PARAMOUNT: phase III study of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC. All Chapters at a glance: please click on box to review 1 2 Maintenance strategies in non-squamous NSCLC 4 3 PARAMOUNT: study design and objectives 5 PARAMOUNT: PFS results PARAMOUNT: patient & disease characteristics, drug administration 6 PARAMOUNT: post-discontinuation therapy 7 PARAMOUNT: safety & tolerability PARAMOUNT: conclusions Increase the duration of disease control Objectives of maintenance therapy1 Maintaining tolerability Improve overall survival Tolerance to maintenance drug is known from induction treatment Potential advantages of continuation maintenance approach2–4 Saves a drug for subsequent treatment lines Maximise the potential of the drug used in 1st-line CR, PR, or SD after 4 cycles of pemetrexed/cisplatin n=539 pemetrexed 500 mg/m2 IV + cisplatin 75 mg/m2 day 1, q 21 days; n=939 Patients enrolled if: Non-squamous* NSCLC patients only • non-squamous* NSCLC • no prior systemic treatment for lung cancer • ECOG PS 0/1 progressive disease 2:1 randomisation PARAMOUNT: pemetrexed/cisplatin followed by pemetrexed for advanced non-squamous* NSCLC1 pemetrexed† 500 mg/m2 IV + BSC day 1, q 21 days; n=359 placebo† + BSC day 1, q 21 days; n=180 Stratified for: • PS (0 vs 1) • disease stage (IIIB vs IV) prior to induction • response to induction (CR/PR vs SD) *Adenocarcinoma, large cell carcinoma and other histologies † Vitamin B12, folic acid and dexamethasone given during induction therapy and in both maintenance arms. BSC=Best Supportive Care PARAMOUNT: study objectives1 Primary objective Secondary objectives • Progression-free survival (PFS) • Overall survival (OS) • Objective tumour response rate (RR) (RECIST 1.0) • Patient-reported outcomes (EQ-5D) • Resource utilisation • Adverse events (AEs) PARAMOUNT: patient characteristics (randomised patients)1 Median age, yrs Age <65 yrs Male Caucasian Smoker Ever smoker Never smoker ECOG PS 0 1 2/3* *Protocol violations pemetrexed n=359 placebo n=180 61 62 238 201 339 339 (66%) (56%) (94%) 112 112 171 (62%) (62%) (95%) 275 82 (77%) (23%) 144 34 (80%) (19%) 115 243 1 (32%) (68%) (<1%) 55 123 2 (31%) (68%) (1%) PARAMOUNT: disease characteristics (randomised patients)1 pemetrexed n=359 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 placebo n=180 328 (91%) 161 (89%) 310 310 24 25 (86%) (7%) (7%) 160 12 8 (89%) (7%) (4%) 166 186 7 (46%) (52%) (2%) 76 94 10 (42%) (52%) (6%) PARAMOUNT: drug administration (randomised patients)1 mean # of cycles patients > 6 cycles dose intensity pemetrexed n=359 4.9 23% 95% placebo n=180 4.2 14% n.a. Data related to the primary endpoint (PFS) data analysis. Figures are likely to change at the time of the final OS analysis. Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1 pemetrexed + BSC (n=359) placebo + BSC (n=180) 1.0 Progression-free survival (%) NOT reflected in the data endpoints Induction = 4 cycles of pemetrexed/cisplatin Investigator-assessed PFS 0.9 0.8 HR=0.62 (95% CI 0.49–0.79); p<0.0001 0.7 0.6 2.8 4.1 HR 0.62 0.5 Median PFS (95% CI) reduction in the Pemetrexed 4.1 (3.2-4.6) risk of progression Placebo 2.8 (2.6-3.1) 38% 0.4 0.3 0.2 0.1 0 0 3 6 9 Time (months) BSC=Best Supportive Care 12 15 Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1 pemetrexed + BSC (n=316) placebo + BSC (n=156) 1.0 Progression-free survival (%) NOT reflected in the data endpoints Induction = 4 cycles of pemetrexed/cisplatin Independently reviewed PFS† 0.9 0.8 HR=0.64 (95% CI 0.51–0.81); p<0.0002 0.7 0.6 2.6 3.9 HR 0.64 0.5 Median PFS (95% CI) Pemetrexed 3.9 (3.0–4.2) Placebo 2.6 (2.2–2.9) 0.4 0.3 0.2 0.1 0 0 3 6 9 Time (months) † 88% of patients were independently reviewed (472/539); BSC=Best Supportive Care 12 15 Progressionfree survival HRs in subgroups1 N HR (95% CI) 539 0.62 (0.59-0.79) IIIB 50 0.55 (0.24-1.26) IV 489 0.62 (0.49-0.80) CR/PR 242 0.48 (0.34-0.67) SD 280 0.74 (0.53-1.04) 0 170 0.53 (0.35-0.79) 1 366 0.67 (0.50-0.90) Non-smoker 116 0.41 (0.24-0.71) Smoker 419 0.70 (0.53-0.90) Male 313 0.74 (0.55-1.00) Female 226 0.49 (0.34-0.72) 447 0.69 (0.54-0.90) ≥70 92 0.35 (0.20-0.63) <65 350 0.70 (0.53-0.94) ≥65 189 0.51 (0.34-0.75) 471 0.62 (0.49-0.80) Large Cell Carcinoma 36 0.39 (0.14-1.07) Other 32 0.64 (0.22-1.89) All Stage Induction response Pre-randomisation ECOG PS PFS results were internally consistent; benefit was seen across all subgroups Smoking status Sex Age (years) <70 Histology Adenocarcinoma 0 0.2 0.4 0.6 0.8 Favours pemetrexed 1 1.2 1.4 1.6 1.8 2.0 Favours placebo PARAMOUNT: median PFS according to response to induction treatment1 Response to induction treatment Complete/Partial response pemetrexed (n=166) n=242, HR=0.48, (0.34-0.67) placebo (n=76) Stable disease pemetrexed (n=186) n=280, HR=0.74, (0.53-1.04) 4.1 (3.1-6.0) 2.6 (1.6-2.9) 4.1 (3.0-4.6) 3.0 (2.8-4.1) placebo (n=94) 0 1 2 3 Survival time (months) Numbers in brackets are the 95% CI values. 4 5 PARAMOUNT: post-discontinuation therapy (PDT-eligible patients)1 Patients with PDT Drug name Erlotinib Docetaxel Gemcitabine Investigational drug Vinorelbine Bevacizumab Cisplatin Other† pemetrexed n=200 placebo n=122 116 (58%) 78 (64%) (64%) 0.35 62 58 15 10 8 3 3 13 (31%) (29%) (8%) (5%) (4%) (2%) (2%) (7%) 45 43 4 4 2 1 1 6 (37%) (35%) (3%) (3%) (2%) (<1%) (<1%) (5%) 0.33 0.27 0.15 0.58 0.33 1.00 1.00 – p-value † 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. Maintenance therapy with pemetrexed: generally well tolerated1 Overall, toxicity was low in both arms pemetrexed n=359 placebo n=180 Patients with ≥ 1 grade 3/4/5 laboratory toxicity 9%* <1%* n=33 n=1 Patients with ≥ 1 grade 3/4/5 non-laboratory toxicity 9% 4% n=32 n=8 * Difference between treatment groups was significant (Fisher’s exact test p ≤0.05). PARAMOUNT: CTCAEs grade 3/4/5 drug-related toxicities (randomised patients)1† Anaemia 4%* n=16 <1%* n= 1 Fatigue 4%* n=15 <1%* n= 1 Neutropenia 4%* n=13 0%* n= 0 Infection 1% n=4 1% n=2 Leucopenia 2% n=6 0% n=0 Pain 1% n=3 0% n=0 Thrombocytopenia 1% n=4 0% n=0 Neuropathy <1% n=1 <1% n=1 0 10 20 30 0 10 20 30 pemetrexed placebo (n=359) (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 3/4/5 adverse events were reported for less than 1% of patients. 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 PARAMOUNT: conclusions1,10 • Pemetrexed continuation maintenance therapy offers significantly PARAMOUNT demonstrates a positive improved PFS • risk/benefit ratio for the administration of Pemetrexed continuation maintenance therapy is well tolerated1,10 pemetrexed continuation maintenance Pemetrexed continuation maintenance therapy: approach to maximise outcomes for patients1,2 Proven efficacy ✔ Acceptable toxicity ✔ Conveniently administered ✔ Keeps other treatments available ✔ Acknowledgements We thank all of the patients and their caregivers for participating in this trial. References 1. Paz-Ares L et al. 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