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 NSCLC1PARAMOUNT:study designand objectives2PARAMOUNT:patient & disease characteristics,drug administration3PARAMOUNT:PFS results4PARAMOUNT:post-discontinuation therapy5PARAMOUNT:safety & tolerability6PARAMOUNT: conclusions7
3 Increase the duration of disease control Objectives of maintenance therapy1MaintainingtolerabilityImprove overall survival
4 Tolerance to maintenance drug is known from induction treatment Maximisethe potentialof the drug used in 1st-linePotential advantages of continuation maintenance approach2–4Savesa drug for subsequent treatmentlines
5 PARAMOUNT: pemetrexed/cisplatin followed by pemetrexed for advanced non-squamous* NSCLC1 2:1 randomisationpemetrexed†500 mg/m2 IV + BSCday 1, q 21 days; n=359pemetrexed 500 mg/m2 IV +cisplatin 75 mg/m2day 1, q 21 days; n=939Non-squamous* NSCLC patients onlyCR, PR, or SD after 4 cycles of pemetrexed/cisplatinn=539progressive diseaseplacebo† + BSCday 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 CarePatients enrolled if:• non-squamous* NSCLC• no prior systemic treatment for lung cancer• ECOG PS 0/1Stratified for:• PS (0 vs 1)• disease stage (IIIB vs IV) prior to induction• response to induction (CR/PR vs SD)
8 PARAMOUNT: disease characteristics (randomised patients)1 placebon=180Disease stage IV*HistologyAdenocarcinoma/bronchoalveolarLarge cellOther non-squamousBest tumour response to inductionCR/PRSDPD/Unknown†* Lung Cancer Staging System Version V† Protocol violationspemetrexedn=35932831024251661867(91%)(86%)(7%)(46%)(52%)(2%)161160128769410(89%)(4%)(42%)(6%)Disease stage IV* (91%) (89%)Adenocarcinoma/bronchoalveolar (86%) (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.pemetrexedn=359placebon=180mean # of cyclespatients > 6 cyclesdose intensity4.94.223%14%95%n.a.
10 Induction = 4 cycles of pemetrexed/cisplatin Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1Progression-free survival (%)Time (months)36912151.00.80.90.18.104.22.168.30.20.1Investigator-assessed PFSInduction = 4 cycles of pemetrexed/cisplatinNOT reflected in the data endpointspemetrexed + BSC (n=359)placebo + BSC (n=180)HR=0.62 (95% CI 0.49–0.79); p<0.0001BSC=Best Supportive CareMedian PFS (95% CI)Pemetrexed 4.1 ( )Placebo 2.8 ( )4.12.8HR 0.62reduction in therisk of progression38%
11 Induction = 4 cycles of pemetrexed/cisplatin Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1Progression-free survival (%)Time (months)36912151.00.80.90.22.214.171.124.30.20.1Independently reviewed PFS†Induction = 4 cycles of pemetrexed/cisplatinNOT reflected in the data endpointspemetrexed + 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 CareMedian PFS (95% CI)Pemetrexed 3.9 (3.0–4.2)Placebo 2.6 (2.2–2.9)3.92.6HR 0.64
12 Progression-free survival HRs in subgroups1 AllStageIIIBIVInduction responseCR/PRSDPre-randomisation ECOG PS1Smoking statusNon-smokerSmokerSexMaleFemaleAge (years)<70≥70<65≥65HistologyAdenocarcinomaLarge Cell CarcinomaOther0.62 ( )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 ( )0.39 ( )0.64 ( )0.20.40.81.21.62.00.61.41.8Favours pemetrexedFavours placebo53950489242280170366116419313226447923501894713632HR (95% CI)NProgression-free survival HRs in subgroups1PFS results were internally consistent; benefit was seen across all subgroups
13 PARAMOUNT: median PFS according to response to induction treatment1 Survival time (months)1235Response to induction treatmentComplete/Partialresponsen=242, HR=0.48,( )Stable diseasen=280, HR=0.74,( )4Numbers in brackets are the 95% CI values.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 placebon=12278(64%)45(37%)43(35%)4(3%)2(2%)1(<1%)6(5%)Patients with PDTDrug nameErlotinibDocetaxelGemcitabineInvestigational drugVinorelbineBevacizumabCisplatinOther†p-value0.350.330.270.150.581.00–pemetrexedn=200116(58%)62(31%)58(29%)15(8%)108(4%)313(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 Maintenance therapy with pemetrexed: generally well tolerated1 Overall, toxicity was low in both armspemetrexedn=359placebon=180Patients with ≥ 1 grade 3/4/5laboratory toxicity9%*n=33<1%*n=1Patients with ≥ 1 grade 3/4/5non-laboratory toxicity9%n=324%n=8* 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† * 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)AnaemiaNeutropeniaFatiguePainLeucopeniaThrombocytopeniaInfectionNeuropathypemetrexed (n=359)1020304%* n=164%* n=132% n=61% n=44%* n=151% n=31% n=4<1% n=1<1%* n= 10%* n= 00% n=0<1%* n= 11% n=20% 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 armsEQ-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 maintenance1,10Pemetrexed continuation maintenance therapy offers significantlyimproved PFSPemetrexed 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.
21 ReferencesPaz-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.Novello S et al. Maintenance therapy in NSCLC: why? To whom? Which agent? J Exp Clin Cancer Res 2011;30:50.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].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.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer V Fort Washington, PA: NCCN, 2011.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.