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

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

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

2 All Chapters at a glance: please click on box to review Maintenance strategies in non-squamous NSCLC Maintenance strategies in non-squamous NSCLC 1 1 PARAMOUNT: patient & disease characteristics, drug administration PARAMOUNT: patient & disease characteristics, drug administration 3 3 PARAMOUNT: PFS results PARAMOUNT: PFS results 4 4 PARAMOUNT: post-discontinuation therapy PARAMOUNT: post-discontinuation therapy 5 5 PARAMOUNT: safety & tolerability PARAMOUNT: safety & tolerability 6 6 PARAMOUNT: conclusions PARAMOUNT: conclusions 7 7 PARAMOUNT: study design and objectives PARAMOUNT: study design and objectives 2 2

3 Increase the duration of disease control Improve overall survival Maintaining tolerability Objectives of maintenance therapy 1

4 Tolerance to maintenance drug is known from induction treatment Potential advantages of continuation maintenance approach 2–4 Maximise the potential of the drug used in 1 st -line Saves a drug for subsequent treatment lines

5 PARAMOUNT: pemetrexed/cisplatin followed by pemetrexed for advanced non-squamous* NSCLC 1 2:1 randomisation pemetrexed † 500 mg/m 2 IV + BSC day 1, q 21 days; n=359 pemetrexed † 500 mg/m 2 IV + BSC day 1, q 21 days; n=359 pemetrexed 500 mg/m 2 IV + cisplatin 75 mg/m 2 day 1, q 21 days; n=939 Non-squamous* NSCLC patients only pemetrexed 500 mg/m 2 IV + cisplatin 75 mg/m 2 day 1, q 21 days; n=939 Non-squamous* NSCLC patients only CR, PR, or SD after 4 cycles of pemetrexed/cisplatin n=539 CR, PR, or SD after 4 cycles of pemetrexed/cisplatin n=539 progressive disease placebo † + BSC day 1, q 21 days; n=180 placebo † + BSC day 1, q 21 days; n=180 *Adenocarcinoma, large cell carcinoma and other histologies † Vitamin B 12, folic acid and dexamethasone given during induction therapy and in both maintenance arms. BSC=Best Supportive Care Patients enrolled if: non-squamous* NSCLC no prior systemic treatment for lung cancer ECOG PS 0/1 Stratified for: PS (0 vs 1) disease stage (IIIB vs IV) prior to induction response to induction (CR/PR vs SD)

6 PARAMOUNT: study objectives 1 Progression-free survival (PFS) Primary objective Secondary objectives Overall survival (OS) Objective tumour response rate (RR) (RECIST 1.0) Patient-reported outcomes (EQ-5D) Resource utilisation Adverse events (AEs)

7 PARAMOUNT: patient characteristics (randomised patients) 1 placebo n=180 placebo n=180 Median age, yrs Age <65 yrs Male Caucasian Smoker Ever smoker Never smoker ECOG PS 0 1 2/3* *Protocol violations (66%) (56%) (94%) (77%) (23%) (32%) (68%) (<1%) (62%) (95%) (80%) (19%) (31%) (68%) (1%) pemetrexed n=359 pemetrexed n= Caucasian339(94%)171(95%)

8 PARAMOUNT: disease characteristics (randomised patients) 1 placebo n=180 placebo n=180 Disease stage IV* Histology Adenocarcinoma/bronchoalveolar Large cell Other non-squamous Best tumour response to induction CR/PR SD PD/Unknown † * Lung Cancer Staging System Version V † Protocol violations pemetrexed n=359 pemetrexed n= (91%) (86%) (7%) (46%) (52%) (2%) (89%) (7%) (4%) (42%) (52%) (6%) Disease stage IV* 328 (91%) 161 (89%) Adenocarcinoma/bronchoalveolar 310 (86%) 160(89%)

9 PARAMOUNT: drug administration (randomised patients) 1 Data related to the primary endpoint (PFS) data analysis. Figures are likely to change at the time of the final OS analysis. pemetrexed n=359 pemetrexed n=359 placebo n=180 placebo n=180 mean # of cyclespatients > 6 cyclesdose intensity % 14% 95% n.a.

10 Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients 1 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 ( ) Placebo 2.8 ( ) HR 0.62 reduction in the risk of progression 38%

11 Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients 1 Progression-free survival (%) Time (months) Independently reviewed PFS † Induction = 4 cycles of pemetrexed/cisplatin NOT reflected in the data endpoints pemetrexed + BSC (n=316) placebo + BSC (n=156) HR=0.64 (95% CI 0.51–0.81); p< † 88% of patients were independently reviewed (472/539); BSC=Best Supportive Care Median PFS (95% CI) Pemetrexed 3.9 (3.0–4.2) Placebo 2.6 (2.2–2.9) HR

12 Progression- free survival HRs in subgroups 1 PFS results were internally consistent; benefit was seen across all subgroups All Stage IIIB IV Induction response CR/PR SD Pre-randomisation ECOG PS 0 1 Smoking status Non-smoker Smoker Sex Male Female Age (years) <70 ≥70 <65 ≥65 Histology Adenocarcinoma Large Cell Carcinoma Other 0.62 ( ) 0.55 ( ) 0.62 ( ) 0.48 ( ) 0.74 ( ) 0.53 ( ) 0.67 ( ) 0.41 ( ) 0.70 ( ) 0.74 ( ) 0.49 ( ) 0.69 ( ) 0.35 ( ) 0.70 ( ) 0.51 ( ) 0.62 ( ) 0.39 ( ) 0.64 ( ) Favours pemetrexedFavours placebo HR (95% CI)N

13 Survival time (months) Response to induction treatment Complete/Partial response n=242, HR=0.48, ( ) Stable disease n=280, HR=0.74, ( ) 4 Numbers in brackets are the 95% CI values. PARAMOUNT: median PFS according to response to induction treatment 1 pemetrexed (n=166) pemetrexed (n=186) 4.1 ( ) 4.1 ( ) placebo (n=76) placebo (n=94) 2.6 ( ) 3.0 ( )

14 PARAMOUNT: post-discontinuation therapy (PDT-eligible patients) 1 placebo n=122 placebo n= (64%) (37%) (35%) (3%) (2%) (<1%) (5%) Patients with PDT Drug name Erlotinib Docetaxel Gemcitabine Investigational drug Vinorelbine Bevacizumab Cisplatin Other † p-value – pemetrexed n=200 pemetrexed n= (58%) (31%) (29%) (8%) (5%) (4%) (2%) (7%) † Systemic therapies administered to 1% or fewer patients in both groups are summarised under “Other”. These therapies included carboplatin, pemetrexed, BIBF 1120, paclitaxel, placebo, aspirin, aflibercept, cyclophosphamide, gefitinib, ifosfamide, vinflunine, and other antineoplastic drugs. (58%)(64%)

15 Overall, toxicity was low in both arms * Difference between treatment groups was significant (Fisher’s exact test p ≤0.05). placebo n=180 placebo n=180 pemetrexed n=359 pemetrexed n=359 Patients with ≥ 1 grade 3/4/5 laboratory toxicity Patients with ≥ 1 grade 3/4/5 non-laboratory toxicity 9%* n=33 9% n=32 <1%* n=1 4% n=8 Maintenance therapy with pemetrexed: generally well tolerated 1

16 * 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 3/4/5 adverse events were reported for less than 1% of patients. placebo (n=180) Anaemia Neutropenia Fatigue Pain Leucopenia Thrombocytopenia Infection Neuropathy pemetrexed (n=359) PARAMOUNT: CTCAEs grade 3/4/5 drug-related toxicities (randomised patients) 1† 4%* n=16 4%* n=13 2% n=6 1% n=4 4%* n=15 1% n=3 1% n=4 <1% n=1 <1%* n= 1 0%* n= 0 0% n=0 <1%* n= 1 1% n=2 0% n=0 <1% n=1

17 PARAMOUNT: health-related quality of life assessment (EQ-5D) 1 Compliance at all time points during maintenance phase was >80% No statistical differences in EQ-5D index score or visual analog scale were observed between treatment arms EQ-5D results suggest that patients can tolerate long-term maintenance treatment with pemetrexed while maintaining their QoL

18 Pemetrexed continuation maintenance therapy offers significantly improved PFS Pemetrexed continuation maintenance therapy is well tolerated PARAMOUNT demonstrates a positive risk/benefit ratio for the administration of pemetrexed continuation maintenance 1,10 PARAMOUNT: conclusions 1,10

19 Pemetrexed continuation maintenance therapy: approach to maximise outcomes for patients 1,2 Proven efficacy ✔ Acceptable toxicity ✔ Conveniently administered ✔ Keeps other treatments available ✔

20 Acknowledgements We thank all of the patients and their caregivers for participating in this trial.

21 References 1.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: Stinchcombe TE, Socinski MA. Treatment paradigms for advanced stage non-small cell lung cancer in the era of multiple lines of therapy. J Thorac Oncol 2009;4:243–50. 3.Novello S et al. Maintenance therapy in NSCLC: why? To whom? Which agent? J Exp Clin Cancer Res 2011;30:50. 4.Fidias P, Novello S. Strategies for prolonged therapy in patients with advanced non–small-cell lung cancer. J Clin Oncol. 2010;28: 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.[Epub ahead of print]. 6.D’Addario G, Felip E. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20:iv68–iv70. 7.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer V Fort Washington, PA: NCCN, 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: Ciuleanu T et al. Maintenance pemetrexed plus best supportive care for non-small-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet 2009;347: ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. November 2011.


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