Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Estudio Paramount cáncer de pulmón 2014

767 views

Published on

Published in: Technology, Business
  • Be the first to comment

  • Be the first to like this

Estudio Paramount cáncer de pulmón 2014

  1. 1. Paz-Ares LG, J Clin Oncol 2013 Aug 8;31(23):2895–902
  2. 2. PARAMOUNT
  3. 3. PARAMOUNT: Study Overview • Most patients have Stage IIIB/IV NSCLC when diagnosed1 • Platinum-based combinations are recommended for first-line treatment2 • Pemetrexed has demonstrated efficacy in advanced ns NSCLC – In combination with cisplatin as first-line doublet3 – As maintenance agent following non-pemetrexed platinum doublet4 • PARAMOUNT evaluated pemetrexed maintenance after induction with pemetrexed/cisplatin doublet: – Primary endpoint was met: pemetrexed significantly reduced risk of disease progression over placebo (HR = 0.62; 95% CI: 0.49-0.79; p<.0001)5 .. 1. http://seer.cancer.gov/statfacts/html/lungb.html 2. Azzoli et al. J Clin Oncol 2011;29(28):3825-31. 3. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51. 4. Ciuleanu et al. Lancet 2009;374(9699):1432-40. 5. Paz-Ares et al. Lancet Oncol 2012;13(3):247-55. 6. Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902
  4. 4. Ciuleanu et al: Maintenance Pemetrexed Plus Best Supportive Care vs. Placebo Plus Best Supportive Care for Non-small Cell Lung Cancer: A Randomized, Double-blind, Phase 3 Study (JMEN) • Phase III, multicenter, randomized, double-blind, placebo-controlled study conducted at 83 centers in 20 countries in patients with stage IIIB or IV NSCLC who had not progressed on 4 cycles of platinum-based chemotherapy • Patients (N = 663) randomized 2:1 to receive i.v. (Day 1), either pemetrexed (500 mg/m2) + BSC (N = 441) or placebo (0.9% NaCl) + BSC (N = 222) in 21-day cycles until disease progression • All patients received vitamin B12, folic acid, and dexamethasone • Primary endpoint: Progression-free survival1 • Secondary endpoints: Overall survival, objective tumor response rate, safety,1 and patient-reported outcomes(QoL)2 1. Ciuleanu et al. Lancet 2009;374(9699):1432-40. 2. Belani et al. Lancet Oncol 2012;13(3):292-9.
  5. 5. • Primary endpoint = progression-free survival (study fully powered for secondary objective of overall survival) • Histology subgroups (adenocarcinoma, large-cell carcinoma, squamous- cell carcinoma, other NSCLC NOS) were prespecified for statistical analysis 1. Ciuleanu et al. Lancet 2009;374(9699):1432-40. Induction regimen 4 cycles Taxane/platinum or gemcitabine/platinum No PD R a n d o m i z e Pemetrexed 500 mg/m2 + BSC on Day 1 / q21d Placebo + BSC on Day 1 / q21d 2:1 PD PD Ciuleanu et al: Maintenance Pemetrexed Plus Best Supportive Care vs. Placebo Plus Best Supportive Care for Non-small Cell Lung Cancer: A Randomized, Double-blind, Phase 3 Study (JMEN)
  6. 6. Baseline Characteristics Characteristics, n (%) Placebo (N = 222) Pemetrexed (N = 441) Histologic type Nonsquamous Adenocarcinoma Large cell carcinoma Other Squamous cell carcinoma 156 (70) 106 (48) 10 (5) 40 (18) 66 (30) 325 (74) 222 (50) 10 (2) 93 (21) 116 (26) Smoking status Smoker Never smoker 158 (71) 63 (28) 324 (73) 113 (26) Best response to first-line therapy CR + PR Stable disease 115 (52) 107 (48) 207 (47) 230 (52)c PS 0 1 85 (38%) 137 (62%) 176 (40%) 263 (60%) Ciuleanu et al. Lancet 2009;374(9699):1432-40. • c3 patients had progressive disease (protocol violation) and 1 unknown after first-line therapy • CR: complete response, PR: partial response
  7. 7. Pemetrexed maintenance therapy is well tolerated and offers significantly improved PFS and OS compared with placebo, making it a new treatment option for patients with advanced ns NSCLC who do not progress after initial induction therapy. Ciuleanu et al. Lancet 2009;374(9699):1432-40. Median PFS (Months) Median OS (Months) Pbo Pem HR (95% CI) p-value Pbo Pem HR (95% CI) p-value All patients (N = 663) 2.6 4.3 0.50 (0.42-0.61) <.0001 10.6 13.4 0.79 (0.65-0.95) .012 Nonsquamous (N = 481) 2.6 4.5 0.44 (0.36-0.55) <.0001 10.3 15.5 0.70 (0.56-0.88) .002 Squamous (N = 182) 2.6 2.8 0.69 (0.49-0.98) .039 10.8 9.9 1.07 (0.77-1.50) .678 Ciuleanu et al: Maintenance Pemetrexed Plus Best Supportive Care vs. Placebo Plus Best Supportive Care for Non-small Cell Lung Cancer: A Randomized, Double-blind, Phase 3 Study (JMEN)
  8. 8. Ciuleanu et al. Lancet 2009;374(9699):1432-40. Ciuleanu et al: Maintenance Pemetrexed Plus Best Supportive Care vs. Placebo Plus Best Supportive Care for Non-small Cell Lung Cancer: A Randomized, Double-blind, Phase 3 Study (JMEN) Población general Población no escamosa 15.5 vs 10.3 m4.5 vs 2.6 m 4.3 vs 2.6 m 13.4 vs 10.6 m
  9. 9. Grade 3/4 Toxicities Toxicity, n (%) Placebo (N = 222) Pemetrexed (N = 434) Hematological Neutropenia 0 13 (3)* Anemia 1 (<1) 12 (3) Leukopenia 1 (<1) 7 (2) Nonhematological Fatigue 1 (0<1) 22 (5)* Anorexia 0 8 (2) Infection 0 7 (2) Nausea 1 (<1) 4 (<1) Ciuleanu et al. Lancet 2009;374(9699):1432-40. • *p<.05 Ciuleanu et al: Maintenance Pemetrexed Plus Best Supportive Care vs. Placebo Plus Best Supportive Care for Non-small Cell Lung Cancer: A Randomized, Double-blind, Phase 3 Study (JMEN)
  10. 10. “En España pendiente de autorización de precio y condiciones de reembolso” PARAMOUNT: Elegibility criteria • Inclusion criteria: Induction phase – Histological or cytological diagnosis of advanced (Stage IIIB/IV) nonsquamous NSCLC – ≥1 measurable lesion per RECIST 1.0 – No prior systemic chemotherapy for lung cancer – ECOG PS of 0 or 1 • Inclusion criteria: Maintenance phasea – Completion of 4 cycles pemetrexed-cisplatin induction therapy, with radiographic evidence of CR, PR, or SD – ECOG PS of 0 or 1 aAll patients randomized to maintenance phase were eligible for efficacy and safety analyses 1. Paz-Ares et al. Lancet Oncol 2012;13(3):247-55. 2. Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
  11. 11. PARAMOUNT: Study Design • Primary objective: Investigator-as PFS • Secondary objectives: – OS – Objective tumor response rate (RR) – Patient-reported outcomes (EQ-5D) – Resource utilization – Adverse events (AEs) 1. Paz-Ares et al. Lancet Oncol 2012;13(3):247-55. 2. Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902. Randomized, placebo-controlled, double-blind, Phase III study Pemetrexed 500 mg/m2; cisplatin 75 mg/m2 Induction Therapy 4 cycles, q21d Continuation Maintenance Therapy q21d until PD Pemetrexed + BSC Placebo + BSC Pemetrexed + Cisplatin CR/PR/SD per RECIST R 2:1 • Previously untreated • PS 0 or 1 • Stage IIIB/IV NS-NSCLC Stratified for: • PS (0 vs. 1) • Disease Stage (IIIB vs. IV) prior to induction • Response to induction (CR/PR vs. SD)
  12. 12. PARAMOUNT: Statistical Analyses • OS was analyzed using the unadjusted Cox proportional hazards regression models (HR, 95% CI) • Powered for secondary endpoint, OS • Final OS: 93% power, assuming a minimum 390 events (30% censoring) and HR = 0.70, 2-sided α = 0.0498 • Planned subgroup analyses of OS performed using stratification and predefined prognostic variables Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
  13. 13. PARAMOUNT: Drug Administration 1. Paz-Ares et al. Presented at: ASCO Annual Meeting, June 1-5, 2012; Chicago, Illinois. Abstract LBA7507. 2. Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902. Maintenance Phase Placebo + BSC (N = 180) Pemetrexed + BSC (N = 359) Patients treateda 178 357 Number of cycles/patient Median 4 4 Range 1-38 1-44 Mean (SD) 5.0 (5.2) 7.9 (8.3) Patients completing >6 cycles, % 18.3 37.0 Patients completing ≥10 cycles, % 11.7 27.6 Dose intensity of planned mean dose, % NA 93.7 Median follow-up, months (95% CI) For all patients 12.5 (11.1-13.7) For alive patients 24.3 (23.2-25.1)
  14. 14. PARAMOUNT: Patient and Disease Characteristics of All Randomized Patientsa aData derived from reporting database at time of OS datalock, bProtocol violations Patient and Disease Characteristics Placebo + BSC (N = 180) Pemetrexed + BSC (N = 359) Gender, male, n (%) 112 (62) 201 (56) Median age at randomization, years 62 61 Age, <65 years, n (%) 112 (62) 238 (66) Origin, Caucasian, n (%) 171 (95) 339 (94) Smoking status, n (%) Smoker Nonsmoker 144 (80) 34 (19) 274 (76) 83 (23) ECOG PS at randomization, n (%) 0 1 2-3b 60 (33) 118 (66) 2 (1) 113 (31) 245 (68) 1 (0.3) Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
  15. 15. PARAMOUNT: Patient and Disease Characteristics of All Randomized Patients (Cont.)a aData derived from reporting database at time of OS datalock Patient and Disease Characteristics Placebo + BSC (N = 180) Pemetrexed + BSC (N = 359) Disease Stage IV before maintenance therapy, n (%) 162 (90) 328 (91) Best tumor response to induction therapy, n (%) CR/PR SD PD/unknown 75 (42) 95 (53) 10 (5) 159 (44) 190 (53) 10 (3.3) Histological classifications, n (%) Adenocarcinoma Large cell carcinoma Other nonsquamous 160 (89) 12 (7) 8 (4) 310 (86) 24 (7) 25 (7) Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
  16. 16. PARAMOUNT: Summary of OS from Randomization Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902. Summary of OS from Randomization Placebo + BSC (N = 180) Pemetrexed + BSC (N = 359) Patient deaths, n (%) 141 (78) 256 (71) Patients censored, n (%) 39 (22) 103 (29) OS Median, months 11.0 13.9 95% CI 10.0-12.5 12.8-16.0 Log -rank p -value .0195 Hazard ratio 0.78 95% CI 0.64-0.96 Wald p-value .0199 Survival rate, % 1-year 45 58 95% CI 38-53 53-63 p-value .0062 2-year 21 32 95% CI 15-28 27-37 p-value .0103
  17. 17. PARAMOUNT: Final OS from Randomization 0 3 6 9 12 15 18 21 24 27 30 33 36 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 SurvivalProbability(%) Time from Randomization (Months) Placebo + BSC Median OS = 11.0 mos (95% CI: 10.0-12.5) Pemetrexed + BSC Median OS = 13.9 mos (95% CI: 12.8-16.0) Log-rank p = .0195 Unadjusted HR: 0.78 (95% CI: 0.64-0.96) Patients at Risk Placebo + BSC Pem + BSC 180 359 169 333 131 272 103 235 78 200 65 166 49 138 35 105 23 79 12 43 8 15 3 2 0 0 Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
  18. 18. PARAMOUNT: Final OS from Induction Placebo + BSC Median OS = 14.0 mos (95% CI: 12.9-15.5) Pemetrexed + BSC Median OS = 16.9 mos (95% CI: 15.8-19.0) Log-rank p = .0191 Unadjusted HR: 0.78 (95% CI: 0.64-0.96) SurvivalProbability(%) Time from Induction (Months) 0 3 6 9 12 15 18 21 24 27 30 33 36 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Patients at Risk Placebo + BSC Pem + BSC 180 359 168 335 132 276 103 234 78 200 63 164 49 138 35 106 23 77 12 42 8 15 3 2 0 0 Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
  19. 19. PARAMOUNT: PFS Reassessed at Time of Final OS (from random) Patients at Risk Placebo + BSC Pem + BSC Progression-freeSurvival(%) Time (Months) Placebo + BSC Median PFS = 2.8 mos (95% CI: 2.6-3.0) Pemetrexed + BSC Median PFS = 4.4 mos (95% CI: 4.1-5.7) Log-rank p<.00001 Unadjusted HR: 0.60 (95% CI: 0.50-0.73) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 180 359 75 215 33 139 16 97 9 67 7 47 6 32 4 22 2 16 0 5 0 0 0 0 0 10 Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
  20. 20. PARAMOUNT: OS from Induction Response Subgroups There was not a significant interaction term of response by treatment (CR/PR vs. SD, p = .731) using the Cox model of response, treatment, and response by treatment interaction OS by CR/PR Induction Response Placebo + BSC Median OS = 11.2 mos (95% CI: 8.4-15.8) Pemetrexed + BSC Median OS = 15.5 mos (95% CI: 12.5-18.8) Log-rank p = .194 Unadjusted HR: 0.81 (95% CI: 0.59-1.11) SurvivalProbability(%) Time from Randomization (Months) 0 3 6 9 12 15 18 21 24 27 30 33 36 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Placebo + BSC Median OS = 11.1 mos (95% CI: 9.8-13.8) Pemetrexed + BSC Median OS = 13.7 mos (95% CI: 12.5-15.8) Log-rank p = .0575 Unadjusted HR: 0.76 (95% CI: 0.57-1.01) OS by SD Induction Response SurvivalProbability(%) Time from Randomization (Months) 0 3 6 9 12 15 18 21 24 27 30 33 36 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Patients at Risk Placebo + BSC Pem + BSC 75 159 68 146 53 120 41 108 33 89 31 79 24 66 18 50 12 37 6 18 5 8 2 0 0 0 95 190 91 180 72 149 57 124 42 108 32 84 23 69 16 52 10 40 6 25 3 7 1 2 0 0 Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
  21. 21. PARAMOUNT: Postdiscontinuation Therapy aData expressed as % of randomized patients; systemic therapies used in ≥1% of patients in either arm are shown. bApproved second-line therapies. cAll patients received pemetrexed as induction therapy Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902. Summary of Postdiscontinuation Therapy Placebo + BSC (N = 180) n, (%) a Pemetrexed + BSC (N = 359) n, (%) a p-value Patients receiving postdiscontinuation therapy 129 (72) 231 (64) .099 Erlotinibb 78 (43) 142 (40) .405 Docetaxelb 78 (43) 116 (32) .013 Gemcitabine 15 (8) 36 (10) .640 Vinorelbine 11 (6) 28 (8) .597 Investigational drug 8 (4) 20 (6) .683 Carboplatin 8 (4) 18 (5) .835 Paclitaxel 6 (3) 9 (3) .587 Pemetrexedb,c 7 (4) 7 (2) .249 Cisplatin 4 (2) 5 (1) .490 Bevacizumab 1 (0.6) 6 (2) .433 Gefitinib 2 (1) 3 (0.8) 1.000 Afatinib 2 (1) 2 (0.6) .604 Placebo 0 (0) 4 (1) .307
  22. 22. PARAMOUNT: Possible Drug-related Laboratory CTCAEs During Maintenance Therapy Data were derived from the February 2011 safety update. Toxicities of any grade occurring in ≥2% of patients in either arm are listed, along with some select toxicities. Toxicities were reported using CTCAE version 3.0 (NCI 2006) *p≤.05 Placebo + BSC (N = 180) Pemetrexed + BSC (N = 359) Laboratory Toxicities Grade 1/2 % Grade 3/4 % Grade 1/2 % Grade 3/4 % Anemia 4.4* 0.6* 11.7* 6.4* Neutropenia 0.6* 0.0* 5.0* 5.8* Leukopenia 0.0* 0.0 2.8* 2.2 Thrombocytopenia 0.0 0.0 2.2 1.9 Creatinine 1.1 0.0 2.8 0.0 ALT 0.6 0.0 2.5 0.3 AST 0.0* 0.0 2.5* 0.0 Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
  23. 23. PARAMOUNT: Possible Drug-related Nonlaboratory CTCAEs During Maintenance Therapy Data were derived from the February 2011 safety update. Toxicities of any grade occurring in ≥2% of patients in either arm are listed, along with some select toxicities. Toxicities were reported using CTCAE version 3.0 (NCI 2006) *p≤.05 Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902. Placebo + BSC (N = 180) Pemetrexed + BSC (N = 359) Nonlaboratory Toxicities Grade 1/2 % Grade 3/4 % Grade 1/2 % Grade 3/4 % Fatigue 10.6* 1.1* 17.5* 4.7* Nausea 2.2* 0.0 13.4* 0.6 Vomiting 1.1* 0.0 7.5* 0.3 Edema, limb 3.3 0.0 6.7 0.0 Neuropathy, sensory 6.1 0.6 5.3 0.3 Mucositis/stomatitis, oral cavity 1.1* 0.0 4.5* 0.6 Anorexia 1.1* 0.0 4.5* 0.3 Diarrhea 2.2 0.0 4.2 0.3 Glomerular filtration rate 1.7 0.0 4.2 0.0 Watery eye (epiphora, tearing) 0.6* 0.0 4.2* 0.0 Pain, any event 2.2 0.0 4.2 1.1 Fever, without neutropenia 0.0* 0.0 2.8* 0.0 Constipation 2.8 0.0 2.5 0.0 Dry eye syndrome 0.0 0.0 2.2 0.0 Rash, desquamation 0.0 0.0 1.4 0.0 Febrile neutropenia 0.0 0.0 0.0 1.9
  24. 24. PARAMOUNT: Conclusions • PARAMOUNT met its primary endpoint by showing significantly improved PFS in patients treated with ALIMTA continuation maintenance therapy as compared with placebo.1 • PARAMOUNT demonstrated that ALIMTA continuation maintenance significantly improves overall survival for patients with advanced nonsquamous* NSCLC, compared with placebo (HR 0.78).2 • The overall survival results were internally consistent across all subgroups, including response to induction (complete/partial response vs stable disease).2 • ALIMTA continuation maintenance had a safety profile similar to that observed in the previous trials with single-agent ALIMTA.2-4 • The EQ-5D† suggests that patients can tolerate long-term ALIMTA maintenance without worsening of quality of life.4 1. Paz-Ares L, et al. Lancet Oncol. 2012;13:247-255. 2. Paz-Ares LG, et al. J Clin Oncol. 2013. doi:10.1200/JCO.2012.47.1102. 3. Ciuleanu T, et al. Lancet. 2009;374:1432-1440. 4. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597. 5. Gridelli C, et al. J Thorac Oncol. 2012;7:1713-1721. * Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type. † Health-related quality of life assessment.
  25. 25. Safety, Resource Use, and Quality of Life in PARAMOUNT: A Phase III Study of Maintenance Pemetrexed Versus Placebo After Induction Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non-small Cell Lung Cancer Cesare Gridelli1, Filippo de Marinis2, Jean-Louis Pujol3, Martin Reck4, Rodryg Ramlau5, Barbara Parente6, Thierry Pieters7, Gary Middleton8, Jesus Corral9, Katherine Winfree10, Symantha Melemed10, Anna Zimmermann10, William John10, Julie Beyrer10, Nadia Chouaki11, Carla Visseren-Grul12, Luis Paz-Ares9 Gridelli et al. J Thorac Oncol 2012;7(11):1713-21
  26. 26. Introduction (Cont.) • The PARAMOUNT study was conducted to assess maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced nonsquamous NSCLC1 • As a secondary objective of PARAMOUNT, QoL was measured using the EQ-5D questionnaire2 • This manuscript focused on the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ- 5D questionnaire in PARAMOUNT 1. Paz-Ares et al. Lancet Oncol 2012;13(3):247-55. 2. Health Policy 1990;16(3):199-208.
  27. 27. Measures • Safety – AEs, standard laboratory tests, physical examination (weight, blood pressure, pulse) • Resource use – Concomitant medications, transfusions, treatment-related hospitalizations, basic supportive care measures • QoL – EQ-5D
  28. 28. Statistical Analyses Safety and resource use • Analyses include all patients treated with ≥1 dose of pemetrexed or cisplatin during the study period • Fisher’s exact test used to compare treatment arms in the maintenance period QoL (EQ-5D) • Analyses included all patients who provided a baseline and ≥1 postbaseline assessment • Paired t-test was used to compare patients’ induction baseline values with postbaseline values during induction
  29. 29. Statistical Analyses (Cont.) • QoL (EQ-5D) (Cont.) – Paired t-test was used to compare treatment differences in mean change from baseline (maintenance) at each maintenance cycle – Mixed-effects analysis of variance model was also used to compare treatment differences over time during maintenance • ECOG PS – Student’s t-test was used to compare changes in ECOG PS from baseline (maintenance)
  30. 30. Resource Use: Concomitant Medications and Nutritional Support aFisher’s exact test p-value comparing maintenance treatments. Significant if p≤.05. bReported for ≥2% of patients in either treatment period or maintenance arm. Induction Maintenance Pemetrexed + Cisplatin (N = 939) % Pemetrexed (N = 359) % Placebo (N = 180) % p-valuea Concomitant medications Analgesics 56.7 48.7 51.7 .524 Anti-emetics 66.7 34.0 36.1 .633 Anti-infectives 26.9 25.3 16.7 .028 ESAs 6.5 10.9 6.1 .084 Transfusions 10.3 13.4 5.0 .003 G-CSF or GM-CSF 6.5 5.3 0.0 <.001 Nutritional supportb Oral 3.2 1.4 0.0 .175
  31. 31. Resource Use: Supportive Care Procedures aFisher’s exact test p-value comparing maintenance treatments. Significant if p≤.05 bReported for ≥2% of patients in either treatment period or maintenance arm Induction Maintenance Procedures: Supportive Careb Pemetrexed + Cisplatin (N = 939) % Pemetrexed (N = 359) % Placebo (N = 180) % p-valuea Computed tomography, spiral 2.9 0.0 0.0 – Electrocardiogram 3.0 0.8 0.0 .554 Examination, laboratory 2.7 0.0 0.0 – Examination, physical 2.6 0.0 0.0 – Examination, vital sign 2.6 0.0 0.0 – Extrathoracic palliative radiotherapy 4.6 0.6 3.3 .019 Injection 2.6 0.8 0.0 .554 Insertion, portacath 2.3 0.0 0.0 – Intravenous fluid administration 2.9 0.8 0.0 .554 Thoracentesis 2.3 1.1 0.6 .669 X-ray, chest 2.0 0.0 0.0 –
  32. 32. Summary of All Hospitalizations aFisher’s exact test p-value comparing maintenance treatments. Significant if p≤.05. Induction Maintenance Pemetrexed + Cisplatin (N = 939) Pemetrexed (N = 359) Placebo (N = 180) p-valuea Patients with ≥1 hospitalizations, n (%) 229 (24.4) 69 (19.2) 32 (17.8) .727 All hospitalizations 295 91 37 Mean (SD) length of stay, nights 7.87 (7.18) 8.57 (7.01) 8.95 (9.66) .807 Median (range) length of stay, nights 5.00 (0.00, 45.00) 6.00 (1.00, 34.00) 6.00 (1.00, 53.00) Patients hospitalized because of drug-related AEs, n (%) 126 (13.4) 30 (8.4) 6 (3.3) .028 Hospitalizations involving drug-related AEs 148 35 7 Mean (SD) length of stay, nights 8.08 (7.06) 8.14 (7.00) 10.57 (8.26) .421 Length of stay, nights, median (range) 6.00 (0.00-45.00) 6.00 (1.00-31.00) 9.00 (2.00-27.00)
  33. 33. Summary of All Hospitalizations (Cont.) aFisher’s exact test p-value comparing maintenance treatments. Significant if p≤.05. Induction Maintenance Pemetrexed + Cisplatin (N = 939) % Pemetrexed (N = 359) % Placebo (N = 180) % p-valuea Patients hospitalized because of nondrug-related AEs, n (%) 139 (14.8) 48 (13.4) 26 (14.4) .791 Hospitalizations not involving drug-related events 167 63 30 Mean (SD) length of stay, nights 8.13 (7.34) 9.17 (7.03) 9.77 (10.40) .747 Median (range) length of stay, nights 5.00 (0.00, 37.00) 8.00 (1.00, 34.00) 6.00 (1.00, 53.00)
  34. 34. EQ-5D Compliance • During induction period: 79.4% • During maintenance period – Placebo arm: 80.9% – Pemetrexed arm: 84.3% – At postdiscontinuation visit • Placebo arm: 44.3% • Pemetrexed arm: 43.9% Compliance was defined as the number of completed EQ-5D assessments divided by the number of expected EQ-5D assessments (ie, patients still on study at that time)
  35. 35. EQ-5D UK Population-based Index Score During Induction: All Enrolled Patients *p≤.05, within-group change from baseline 0.60 0.70 0.80 0.00 0.01 0.03 0.03 Top of bar = mean value at that cycle for pemetrexed + cisplatin Induction Cycles N = 445 N = 682 N = 583 N = 522 MeanScore(Scale-0.59to+1.0) Improvement * * Mean value at baseline (Cycle 0) Mean change from baseline 1 2 3 4 * *
  36. 36. EQ-5D VAS Rating During Induction: All Enrolled Patients No p≤.05, within-group change from baseline 67 68 69 70 71 -0.47 -0.22 0.60 1.13 MeanRating(scale0to100) Improvement 1 2 3 4Induction Cycles N = 440 N = 681 N = 573 N = 517 Top of bar = mean value at that cycle for pemetrexed + cisplatin Mean change from baseline Mean value at baseline (Cycle 0)
  37. 37. EQ-5D UK Population-based Index Score During Maintenance: All Randomized Patients *p≤.05, comparing the difference in mean changes from baseline between treatment arms 0.65 0.70 0.75 0.80 0.85 0.90 -0.01 0.01 0.01 0.01 -0.02 0.04 0.02 0.01 0.00 0.03 -0.01 -0.00 * Maintenance Cycles 1 2 3 4 5 6 N = 265 132 241 129 160 83 149 66 108 48 98 36 MeanScore(scale-0.59to+1.0) Improvement Top of bar = mean value at that cycle for pemetrexed Top of bar = mean value at that cycle for placebo Mean value at baseline (Cycle 0) Mean change from baseline
  38. 38. EQ-5D VAS Rating During Maintenance: All Randomized Patients *p≤.05, comparing the difference in mean changes from baseline between treatment arms 65 70 75 80 1.42 1.65 5.76 6.15 3.15 1.82 4.90 0.69 1.24 1.55 5.99 3.01* * Maintenance Cycles 1 2 3 4 5 6 N = 266 126 239 127 162 81 147 65 107 48 98 36 Improvement MeanRating(scale0to100) Top of bar = mean value at that cycle for pemetrexed Top of bar = mean value at that cycle for placebo Mean value at baseline (Cycle 0) Mean change from baseline * *
  39. 39. Change in ECOG PS from Baseline Placebo N = 180 Pemetrexed N = 359 Worse, % 12.6 14.7 No Change, % 77.3 77.8 Better, % 10.2 7.5 There were no significant differences in ECOG PS between placebo and pemetrexed arms (p = .3673)
  40. 40. Discussion: Safety • Safety of pemetrexed-cisplatin induction therapy was similar to a previous study of pemetrexed-cisplatin as a first-line treatment1 • Single-agent maintenance pemetrexed safety was similar to previous maintenance study of pemetrexed2 – Few (<5%) Grade 3/4 events: anemia, fatigue, neutropenia – Few (≤10%) Grade 1/2 events: nausea, anemia, vomiting, neutropenia 1. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51. 2. Ciuleanu et al. Lancet 2009;374(9699):1432-40.
  41. 41. Discussion: Safety (Cont.) • Skin and renal toxicity described in the literature were rare, mainly low-grade events, and similarly distributed between treatment arms1,2 • Exposure to >6 maintenance cycles vs. ≤6 maintenance cycles of pemetrexed showed higher incidence of Grade 3/4 neutropenia (8.3% vs. 2.2%, p = .015) but did not result in increased infections (1.2% vs. 2.9%, p = .691) 1. Equia et al. J Thorac Oncol 2011;6(12):2083-9. 2. Glezerman et al. Am J Kidney Dis 2011;58(5):817-20.
  42. 42. Discussion: Resource Use • Resource use during induction was common for traditionally cisplatin-related toxicities (antiemetics 66.7%, hospitalizations for drug-related AEs 13.4%) • Resource use during maintenance was low and comparable to previous single-agent pemetrexed studies1-3 – Significantly higher use of transfusions, CSFs, anti-infectives, and hospitalizations due to study drug with pemetrexed vs. placebo but differences in comparison with placebo were small (5%-8% differences) 1. Cileneau et al. Lancet 2009;374(9699):1432-40. 2. Hanna et al. J Clin Oncol 2004;22(9):1589- 97. 3. Belani et al. Lancet Oncol 2012;13(3):292- 9.
  43. 43. Discussion: EQ-5D • Good compliance on completing the EQ-5D questionnaire (~80%-85% during induction and maintenance) • No overall treatment differences were observed in the EQ-5D index scores and VAS ratings • Statistically significant differences between pemetrexed and placebo in a few cycles, but no changes during maintenance treatment exceeded the MID thresholds reported by Pickard and colleagues (2007)
  44. 44. Discussion: EQ-5D (Cont.) • The majority of patients were able to maintain PS and a similar number of patients between treatment arms showed improvement or worsening in PS • Maintenance pemetrexed did not have a detrimental effect on QoL – Most patients maintained their relatively good overall QoL as measured by EQ-5D or changes from baseline in ECOG PS (most remained PS 0 or 1)
  45. 45. Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
  46. 46. Background JMDB Trial: Key Findingsa In patients with advanced NSCLC • Overall survival for pemetrexed/cisplatin was noninferior to gemcitabine/cisplatin1 • Other efficacy outcomes were also comparable between the 2 regimens1 • Pemetrexed/cisplatin had a better safety profile compared with gemcitabine/cisplatin1 Compared with gemcitabine/cisplatin, pemetrexed/cisplatin regimen showed a statistically superior overall survival in patients with nonsquamous histology (p = .011)1,2 aThese findings are the independent opinion of the publication’s authors 1. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51. 2. Scagliotti et al. Oncologist 2009;14(3):253-63.
  47. 47. Background (Cont.) PARAMOUNT Trial: Key Findingsa In patients with advanced nonsquamous NSCLC, pemetrexed/cisplatin induction therapy followed by pemetrexed maintenance significantly improved progression- free survival (p<.0001) compared with placebo1 Compared with placebo, pemetrexed maintenance arm had a significantly higher incidence of drug-related Grade > 3 laboratory toxicity (9% vs. <1%; p≤.05)1 aThese findings are the independent opinion of the publication’s authors 1. Paz-Ares et al. Lancet Oncol 2012;13(3):247-255.
  48. 48. Objective Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160. To compare indirectly the efficacy and safety results from two Phase 3 trials, JMDB and PARAMOUNT (induction phase prior to randomization), involving first- line pemetrexed/cisplatin treatment of chemonaïve patients with advanced nonsquamous NSCLC
  49. 49. Patient Population 1. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51. 2. Scagliotti et al. Oncologist 2009;14(3):253-63. 3. Paz-Ares et al. Lancet Oncol 2012;13(3):247-255. JMDB trial: Nonsquamous subpopulation (N = 618) from the pemetrexed/cisplatin treatment group1,2 PARAMOUNT trial: All patients (N = 939) who received pemetrexed/cisplatin induction therapy (prior to randomization to pemetrexed continuation maintenance or placebo)3
  50. 50. Study design: JMDB and PARAMOUNT aIncludes all patients who received pemetrexed/cisplatin as induction treatment All patients received vitamin B12, folic acid, and dexamethasone in both trials Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160. • Pemetrexed (500 mg/m2) • Cisplatin (75 mg/m2) Day 1 every 21 days Efficacy and safety assessment of JMDB and PARAMOUNTb treated population PARAMOUNT Inclusion criteria • Nonsquamous NSCLC • Stage IIIB/IV • No prior systemic therapy • ECOG PS 0/1 up to 4 cycles • Pemetrexed (500 mg/m2) • Cisplatin (75 mg/m2) Day 1 every 21 days JMDB Inclusion criteria • All histologies NSCLC • Stage IIIB/IV • No prior systemic therapy • ECOG PS 0/1 Randomizationa up to 6 cycles Nonsquamous population Induction Phase Or Gemcitabine + cisplatin
  51. 51. Baseline Demographics and Disease Characteristics JMDB Trial N = 618 PARAMOUNT Trial N = 939 Age, median, years 60.7 61.3 Gender, % Female 36 39 Male 64 61 ECOG PS, % 0 35 32 1 65 68 NSCLC stage, % IIIB 21 11a IV 79 90a Histology, % Adenocarcinoma 71 87 Large cell carcinoma 12 7 Other or unknown 17 6 aSum is not equal to 100% due to rounding Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
  52. 52. JMDB Trial N = 618 PARAMOUNT Trial N = 939 Patients received study treatment, n 604 939 Treatment cycles administered Median (range) 5.0 (1-7) 4.0 (1-4) Mean (SD) 4.4 (1.8) 3.3 (1.1) Treatment cycles completeda ≥4 cycles, n (%) 432 (70) 637 (68) ≥6 cycles, n (%) 284 (46) NA Dose intensity, %b Pemetrexed 95.1 95.2 Cisplatin 95.1 94.7
  53. 53. Response JMDB Trial N = 618 n (%) PARAMOUNT Trial N = 939 n (%) Complete response 1 (0.2) 1 (0.1) Partial response 176 (29) 282 (30) Response ratea 177 (29)b 283 (30) Stable disease 217 (35) 417 (44) Disease control ratec 394 (64) 700 (75) Progressive disease 158 (26) 114 (12) Unknown/not done 66 (11) 125 (13) aResponse rate = complete response + partial response bResponse was achieved for 90.5% of patients within the first 4 cycles cDisease control rate = complete response + partial response + stable disease Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
  54. 54. Drug-related Toxicity JMDB Trial N = 604a n (%) PARAMOUNT Trial N = 939a n (%) Drug-related deathsb 6 (1) 11 (1) Drug-related SAEs 99 (16) 133 (14) Discontinuations due to AE 66 (11) 51 (5) ≥1 Grade 3/4 drug-relatedc Laboratory toxicities 129 (21) 129 (14) Nonlaboratory toxicities 132 (22) 139 (15) aStudy-drug treated population bDuring study treatment due to previously described drug-related hematologic, gastrointestinal, and renal toxicity cGraded according to common terminology criteria for adverse events Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
  55. 55. Grade 3/4 Drug-related Hematologic Toxicitiesa JMDB Trialb N = 604 n (%) PARAMOUNT Trial N = 939 n (%) Neutropenia 90 (15) 79 (8) Anemia 30 (5) 34 (4) Thrombocytopenia 22 (4) 18 (2) Leukopenia 25 (4) 10 (1) aIncludes events occurring on therapy or within 30 days of final study drug dose and graded according to common terminology criteria for adverse events bStudy-drug treated population Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
  56. 56. Grade 3/4 Drug-related Nonlaboratory Toxicitiesa JMDB Trial N = 604b n (%) PARAMOUNT Trial N = 939 n (%) Nausea 48 (8) 29 (3) Fatigue 40 (7) 27 (3) Vomiting 38 (6) 34 (4) Anorexia 11 (2) 9 (1) Febrile neutropenia 8 (1) 11 (1) Diarrhea 7 (1) 12 (1) Dehydration 7 (1) 9 (1) aIncludes events occurring at >1% incidence on therapy or within 30 days of final study drug dose and graded according to common terminology criteria for adverse events bStudy-drug treated population Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
  57. 57. Supportive Care JMDB Trial N = 604a n (%) PARAMOUNT Trial N = 939 n (%) Antiemetics 89 67 Antibiotics 29 22 Transfusions 15 14 Erythropoiesis-stimulating agents 11 7 G-CSF/GM-CSF 3 7 aStudy-drug treated population Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
  58. 58. Conclusionsa Results of the pemetrexed/cisplatin induction therapy of the PARAMOUNT were consistent with the findings of the pemetrexed/cisplatin-treated nonsquamous subpopulation of the JMDB trial1 Response rates and disease control rates with first-line pemetrexed/cisplatin treatment of advanced nonsquamous NSCLC were consistent in both trials1 Types of AEs reported in the two trials were similar; however, the frequency of some of the AEs and the usage of antiemetics was higher on the JMDB trial, possibly due to the greater number of cycles of cisplatin administered1 Toxicity profiles in both trials were consistent with the known safety profiles of pemetrexed/cisplatin2,3 aThese conclusions are the independent opinion of the publication’s authors 1. Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160. 2. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51. 3. Vogelzang et al. J Clin Oncol 2003;21(14):2636-44.
  59. 59. Conclusiones • PARAMOUNT: demuestra eficacia de pemetrexed de mantenimiento vs placebo: – Mejoría en la SLP – Mejoría SG • Perfil de toxicidad favorable, similar a estudios en monoterapia previos • No empeoramiento en calidad de vida ni en PS • Consumo bajo de recursos
  60. 60. Annals of Oncology, 25 de marzo de 2014

×