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

Can we select patients most likely to benefit from pemetrexed continuation maintenance?. ESALM00125. Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months 1. Pemetrexed Arm %Pts Median age (yrs) Sex/ethnic group Age <65 Male Caucasian

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

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  1. Can we select patients most likely to benefit from pemetrexed continuation maintenance? ESALM00125

  2. Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1 Pemetrexed Arm %PtsMedian age (yrs) Sex/ethnic groupAge <65Male 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

  3. Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1 Induction response CR/PR SD PD/Unknown 44 53 3 44 55 1 45 54 2 48 50 2 47 51 3 Pemetrexed Arm %PtsMedian age (yrs) Sex/ethnic groupAge <65Male 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 ECOG PS 0 1 39 61 53 47 32 68 42 59 46 54

  4. Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1 Pemetrexed Arm %PtsMedian age (yrs) Sex/ethnic groupAge <65Male 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 PARAMOUNT data shows OS benefit seen across all subgroups

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

  6. Did PARAMOUNT assess patients’ Quality of Life?

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

  8. EQ-5D: EuroQol 5-dimensional questionnaire3 Questionnaire VAS (Visual Analog Scale) Best imaginable healthstate Worst imaginable healthstate 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-CareI 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/DiscomfortI have no pain or discomfort ☐I have moderate pain or discomfort ☐I have extreme pain or discomfort ☐ Anxiety/DepressionI am not anxious or depressed ☐I am moderately anxious or depressed ☐I am extremely anxious or depressed ☐ ✔ ✔ ✔ ✔ ✔

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

  10. PARAMOUNT: EQ-5D results and safety data EQ-5D results3 Safety data4

  11. What are the QoL and safety results in PARAMOUNT?

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

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

  14. QoL and safety in PARAMOUNT Rate of AEs possibly related to maintenance pemetrexed vs placebo2,† Anaemia 4%* n=16 <1%* n=1 Fatigue 4%* n=15 <1%* n=1 Low rate of discontinuations due to adverse events3 9.2% for maintenance pemetrexed 3.9% for placebo Neutropenia 4%* n=13 0%* n=1 Infection 1% n=4 1% n=2 Leucopenia 2% n=6 0%* n=1 Pain 1% n=3 0% n=1 Thrombo-cytopenia 1% n=4 0% n=1 Neuropathy 1% n=1 1% n=1 0 10 20 30 0 10 20 30 Pemetrexed (n=359) placebo (n=180) * 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. Adopted from: 1,2

  15. 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 0 % Change from Baseline in ECOG Performance Status Worse 14.7% 12.6% No Change Better 77.8% 77.3% 7.5% 10.2% Pemetrexed Placebo * 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. Adopted from: 1,2

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

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

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

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

  20. QoL and safety in PARAMOUNT • Survivalsignificantlyimprovedwithpemetrexedcontinuationmaintenancetherapyvs placebo5 • HR=0.78 (95% CI: 0.64-0.96)5 • Nostatisticaldifferencesobserved in patient-reportedQoLbetweenmaintenancetreatment arms3

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

  22. Overall survival from randomisation Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC6 pemetrexed+ BSC (n=359) placebo + BSC (n=180) HR=0.78 (95% CI 0.64–0.96); p=0.0195 1.0 Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints Survival probabality (%) 0.9 0.8 0.7 32% 24-months survival rate 0.6 0.5 0.4 32% 0.3 0.2 21% 0.1 0 0 6 18 24 30 36 12 Time from randomisation (months)

  23. Summary of maintenance therapy4 Adopted from: 4

  24. Possible drug-related CTCAEs occurring in all cycles of maintenance therapy4 * creatinine, GFR, ranal failure, and genitourinary-other.

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

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

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

  28. Are PARAMOUNT QoL and safety results consistent with JMEN?

  29. Maintenance pemetrexed in PARAMOUNT2 and JMEN7,8 • PARAMOUNT • 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

  30. JMEN: Drug-related toxic effects8 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. Adopted from: 4

  31. PARAMOUNT: CTCAEs possibly related to study drug during maintenance3 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. Adopted from: 4

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

  33. QoL in PARAMOUNT and JMEN Mean maximum improvement in LCSS items7 p=0.592 p=0.897 p=0.897 p=0.136 p=0.959 p=0.959 12 10 8 6 4 2 0 Meanmaximumimprovement (mm) p=0.533 p=0.204 p=0.192 p=0.039 p=0.831 Fatigue Overall quality of life Loss of appetite Fatigue Coogh Dyspnoea Haemo-lysis Pain Symptom distress Inter-ference with activity Overall quality of life Pemetrexed Placebo Adopted from: 1,2

  34. QoL in PARAMOUNT and JMEN Overall survival from randomisation Patients are able to maintain their overall good quality of life3 Quality of lifeBest imaginable health state Worst imaginable health state pemetrexed+ BSC (n=359) placebo + BSC (n=180) HR=0.78 (95% CI 0.64–0.96); p=0.0195 1.0 Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints Survival probabality (%) 0.9 0.8 0.7 32% 24-months survival rate 0.6 0.5 0.4 32% 0.3 0.2 21% 0.1 0 0 6 18 24 30 36 12 Time from randomisation (months)

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

  36. The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10 The robust PARAMOUNT resultsarebased on a numberof valid points

  37. The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10 Directionofmagnitudeof PFS and OS resultsareconsistentandfavourpemetrexedcontinuationmaintenance 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)

  38. The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10 Directionofmagnitudeof PFS and OS resultsareconsistentandfavourpemetrexedcontinuationmaintenance Investigator-determined PFS resultsconfirmedbyindependentreview PFS: Primary endpoint 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 pemetrexed+ BSC (n=358) placebo + BSC (n=180) HR 0.62 (0.49–0.79) Survivalprobability (%) 0 3 6 9 12 15 Time (months)

  39. The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10 Directionofmagnitudeof PFS and OS resultsareconsistentandfavourpemetrexedcontinuationmaintenance Investigator-determined PFS resultsconfirmedbyindependentreview CR/PR patients: OS HR=0.81 SD patients: OS HR=0.76 Relative treatmenteffectofpemetrexedconsistentacrosssubgroups Favours pemetrexed 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0 Favours placebo

  40. The robust findings of PARAMOUNT and their likely impact on the current treatment paradigm2,5,10 Directionofmagnitudeof PFS and OS resultsareconsistentandfavourpemetrexedcontinuationmaintenance Investigator-determined PFS resultsconfirmedbyindependentreview pemetrexed (n=359) %* placebo (n=180) %* Patients with PDT Drug name Erlotinib Docetaxel† Gemcitabine Vinorelbine Investigational drug Carboplatin Paclitaxel Pemetrexed Cisplatin 72 43 43 8 6 4 4 3 4 2 64 40 32 10 8 6 5 3 2 1 64 72 Relative treatmenteffectofpemetrexedconsistentacrosssubgroups Post-discontinuationtreatmentoptionswerewellbalancedbetweenthetwoarms * 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).

  41. What are the key takeaways for clinical practice?

  42. Key PARAMOUNT takeaways 2 Significant OS benefit in favorofPemetrexedContinuation Maintenance10 OS Benefitconsistentacross all sub-groups, withacceptable toxicity2,10 PARAMOUNT: firststudytoshowthatContinuation Maintenance has an impact on disease course10 Resultsconfirmtheimportanceofchoosingthebesttreatmentup-front, based on histologyandotherpatientcharacteristics2,10 3 1 4

  43. 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.

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