2. 1-line Treatment of Advanced-NSCLC WT Cesare Gridelli Division of Medical Oncology “S.G. Moscati” Hospital – Avellino (Italy) cgridelli@libero.it cgridelli@libero.it

3. 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) 1 2 2 3

4. 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

5. 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)

6. 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)

7. 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):2542-2550. Hazard ratio, 0.79; P =0.003 100 80 60 40 20 0 Overall Survival, % 423024181260 Month 36 BPC group (305 events in 417 patients) PC group (344 events in 433 patients)

8. 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 0.8 0.6 0.4 0.2 0 0612182430364248 Avastin + CP (n=300) CP (n=302) 10.314.2

9. 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)

10. 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):3543-3551. Survival Probability CG10.4; 9.6, 11.2 CP11.8; 10.4, 13.2 1.0 0.8 0.6 0.4 0.2 0.0 0612182430 Survival Time (months) in Patients With Squamous Cell Carcinoma Survival Probability 1.0 0.8 0.6 0.4 0.2 0.0 0612182430 PFS Probability 1.0 0.8 0.6 0.4 0.2 0.0 0612182430 PFS (months) in Patients With Squamous Cell Carcinoma PFS Probability 1.0 0.8 0.6 0.4 0.2 0.0 0612182430 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

11. 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)

12. Maintenance Therapy in NSCLC Patient Selection Histology Adenocarcinoma subtypes Squamous cell carcinoma Clinical Features Age: Adults 18-70 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

13. 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

14. OS from randomization in all patients 0369121518212427303336 Time (months) OS probability 1.0 0.8 0.6 0.4 0.2 0 Erlotinib (n=438) Placebo (n=451) 11.0 12.0 *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=0.0088 Cappuzzo et al,WCLC 2009

15. OS probability 1.0 0.8 0.6 0.4 0.2 0 0369121518212427303336 Time (months) 9.611.9 1.0 0.8 0.6 0.4 0.2 0 0369121518212427303336 Time (months) 12.012.5 Log-rank p=0.0019 HR=0.72 (0.59–0.89 ) Erlotinib (n=252) Placebo (n=235) Log-rank p=0.6181 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

16. 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)

17. PARAMOUNT: Investigator Assessed PFS (from Maintenance) Pemetrexed: median =4.1 mos (3.2-4.6) Placebo: median =2.8 mos (2.6-3.1) Log-rank P=0.00006 Unadjusted HR: 0.62 (0.49-0.79) Patients at Risk Pem + BSCN=359132 57 214 0 Placebo + BSCN=180 52 15 50 0 Pem + BSC Placebo + BSC

18. PARAMOUNT: Final OS from Randomization Patients at Risk Pem + BSC35933327223520016613810579 43152 0 Placebo + BSC180169131103 78 65 49 35 23 12 83 0 Time from Randomization (Months) 0 3 6 9 12 15 18 21 24 27 30 33 36 Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 PemPlacebo OS Median (mo) (95% CI) 13.9 (12.8-16.0) 11.0 (10.0-12.5) Censoring (%)28.721.7 Survival Rate (%) (95% CI) 1-year58 (53-63)45 (38-53) 2-year32 (27-37)21 (15-28) Log-rank P = 0.0195 Unadjusted HR: 0.78 (95% CI: 0.64–0.96)

19. PARAMOUNT: Final OS from Induction Survival Probability Time from Induction (Months) 0 3 6 9 12 15 18 21 24 27 30 33 36 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 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=0.0191 HR=0.78 (95% CI: 0.64–0.96) Patients at Risk Pem + BSC359335276234200164138 106 77 42 15 2 0 Placebo + BSC180168132103 78 63 49 35 23 12 8 3 0

20. 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 =0.0191 0.8 0.6 0.4 0.2 0.0 Placebo + BSC Median OS=14.0 months (95% CI, 12.9–15.5) 3633302724211815129630 3633302724211815129630 3633302724211815129630 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0

21. 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):1713-1721. Improvement Mean Score (Scale -0.59 to +1.00) N=2651322411291608314966108489836 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=2661262391271628114765107489836 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

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

23. PARAMOUNT: Long Term Safety CTCAE Grade 3/4/5 term >10 cycles Pemetrexed* n = 84 (%) ≤10 cycles Pemetrexed n = 275 (%) P-value All laboratory13.18.00.194 All non-laboratory8.39.11.00 Neutropenia † 8.32.20.015 Infections1.22.90.691 * 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.

26. Grade 1-4 Adverse Events Event (%) ≥70 Yrs Subgroup<70 Yrs Subgroup Gr 1Gr 2Gr 3/4Gr 1Gr 2Gr 3/4 pemplcpemplcpemplcpemplcpemplcpemplc Fatigue8515565969550 Anemia851081204010260.7 Neutropenia60801701030.740 Febrile Neutropenia000000000020 Leukopenia204040101020 Thrombocytopenia600020100.7020 Renal*45600030.74 10 Rash030000320.7000 Edema634000444000

27. 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

28. *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