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

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

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

4. 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

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

6. PARAMOUNT: study objectives1 Primary objective • Progression-free survival (PFS) • Overall survival (OS) • Objective tumour response rate (RR) (RECIST 1.0) Secondary objectives • Patient-reported outcomes (EQ-5D) • Resource utilisation • Adverse events (AEs)

7. PARAMOUNT: patient characteristics (randomised patients)1 pemetrexed n=359 placebo n=180 Median age, yrs Age <65 yrs Male Caucasian Smoker Ever smoker Never smoker ECOG PS 0 1 2/3* 238 201 339 275 82 115 243 1 (66%) (56%) (94%) (77%) (23%) (32%) (68%) (<1%) 112 112 171 144 34 55 123 2 (62%) (62%) (95%) (80%) (19%) (31%) (68%) (1%) 61 62 Caucasian 339 (94%) 171 (95%) *Protocol violations

8. PARAMOUNT: disease characteristics (randomised patients)1 pemetrexed n=359 placebo n=180 (91%) (86%) (7%) (7%) (46%) (52%) (2%) (89%) (89%) (7%) (4%) (42%) (52%) (6%) 328 310 24 25 166 186 7 161 160 12 8 76 94 10 Disease stage IV* Histology Adenocarcinoma/bronchoalveolar Large cell Other non-squamous Best tumour response to induction CR/PR SD PD/Unknown† Disease stage IV* 328 (91%) 161 (89%) Adenocarcinoma/bronchoalveolar 310 (86%) 160 (89%) * Lung Cancer Staging System Version V † Protocol violations

9. PARAMOUNT: drug administration (randomised patients)1 mean # of cycles patients > 6 cycles dose intensity pemetrexed n=359 4.9 4.2 23% 14% 95% n.a. placebo n=180 Data related to the primary endpoint (PFS) data analysis. Figures are likely to change at the time of the final OS analysis.

10. Investigator-assessed PFS Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1 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. Independently reviewed PFS† Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1 1.0 pemetrexed + BSC (n=316) placebo + BSC (n=156) HR=0.64 (95% CI 0.51–0.81); p<0.0002 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 3.9 (3.0–4.2) Placebo 2.6 (2.2–2.9) 0.6 2.6 3.9 HR 0.64 0.5 0.4 0.3 0.2 0.1 0 9 6 0 3 12 15 Time (months) † 88% of patients were independently reviewed (472/539); BSC=Best Supportive Care

12. N HR (95% CI) 539 50 489 242 280 170 366 116 419 313 226 447 92 350 189 471 36 32 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) 0.62 (0.49-0.80) 0.39 (0.14-1.07) 0.64 (0.22-1.89) 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 Progression-free survival HRs in subgroups1 PFS results were internally consistent; benefit was seen across all subgroups 1.4 0 0.2 0.4 0.6 0.8 1 1.2 1.6 1.8 2.0 Favours pemetrexed Favours placebo

13. PARAMOUNT: median PFS according to responseto induction treatment1 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.

14. PARAMOUNT: post-discontinuation therapy (PDT-eligible patients)1 pemetrexed n=200 placebo n=122 p-value Patients with PDT Drug name Erlotinib Docetaxel Gemcitabine Investigational drug Vinorelbine Bevacizumab Cisplatin Other† 78 45 43 4 4 2 1 1 6 (64%) (37%) (35%) (3%) (3%) (2%) (<1%) (<1%) (5%) 0.35 0.33 0.27 0.15 0.58 0.33 1.00 1.00 – 116 62 58 15 10 8 3 3 13 (58%) (31%) (29%) (8%) (5%) (4%) (2%) (2%) (7%) (58%) (64%) † 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.

15. Maintenance therapy with pemetrexed: generally well tolerated1 Overall, toxicity was low in both arms pemetrexed n=359 placebo n=180 9%* n=33 <1%* n=1 Patients with ≥ 1 grade 3/4/5 laboratory toxicity 9% n=32 4% n=8 Patients with ≥ 1 grade 3/4/5 non-laboratory toxicity * Difference between treatment groups was significant (Fisher’s exact test p ≤0.05).

16. PARAMOUNT: CTCAEs grade 3/4/5 drug-related toxicities (randomised patients)1† 4%* n=16 4%* n=15 Anaemia Fatigue <1%* n= 1 <1%* n= 1 4%* n=13 1% n=4 Infection Neutropenia 0%* n= 0 1% n=2 1% n=3 2% n=6 Pain Leucopenia 0% n=0 0% n=0 <1% n=1 1% n=4 Thrombocytopenia Neuropathy <1% n=1 0% n=0 0 10 20 30 0 10 20 30 placebo(n=180) pemetrexed(n=359) * 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) Alanineaminotransferase, 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.

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. 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

19. Pemetrexed continuation maintenance therapy:approach to maximise outcomes for patients1,2 • 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.

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