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All questions at a glance: please click on question to review

Questions and answers about PARAMOUNT: phase III study of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC. All questions at a glance: please click on question to review. 2. 3. 1.

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All questions at a glance: please click on question to review

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  1. Questions and answers about PARAMOUNT: phase III study of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC.

  2. All questions at a glance: please click on question to review 2 3 1 What is the impact of the PARAMOUNT survival results on the treatment paradigm in advanced NSCLC? PARAMOUNT study design: why were 4 cycles of induction used? Does PARAMOUNT address the question of pemetrexed clinical resistance? 4 Based on the results of PARAMOUNT, can response to induction determine who should receive maintenance therapy? 5 6 Did study patients get 2nd-line treatments? Were there any differences between the two study arms? Are the PARAMOUNTresults meaningful from a patient perspective? 7 8 9 How do the results of the pemetrexed/cisplatin induction regimen of PARAMOUNT compare with those of the pemetrexed/cisplatin-treated non-squamous patients in study JMDB? How is PARAMOUNT different from study JMEN? Can we compare pemetrexed continuation versus pemetrexed switch maintenance therapies?

  3. PARAMOUNT study design: why were 4 cycles of induction used?

  4. Current recommendations for number of cycles in 1st-line treatment • ASCO and ESMO: 4 to 6 cycles of a platinum-based regimen • JMDB: 91% of CR or PR occurred in the first 4 cycles*,7,8 * of all responders

  5. Does PARAMOUNT address the question of pemetrexed clinical resistance?

  6. Investigator-assessed PFS Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients9 1.0 pemetrexed+ BSC (n=359) placebo + BSC (n=180) HR=0.62 (95% CI 0.49–0.79); p<0.0001 Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints Progression-free survival (%) 0.9 0.8 0.7 Median PFS (95% CI) Pemetrexed 4.1 (3.2–4.6) Placebo 2.8 (2.6–3.1) HR 0.62 38% reduction in the risk of progression 0.6 2.8 4.1 0.5 0.4 0.3 0.2 0.1 0 0 3 9 12 15 6 Time (months) BSC=Best Supportive Care

  7. PARAMOUNT: median PFS according to response to induction treatment9 Response to induction treatment Complete/Partial response n=242, HR=0.48(0.34–0.67) Stable disease n=280, HR=0.74 (0.53–1.04) pemetrexed (n=166) 4.1 (3.1–6.0) placebo (n=76) 2.6 (1.6–2.9) 4.1 (3.0–4.6) pemetrexed (n=186) 3.0 (2.8–4.1) placebo (n=94) 0 2 3 4 5 1 Survival time (months) Numbers in brackets are the 95% CI values.

  8. What is the impact of the PARAMOUNT survival results on the treatment paradigm in advanced NSCLC?

  9. PARAMOUNT study was powered 9,10,11 • for PFS – primary end-point • for OS – primary end-point

  10. Investigator-assessed PFS Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients 9 1.0 pemetrexed+ BSC (n=359) placebo + BSC (n=180) HR=0.62 (95% CI 0.49–0.79); p<0.0001 Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints Progression-free survival (%) 0.9 0.8 0.7 Median PFS (95% CI) Pemetrexed 4.1 (3.2–4.6) Placebo 2.8 (2.6–3.1) HR 0.62 38% reduction in the risk of progression 0.6 2.8 4.1 0.5 0.4 0.3 0.2 0.1 0 0 3 9 12 15 6 Time (months) BSC=Best Supportive Care

  11. Overall survival from randomisation Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC10 1.0 pemetrexed+ BSC (n=359) placebo + BSC (n=180) HR=0.78 (95% CI 0.64–0.96); p=0.0195 Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints Survival probabality (%) 0.9 0.8 0.7 0.6 11.0 13.9 HR 0.78 0.5 0.4 0.3 0.2 0.1 0 0 6 18 24 30 36 12 Time from randomisation (months) BSC=Best Supportive Care

  12. Overall survival from randomisation Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC10 1.0 pemetrexed+ BSC (n=359) placebo + BSC (n=180) HR=0.78 (95% CI 0.64–0.96); p=0.0195 Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints Survival probabality (%) 0.9 0.8 0.7 0.6 32% 24-months survival rate 0.5 0.4 32% 0.3 0.2 21% 0.1 0 0 6 18 24 30 36 12 Time from randomisation (months) BSC=Best Supportive Care

  13. Overall survival from induction PARAMOUNT: Final OS from induction 9,10 1.0 pemetrexed+ BSC (n=359) placebo + BSC (n=180) HR=0.78 (95% CI 0.64–0.96); p=0.0191 Survival probability (%) 0.9 0.8 0.7 0.6 14.0 16.9 0.5 0.4 0.3 0.2 0.1 0 0 6 18 24 30 36 12 Time from randomisation (months) BSC=Best Supportive Care

  14. PARAMOUNT: PFS and OS results 9,10 PFS HR 0.62 p<0.0001 95% CI 0.49 – 0.79 OS* HR 0.78 p=0.0195 95% CI 0.64 – 0.96 * Overall survival from randomisation

  15. Based on the results of PARAMOUNT, can response to induction determine who should receive maintenance therapy?

  16. Progression-free survival HRs in subgroups9,11 N HR (95% CI) 0.78 0.79 0.82 0.81 0.76 0.82 0.70 0.75 0.83 0.82 0.73 0.75 0.89 0.82 0.71 0.80 0.44 0.81 All Stage Induction response Pre-randomisation ECOG PS Smoking status Sex Age (years) Histology IV IIIB CR/PR SD 1 0 Never-smoker Smoker Male Female <70 ≥70 <65 ≥65 Adenocarcinoma Large cell carcinoma Other 539 490 49 234 285 363 173 117 418 313 226 447 92 350 189 471 36 32 Favours pemetrexed Favours placebo 1.4 0 0.2 0.4 0.6 0.8 1 1.2 1.6 1.8 2.0

  17. Pemetrexed continuation maintenance helps improve survival for patients achieving either SD or a tumour response following pemetrexed-based induction10 N HR (95% CI) All 539 0.78 pemetrexed+ BSC placebo + BSC pemetrexed+ BSC placebo + BSC Induction response CR/PR 234 0.81 SD 285 0.76 Favours pemetrexed Favours placebo 1.4 0 0.2 0.4 0.6 0.8 1 1.2 1.6 1.8 2.0 1.0 1.0 HR 0.76 HR 0.81 Survival probability (%) Survival probability (%) 0.9 0.9 0.8 0.8 0.7 0.7 CR/PR HR 0.81 SD HR 0.76 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 0 6 18 24 6 18 24 30 36 30 36 12 12 Time from randomisation (months) Time from randomisation (months)

  18. Did study patients get 2nd-line treatments? Were there any difference between the two study arms?

  19. PARAMOUNT: post-discontinuation therapy (PDT-eligible patients)10 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 * 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).

  20. Are the PARAMOUNT results meaningful from a patient perspective?

  21. What matters to patients • longer survival time • potential additional toxicity

  22. Overall survival from randomisation Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC10 1.0 pemetrexed+ BSC (n=359) placebo + BSC (n=180) HR=0.78 (95% CI 0.64–0.96); p=0.0195 Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints Survival probabality (%) 0.9 0.8 0.7 0.6 11.0 13.9 HR 0.78 0.5 0.4 0.3 0.2 0.1 0 0 6 18 24 30 36 12 Time from randomisation (months) BSC=Best Supportive Care

  23. 2-year survival rate10 placebo+ BSC 21% pemetrexed + BSC 32% 21% 32%

  24. PARAMOUNT: possible drug related CTCAEs*,10 6.4% 4.7% Anaemia† Fatigue† 0.6% 1.1% 5.8% Neutropenia† 0.3% Vomiting 0%% 0% 2.2% Leucopenia 0.6% Mucositis/ stomatitis‡ 0% 0% 0.6% Nausea 0.3% 0% Neuropathy 0.6% 0.3% ALT (SGPT) 0% 0 10 20 30 0 10 20 30 placebo(n=180) pemetrexed(n=359) Values expressed as % of randomised patients * Data derived from the March 2011 safety update. Toxicities of any grade, occurring in ≥5% of patients in either arm, are listed, along with some select toxicities. † p< 0.05 Fisher’s exact test of Gr 3/4 toxicities. ‡ Combined term.

  25. PARAMOUNT: EQ-5D results9 • EQ-5D results suggest that patients can tolerate long-term maintenance treatmentwith pemetrexed while maintaining their QoL

  26. What matters to patients PARAMOUNT demonstrated that pemetrexed continuation maintenance • has a positive risk/benefit ratio • can meet all the requirements for an acceptable continuation maintenance therapy • longer survival time • potential additional toxicity

  27. How do the results of the pemetrexed/cisplatin induction regimen of PARAMOUNT compare with those of the pemetrexed/cisplatin-treated non-squamous patients in study JMDB?

  28. PARAMOUNT induction vs JMDB8 PARAMOUNT JMDB 71% 68% Induction Completing ≥ 4 cycles Response and control Tumour response rates Disease control rates 28.6% 63.8% 30.1% 74.5% Toxicity Laboratory toxicities Non-laboratory toxicities 13.7% 14.8% 21.4% 21.9%

  29. How is PARAMOUNT different from study JMEN?

  30. How is PARAMOUNT different from Study JMEN?9,12 PARAMOUNT JMEN Primary endpoints Powered for OS Maintenance therapy Double-blind, placebo-controlled Induction therapy(4 cycles for both studies) Study included Study population External environment at study completion PFS PFS Yes(18–24 mos btwn PFS & OS) Yes(1 yr btwn PFS & OS) Pemetrexed vs placebo Pemetrexed vs placebo Yes Yes Pemetrexed + cisplatin Docetaxel + platinum Paclitaxel + platinum Gemcitabine + platinum Induction plus maintenance Maintenance only Non-squamous* onlyprimarily EU All histologiesglobal Pemetrexed and erlotinibapproved in maintenance No therapies approved for maintenance *Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type.

  31. Can we compare pemetrexed continuation versus pemetrexed switch maintenance therapies?

  32. PARAMOUNT9 vs JMEN12 Select the most suitable treatment upfront based on histology, along with other tumour and patient characteristics Maximise outcomes and patient survival Keep other effective treatments available for further lines Gain positive risk/benefit Approach to maximise outcomes for patients throughout their multiple lines of therapy

  33. References D’Addario G, et al. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(suppl 4):68-70. Pfister DG, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol. 2004;22:330-353. Azzoli CG, Temin S, Aliff T, et al. 2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer. J Clin Oncol. 2011 Sep 6. Lustberg MB, et al. Optimal duration of chemotherapy in advanced non-small cell lung cancer. Curr Treat Options Oncol. 2007;8:38-46. Socinski MA, et al. Duration of first-line chemotherapy in advanced non small-cell lung cancer: less is more in the era of effective subsequent therapies. J Clin Oncol. 2007;25:5155-5157. Soon YY, et al. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:3277-3283. Scagliotti GV, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551. Scagliotti GV, et al. Poster presented at: 14th World Conference on Lung Cancer; July 3-7, 2011; Amsterdam, The Netherlands. 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 Paz-Ares L. Presentation at: American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, USA ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. December 2011. Ciuleanu T et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet 2009;347:1432-40.

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