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

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Presentation on theme: "Questions and answers about PARAMOUNT: phase III study of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC."— Presentation transcript:

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

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

4 Current recommendations for number of cycles in 1 st -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 Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients 9 Progression-free survival (%) Time (months) Investigator-assessed PFS Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints pemetrexed + BSC (n=359) placebo + BSC (n=180) HR=0.62 (95% CI 0.49–0.79); p< BSC=Best Supportive Care Median PFS (95% CI) Pemetrexed 4.1 (3.2–4.6) Placebo 2.8 (2.6–3.1) HR 0.62 reduction in the risk of progression 38%

7 Survival time (months) 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) 4 placebo (n=76) placebo (n=94) 2.6 (1.6–2.9) 3.0 (2.8–4.1) Numbers in brackets are the 95% CI values. PARAMOUNT: median PFS according to response to induction treatment 9 pemetrexed (n=166) pemetrexed (n=186) 4.1 (3.1–6.0) 4.1 (3.0–4.6)

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 Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients 9 Progression-free survival (%) Time (months) Investigator-assessed PFS Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints pemetrexed + BSC (n=359) placebo + BSC (n=180) HR=0.62 (95% CI 0.49–0.79); p< BSC=Best Supportive Care Median PFS (95% CI) Pemetrexed 4.1 (3.2–4.6) Placebo 2.8 (2.6–3.1) HR 0.62 reduction in the risk of progression 38%

11 Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC 10 BSC=Best Supportive Care Survival probabality (%) Time from randomisation (months) 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= HR

12 Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC 10 Time from randomisation (months) 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= BSC=Best Supportive Care 32% 21% months survival rate 32% Survival probabality (%)

13 PARAMOUNT: Final OS from induction 9,10 Survival probability (%) Time from randomisation (months) Overall survival from induction pemetrexed + BSC (n=359) placebo + BSC (n=180) HR=0.78 (95% CI 0.64–0.96); p= BSC=Best Supportive Care

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

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

16 Progression-free survival HRs in subgroups 9, Favours placebo 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 Favours pemetrexed HR (95% CI)N

17 Pemetrexed continuation maintenance helps improve survival for patients achieving either SD or a tumour response following pemetrexed-based induction 10 Survival probability (%) Time from randomisation (months) pemetrexed + BSC placebo + BSC 36 HR 0.81 CR/PR HR Survival probability (%) Time from randomisation (months) HR 0.76 pemetrexed + BSC placebo + BSC SD HR HR (95% CI)N All Induction response CR/PR SD Favours pemetrexedFavours placebo

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

19 placebo (n=180) %* placebo (n=180) %* pemetrexed (n=359) %* pemetrexed (n=359) %* 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). 64 PARAMOUNT: post-discontinuation therapy (PDT-eligible patients) 10 72

20 Are the PARAMOUNT results meaningful from a patient perspective?

21 What matters to patients longer survival time potential additional toxicity

22 Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC 10 BSC=Best Supportive Care Survival probabality (%) Time from randomisation (months) 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= HR

23 21% 32% 2-year survival rate 10 pemetrexed + BSC 32% placebo + BSC 21%

24 * 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. placebo (n=180) Fatigue † Mucositis/ stomatitis ‡ Vomiting Neuropathy pemetrexed (n=359) Anaemia † Neutropenia † Leucopenia Nausea ALT (SGPT) Values expressed as % of randomised patients PARAMOUNT: possible drug related CTCAEs*,10 4.7% 0.6% 0.3% 6.4% 0.6% 5.8% 0% 2.2% 0% 0.6% 0% 1.1% 0% 0.6% 0.3% 0%

25 PARAMOUNT: EQ-5D results 9 EQ-5D results suggest that patients can tolerate long-term maintenance treatment with pemetrexed while maintaining their QoL

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

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 JMDB 8 Induction Completing ≥ 4 cycles JMDB 71% PARAMOUNT 68% 28.6% 63.8% 30.1% 74.5% Response and control Tumour response rates Disease control rates 21.4% 21.9% 13.7% 14.8% Toxicity Laboratory toxicities Non-laboratory toxicities

29 How is PARAMOUNT different from study JMEN?

30 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 JMEN PARAMOUNT PFS Yes (18–24 mos btwn PFS & OS) Pemetrexed vs placebo Yes Pemetrexed and erlotinib approved in maintenance PFS Yes (1 yr btwn PFS & OS) Pemetrexed vs placebo Yes No therapies approved for maintenance *Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type. How is PARAMOUNT different from Study JMEN? 9,12 Pemetrexed + cisplatin Docetaxel + platinum Paclitaxel + platinum Gemcitabine + platinum Induction plus maintenance Non-squamous* only primarily EU Maintenance only All histologies global

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

32 PARAMOUNT 9 vs JMEN 12 Select the most suitable treatment upfront based on histology, along with other tumour and patient characteristics Gain positive risk/benefit Maximise outcomes and patient survival Keep other effective treatments available for further lines Approach to maximise outcomes for patients throughout their multiple lines of therapy

33 References 1.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): Pfister DG, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update J Clin Oncol. 2004;22: Azzoli CG, Temin S, Aliff T, et al 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 Sep 6. 4.Lustberg MB, et al. Optimal duration of chemotherapy in advanced non-small cell lung cancer. Curr Treat Options Oncol. 2007;8: 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: 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: 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: Scagliotti GV, et al. Poster presented at: 14th World Conference on Lung Cancer; July 3-7, 2011; Amsterdam, The Netherlands. 9.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: Paz-Ares L. Presentation at: American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, USA 11.ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. December 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:


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