Can we select patients most likely to benefit from pemetrexed continuation maintenance? SEONC00109

Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1 Pemetrexed Arm %Pts Median age (yrs) Sex/ethnic group Age <65 Male Caucasian Smoker Ever smoker Never smoker ECOG PS 0 1 Stage IV Histology Adenocarcinoma Large cell Induction response CR/PR SD PD/Unknown Baseline 61 66 56 94 76 23 32 68 91 86 7 44 53 3 6 mos 61 65 55 95 72 27 39 61 92 89 6 44 55 1 6 mos 61 65 55 95 72 27 39 61 92 89 6 44 55 1 12 mos 62 62 54 96 69 30 42 59 92 89 7 45 54 2 12 mos 62 62 54 96 69 30 42 59 92 89 7 45 54 2 18 mos 62 62 47 96 66 33 46 54 92 88 7 48 50 2 18 mos 62 62 47 96 66 33 46 54 92 88 7 48 50 2 24mos 63 61 49 96 68 30 53 47 90 89 6 47 51 3 24mos 63 61 49 96 68 30 53 47 90 89 6 47 51 3

Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1 Pemetrexed Arm %Pts Median age (yrs) Sex/ethnic group Age <65 Male Caucasian Smoker Ever smoker Never smoker ECOG PS 0 1 Stage IV Histology Adenocarcinoma Large cell Induction response CR/PR SD PD/Unknown Baseline 61 66 56 94 76 23 32 68 91 86 7 44 53 3 6 mos 61 65 55 95 72 27 39 61 92 89 6 44 55 1 12 mos 62 62 54 96 69 30 42 59 92 89 7 45 54 2 18 mos 62 62 47 96 66 33 46 54 92 88 7 48 50 2 24mos 63 61 49 96 68 30 53 47 90 89 6 47 51 3 32 68 ECOG PS 0 1 39 61 42 59 46 54 53 47 44 53 3 Induction response CR/PR SD PD/Unknown 44 55 1 45 54 2 48 50 2 47 51 3

OS benefit seen across all subgroups Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1 Pemetrexed Arm %Pts Median age (yrs) Sex/ethnic group Age <65 Male Caucasian Smoker Ever smoker Never smoker ECOG PS 0 1 Stage IV Histology Adenocarcinoma Large cell Induction response CR/PR SD PD/Unknown OS benefit seen across all subgroups Baseline 61 66 56 94 76 23 32 68 91 86 7 44 53 3 6 mos 61 65 55 95 72 27 39 61 92 89 6 44 55 1 12 mos 62 62 54 96 69 30 42 59 92 89 7 45 54 2 18 mos 62 62 47 96 66 33 46 54 92 88 7 48 50 2 24mos 63 61 49 96 68 30 53 47 90 89 6 47 51 3 PARAMOUNT data shows

Maintenance Treatment Decision Basis for maintenance treatment decision Maintenance Treatment Decision Overall treatment goals Performance status Tolerance to induction therapy

Did PARAMOUNT assess patients’ Quality of Life?

1 2 PARAMOUNT: study objectives2 Primary objective Secondary objective Progression-free survival (PFS) 1 Primary objective 2 Overall survival (OS) Objective tumor resposne rate (RR) (RESIST 1.0) Patient-reported outcomes (EQ-5D) Resource utilisation Adverse events (AEs) Secondary objective

EQ-5D: EuroQol 5-dimensional questionnaire3 By placing a tick in one box in each group below, please indicate which statements best describe your own health state today. Mobility I have no problems in walking about ☐ I have some problems in walking about ☐ I am confined to bed ☐ Self-Care I have no problems with self-care ☐ I have some problems washing or dressing myself ☐ I am unable to wash or dress myself ☐ Usual Activities (e.g. work, study, housework, family or leisure activities) I have no problems with performing my usual activities ☐ I have some problems with performing my usual activities ☐ I am unable to perform my usual activities ☐ Pain/Discomfort I have no pain or discomfort ☐ I have moderate pain or discomfort ☐ I have extreme pain or discomfort ☐ Anxiety/Depression I am not anxious or depressed ☐ I am moderately anxious or depressed ☐ I am extremely anxious or depressed ☐ ✔ Best imaginable health state Worst imaginable health state VAS (Visual Analog Scale)

High EQ-5D compliance3 84.3% 80.9% 79.4% Pemetrexed arm Placeboarm Induction 84.3% 80.9% 79.4%

PARAMOUNT: EQ-5D results and safety data >10 MTC Cycles Grade 1 Grade 2 Grade 3/4 Event (%) PEM PBO Fatigue 15 13 8 6 Renal* 4 1 Rash Edema Anemia 12 7 Neutropenia 11

What are the QoL and safety results in PARAMOUNT?

QoL and safety in PARAMOUNT Good Overall QoL during maintenance Induction therapy Maintenance therapy

QoL and safety in PARAMOUNT Good Overall QoL during maintenance Induction therapy Maintenance therapy

Low rate of discontinuations due to adverse events3 QoL and safety in PARAMOUNT Rate of AEs possibly related to maintenance pemetrexed vs placebo2,† Low rate of discontinuations due to adverse events3   9.2% for maintenance pemetrexed 3.9% for placebo Anaemia Neutropenia Leucopenia Thrombo-cytopenia Fatigue Infection Pain Neuropathy Pemetrexed (n=359) placebo (n=180) 0 10 20 30 4%* n=16 <1%* n=1 4%* n=13 0%* n=1 2% n=6 1% n=4 0% n=1 4%* n=15 <1%* n=1 1% n=4 1% n=2 1% n=3 0% n=1 1% n=1 * Difference between treatment groups was significant (Fisher’s exact test p≤0.05). † Adverse events were reported using Common Terminology Criteria for Adverse Events version 3.0 (NCI 2006). Alanine aminotransferase, Nausea, Vomiting, Mucositis or stomatitis, Oedema, Anorexia, Diarrhoea, Watery eye, Constipation Grade 3/4 adverse events were reported for less than 1% of patients. Adapted from: 1,2

% Change from Baseline in ECOG Performance Status QoL and safety in PARAMOUNT Change in ECOG PS from randomisation to last maintenance treatment3 100 90 80 70 60 50 40 30 20 10 % Change from Baseline in ECOG Performance Status Pemetrexed Placebo Worse No Change Better 14.7% 12.6% 77.8% 77.3% 7.5% 10.2% * Difference between treatment groups was significant (Fisher’s exact test p≤0.05). † Adverse events were reported using Common Terminology Criteria for Adverse Events version 3.0 (NCI 2006). Alanine aminotransferase, Nausea, Vomiting, Mucositis or stomatitis, Oedema, Anorexia, Diarrhoea, Watery eye, Constipation Grade 3/4 adverse events were reported for less than 1% of patients. Adapted from: 1,2

QoL and safety in PARAMOUNT EQ-5D index scores: Quality of life was maintained throughout treatment3 0.8 0.7 0.6 Improvement Mean score Induction cycles 1 2 3 4 1 2 3 4 5 6 * p≤0.05, within-group change from baseline. † p≤0.05, comparing the difference in mean changes from baseline between treatment arms. Adapted from: 3

QoL and safety in PARAMOUNT EQ-5D index scores: Quality of life was maintained throughout treatment3 0.8 0.7 0.6 Improvement Mean score Induction cycles Maintenance cycles Pemetrexed Placebo 1 2 3 4 1 2 3 4 5 6 * p≤0.05, within-group change from baseline. † p≤0.05, comparing the difference in mean changes from baseline between treatment arms. Adapted from: 3

QoL and safety in PARAMOUNT VAS: No overall treatment differences in quality of life were observed during induction3 0.8 0.7 0.6 Improvement Mean score Induction cycles Maintenance cycles Pemetrexed Placebo 1 2 3 4 1 2 3 4 5 6 † p≤0.05, comparing the difference in mean changes from baseline between treatment arms. Adapted from: 3

QoL and safety in PARAMOUNT VAS: No overall treatment differences in quality of life were observed during induction3 0.8 0.7 0.6 Improvement Mean score Induction cycles Maintenance cycles Pemetrexed Placebo 1 2 3 4 1 2 3 4 5 6 † p≤0.05, comparing the difference in mean changes from baseline between treatment arms. Adapted from: 3

QoL and safety in PARAMOUNT Survival significantly improved with pemetrexed continuation maintenance therapy vs placebo5 HR=0.78 (95% CI: 0.64-0.96)5 No statistical differences observed in patient-reported QoL between maintenance treatment arms3

Does long-term pemetrexed maintenance have an impact on QoL?

Induction = 4 cycles of pemetrexed/cisplatin Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC6 Time from randomisation (months) 6 12 18 24 30 1.0 0.8 0.9 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Overall survival from randomisation Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints pemetrexed + BSC (n=359) placebo + BSC (n=180) HR=0.78 (95% CI 0.64–0.96); p=0.0195 36 Survival probabality (%) 24-months survival rate 32% 32% 21%

Summary of maintenance therapy4 Pemetrexed (n=359) Placebo (n=180) Median number of cycles (range) 4 (1–44) 4 (1–38) Mean number of cycles 8 5 % of pts receiving MTC ≤10 cycles 76 90 >10 cycles 24 9 % discontinuations due to possibly drug-related AE 12 4 Median number of cycles (range) 4 (1–44) 4 (1–38) Mean number of cycles 8 5 >10 cycles 24 9 Adapted from: 4

Possible drug-related CTCAEs occurring in all cycles of maintenance therapy4 >10 MTC Cycles Grade 1 Grade 2 Grade 3/4 Event (%) PEM PBO Fatigue 15 13 8 6 Renal* 4 1 Rash Edema Anemia 12 7 Neutropenia 11 * creatinine, GFR, ranal failure, and genitourinary-other.

No significant differences in drug-related grade 3/5 toxicities – except grade 3/4 neutropenia3 maintenance cycles ≤6 >6 50 0 50 Neutropenia Grade 3/4 2.2% 8.3% p=0.015 Infections Grade 3/5 2.9% 1.2% p=0.691

Possible drug-related grade 1/2 adverse events3 maintenance cycles ≤6 >6 Nausea 50 0 50 Neutropenia Sensory neuropathy Ocular/visual events Headache 8.7% 16.7% p=0.044 2.5% 11.9% p=0.001 1.5% 6.0% p=0.036 2.5% 13.1% p=0.001 0.4% 3.6% p=0.041

Majority of patients maintain QoL Long-term pemetrexed maintenance impact on QoL EQ-5D results Pemetrexed well-tolerated safety profile PS changes Majority of patients maintain QoL

Are PARAMOUNT QoL and safety results consistent with JMEN?

PARAMOUNT JMEN Maintenance pemetrexed in PARAMOUNT2 and JMEN7,8 Paz-Ares et al. 2012 Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial • Well-tolerated safety profile, consistently reported • QoL is well maintained and similar to placebo JMEN Ciuleanu et al. 2009 Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study

JMEN: Drug-related toxic effects8 Grades 3 or 4 Pemetrexed Placebo Hematologic toxicities Neutropenia* 13 (3%) Anemia 12 1 (<1%) Leukoperia 7 (2%) Non-hematologic toxicities ALT AST Fatigue† 22 (5%) Anorexia 8 Infection Diarrhoea 2 Nausea 4 Vomiting Sensory neuropathy 3 Mukositis stomatitis Rash Neutropenia* 13 (3%) Fatigue† 22 (5%) 1 (<1%) ALT=alanine aminotransferase. AST=aspartate aminotransferase. *p<0.05 for grade 3 or 4 rates of neutropenia and fatigue between study groups. †Updated safety analysis done 6 months after initial analysis of progression-free survival. For the purpose of this table, a cut-off of 5% was used for inclusion of all events for which the investigator considered a possible link with pemetrexed. Adapted from: 4

PARAMOUNT: CTCAEs possibly related to study drug during maintenance3 Grades 3 or 4 Pemetrexed Placebo Toxicity* Laboratory Anemia 16 1 (0.6%) Neutropenia 13 Non-laboratory Fatigue (asthenia, lethargy, malaise) 15 (4%) Anorexia (0.3%) Constipation Diarrhea Mucositis stomatitis Nausea Vomoting Edema Sensory neuropathy Watery eye (epiphora, tearing) Pain 3 (0.8%) Anemia 16 1 (0.6%) Neutropenia 13 Fatigue (asthenia, lethargy, malaise) 15 (4%) 1 (0.6%) Toxicities were reported using CTCAE version 3.0 (National Cancer Institute 2006). Toxicities occurring in ≥ 3% of patients on either or both arms are listed. Two grade 5 events (deaths) considered possibly related to study drug occurred during the maintenance period: pemetrexed – pneumonia; placebo-sudden death. Difference between treatment arms is statistically significant (Fisher‘s exact test p ≤0.05). CTCAE, Common Terminology Criteria for Adverse Events. Adapted from: 4

QoL in PARAMOUNT and JMEN QoL Measurement PARAMOUNT3 EQ-5D JMEN7 LCSS

Overall quality of life QoL in PARAMOUNT and JMEN Mean maximum improvement in LCSS items7 12 10 8 6 4 2 Mean maximum improvement (mm) Pemetrexed Placebo Inter-ference with activity Symptom distress Pain Haemo-lysis Dyspnoea Coogh Loss of appetite p=0.592 p=0.533 p=0.039 p=0.831 p=0.204 p=0.192 p=0.136 Overall quality of life p=0.897 Fatigue p=0.959 Overall quality of life p=0.959 Fatigue p=0.897 Adapted from: 1,2

Induction = 4 cycles of pemetrexed/cisplatin QoL in PARAMOUNT and JMEN Patients are able to maintain their overall good quality of life3 Quality of lifeBest imaginable health state Worst imaginable health state Time from randomisation (months) 6 12 18 24 30 1.0 0.8 0.9 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Overall survival from randomisation Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints pemetrexed + BSC (n=359) placebo + BSC (n=180) HR=0.78 (95% CI 0.64–0.96); p=0.0195 32% 21% 36 24-months survival rate Survival probabality (%)

How robust are the findings of PARAMOUNT to support a change in the treatment paradigm?

The robust PARAMOUNT results are based on a number of valid points The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10 The robust PARAMOUNT results are based on a number of valid points

OS: 16.9 vs 14.0 months from induction The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10 PFS: 4.1 vs 2.8 months HR 0.62 (95% CI 0.49-0.79; p<0.0001) OS: 16.9 vs 14.0 months from induction HR 0.78 (95% CI 0.64-0.96; p=0.0195) Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance

Survival probability (%) The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10 PFS: Primary endpoint 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Survival probability (%) 0 3 6 9 12 15 pemetrexed + BSC (n=358) placebo + BSC (n=180) HR 0.62 (0.49–0.79) Time (months) Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance Investigator-determined PFS results confirmed by independent review

CR/PR patients: OS HR=0.81 SD patients: OS HR=0.76 The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10 Favours pemetrexed 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0 Favours placebo Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance Investigator-determined PFS results confirmed by independent review Subgroup OS Hazard Ratio N HR (95% CI) All 539 0.78 Stage IV 490 0.79 IIIB 49 0.82 Induction response CR/PR 234 0.81 SD 285 0.76 Pre-randomisation ECOG PS 1 363 173 0.70 Smoking status Never-smoker 117 0.75 Smoker 418 0.83 Sex Male 313 Female 226 0.73 Age (years) <70 447 ≥70 92 0.89 <65 350 ≥65 189 0.71 Histology Adenocarcinoma 471 0.80 Large cell carcinoma 36 0.44 Other 32 CR/PR patients: OS HR=0.81 SD patients: OS HR=0.76 Relative treatment effect of pemetrexed consistent across subgroups

The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10 placebo (n=180) %* 72 43 8 6 4 3 2 pemetrexed (n=359) %* 64 40 32 10 5 1 Patients with PDT Drug name Erlotinib Docetaxel† Gemcitabine Vinorelbine Investigational drug Carboplatin Paclitaxel Pemetrexed Cisplatin * Data expressed as % of randomized patients. Systemic therapies used in ≥2% of patients in either arm are shown. † Only docetaxel usage differed significantly between arms (p=0.013). Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance Investigator-determined PFS results confirmed by independent review Relative treatment effect of pemetrexed consistent across subgroups Post-discontinuation treatment options were well balanced between the two arms

What are the key takeaways for clinical practice?

Key PARAMOUNT takeaways 2 4 1 3 Results confirm the importance of choosing the best treatment up-front, based on histology and other patient characteristics2,10 OS Benefit consistent across all sub-groups, with acceptable toxicity2,10 Significant OS benefit in favor of Pemetrexed Continuation Maintenance10 PARAMOUNT: first study to show that Continuation Maintenance has an impact on disease course10

References Reck M et al. PARAMOUNT: Descriptive subgroup analyses of final overall survival (OS) for the phase III study of maintenance pemetrexed (PEM) versus placebo (PLB) following induction treatment with PEM plus cisplatin (CIS) for advanced nonsquamous (NS) non-small cell lung cancer. ESMO Congress, Vienna, Austria, 2012. Abstract 1235PD. Paz-Ares L et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 2012;13:247-255. Gridelli C et al. Safety, resource use, and quality of life in PARAMOUNT: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012;7(11):1713-1721. Pujol JL et al. Updated safety and quality of life results of PARAMOUNT study: maintenance pemetrexed + best supportive care (BSC) vs placebo plus BSC immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. ESMO Congress, Vienna, Austria, 2012. Abstract 3376. Paz-Ares L et al. PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (PLB) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC). J Clin Oncol 30, 2012 (suppl; abstr LBA7507). ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. November 2012. Belani CP et al. Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study. Lancet Oncol 2012;13:292-299. Ciuleanu T et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009;374:1432-1440. Hanna N et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–1597.