Summary ID# Clinical Study Summary: Study H3E-EW-B012

Transcription

1 Page 1 Summary ID# Clinical Study Summary: Study H3E-EW-B012 First-line Treatment of Non-Small Cell Lung Cancer under Routine Conditions: Observational Study on Overall Survival Date summary electronically approved by Lilly: Approval Date: 18-Apr-2013 GMT

2 Page 2 Title of Study: First-line Treatment of Non-Small Cell Lung Cancer under Routine Conditions: Observational Study on Overall Survival Number of Investigators: This multicenter study included 197 physicians. Study Centers: This study was conducted at 197 study centers in 11 European countries. Length of Study: 18 months or until discontinuation for any reason Phase of Development: (including death) Observational Study Date of first patient visit: 17 April 2009 Date of last patient visit: 31 July 2012 Objectives: The primary objective of this study was to evaluate overall survival (OS) in patients with advanced or metastatic (Stage IIIB-IV) non-small cell lung cancer (NSCLC) receiving platinum-based doublet chemotherapies, with or without additional targeted agents, as first-line treatment in a routine disease management, daily practice setting. The secondary objectives were to: evaluate the one-year survival rate, progression-free survival (PFS) and best tumor response during first-line treatment in different treatment cohorts evaluate OS, one-year survival rate, PFS and best tumor response in patients with different histological subtypes of NSCLC evaluate OS, one-year survival rate, PFS and best tumor response in patients with or without additional targeted therapy identify the percentage of patients not receiving a definite histopathological or cytopathological subtype diagnosis by World Health Organization (WHO) classification and the underlying reasons (e.g. budget constraints, lack of immunohistochemistry) identify the frequency of use of other biomarkers in this patient population (e.g. excision repair cross complementation 1 [ERCC-1], ribonucleotide reductase M1 [RRM1], epidermal growth factor receptor [EGFR]-status). identify the key-factors associated with the choice of first-line treatment describe treatment pathways for patients after first-line treatment assess resource utilization during first-line treatment (hospitalizations; use of colony stimulating factors [CSFs] and transfusions [red blood cell and thrombocytes]). explore possible differences in choice of first-line treatment between office- and hospital-based physicians Study Design: This was a non-interventional, non-randomized, European multi-centre, prospective observational study conducted in 11 countries. The study was designed to observe patient outcomes including OS (primary objective), and the use of histopathological subtyping and other biomarker tests for therapeutic decision-making (secondary objectives) in patients with advanced NSCLC. Specialist physicians routinely involved in first-line treatment of patients with advanced NSCLC were selected for participation in this study. Patients receiving different platinum-based doublet chemotherapy, with or without an additional targeted agent, as first-line treatment for advanced NSCLC were eligible for this study. Patient visits and evaluations were completed within the physician s routine clinical practice. The timing and dosage of therapy was chosen at the discretion of the physician. Patients were followed for at least 18 months or until discontinuation for any reason (including death) or the end of study.

3 Page 3 Number of Patients: Planned: 1334 patients were planned. Actual: 1617 patients were screened. Treated: A total of 1567 patients entered the study; 1564 patients were evaluable and had received at least 1 dose of first-line therapy. First-line therapy was grouped into 5 treatment cohorts based upon treatment assigned by the physicians: pemetrexed + platinum (n=569) gemcitabine + platinum (n=360) taxanes + platinum (n=295) vinorelbine + platinum (n=300) other + platinum (n=40) Completed: There have been 950 deaths (61%) and 253 patients (16%) have completed the observation period. Diagnosis and Main Criteria for Inclusion: Patients in this study met all of the following criteria: were at least 18 years of age or older had a histological or cytological diagnosis of advanced stage (IIIB or IV) NSCLC received first-line treatment for advanced NSCLC with a platinum-based doublet chemotherapy, with or without an additional targeted agent. Patients may or may not have received prior adjuvant or neoadjuvant therapy. were not participating simultaneously in a study including administration of any investigational drug or procedure at entry into this study had signed informed consent Drug Regimen: -based (either cisplatin, carboplatin or oxaliplatin) chemotherapy doublet regimens with either pemetrexed, gemcitabine, a taxane (docetaxel or paclitaxel), vinorelbine, or other were selected as first-line treatment at the discretion of the physicians in this study. -based chemotherapy was given, with or without a targeted agent (bevacizumab, gefitinib, or other), in the normal routine setting of the physician s office or hospitalbased environment. The timing and dosage of therapy was chosen at the discretion of the physician. For analyses, patients were grouped into one of the most prevalent treatment cohorts: pemetrexed + platinum; gemcitabine + platinum; taxanes + platinum; vinorelbine + platinum; and other + platinum. The other + platinum treatment cohort included: etoposide, ifosfamide, irinotecan, topotecan, and concomitant radiotherapy. Duration of Treatment: The study was planned to collect at least 18 months of data until discontinuation for any reason (including death), the end of study, or loss to follow-up. The observation period started at the initiation of first-line therapy. For any patient lost to follow-up, or who dropped out of the study, the analyses included all data up to the point of their last data collection. Data was collected at: Baseline visit initiation of first-line treatment End of first-line treatment Further anti-cancer treatment (maintenance, second-line, third-line therapies, etc.) Final visit death, discontinuation, loss to follow-up or end of study

4 Page 4 Variables: Efficacy: The primary efficacy endpoint OS, was measured by Kaplan-Meier techniques. The secondary efficacy endpoints were 1-year survival, PFS evaluated by Kaplan-Meier techniques and best response achieved during first-line treatment, described by frequencies and percentages. These analyses were done after histological subtyping of NSCLC according to WHO classification. Use of any additional targeted therapy was recorded. Safety: Investigators were instructed to report non-serious adverse events (AEs) and all serious adverse events following normal practice as required by applicable laws, regulations and practices (see protocol, Section 5 for details). No AEs were collected in the study database, and thus, no specific safety analyses were attempted. Bioanalytical: Data were collected on the frequency and use of histological subtyping and biomarkers associated with these subtypes. Immunohistochemical (IHC) biomarkers and other biomarkers such as thymidylate synthase (TS), ERCC-1, RRM1, and EGFR-status were collected in this study. Health Outcomes: Resource use was collected by type, number and duration of hospitalizations and outpatient visits. Use of colony-stimulating factors (CSFs) and transfusions were also monitored. Other: Data were collected on the physician s treatment facilities (whether they were office-or hospital-based) and how this may have affected treatment. Data were gathered on key factors that physicians considered when choosing first-line therapy for their patients, as well as the use of targeted agents and treatment pathways that were utilized (maintenance therapy, second and third-line therapies, etc.). The percentage of patients receiving a definite histopathological or cytopathological subtype diagnosis was collected. Evaluation Methods: This study was exploratory only; no confirmatory statistical tests were performed. Estimates of survival were derived by Kaplan-Meier techniques. For each patient who was not known to have died as of the data cut-off date for a particular analysis, OS was censored at the last known date the patient was alive. Progression free survival time was measured from the date of start of first-line treatment to the date of progression, or the date of death due to any cause, whichever occurred earlier. If a patient was not known to have died or have disease progression at the end of the first-line treatment, censoring was taken according to the following algorithm: If discontinuation was recorded on the End of First-line Treatment Form, the PFS time was censored at this date; otherwise, information was recorded in the Subject Summary Form. If death was not recorded, PFS time was censored at the date of loss to follow-up or date of discontinuation from the study. All other patient, physician and treatment characteristics were described using appropriate summary statistics. The sample size was guided by the precision of the estimates. Assuming a 5% loss to follow-up rate, a minimum total of 1334 patients were needed to provide OS estimates in the smallest treatment cohort with a 95% confidence interval (CI) width between 40% and 50% of the median OS. Patients included in the Other + treatment cohort (n=40 patients) were described, but the treatment cohort was excluded from the evaluation of treatment outcomes and survival, due to the small size and heterogeneity of this cohort, to avoid any unreliable estimates. Summary: Study H3E-EW-B012 (also known as the FRAME study), was a prospective, observational study involving 1564 patients who received first-line treatment for advanced or metastatic (stage IIIB-IV) non-small cell lung cancer (NSCLC). The study was designed to evaluate overall survival (OS) in treatment cohorts receiving different platinum-based doublet chemotherapies, with or without an additional targeted agent, in a routine disease management, daily practice setting. doublet chemotherapy was evaluated as it remains the standard of care for first-line treatment of advanced NSCLC (Pallis and Georgoulias, 2012; D Addario and Felip 2008; Pfister et al. 2004). therapies chosen by the physicians in this study were cisplatin (n=852), carboplatin (n=708) and oxaliplatin (n=4) and were coupled with cytostatic agents such as pemetrexed, gemcitabine, taxanes (docetaxel or paclitaxel), and vinorelbine. The targeted agents chosen were bevacizumab, gefitinib and other. Patients were observed for at least 18 months, until discontinuation for any reason (including death), or loss to follow-up, whichever occurred first. Treatment was solely at the discretion of the physicians (Table B012.1). Patients received a median of 4 cycles (interquartile range 3-5 cycles) of first-line therapy; i.e. 50% of patients received 3-5 cycles of first-line therapy.

5 Page 5 Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: FRAME_BLrelock_TFLs_Final22OCT2012.doc. Tables: 1.1.1a,1.1.4, and Multiple entries were possible (patients could be excluded for multiple reasons); Consisted of: cisplatin (n=852); carboplatin (n=708); and oxaliplatin (n= 4); * other included a platinum plus: Etoposide (n=33); Ifosfamide (n=2); Irinotecan (n=1); Topotecan (n=3); and Concomitant radiotherapy (n=1). Figure B Patient disposition.

6 Page 6 Patient Demographics and Disease Characteristics: There were a total of 1617 patients who were screened for this study between April 2009 and February Patients were entered from 11 European countries: Belgium (n=58); Denmark (n=31); Finland (n-51); France (n=463); Germany (n=483); Italy (n=132); the Netherlands (n=91); Poland (n=118); Portugal (n=28); Spain (n=112); and Sweden (n=50). There were 50 patients considered ineligible for the study for the following reasons (some patients were reported in more than one category): informed consent was missing (n=5); entry criteria was not met (n=48); there was no platinum-based doublet received (n=43); and no staging information was available (n=2). Additionally, between the baseline database lock in February 2012, and the final database lock in August, 2012, 3 of the 1567 patients were found to be ineligible for analysis due to missing informed consent (n=1); and missing principal investigator signatures (n=2). These patients were in the following treatment cohorts: taxane + platinum (n=1); vinorelbine + platinum (n=1), and gemcitabine + platinum (n=1). Therefore, a total of 1564 patients were eligible for analysis; 1524 of these patients received a platinum-doublet with either pemetrexed (n=569; 36.3%), gemcitabine (n=360; 23.0%), taxane (n=295; 18.9%), or vinorelbine (n=300; 19.2%). + platinum comprised the largest treatment cohort with 569 patients. There were 40 (2.6%) patients who received other chemotherapy + platinum (Figure B012.1). These 40 patients received etoposide (n=33); topotecan (n=3), ifosfamide (n=2), irinotecan (n=1) and concomitant radiotherapy (n=1). Due to the small sample size and heterogeneity of other + platinum treatment cohort( n=40), this cohort was described but not summarized for survival, best response or the resource utilization objectives of this study. The majority of patients in this study were male (n=1121; 71.7%), of non-asian descent (n=1507; 96.4%) and had a performance status (PS) of 0/1 (n=1285; 82.1%) at baseline. Median age among the treatment cohorts was 64 years (range 33-87). Many patients were former smokers (n=821; 52.5%), presented with Stage IV NSCLC (n=1199;76.7%), and had at least 1 metastatic site (n=1395; 89.2%). The majority of the patients were chemonaive (n=1546; 98.8%) with only 18 patients who received prior chemotherapy (1.2%); 11 received adjuvant therapy, 7 received neoadjuvant therapy, and 1 patient had both adjuvant and neoadjuvant therapy. Other prior treatments received included radiotherapy (n=198; 12.7%) and surgery (n=162; 10.4 %). Patients with nonsquamous histology comprised the largest group in this study (n=1103; 70.5%). The nonsquamous patients were further subtyped into adenocarcinoma (n=861; 78.0%); large cell carcinoma (n=81; 7.3%) and not otherwise specified (NOS) carcinoma (n=161; 14.6%). There were 382 (24.4%) squamous patients and 52 (3.3%) patients with other histology, consisting of adenosquamous carcinoma (n=23; 1.5%), sarcomatoid carcinoma (n=9; 0.6%) and other carcinoma (n=20; 1.3%). A total of 253 (16.2%) patients were alive at the end of the observation period and 950 (60.7%) patient deaths have occurred. There were a total of 361 (23.1%) discontinuations from the study for the following reasons: 271 were lost to follow-up 4 due to sponsor decision (need to clarify this) 60 due to physician decision 22 due to patient decision, and 4 were participating in other clinical trials. Patient demographics and disease characteristics are detailed in Table B012.1.

7 Table B Page 7 Patient Demographics and Disease Characteristics + platinum (n=569) Gemcitabine + platinum (n=360) Gender, % Male/Female 66.6/ /21.7 Age, Median (range), yrs 62 (33-86) 65 (38-84) Origin, % Non-Asian Asian NA Smoking status, %b Former Current Never Missing ECOG PS, % Missing Disease stage, % (Lung Cancer Staging Guidelines, Version 5). Stage IIIB (wet) Stage IV Basis for diagnosis, % Histopathological Cytological Both Nonsquamous NSCLC, % Adenocarcinoma Large cell NSCLC NOS Squamous cell Other Taxanes + platinum (n=295) Vinorelbine + platinum (n=300) Othera + (n=40) (n=1564) 73.9/ (37-87) 71.0/ (34-83) 72.5/ (41-83) 71.7/ (33-87) Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: FRAME_BLrelock_TFLs_Final22OCT2012.doc. Tables: , 3.2.1, 3.2.2, a, a, Abbreviations: ECOG PS=Eastern Cooperative Oncology Group performance status; n= number of patients; N=total number of patients; NA=not assessed; NOS= not otherwise specified; yrs: years. a Other treatment included etoposide (33 patients), topotecan (3), ifosfamide (2), irinotecan (1), or concomitant radiotherapy (1). b Smoking status was defined as follows: never smoker = smoked less than 100 cigarettes, cigars, or pipefuls in lifetime; former smoker = has smoked but stopped before baseline; current smoker = continues to smoke at baseline.

8 Page 8 Analysis of Overall Survival: The primary objective of this study was to evaluate overall survival following initiation of first-line treatment with a platinum doublet, under routine disease management conditions, with or without an additional targeted agent. Treatment cohorts (excluding the other + platinum treatment cohort [n=40]) are shown in Figure B Median overall survival among all treatment cohorts assessed was 10.3 months (95% CI [9.5,11.2]; range 9.1 to 10.7). The probability of 1 year survival among all treatment cohorts assessed was 44.8% (95% CI [42.0, 47.5], range 41.5% 46.8%). Figure B Overall Survival by Treatment Cohort. Median OS and the probability for 1-year survival for the 4 different treatment cohorts are presented with their corresponding 95% CIs in Table B Table B Summary of Overall Survival Analysis + (n=569) (n=360) (n=295) (n=300) (n=1524) Median OS (mos) (9.40, 12.32) (8.44, 11.83) 9.13 (8.05, 11.33) (8.87, 12.75) (9.53,11.20) Probability of 1 yr OS 45.8% (41.3, 50.3) 43.8% (38.3, 49.3) 41.5% (35.5, 47.5) 46.8% (40.4, 53.1) 44.8% (42.0, 47.5) Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs_05MAR2013. Note: Other + Treatment Cohort (n=40) was excluded from the survival analysis due to the small sample size. Abbreviations: CI = confidence interval; mos = months; OS = overall survival; n= number of patients; NA = not available; yr = year.

9 Page 9 Survival with and without Targeted Agents: A low percentage of patients in this study (8.4% of total; n=131) received a targeted agent. The most commonly given targeted agents were bevacizumab (n=114; 7.3%), gefitinib (n=3; 0.2%), and other (n=13; 1%). Two of the 131 patients were in the Other cohort and therefore 129 patients that received a targeted agent were assessed. The use of these concurrent targeted agents was highest in the pemetrexed treatment cohort (n=63; 11.1%) and the taxane treatment cohort (n=37; 12.5%). Survival estimates among the treatment cohorts for those receiving targeted agents are not reliable to report due to the small sample sizes (Table B012.3). Median OS for all patients who received a targeted agent was 14.5 months (range between cohorts ). The probability of 1 year survival for these patients was 55.9% (range ). Table B With Targeted Agent Median OS (mos) Probability of 1 yr OS Without Targeted Agent Median OS (mos) Probability of 1 yr OS Overall Survival Analysis With/Without Targeted Agents + (n=63) (9.92, 16.85) (n=23) (5.65, NA) (n=37) (8.38, 19.38) (n=6) 5.39 (3.71, NA) (9.92, 16.59) 58.1% (46.1, 70.0) 46.4% (27.5, 65.4) 55.9% (41.3, 70.4) 22.2% (0, 59.9) 55.9% (47.2, 64.6) + (n=506) (8.97, 11.73) (n=337) (8.44, 11.79) (n=258) 8.77 (7.43, 10.28) (n=294) (9.33, 12.85) (9.30, 10.84) 43.8% (39.0, 48.6) 43.3% (37.6, 49.0) 38.7% (32.4, 45.0) 47.2% (40.8, 53.7) 43.5% (40.7, 46.4) (n=129) (n=1395) Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs_05MAR2013 Targeted Agents included: Bevacizumab (n=113), gefitinib (n=3), and other (n=13). Note: Other + Treatment Cohort (n=40) was excluded from the survival analysis due to the small sample size. Abbreviations: CI = confidence interval; n = number of patients; OS = overall survival; NA = not available; yr = year. Overall Survival by Histology: Patients with nonsquamous histology (n=1103; 72.4%) had a median survival of 9.8 months and patients with squamous cell histology (n=373; 24.5%) had a median survival of 11.8 months. Patients with other histology (n=48; 3.1%) had a median survival of 10.0 months (Table B012.4).

10 Table B Page 10 Overall Survival by Histology + (n=553) (n=201) (n=189) (n=160) (n=1103) Median OS (mos) (9.36, 11.99) 8.41 (6.97, 10.64) 8.15 (7.39, 10.05) (7.95, 13.14) 9.79 (8.87, 10.68) Probability of 1 yr OS 45.4% (40.8, 49.9) 39.9% (32.7, 47.1) 37.2% (29.9, 44.6) 45.5 % (37.0, 54.1) 43.2 (40.0, 46.4) + (n=6) (0.43, 16.39) (n=148) (10.02, 14.09) (n=91) (8.77, 14.13) (n=128) (8.58, 13.37) 21.5% (12.1, 30.9) 50.2 % (41.7, 58.7) 48.0 % (37.5, 58.6) 47.3 % (37.6, 57.0) Median OS (mos) + (n=10) (1.51, 18.10) (n=11) 8.05 (3.32, NA) (n=15) (1.45, 14.29) (n=12) 8.08 (5.85, 18.92) (6.87, 16.95) Probability of 1 yr OS 51.1 % (33.3, 69.0) 21.8 % (0.0, 48.0) 15.3 % (8.4, 22.1) 33.6% (11.2, 56.1) 41.7 % (28.2, 55.2) Nonsquamous Squamous Median OS (mos) Probability of 1 yr OS Other* (n=373) (10.55, 12.91) 49.2 % (43.7, 54.7) (n=48) Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs_05MAR2013 Note: *Other category included: 23 patients with adenosquamous carcinoma, 9 patients with sarcomatoid carcinoma and 20 patients with other carcinoma. This table excludes the Other treatment cohort of 40 patients. Abbreviations: CI = confidence interval; Mos = months; N = number of patients; OS = overall survival; Yr = year. Nonsquamous patients were further subcategorized by pathological diagnosis for those patients with adenocarcinoma, large cell carcinoma and NOS (Figure B012.3). Adenocarcinoma patients comprised the largest group (n=861) and exhibited an OS of months (Table B012.5). Table B Overall Survival for Nonsquamous Patients Nonsquamous Adenocarcinoma (n =861) Large Cell (n= 81) NOS (n = 161) (n=1103) Median OS (mos) (9.07, 11.53) 7.66 (6.28, 8.90) 9.63 (7.10, 12.16) 9.79 (8.87, 10.68) Probability of 1 year OS 44.8% (41.2, 48.4) 26.0% (16.0, 36.0) 41.4% (33.1, 49.7) 43.2% (40.0, 46.4) Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs_05MAR2013 Abbreviations: Mos=months; CI=Confidence intervals; mos = months; N=total population size; NOS = not otherwise specified; OS = overall survival; HR=Hazard Ratio.

11 Page 11 Figure B Overall Survival (months) by pathological diagnosis: (NOS versus Adenocarcinoma versus large cell carcinoma versus squamous cell carcinoma).

12 Page 12 Progression-free Survival: Median PFS for all 4 treatment cohorts was 6.1 months (range ) (Figure B012.4; Table B012.6). The probability of 1 year PFS was 28% for all 4 treatment cohorts (range 26% 31%). Median PFS for patients who received a targeted agent was 8.9 months overall and ranged from months for the 4 treatment cohorts (Table B012.7). Figure B Progression Free Survival (months). Survival Function.

13 Table B Page 13 Progression-Free Survival + (n=569) (n=360) (n=295) (n=300) (N=1524) Median PFS (mos) 5.82 (5.13, 6.97) 6.44 (5.09, 7.82) 6.37 (4.37, 6.93) 5.98 (5.06, 7.52) 6.11 (5.45, 6.70) Probability of 1 yr PFS 26.5% (22.5, 30.5) 30.7% (25.5, 35.9) 26.0% (20.5, 31.5) 29.8% (23.9, 35.6) 28.0% (25.5, 30.6) Overall Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs_05MAR2013 Note: This table excludes the Other treatment cohort of 40 patients. Abbreviations: CI = confidence interval; Mos = months; n = number of patients; NA = not available; PFS = progression-free survival; Yr = year. Table B Progression-Free Survival With/Without Targeted Agents + (n=63) (n=23) (n=37) (n=6) (n=129) Median PFS (mos) (7.79, 12.91) 8.94 (3.25, NA) 8.81 (4.96, 10.51) 3.66 (0.76, NA) 8.94 (6.74, 11.37) Probability of 1 yr PFS 40.4% (27.8, 53.0) 42.7% (23.8, 61.6) 29.1% (14.6, 43.5) 33.3% (00.0, 71.1) 38.5% (29.7, 47.3) + (n=506) 5.42 (4.70, 6.28) 24.5% (20.4, 28.7) (n=337) 6.31 (4.96, 7.59) 29.5% (24.1, 34.9) (n=258) 5.78 (3.91, 6.83) 24.9% (19.1, 30.8) (n=294) 6.01 (5.09, 7.69) 29.8% (23.9, 35.7) With Targeted Agent Without Targeted Agent Median PFS (mos) Probability of 1 yr PFS (n=1395) 5.75 (5.22, 6.44) 26.9% (24.3, 29.6) Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs_05MAR2013 Note: This table excludes the Other treatment cohort of 40 patients. Abbreviations: CI = confidence interval; Mos = months; n = number of patients; NA = not available; PFS = progression-free survival; Yr = year.

14 Page 14 Nonsquamous patients (n=1103) were progression-free for 5.6 months (range ) and squamous patients (n=373) were progression-free for 7.5 months (range ). (Table B012.8). Table B Progression-Free Survival by Histology + (n=553) (n=201) (n=189) (n=160) (n=1103) Median PFS (mos) 5.82 (5.13, 7.00) 5.68 (4.37, 6.93) 4.73 (3.68, 6.54) 5.26 (4.11, 7.52) 5.59 (5.09, 6.41) Probability of 1 year PFS 26.8% (22.7, 30.9) 27.7% (20.8, 34.5) 20.8% (14.3, 27.2) 27.7% (20.0, 35.4) 26.1% (23.2, 29.0) + (n=6) (n=148) (n=91) (n=128) (n=373) Median PFS (mos) 5.85 (0.03, NA) 7.66 (5.29, 9.07) 8.31 (6.44, 11.47) 6.87 (4.60, 8.38) 7.52 (6.44, 8.38) Probability of 1 year PFS 22.2% (0.00, 59.9) + (n=10) 34.4% (26.3, 42.5) (n=11) 35% (24.8, 45.3) (n=15) 30.2% (21.2, 39.1) (n=12) 33.5% (28.2, 38.7) Median PFS (mos) 4.14 (0.72, 8.94) 7.26 (1.61, NA) 2.89 (1.41, NA) NA (1.51, NA) 5.06 (2.04, 8.94) Probability of 1 year PFS 7.9% (00.0, 21.1) 21.8% (00.0, 55.6) 27.1% (2.7, 51.4) 58.3% (30.4, 86.2) 28.4% (15.0, 41.8) Nonsquamous Squamous Other* (n=48) Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs_05MAR2013 Note: *Other category included: 23 patients with adenosquamous carcinoma, 9 patients with sarcomatoid carcinoma and 20 patients with other carcinoma. This table excludes the Other treatment cohort of 40 patients. Abbreviations: CI = confidence interval; n = number of patients; NA = not available; PFS = progression-free survival. For the nonsquamous patients, those with adenocarcinoma exhibited median PFS of 5.82 months (Table B012.9; Figure B012.5). Table B Progression-Free Survival for Nonsquamous Patients Adenocarcinoma (n = 861) Large Cell (n = 81) NOS (n =161) (n=1103) Median PFS (mos) 5.82 (5.22, 6.67) 4.63 (3.61, 5.68) ( 3.71, 6.80) 5.59 (5.09, 6.41) Probability of 1 yr PFS 27.0% (23.8, 30.3) 13.2% (5.1, 21.3) 25.9% (18.4, 33.4) 26.1% (23.2, 29.0) Nonsquamous Output Location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs_05MAR2013 Abbreviations: CI = confidence interval; Mos = months; n = number of patients; NOS = not otherwise specified; PFS = progression-free survival; Yr = year

15 Figure B Page 15 Progression-Free Survival (months) by pathological diagnosis: (NOS versus adenocarcinoma versus large cell carcinoma versus squamous cell carcinoma). Best Tumor Response: Best response during first-line treatment was assessed by the investigators. Overall response rate (ORR) was defined as the proportion of patients whose best response was complete response (CR) or partial response (PR) divided by the total number of patients. ORR for the 4 treatment cohorts was 36.1% (95% CI: 33.7, 38.6), with 31 patients (2.0%) exhibiting a CR, 519 exhibiting a PR (34.1%), and 402 (26.4%) patients exhibiting stable disease. Disease Control Rate (DCR) was defined as the proportion of patients whose best response was CR, PR or SD divided by the total number of patients. Overall response for the patients who received a targeted agent was 48.8% (95% CI: 39.9, 57.8) and DCR was 78.3% (95% CI: 70.2% %) (Table B012.10).

16 Table B Page 16 Best Response Achieved During First-Line Treatment + (n=569) (n=360) (n=295) (n=300) (n=1524) CR 14 (2.5%) 7 (1.9%) 2 (0.7%) 8 (2.7%) 31 (2.0%) PR 186 (32.7%) 130 (36.1%) 105 (35.6%) 98 (32.7%) 519 (34.1%) SD 160 (28.1%) 87 (24.2%) 71 (24.1%) 84 (28.0%) 402 (26.4%) PD 142 (25.0%) 81 (22.5%) 76 (25.8%) 63 (21.0%) 362 (23.8%) ORR DCR 200 (35.1%) (31.2, 39.2) 360 (63.3%) (59.2, 67.2) 137 (38.1) (33.0, 43.3) 224 (62.2%) (57.0, 67.3) 107 (36.3%) (30.8, 42.0) 178 (60.3%) (54.5, 66.0) 106 (35.3%) (29.9, 41.0) 190 (63.3%) (57.6, 68.8) 550 (36.1%) (33.7, 38.6) 952 (62.5%) (60.0, 64.9) Unknown 67 (11.8%) 55 (15.3%) 41 (13.9%) 47 (15.7%) 210 (13.8%) + (n=63) 28 (44.4%) (31.9, 57.5) 50 (79.4%) (67.3, 88.5) (n=23) 10 (43.5%) (23.2, 65.5) 19 (82.6%) (61.2, 95.1) (n=37) 22 (59.5%) (42.1, 75.3) 27 (73.0%) (55.9, 86.2) (n=6) 3 (50.0%) (11.8, 88.2) 5 (83.3%) (25.9, 99.6) 63 (48.8%) (39.9, 57.8) 101 (78.3%) (70.2, 85.1) PD 9 (14.3%) 3 (13.0%) 6 (16.2%) 0 18 (14.0%) Unknown 4 (6.3%) 1 (4.3%) 4 (10.8%) 1 (16.7%) 10 (7.8%) Without Targeted Agent ORR DCR + (n=506) 172 (34.0%) (29.9, 38.3) 310 (61.3%) (56.9, 65.5) (n=337) 127 (37.7) (32.5, 43.1) 205 (60.8%) (55.4, 66.1) (n=258) 85 (32.9%) (27.2, 39.1) 151 (58.5%) (52.3, 64.6) (n=294) 103 (35.0%) (29.6, 40.8) 185 (62.9%) (57.1, 68.5) (n=1395) 487 (34.9%) (32.4, 37.5) 851 (61.0%) (58.4, 63.6) PD 133 (26.3%) 78 (23.1%) 70 (27.1%) 63 (21.4%) 344 (24.7%) Unknown 63 (12.5%) 54 (16.0%) 37 (14.3%) 46 (15.6%) 200 (14.3%) Best Response n (%) With Targeted Agent ORR DCR (n=129) Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs 05MAR2013 Note: This table excludes the Other treatment cohort of 40 patients. Abbreviations: CR = complete response; DCR = disease control rate; n = number of patients; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.

17 Page 17 Overall response rate during first-line treatment among the different histological subtypes (nonsquamous, squamous and other) ranged between 34% - 42%. Nonsquamous patients, (n=1103; 72.4%) had an ORR of 34.3%; squamous patients (n=373; 24.5%) had an ORR of 40.8%. ORR and the DCR are displayed l in Table B below. Table B Best Response Nonsquamous Patients Best Tumor Response by Histology + (n=553) (n=201) (n=189) (n=160) (n=1103) ORR 193 (34.9%) (30.93, 39.04) 71 (35.3%) 28.73, 42.36) 61 (32.3%) (25.67, 39.44) 53 (33.1%) (25.90, 40.99) 378 (34.3%) (31.47, 37.16) DCR 348 (62.9%) (58.75, 66.97) 123 (61.2%) (54.08, 67.97) 109 (57.7%) (50.29, 64.81) 100 (62.5%) (54.51, 70.02) 680 (61.7%) (58.71, 64.53) PD 140 (25.3%) 44 (21.9%) 55 (29.1%) 35 (21.9%) 274 (24.8) Unknown 65 (11.8%) 34 (16.9%) 25 (13.2%) 25 (15.6%) 149 (13.5%) + (n=6) (n=148) (n=91) (n=128) (n=373) ORR 3 (50.0%) (11.81, 88.19) 63 (42.6%) (34.49, 50.95) 39 (42.9%) (32.53, 53.66) 47 (36.7%) (28.38, 45.69) 152 (40.8%) (35.72, 45.93) DCR 4 (66.7%) (22.28, 95.67) 96 (64.9%) (56.60, 72.52) 61 (67.0%) (56.39, 76.53) 82 (64.1) (55.11, 72.35) 243 (65.1%) (60.07, 69.98) 0 31 (20.9%) 15 (16.5%) 25 (19.5%) 71 (19.0%) 2 (33.3%) 21 (14.2%) 15 (16.5%) 21 (16.4%) 59 (15.8%) + (n=10) (n=11) (n=15) (n=12) (n=48) ORR DCR (95% CI ) PD 4 (40.0%) (12.16, 73.76) 8 (80.0%) (44.39, 97.48) 2 (20.0% 3 (27.3%) (6.02, 60.97) 5 (45.5%) (16.75, 76.62) 6 (54.5%) 7 (46.7%) (21.27, 73.41) 8 (53.3%) (26.59, 78.73) 6 (40.0) 6 (50.0%) (21.09, 78.91) 8 (66.7%) (34.89, 90.08) 3 (25.0) 20 (41.7%) (27.61, 56.79) 29 (60.4%) (45.27, 74.23) 17 (35.4%) Unknown (6.7%) 1 (8.3%) 2 (4.2%) n (%) Squamous Patients n (%) PD Unknown, n (%) Other Patients* n (%) Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs_05MAR2013 Note: Note: *Other category included: 23 patients with adenosquamous carcinoma, 9 patients with sarcomatoid carcinoma and 20 patients with other carcinoma. This table excludes the Other treatment cohort of 40 patients. Abbreviations: CR = complete response; DCR = disease control rate; n = number of patients; ORR = overall response rate; PD = progressive disease; PR = partial response.

18 Page 18 Percentage of Patients Not Receiving a Histological or Cytologic Diagnosis: Histology was consistently the basis for pathological diagnosis for the majority of patients (histology alone 70.6%; cytology alone in 20.3%; and histology + cytology in 9.1%) across all treatment cohorts and across all NSCLC subtypes. For patients treated with bevacizumab, histology was the basis for diagnosis in 93.0% (histology alone 81.6% and histology + cytology 11.4%). Cytology alone was more often the basis for diagnosis of NSCLC NOS (39.5%) than it was for the specific NSCLC subtypes. The NSCLC subtype was NOS for 172 patients, with the primary reasons (available in 163 patients) recorded as subtyping not technically possible (43%) and not important for treatment decision (41%). Frequency of Use of Biomarkers: For the majority of patients (53.5%), at least one IHC marker was used to determine NSCLC subtype. The most common IHC markers used were thyroid transcription factor-1 (TTF-1; 47.6%) and cytokeratin 7 (CK7; 38.6%). The following immunohistochemical (IHC) markers were reported to be tested via IHC staining to determine histological subtype: thyroid transcription factor-1 (TTF-1) p63 protein cytokeratin 14 (CK14) cytokeratin 7 (CK7) cytokeratin 5/6 (CK 5/6) CD56 other subtype markers More than half of the patients (54%; n=837) in all 5 treatment cohorts, had at least one IHC marker tested to determine NSCLC subtype at baseline. Additional biomarkers were less frequently used for subtyping, with the most common being epidermal growth factor receptor (EGFR) mutation status. Thymidylate synthase, ERCC-1 and RRM1 were infrequently tested. EGFR mutation tests were performed on 407 (26.0%) patients and 36 (8.8%) were found to be EGFR mutation positive; 302 (74.2%) were mutation negative; 66 (16.2%) were unknown. Of the 36 patients whose tumors were EGFR mutation positive, 19 (52.8%) received pemetrexed and 8 (22.2%) received gemcitabine. None of the 36 EGFR mutation positive patients received a targeted agent.

19 Page 19 Key Factors Associated with Choice of 1st-Line Treatment: For the majority of patients (n=1214, 77.6%) physicians reported histopathological/cytological diagnosis as the key factor for selecting first-line treatment. Other key factor s identified by the physicians were performance status (991, 63.4%), age (827, 52.9%) comorbidities (577, 36.9%) and individual physician experience (577, 36.9%). More than one factor was identified for each physician treatment decision. Treatment Pathways after First-Line Treatment: Anticancer treatment after first-line therapy was captured, and among those patients who completed firstline treatment, 783 (51.4%) received further treatment (126 received maintenance, 645 received 2nd-line treatment, and 158 received 3rd line treatment), (Figure B012.6). Further treatment pathways were captured beyond 3rd-line therapy, but are not reported here due to low numbers and the variety of treatment pathways. Other treatments given were radiation and surgical intervention, as well as different combinations of drugs that the physicians classified as other. Figure B Further anticancer treatments. Note: Other treatment option was selected by the physicians as an alternative to selecting a specific line of treatment choice and contained different combinations of chemotherapy regimens, as well as radiation and surgery.

20 Page 20 Resource Utilization During First-Line Treatment: Resource use during first-line treatment was evaluated based on the volume of hospitalizations and outpatient visits, as well as the use of transfusions, colony-stimulating factors, concomitant medications and radiation therapy. There were a total of 835 (54.8%) patients that required at least 1 hospitalization during first-line therapy and 718 patients (47.1%) that required an outpatient visit. Most of these hospital visits (n=507; 60.7%) were preplanned visits (to receive planned therapy. There were 463 (55.4%) unplanned hospital visits and these visits were due to adverse events (n=251; 54.2%) or deterioration of disease status (n=178; 38.4%). Most outpatient visits were preplanned (n=589; 82%). Less than 20% of the patients required at least 1 transfusion (n=291; 19.1%) or received CSFs (G-CSF, GM-CSF, or erythropoietin [n=296; 19.4%]). A total of 274 (94.2%) patients of those receiving a transfusion, received packed red blood cells, 39 patients (13.4%) received platelet therapy for thrombocytopenia and 4 patients received whole blood (1.4%). Concomitant therapy use was high overall (n=1447; 94.9%) within all 4 treatment cohorts, ranging from 93% - 97%. Antiemetics and antinauseants were the most often reported concomitant medications (n=1181; 81.6%). Concomitant use of steroids was reported for 839 patients (58.0%). Concomitant radiation therapy was reported for 427 patients (28.0%). Overall, 66% of the radiotherapy treatments were given concurrently with platinum-based chemotherapy and 34% of the treatments were given following chemotherapy. The sites most often radiated were: lung (36%), bone (29%), brain (28%), and lymph nodes (15%). The other treatment cohort [n=40] was excluded from the summary of resource use. Table B Resource Utilization n (%) Hospitalizations Preplanned Visits Outpatient Visits Preplanned Visits Resource Utilization During First-Line Treatment + (n=569) (n=360) (n=295) (n=300) (n=1524) 325 (57.1%) 180 (50.0) 159 (53.9%) 171 (57.0%) 835 (54.8%) 230 (70.8%) 81 (45.0%) 106 (66.7%) 90 (52.6%) 507 (60.7%) 258 (45.3%) 161 (44.7%) 139 (47.1%) 160 (53.3%) 718 (47.1%) 214 (82.9%) 130 (80.7%) 112 (80.6%) 133 (83.1%) 589 (82.0%) Erythrocyte Transfusions 91 (16.0%) 85 (23.6%) 43 (14.6%) 72 (24.0%) 291 (19.1%) (at least 1) Packed Red Blood 85 (93.4%) 77 (90.6%) 43 (100.0%) 69 (95.8%) 274 (94.2%) Platelets 16 (17.6%) 17 (20.0%) 2 (4.7%) 4 (5.6%) 39 (13.4%) Whole Blood 3 (3.3%) 1 (1.2%) (1.4%) Unknown 1 (1.1%) 2 (2.4%) 0 2 (1.4%) 4 (1.4%) CSFs (at least 1) 105 (18.5%) 65 (18.1%) 62 (21.0%) 64 (21.3%) 296 (19.4%) Concomitant Therapy 551 (96.8%) 337 (93.6%) 281 (95.3%) 278 (92.7%) 1447 (94.9%) Antiemetics/ 446 (80.9%) 267 (79.2%) 242 (86.1%) 226 (81.3%) 1181 (81.6%) Antinauseants Steroids 348 (63.2%) 191 (56.7%) 152 (54.1%) 148 (53.2%) 839 (58.0%) Radiation Therapy 145 (25.5%) 78 (21.7%) 94 (31.9%) 110 (36.7%) 427 (28.0%) Output location: lillyce/prd/ly231514/h3e-ew-b012/final/programs_stat/tfl_output: Final_V01_FRAME_TFLs_05MAR2013 Abbreviations: CSF = Colony-stimulating factors.

21 Page 21 Differences in Treatment between Office and Hospital-Based Physicians: Specialist physicians (n=197) from 11 European countries routinely involved in the treatment of first-line therapy for patients with advanced NSCLC were involved in this study. A majority of these physicians were from Germany (47%) and France (22%). On average, these physicians had 20 years of practice experience; 50% of the physicians had years of experience. Participating physicians were most often specialists in oncology (108, 55%) or pneumonology (84, 43%); 3 were categorized as other (2%). Most physicians worked in public practice (119, 60%), 25 (13%) in private practice and 50 (25%) in combination. Most physicians were hospital-based (134, 68%); 58 (29%) were office-based and 3 (2%) were both (no location was listed for 2 physicians). Both office-based and hospital-based physicians chose first-line treatment for their patients most often based on a pathological diagnosis (69% and 80% respectively). First-line therapy chosen by office-based physicians was most often pemetrexed + platinum (26.8%) or a taxane + platinum (26.8%). Hospitalbased physicians most often chose pemetrexed + platinum (38.6%) or gemcitabine + platinum (24.4%) and often. based their therapy decisions upon experience, more so than office-based physicians (62.4% versus 31.3%). Hospital-based physicians also chose therapy for their patients more often based upon performance status (66.8% versus 48.8%). Hospital-based physicians more frequently initiated IHC marker tests (58%) than office-based physicians (37%), but office-based physicians were more likely to recommend concurrent targeted agents (13.8% versus 6.8%). Conclusions: In this observational study of first-line treatment for advanced NSCLC in Europe: Median OS among the 4 treatment cohorts was 10.3 months (95% CI: ). For those patients who received a targeted agent (n=129, 8.5%), median OS was 14.5 months (95% CI: ). The probability of 1 year survival was 45% (95% CI: ) among the treatment cohorts assessed. Patients with nonsquamous histology had a median OS of 9.8 months. Patient with squamous histology had a median OS of 11.8 months. The 1 year survival probability was 43% for nonsquamous histology and 49% for squamous histology patients. Median PFS among the 4 treatment cohorts was 6.1 months. For those patients who received a targeted agent, median PFS was 8.9 months. The probability of 1 year PFS was 28% among the treatment cohorts assessed. Nonsquamous patients had a median PFS of 5.6 months and squamous patients had a median PFS of 7.5 months. The probability of 1 year PFS was 34% for squamous patients and 26% for nonsquamous patients. ORR and DCR among the 4 platinum treatment cohorts was 36% and 63%, respectively. For patients who received a targeted agent, ORR and DCR were 49% and 78%, respectively. Nonsquamous patients had an ORR and DCR of 34% and 62%; squamous patients had an ORR and DCR of 41% and 65%, respectively. 80% of patients had a histopathological diagnosis and 20% had only cytological diagnosis. Immunohistochemical biomarkers were tested in approximately half of the population (54%) with at least one additional biomarker being tested in 21% of the patients (most often EGFR). Physicians based their treatment decisions most often on pathological diagnosis (78%), patient s performance status (63%), age (53%) and comorbidities (37%). Among the patients who completed first-line treatment, 783 (51%) received further treatment. In total, 126 (16%) received maintenance treatment and 645 (82%) received 2nd-line treatment. Resource utilization showed that 52% of the patients were hospitalized at some point during first-line therapy; 59% of these patients were hospitalized for unplanned reasons for either an adverse events (54%) or deterioration of disease status (38%). Antiemetics and antinauseants were the most often reported concomitant medications used (n=1181; 81.6%).

22 Page 22 There were differences noted between hospital- and office-based physicians in the frequency of biomarkers tests, choice of first-line treatment, treatment decisions based on individual physician's experience and patient s performance status. Office-based physicians recommended concurrent targeted agents more often than hospital-based physicians (14% versus 7%).

23 Page 23 References: D Addario G, Felip R. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008;19(suppl2):ii Pallis AG and Georgoulias V. Is there a standard regimen for first-line treatment of advanced/metastatic NonSmall-Cell Lung Cancer? What has meta-analyses contributed to today's standard of care. Lung Cancer. 2012;75; Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker S Jr, Olak J, Stover D, Strawn JR, Turrisi AT, Somerfield MR; American Society of Clinical Oncology American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update. J Clin Oncol. 2003;22(2):