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 Maintenance strategies in non-squamous NSCLC 1 PARAMOUNT: study design and objectives 2 PARAMOUNT: patient & disease characteristics, drug administration 3 PARAMOUNT: PFS results 4 PARAMOUNT: post-discontinuation therapy 5 PARAMOUNT: safety & tolerability 6 PARAMOUNT: conclusions 7

Increase the duration of disease control Objectives of maintenance therapy1 Maintaining tolerability Improve overall survival

Tolerance to maintenance drug is known from induction treatment Maximise the potential of the drug used in 1st-line Potential advantages of continuation maintenance approach2–4 Saves a drug for subsequent treatment lines

PARAMOUNT: pemetrexed/cisplatin followed by pemetrexed for advanced non-squamous* NSCLC1 2:1 randomisation pemetrexed† 500 mg/m2 IV + BSC day 1, q 21 days; n=359 pemetrexed 500 mg/m2 IV + cisplatin 75 mg/m2 day 1, q 21 days; n=939 Non-squamous* NSCLC patients only CR, PR, or SD after 4 cycles of pemetrexed/cisplatin n=539 progressive disease placebo† + BSC day 1, q 21 days; n=180 *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 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)

PARAMOUNT: study objectives1 • 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)

PARAMOUNT: patient characteristics (randomised patients)1 placebo n=180 Median age, yrs Age <65 yrs Male Caucasian Smoker Ever smoker Never smoker ECOG PS 1 2/3* *Protocol violations 238 (66%) 201 (56%) 339 (94%) 275 (77%) 82 (23%) 115 (32%) 243 (68%) (<1%) 112 (62%) 171 (95%) 144 (80%) 34 (19%) 55 (31%) 123 2 (1%) pemetrexed n=359 61 62 Caucasian 339 (94%) 171 (95%)

PARAMOUNT: disease characteristics (randomised patients)1 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=359 328 310 24 25 166 186 7 (91%) (86%) (7%) (46%) (52%) (2%) 161 160 12 8 76 94 10 (89%) (4%) (42%) (6%) Disease stage IV* 328 (91%) 161 (89%) Adenocarcinoma/bronchoalveolar 310 (86%) 160 (89%)

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 placebo n=180 mean # of cycles patients > 6 cycles dose intensity 4.9 4.2 23% 14% 95% n.a.

Induction = 4 cycles of pemetrexed/cisplatin Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1 Progression-free survival (%) Time (months) 3 6 9 12 15 1.0 0.8 0.9 0.7 0.6 0.5 0.4 0.3 0.2 0.1 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<0.0001 BSC=Best Supportive Care Median PFS (95% CI) Pemetrexed 4.1 (3.2-4.6) Placebo 2.8 (2.6-3.1) 4.1 2.8 HR 0.62 reduction in the risk of progression 38%

Induction = 4 cycles of pemetrexed/cisplatin Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1 Progression-free survival (%) Time (months) 3 6 9 12 15 1.0 0.8 0.9 0.7 0.6 0.5 0.4 0.3 0.2 0.1 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<0.0002 † 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) 3.9 2.6 HR 0.64

Progression-free survival HRs in subgroups1 All Stage IIIB IV Induction response CR/PR SD Pre-randomisation ECOG PS 1 Smoking status Non-smoker Smoker Sex Male Female Age (years) <70 ≥70 <65 ≥65 Histology Adenocarcinoma Large Cell Carcinoma Other 0.62 (0.59-0.79) 0.55 (0.24-1.26) 0.62 (0.49-0.80) 0.48 (0.34-0.67) 0.74 (0.53-1.04) 0.53 (0.35-0.79) 0.67 (0.50-0.90) 0.41 (0.24-0.71) 0.70 (0.53-0.90) 0.74 (0.55-1.00) 0.49 (0.34-0.72) 0.69 (0.54-0.90) 0.35 (0.20-0.63) 0.70 (0.53-0.94) 0.51 (0.34-0.75) 0.39 (0.14-1.07) 0.64 (0.22-1.89) 0.2 0.4 0.8 1.2 1.6 2.0 0.6 1.4 1.8 Favours pemetrexed Favours placebo 539 50 489 242 280 170 366 116 419 313 226 447 92 350 189 471 36 32 HR (95% CI) N Progression-free survival HRs in subgroups1 PFS results were internally consistent; benefit was seen across all subgroups

PARAMOUNT: median PFS according to response to induction treatment1 Survival time (months) 1 2 3 5 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 Numbers in brackets are the 95% CI values. pemetrexed (n=166) pemetrexed (n=186) 4.1 (3.1-6.0) 4.1 (3.0-4.6) placebo (n=76) placebo (n=94) 2.6 (1.6-2.9) 3.0 (2.8-4.1)

PARAMOUNT: post-discontinuation therapy (PDT-eligible patients)1 placebo n=122 78 (64%) 45 (37%) 43 (35%) 4 (3%) 2 (2%) 1 (<1%) 6 (5%) Patients with PDT Drug name Erlotinib Docetaxel Gemcitabine Investigational drug Vinorelbine Bevacizumab Cisplatin Other† p-value 0.35 0.33 0.27 0.15 0.58 1.00 – pemetrexed n=200 116 (58%) 62 (31%) 58 (29%) 15 (8%) 10 8 (4%) 3 13 (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%)

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%* n=33 <1%* n=1 Patients with ≥ 1 grade 3/4/5 non-laboratory toxicity 9% n=32 4% 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† * 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) 10 20 30 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

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 PARAMOUNT demonstrates a positive risk/benefit ratio for the administration of pemetrexed continuation maintenance1,10 Pemetrexed continuation maintenance therapy offers significantly improved PFS Pemetrexed continuation maintenance therapy is well tolerated

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.

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