs 9,6 months, HR=0.73, p=0,0003 Barlesi et al. ESMO 2016

Atezolizumab 2L NSCLC Grade 3-4 AEs 37% vs 54%; leading to treatment withdrawal 8% vs 19% Barlesi et al. ESMO 2016

Atezolizumab 2L NSCLC No histology differences, so PD-L1 needed? Barlesi et al. ESMO 2016

Agenda CNMP escamoso vs no escamoso: diferencias? Opciones de tratamiento 1L Opciones de tratamiento 2L Futuro Conclusiones

Abraxane based CT + Necitumumab

Targeted therapies RTK PI3K Developmental DNA repair RB EGFR ampl FGFR ampl AZD4547 Ponatinib Dovitinib Nintedanib PI3K mutation pten delection AKT activation BASALT 1-3 Negative SOX amplification/ overexpression Buen pronóstico PARP inh CDK4-6 inh DDR-2 mut Dasatinib Shtivelman E, et al. Oncotarget 2014 Stead LF, et al. Plos One 2013

Nivo+CT=CheckMate 012 n =12 n=15 n=15 n=14 33% 47% 47% 43% Rizvi NA, et al. JCO 2016

Nivo+CT=CheckMate 012 Rizvi NA, et al. JCO 2016

Nivolumab plus Ipilimumab Nivo 3 Q2W (n = 52) Nivo 3 Q2W + Ipi 1 Q12W (n = 38) Nivo 3 Q2W + Ipi 1 Q6W (n = 39) Any grade Grade 3 4 Any grade Grade 3 4 Any grade Grade 3 4 Treatment-related AEs, % 73 19 84 42 74 31 Treatment-related AEs leading to discontinuation, % 12 12 18 8 18 8 Gettinger S, et al. WCLC 2016

PFS (%) PFS (%) Nivolumab plus Ipilimumab All treated patients (n = 77) 1% PD-L1 (n = 46) 50% PD-L1 (n = 13) 100 80 Median 8.0 months (95% CI 4.1, 13.2) 100 80 Median 12.7 months (95% CI 7.8, 23.0) 100 80 Median NR (95% CI 7.8, NR) Nivo 3 Q2W + Ipi 1 Q6/12W 60 40 60 40 60 40 20 20 20 0 0 6 12 18 24 30 36 42 48 0 0 6 12 18 24 30 36 42 48 0 0 6 12 18 24 30 36 42 48 All treated patients (n = 52) 1% PD-L1 (n = 32) 50% PD-L1 (n = 12) 100 80 Median 3.6 months (95% CI 2.3, 6.6) 100 80 Median 3.5 months (95% CI 2.2, 6.6) 100 80 Median 8.3 months (95% CI 2.2, NR) Nivo 3 Q2W 60 60 60 40 40 40 20 20 20 0 0 6 12 18 24 30 36 42 48 Months 0 0 6 12 18 24 30 36 42 48 Months 0 0 6 12 18 24 30 36 42 48 Months Gettinger S, et al. WCLC 2016 45

OS (%) OS (%) Nivolumab plus Ipilimumab All treated patients (n = 77) 1% PD-L1 (n = 46) 50% PD-L1 (n = 13) 100 100 100 80 80 80 Nivo 3 Q2W + ipi 1 Q6/12W 60 40 60 40 60 40 20 1-year OS rate: 76% 0 0 6 12 18 24 30 36 42 48 20 1-year OS rate: 87% 0 0 6 12 18 24 30 36 42 48 20 1-year OS rate: 100% 0 0 6 12 18 24 30 36 42 48 All treated patients (n = 52) 1% PD-L1 (n = 32) 50% PD-L1 (n = 12) 100 100 100 80 80 80 Nivo 3 Q2W 60 60 60 40 40 40 20 1-year OS rate: 73% 0 0 6 12 18 24 30 36 42 48 20 1-year OS rate: 69% 0 0 6 12 18 24 30 36 42 48 20 1-year OS rate: 83% 0 0 6 12 18 24 30 36 42 48 Months Months Months Gettinger S, et al. WCLC 2016 46

Agenda CNMP escamoso vs no escamoso: diferencias? Opciones de tratamiento 1L Opciones de tratamiento 2L Futuro Conclusiones

Conclusiones Stage IV Squamous NSCLC ECOG 0-1, PD-L1>50% No CI Immunotherapy Pembrolizumab CT +/- Necitumumab (EGFR IHC + >1%) Docetaxel +/- Ramucirumab Afatinib CT+/-Necitumumab (EGFR IHC + >1%) Nivolumab/Pembro/Atezolizumab (Pembro PD-L1>1%) Docetaxel+/-Ramucirumab Afatinib

CASE REPORT 60 yo male, active smoker, HTA (Enalapril 10 mg od) Aug 2013: Left thoracic pain, dysphnea with an acute hemoptysis

CASE REPORT PR 1L: Cis/Gem + Necitumumab (Ph II JFCK trial) x 6 cycles ORR=PR and Toxicity=G1 rash, G1 hypomg, G1 paronychias

CASE REPORT PFS 13 m Dec 14: Pembrolizumab 10 mg/kg/3 w KeyNote 010 Ph 3 Trial ORR=PR and NO G3-4 toxicity

CASE REPORT Dec 2016 (PFS 24 months) ORR=PR and Toxicity=G2 pneumonitis and G1 hypotiroidism/rash OS=40 months (>3 y!)

Thanks jesuscorraljaime@hotmail.com