1-line Treatment of Advanced-NSCLC WT Cesare Gridelli Division of Medical Oncology “S.G. Moscati” Hospital – Avellino (Italy)

First-Line Treatment of A-NSCLC in EU EGFR-mutation analysis Non-squamous cell carcinoma Metastatic NSCLC, PS 0-2 Squamous cell carcinoma EGFR mutation (del 19 or L858R in exon 21) EGFR wild type (or not done) EGFR-TKI Radiotherapy CNS Central airways Bone Soft tissue Platinum plus Pemetrexed or gemcitabine or taxanes or vinorelbine OR Platinum combination plus Bevacizumab* (PS 0,1) Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly) Platinum plus Gemcitabine or taxane or vinorelbine Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly)

First-Line Treatment of Advanced NSCLC NCCN Guidelines Adenocarcinoma Large cells NSCLC NOS Squamous cell carcinoma EGFR mutation and ALK negative EGFR mutation positive ALK positive PS 0-1 PS 2 PS 3-4 Erlotinib Crizotinib Doublet chemotherapy (category 1) OR Cetuximab/vinorelbine/ cisplatin (category 2B) Chemotherapy Best supportive care PS 0-1 PS 2 PS 3-4 Doublet chemotherapy (category 1) OR Bevacizumab + chemotherapy (if criteria met) OR Cisplatin/pemetrexed (category 1) (if criteria met) OR Cetuximab/vinorelbine/cisplatin (category 2B) Chemotherapy Best supportive care only

First-Line Treatment of Advanced NSCLC EGFR-mutation analysis Non-squamous cell carcinoma Metastatic NSCLC, PS 0-2 Squamous cell carcinoma EGFR mutation (del 19 or L858R in exon 21) EGFR wild type (or not done) EGFR-TKI Radiotherapy CNS Central airways Bone Soft tissue Platinum plus Pemetrexed or gemcitabine or taxanes or vinorelbine OR Platinum combination plus Bevacizumab PS 0,1) Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly) Platinum plus Gemcitabine or taxane or vinorelbine Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly)

First-Line Treatment of Advanced NSCLC EGFR-mutation analysis Non-squamous cell carcinoma Metastatic NSCLC, PS 0-2 Squamous cell carcinoma EGFR mutation (del 19 or L858R in exon 21) EGFR wild type (or not done) EGFR-TKI Radiotherapy CNS Central airways Bone Soft tissue Platinum plus Pemetrexed or gemcitabine or taxanes or vinorelbine OR Platinum combination plus Bevacizumab PS 0,1) Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly) Platinum plus Gemcitabine or taxane or vinorelbine Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly)

BPC, bevacizumab-paclitaxel-carboplatin; PC, paclitaxel-carboplatin. The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab versus 10.3 months in the chemotherapy-alone group. Sandler A, et al. N Engl J Med. 2006;355(24): Hazard ratio, 0.79; P = Overall Survival, % Month 36 BPC group (305 events in 417 patients) PC group (344 events in 433 patients)

Avastin-based therapy (n=602) – extends OS to 14.2 months – 31% reduction in the risk of death (HR=0.69) Duration of OS (months) Probability of OS Avastin + CP (n=300) CP (n=302)

First-Line Treatment of Advanced NSCLC ESMO Guidelines EGFR-mutation analysis Non-squamous cell carcinoma Metastatic NSCLC, PS 0-2 Squamous cell carcinoma EGFR mutation (del 19 or L858R in exon 21) EGFR wild type (or not done) EGFR-TKI Radiotherapy CNS Central airways Bone Soft tissue Platinum plus Pemetrexed or gemcitabine or taxanes or vinorelbine OR Platinum combination plus Bevacizumab PS 0,1) Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly) Platinum plus Gemcitabine or taxane or vinorelbine Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly)

Cisplatin With Pemetrexed or Gemcitabine JMDB Trial Cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine in NSCLC CP, cisplatin-pemetrexed. Scagliotti GV, et al. J Clin Oncol. 2008;26(21): Survival Probability CG10.4; 9.6, 11.2 CP11.8; 10.4, Survival Time (months) in Patients With Squamous Cell Carcinoma Survival Probability PFS Probability PFS (months) in Patients With Squamous Cell Carcinoma PFS Probability Survival Time (months) in Patients With Non-squamous Histology PFS (months) in Patients With Non-squamous Histology CP vs CG Adjusted HR; 95% CI 0.81; 0.70, 0.94 Median; 95% CI CG4.7; 4.4, 5.4 CP5.3; 4.8, 5.7 CP vs CG Adjusted HR; 95% CI 0.90; 0.79, 1.02 Median; 95% CI CG5.5; 4.6, 5.9 CP4.4; 4.1, 4.9 CP vs CG Adjusted HR; 95% CI 1.36; 1.12, 1.65 Median; 95% CI CG10.8; 9.5, 12.1 CP9.4; 8.4, 10.2 CP vs CG Adjusted HR; 95% CI 1.23; 1.00, 1.51 Median; 95% CI

Maintenance Therapy Continuation vs Switch QoL Symptom control Toxicities ‘Continuation’ maintenance with the chemo drug X ‘Switch’ maintenance with a new chemo drug ‘Continuation’ maintenance with TT (eg, bevacizumab) P + X ± TT × 4 cycles 50% Selection of patients with a better prognosis Stabilisation or objective response ‘Switch’ maintenance with a new drug TT (EGFR TKI for SD patients)

Maintenance Therapy in NSCLC Patient Selection Histology Adenocarcinoma subtypes Squamous cell carcinoma Clinical Features Age: Adults years (fit, elderly) Gender: Any ECOG PS 0-1, KPS>80 ECOG PS 2 (selected cases for TKI) Genetics EGFR Wild type – chemotherapy EGFR Mutant – TKI (TKI responders; Asian, women, never smoker, having adenocarcinoma) k -ras mutation – chemotherapy EML4-ALK – Crizotinib Suitable Subset of Patients Clinical benefit; stable disease or regression after induction chemotherapy Well-preserved organ function No major comorbidity

SATURN: Sequential Tarceva in unresectable NSCLC No progression (n=899) Progression Tumour samples (mandatory) Erlotinib 150mg/dayPlacebo Until PD, death or unacceptable toxicity Randomisation with stratification EGFR protein expression (IHC) results Study Period Screening Period Until PD, death or unacceptable toxicity TITAN Stage IIIb/IV NSCLC 4 cycles of a first-line standard platinum-based doublet Planned Recruitment = 1,700

OS from randomization in all patients Time (months) OS probability Erlotinib (n=438) Placebo (n=451) *OS is measured from time of randomisation into the maintenance phase; ITT = intent-to-treat population HR=0.81 (0.70–0.95) Log-rank p= Cappuzzo et al,WCLC 2009

OS probability Time (months) Time (months) Log-rank p= HR=0.72 (0.59–0.89 ) Erlotinib (n=252) Placebo (n=235) Log-rank p= HR=0.94 (0.74–1.20) Erlotinib (n=184) Placebo (n=210) SDCR/PR Measured from time of randomisation into the maintenance phase OS according to response to first-line chemo Multivariate HR for OS in SD population 0.71, p=0.0019

PARAMOUNT: Study Design Study Treatment Period Progression Induction Therapy (4 cycles)Maintenance Therapy (Until PD) 21 to 42 Days 500 mg/m 2 Pemetrexed + 75 mg/m 2 Cisplatin, d1, q21d CR, PR, SD PD Placebo + BSC, d1, q21d 500 mg/m 2 Pemetrexed + BSC, d1, q21d 2:1 Randomization Patients enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD)

PARAMOUNT: Investigator Assessed PFS (from Maintenance) Pemetrexed: median =4.1 mos ( ) Placebo: median =2.8 mos ( ) Log-rank P= Unadjusted HR: 0.62 ( ) Patients at Risk Pem + BSCN= Placebo + BSCN= Pem + BSC Placebo + BSC

PARAMOUNT: Final OS from Randomization Patients at Risk Pem + BSC Placebo + BSC Time from Randomization (Months) Survival Probability PemPlacebo OS Median (mo) (95% CI) 13.9 ( ) 11.0 ( ) Censoring (%) Survival Rate (%) (95% CI) 1-year58 (53-63)45 (38-53) 2-year32 (27-37)21 (15-28) Log-rank P = Unadjusted HR: 0.78 (95% CI: 0.64–0.96)

PARAMOUNT: Final OS from Induction Survival Probability Time from Induction (Months) Pemetrexed Median OS =16.9 mos (95% CI: 15.8–19.0) Placebo Median OS =14.0 mos (95% CI: 12.9–15.5) Log-rank P= HR=0.78 (95% CI: 0.64–0.96) Patients at Risk Pem + BSC Placebo + BSC

Survival Probability Time From Randomisation, months CR/PR HR=0.81 (0.59–1.11) Stable Disease HR=0.76 (0.57–1.01) Time From Induction, months Survival Probability 1.0 Pemetrexed + BSC Median OS=16.9 months (95% CI, 15.8–19.0) HR=0.78 (95% CI, 0.64–0.96) Log-rank P = Placebo + BSC Median OS=14.0 months (95% CI, 12.9–15.5)

EQ-5D, EuroQol 5-dimensional questionnaire; VAS, visual analog scale. * P ≤0.05, comparing the difference in mean changes from baseline between treatment arms. Gridelli C, et al. J Thorac Oncol. 2012;7(11): Improvement Mean Score (Scale to +1.00) N= Maintenance Cycles ∆0.01 ∆0.00 ∆0.03 ∆-0.01 ∆0.02 ∆0.01 ∆-0.02 ∆0.04 Mean value at baseline (Cycle 0) Mean change from baseline ∆ Improvement Mean Rating (Scale 0 to 100) N= Maintenance Cycles ∆1.65 ∆1.42 ∆3.15 ∆1.24 ∆1.82 ∆4.90 ∆0.69 ∆6.15 ∆1.55 ∆5.99 ∆3.01 ∆5.76 * ** EQ-5D UK population-based index scoreEQ-5D VAS

Change in ECOG Performance Status from Baseline to Last Maintenance Treatment 7.8%9.0% 76.2% 78.6% 16.0% 12.4%

PARAMOUNT: Long Term Safety CTCAE Grade 3/4/5 term >10 cycles Pemetrexed* n = 84 (%) ≤10 cycles Pemetrexed n = 275 (%) P-value All laboratory All non-laboratory Neutropenia † Infections * 10 cycles = 10 total cycles (4 induction cycles + 6 maintenance cycles) † Although incidence of G 3-4 neutropenia higher with long-term use; this did not translate into increased G 3-4 infections.

Grade 1-4 Adverse Events Event (%) ≥70 Yrs Subgroup<70 Yrs Subgroup Gr 1Gr 2Gr 3/4Gr 1Gr 2Gr 3/4 pemplcpemplcpemplcpemplcpemplcpemplc Fatigue Anemia Neutropenia Febrile Neutropenia Leukopenia Thrombocytopenia Renal* Rash Edema

Palliative radiation during pemetrexed plus cisplatin first-line treatment for advanced non-small cell lung cancer (NSCLC): Patient safety in the JMDB and PARAMOUNT trials 1 Giorgio V Scagliotti, 2 Cesare Gridelli, 3 Filippo de Marinis, 4 Bonne Biesma, 5 Martin Reck, 6 Belen San Antonio, 7 Annamaria Hayden Zimmermann, 8 Carla Visseren-Grul, 9 Nadia Chouaki, 10 Luis Paz-Ares 1 University of Torino, San Luigi Hospital, Orbassano (Torino), Italy; 2 San Giuseppe Moscati Hospital, Avellino, Italy; 3 San Camillo - Forlanini Hospital, Rome, Italy; 4 Jeroen Bosch Hospital, Hertogenbosch, Netherlands; 5 Hospital Grosshansdorf, Grosshansdorf, Germany; 6 Eli Lilly and Company, Madrid, Spain; 7 Eli Lilly and Company, Indianapolis, IN, USA; 8 Eli Lilly and Company, Houten, Netherlands; 9 Eli Lilly and Company, Paris, France; 10 Seville University Hospital, Seville, Spain J Thorac Oncol, in press

*In JMDB two patients experienced AEs; 1 Grade 2 (Gr 2) anemia and 1 Gr 2 radiation dermatitis. *In Paramount 10 patients experienced AEs during the induction phase of treatment Other events commonly associated with the administration of chemotherapy and XRT, such as lung toxicities (e.g. pneumonitis) and esophagitis, were not reported. Possibly drug-related adverse events during palliative XRT or within 2 weeks after the end of the last fraction in JMDB and PARAMOUNT (N=65) Possibly drug-related adverse events during palliative XRT or within 2 weeks after the end of the last fraction in JMDB and PARAMOUNT (N=65) Patients Receiving Palliative XRT During Pem/Cis Treatment (N=65) Patients with adverse events n=12 (18.5%) CTCAEGr 1, n (%)Gr 2, n (%)Gr 3-4, n (%) Hematologic Anemia1 (1.5)*4 (6.1)3 (4.6) Leukocytes02 (3.1)0 Platelets01 (1.5)0 Nonhematologic Rash/dermatitis1 (1.5) 0 Rash/desquamation1 (1.5) 0 Radiation dermatitis0*1 (1.5)0 Dose range for 12 patients with AEs 8-34 Gy Half of patients with adverse events received palliative radiation within 7 days of the last chemotherapy Of the patients with brain metastases (n=5) none reported adverse events related to palliative XRT