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Estudio Paramount cáncer de pulmón 2014

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  • Abbreviations:q21d: every 21 days, PD: progressive disease, PS: performance status, NS-NSCLC: nonsquamous non-small cell lung cancer, CR: complete response, PR: partial response, SD: stable disease, RECIST: response evaluation criteria in solid tumors, R: randomization, BSC: best supportive care, ECOG: Eastern Cooperative Oncology GroupKey Points:Patients were eligible for the induction phase of the study if they had: cytological or histological diagnosis of advanced nonsquamous NSCLC (Stage IIIB or IV), no previous systemic chemotherapy, 1 or more measurable lesions per RECIST criteria, and an ECOG performance status of 0 or 1.1Patients who completed 4 cycles of pemetrexed/cisplatin induction therapy with documented radiographical evidence of a partial or complete tumor response or stable disease were eligible for randomization into the maintenance phase of the study.1Patients began maintenance therapy within 7 days of randomization and 21-42 days from Day 1 of the 4th cycle of induction therapy.1Maintenance therapy was continued until disease progression, unacceptable adverse events, or decision of the patient or physician; patients were followed up until death or study closure.1939 patients enrolled on induction therapy; 539 patients were randomized to maintenance therapy (2:1): 359 pemetrexed patients and 180 placebo patients.1References:Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J ClinOncol 2013;(Accepted).Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. 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(3):247-55.
  • Abbreviations:OS: overall survival, HR: hazard ratio, CI: confidence intervalKey Points:PARAMOUNT study was 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 Alpha was controlled for both preliminary analysis (α = 0.0001) and final analysis (α = 0.0498) of OS
  • Abbreviations:BSC: best supportive care, SD: standard deviation, CI: confidence intervalReferences:Paz-Ares L, De Marinis F, Dediu M, Thomas M, Pujol J, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John WJ, Chouaki N, Zimmermann A, Visseren-Grul C, Gridelli C. PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (plb) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC). Presented at: ASCO Annual Meeting, June 1-5, 2012; Chicago, Illinois. Abstract LBA7507.
  • Abbreviations:BSC: best supportive care, CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease, OS: overall survival, PS: performance status, ECOG: Eastern Cooperative Oncology Group, NSCLC: non-small cell lung cancerKey Points:Characteristics of randomized patients were well balanced between treatment arms.The study was limited to patients with a PS of 0 or 1, with two thirds of the patients having a PS of 1. The 3 patients who had an ECOG PS of 2/3 at randomization were considered protocol violations.Almost half of the patients had a response (CR/PR) after 4 cycles of pemetrexed/cisplatin induction treatment. Patients who had a best tumor response of PD or unknown after induction therapy were considered protocol violations.Histological classifications were grouped by World Health Organization classification of lung tumors, and patients with squamous cell carcinoma were not eligible to enroll.Histological classifications of “other” or “indeterminate” represent patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma or large cell carcinoma. This includes NSCLC not otherwise specified, poorly differentiated, and adenocarcinoma, mucinous.
  • Abbreviations:BSC: best supportive care, CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease, OS: overall survival, PS: performance status, ECOG: Eastern Cooperative Oncology Group, NSCLC: non-small cell lung cancerKey Points:Characteristics of randomized patients were well balanced between treatment arms.The study was limited to patients with a PS of 0 or 1, with two thirds of the patients having a PS of 1. The 3 patients who had an ECOG PS of 2/3 at randomization were considered protocol violations.Almost half of the patients had a response (CR/PR) after 4 cycles of pemetrexed/cisplatin induction treatment. Patients who had a best tumor response of PD or unknown after induction therapy were considered protocol violations.Histological classifications were grouped by World Health Organization classification of lung tumors, and patients with squamous cell carcinoma were not eligible to enroll.Histological classifications of “other” or “indeterminate” represent patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma or large cell carcinoma. This includes NSCLC not otherwise specified, poorly differentiated, and adenocarcinoma, mucinous.
  • Abbreviations:OS: overall survival, BSC: best supportive care, CI: confidence intervalKey Points:PARAMOUNT met its secondary endpoint, demonstrating a statistically significant longer OS (improvement of almost 3 months in median OS) for patients treated with maintenance pemetrexed compared to placebo, as demonstrated by the HR of 0.78 and p = .0195.Stated another way, treatment with pemetrexed maintenance therapy was associated with a 22% reduction in the risk of death.Likewise, 1-year and 2-year survival were significantly longer for patients taking pemetrexed than those taking placebo.
  • Abbreviations:OS: overall survival, BSC: best supportive care, mos: months, CI: confidence interval, HR: hazard ratio, Pem: pemetrexed
  • Abbreviations:OS: overall survival, BSC: best supportive care, mos: months, CI: confidence interval, HR: hazard ratio, Pem: pemetrexedKey Point:Assessment of OS from the start of induction therapy was consistent with the primary analysis, with no change in the HR.
  • Peme00052128Abbreviations:PFS: progression-free survival, OS: overall survival, BSC: best supportive care, mos: months, CI: confidence interval, HR: hazard ratio, Pem: pemetrexedKey Point:Reassessment of investigator-assessed PFS at the time of the final OS analysis showed similar unadjusted HR of 0.60 (95% CI: 0.50-0.73, p<.00001) to the HR reported at the time of the primary PFS analysis of 0.62 (95% CI: 0.49-0.79, p<.0001).Reference:Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013;(Accepted).
  • Peme00052128Abbreviations:OS: overall survival, CR: complete response, PR: partial response, SD: stable disease, BSC: best supportive care, mos: months, CI: confidence interval, HR: hazard ratio, Pem: pemetrexedKey Point:The PARAMOUNT study demonstrates that patients receiving pemetrexed maintenance therapy experience a benefit in OS regardless of prior response to induction treatment (PR/CR or SD).Reference:Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013;(Accepted).
  • Peme00052128Abbreviation:BSC: best supportive careKey Points:Postdiscontinuation therapy (PDT) was given at the discretion of the investigator. A similar percentage of patients received PDT in each arm: placebo (72%), pemetrexed (64%).The PDT selections were well balanced between treatment groups, with the exception of docetaxel (43.3% placebo arm, 32.3% pemetrexed arm).The majority of patients received an approved 2nd-line treatment (docetaxel or erlotinib).As expected, the use of pemetrexed as 2nd-line treatment was low in both arms (3.9% placebo vs. 1.9% pemetrexed), since all patients have received pemetrexed induction treatment. Reference:Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013;(Accepted).
  • Peme00052128Abbreviations:CTCAE: Common Terminology Criteria for Adverse Events, BSC: best supportive care, ALT: alanine aminotransferase, AST: aspartate aminotransferase, NCI: National Cancer InstituteKey Points:In PARAMOUNT, there was a low incidence (<7%) of drug-related Grade 3/4 laboratory toxicities during maintenance therapy.Patients receiving pemetrexed had a significantly greater incidence of drug-related Grade 1/2 and Grade 3/4 anemia and neutropenia compared with placebo. There were no Grade 5 drug-related laboratory toxicities (deaths).No significant differences in drug-related Grade 3/4 toxicities were observed with longer exposure to pemetrexed (>6 cycles), except for a numeric increase in Grade 3/4 neutropenia (9% vs. 4%, p = .062). However, the greater incidence of Grade 3/4 neutropenia with long-term pemetrexed exposure did not result in increased Grade 3/4 infections (3.5% in patients receiving ≤6 cycles vs. 1.5% in those receiving >6, p = .334).Background:Fisher’s exact test (p≤.05) was used to determine the significant difference between treatment groups.Reference:Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013;(Accepted).
  • Peme00052128Abbreviations:CTCAE: Common Terminology Criteria for Adverse Events, BSC: best supportive care, NCI: National Cancer InstituteKey Points:In PARAMOUNT, there was a low incidence (<5%) of drug-related Grade 3/4 nonlaboratory toxicities during maintenance therapy.Patients receiving pemetrexed had a significantly greater incidence of drug-related nonlaboratory toxicities, including Grade 1/2 fatigue, nausea, vomiting, mucositis/stomatitis, anorexia, and watery eye, as well as Grade 3/4 fatigue compared with placebo.Three Grade 5 drug-related nonlaboratory toxicites (deaths) occurred during the maintenance treatment period; 1 on pemetrexed (pneumonia) and 2 on placebo (respiratory arrest and sudden death, not otherwise specified).Background:Fisher’s exact test (p≤.05) was used to determine the significant difference between treatment groups.Reference:Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013;(Accepted).
  • Complete References for Citation:Paz-Ares L, de Marinis F, Dediu M, 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;13:247-255.Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013. doi:10.1200/JCO.2012.47.1102. CiuleanuT, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-1440.Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589-1597.Gridelli C, de Marinis F, Pujol J-L, et al. 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. J Thorac Oncol. 2012;7:1713-1721.
  • S. Giuseppe Moscati Hospital, Avellino, ItalySan Camillo - Forlanini Hospital, Rome, ItalyMontpellier Academic Hospital, Montpellier, FranceKrankenhaus Großhansdorf, Großhansdorf, GermanyWielkopolskie Centrum Pulmonologii Torakochirurgii, PoznanUniversity of Medical Sciences, PolandCentro Hospitalar de Vila Nova de Gaia, Vila Nova de Gaia, PortugalCliniques Universitaires Saint-Luc, Brussels, BelgiumRoyal Surrey County Hospital NHS Trust Saint Luke’s Cancer Centre, Guildford, United KingdomInstituto de Biomedicina de Sevilla (IBIS) and Virgen del Rocio University Hospital, Seville, SpainEli Lilly and Company, Indianapolis, IN, USAEli Lilly and Company, Suresnes, Hauts de Seine, FranceEli Lilly and Company, Houten, The NetherlandsReference:Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;(In press).
  • Abbreviations:NSCLC: non-small cell lung cancer, QoL: quality of life, EQ-5D: EuroQoL 5-dimensionalReferences:Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. 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(3):247-55. EuroQol--a new facility for the measurement of health-related quality of life. The EuroQol Group. Health Policy 1990;16(3):199-208.Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:AEs: adverse events, QoL: quality of life, EQ-5D: EuroQoL-5 dimensionalKey Points:Safety evaluations were based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.1 [Pg 12, Para 3]Resource use was evaluated separately for the induction and maintenance periods. [Pg 13, Para 1]Investigators followed current American Society of Clinical Oncology and European Society for Medical Oncology guidelines for the use of colony-stimulating factors and erythropoiesis-stimulating agents. [Pg 13, Para 1]The EQ-5D is a self-administered health-status questionnaire consisting of two parts.2,3 [Pg 13, Para 2]The first part includes five descriptive questions on which the patient rates his/her health regarding mobility, self care, usual activities, pain/discomfort, and anxiety/depression.The second part is a visual analog scale (VAS) that allows patients to rate their present health status. Possible scores range from 0 (worst imaginable health state) to 100 (best imaginable health state).Patients completed the EQ-5D questionnaire once at baseline (after consent but before the start of induction treatment, within 2 weeks of cycle 1), at each visit (once per cycle) before treatment administration, and once during the 30-day post-discontinuation follow-up visit. [Pg 14, Para 2]Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.References:Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Bethesda, MD: National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP). 2006. Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_30. Last accessed August 17, 2012.Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and testing of the D1 valuation model. Med Care 2005;43(3):203-20.Rabin R, Oemar M, Oppe M; EuroQol Group. EQ-5D-3L User Guide: Basic information on how to use the EQ-5D-3L instrument. Version 4.0. April 2011. Rotterdam, Netherlands: EuroQol Group 2011. Available at: http://www.euroqol.org/eq-5d/publications/user-guide.html. Last accessed August 17, 2012.Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:EQ-5D: EuroQoL-5 dimensional, VAS: visual analog scaleKey Points:Patients were included in the evaluation of safety and resource use if they were treated with ≥1 dose of pemetrexed or cisplatin during the induction period or if they were randomized and treated with ≥1 dose of pemetrexed or placebo during the maintenance period. [Pg 14, Para 3]Safety and resource use were summarized for all patients enrolled in the induction period and for all randomized patients in the maintenance period by treatment arm. [Pg 14, Para 3]Frequency distributions, including measures of central tendency and variability (for example, means, medians, and standard deviations), were calculated for individual items and for the total scale of the EQ-5D. [Pg 15, Para 1]Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.Reference:Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:VAS: Visual Analog Scale, ECOG: Eastern Cooperative Oncology Group, PS: performance statusBackground:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.Reference:Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:ESA: erythropoietic-stimulating agents, G-CSF: granulocyte colony-stimulating factor, GM-CSF: granulocyte macrophage colony-stimulating factorKey Points:Resource use was higher with pemetrexed-cisplatin during the induction period than with single-agent pemetrexed during the maintenance period, including anti-emetic use (66.7% compared with 34.0%).During the maintenance period, a higher percentage of patients on the pemetrexed arm required the following concomitant medications compared with the placebo arm: transfusions (13.4% versus 5.0%, p = .003), granulocyte colony- or granulocyte macrophage colony-stimulating factors (5.3% versus 0.0%, p <.001), and anti-infectives (25.3% versus 16.7%, p = .028).Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.Reference: Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Key Points:Resource use was higher with pemetrexed-cisplatin during the induction period than with single-agent pemetrexed during the maintenance period, including anti-emetic use (66.7% compared with 34.0%).During the maintenance period, a higher percentage of patients on the pemetrexed arm required the following concomitant medications compared with the placebo arm: transfusions (13.4% versus 5.0%, p = .003), granulocyte colony- or granulocyte macrophage colony-stimulating factors (5.3% versus 0.0%, p <.001), and anti-infectives (25.3% versus 16.7%, p = .028).Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.Reference: Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:SD: standard deviation, AEs: adverse events.Key Points:Resource use was higher with pemetrexed-cisplatin during the induction period than with single-agent pemetrexed during the maintenance period, including hospitalizations due to drug-related AEs (13.4% compared with 8.4%).The overall rate of hospitalizations due to AEs was similar between treatment arms (pemetrexed = 19.2% and placebo = 17.8%; p = .727). The maintenance pemetrexed arm had a higher rate of hospitalizations due to drug-related AEs compared with the placebo arm (8.4% versus 3.3%, p = .028).Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.Reference: Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:AEs: adverse events, SD: standard deviationKey Points:Resource use was higher with pemetrexed-cisplatin during the induction period than with single-agent pemetrexed during the maintenance period, including hospitalizations due to drug-related AEs (13.4% compared with 8.4%).The overall rate of hospitalizations due to AEs was similar between treatment arms (pemetrexed = 19.2% and placebo = 17.8%; p = 0.727). Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.Reference: Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:EQ-5D: Euro Qol 5-dimensional questionnaire, QoL: Quality of Life, NSCLC: non-small cell lung cancer Key Point:The most common reason for missing assessments during the maintenance period was failure by study sites to administer the questionnaire (placebo: 26%, pemetrexed arm: 32%)Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.The EQ-5D is a self-administered health-status questionnaire, which consists of two parts. The first part includes five descriptive questions on which the patient rates his/her health regarding mobility, self care, usual activities, pain/discomfort, and anxiety/depression.Each of the five attributes has three levels: no problem, some problems, and major problems, thus defining 243 possible health states, to which the EuroQol committee added “unconscious” and “dead” for a total of 245. The possible values for health utility ranges from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension) on a scale where 0 represents death and 1 represents the best possible health state.Reference: Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:EQ-5D: Euro Qol 5-dimensional questionnaire, QoL: Quality of Life Key Points:Population-based index scores have been established for both the US and the UK. The UK population-based weights were used in this study, since the majority of the patients were at sites in Europe (90%) and there were no sites in the United States.At each cycle, patients with both baseline and postbaseline data are included. Thus the denominators and mean baseline values shown represent only those patients with both baseline and postbaseline data at that cycle, which varies across cycles.Patient-reported QoL was measured using the EQ-5D.Statistically significant improvements from baseline were observed during the induction period, in EQ-5D index scores at cycle 3 (mean change from baseline 0.03, p = .003) and cycle 4 (mean change from baseline 0.03, p = .001).Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.The EQ-5D is a self-administered health-status questionnaire, which consists of two parts. The first part includes five descriptive questions on which the patient rates his/her health regarding mobility, self care, usual activities, pain/discomfort, and anxiety/depression.Each of the five attributes has three levels: no problem, some problems, and major problems, thus defining 243 possible health states, to which the EuroQol committee added “unconscious” and “dead” for a total of 245. The possible values for health utility ranges from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension) on a scale where 0 represents death and 1 represents the best possible health state.Reference: Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:EQ-5D: Euro Qol 5-dimensional questionnaire, VAS: Visual Analog Scale, QoL: Quality of LifeKey Points:At each cycle, patients with both baseline and postbaseline data are included. Thus the denominators and mean baseline values shown represent only those patients with both baseline and postbaseline data at that cycle, which varies across cycles.Patient-reported QoL was measured using the EQ-5D.No significant VAS changes were observed during the induction period, although numerical improvement on the VAS was observed at cycle 3 (mean change from baseline 0.60) and cycle 4 (mean change from baseline 1.13).Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.VAS is a part of the EQ-5D that allows patients to rate their present health status. Possible scores range from 0 (worst imaginable health state) to 100 (best imaginable health state).Reference: Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviation:EQ-5D: Euro Qol 5-dimensional questionnaireKey Points:At each cycle, patients with both baseline and postbaseline data are included. Thus the denominators and mean baseline values shown represent only those patients with both baseline and postbaseline data at that cycle, which varies across cycles.Statistically significant differences were observed between the pemetrexed and placebo arms in mean changes from baseline on the index score at cycle 6 (pemetrexed -0.02, placebo 0.04, p = .050).Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.Most common reason for missing assessments during the maintenance period was failure by study sites to administer the questionnaire (missing questionnaires: 32% pemetrexed arm versus 26% placebo arm)No overall treatment differences were observed in the MMRM measures analyses of the EQ-5D index score and VAS rating (data not shown).Reference: Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:EQ-5D: Euro Qol 5-dimensional questionnaire, VAS: Visual Analog ScaleKey Points:At each cycle, patients with both baseline and postbaseline data are included. Thus the denominators and mean baseline values shown represent only those patients with both baseline and postbaseline data at that cycle, which varies across cycles.In the comparison of treatment differences using a paired t-test, statistically significant differences were observed between the pemetrexed and placebo arms in mean changes from baseline on the VAS rating at cycle 4 (pemetrexed 0.69, placebo 6.15, p = .010) and cycle 5 (pemetrexed 1.55, placebo 5.99, p = .044).Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.No overall treatment differences were observed in the MMRM measures analyses of the EQ-5D index score and VAS rating (data not shown).Reference: Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:ECOG: Eastern Cooperative Oncology Group, PS: performance status, NSCLC: non-small cell lung cancer, EQ-5D: Euro Qol 5-dimensional questionnaire, MMRM: mixed-effects model repeated measures, VAS: visual analogue scaleKey Points:The majority of patients were able to maintain PS and a similar number of patients between treatment arms showed improvement or worsening in PS.At baseline:31.5% of patients had a PS of 0.67.9% of patients had a PS of 1. Of these patients, 42 improved (pemetrexed arm: 25, placebo arm: 17)Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.No overall treatment differences were observed in the MMRM measures analyses of the EQ-5D index score and VAS rating (data not shown).Reference: Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviation: AE: adverse eventBackground:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.References:Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J ClinOncol 2008;26(21):3543-51.Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, Phase III study. Lancet 2009;374(9699):1432-40.Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.References:Eguia B, Ruppert AM, Fillon J, Lavolé A, Gounant V, Epaud C, Milleron B, Moguelet P, Wislez M, Frances C, Cadranel J. Skin toxicities compromise prolonged pemetrexed treatment. J ThoracOncol 2011;6(12):2083-9.Glezerman IG, Pietanza MC, Miller V, Seshan SV. Kidney tubular toxicity of maintenance pemetrexed therapy. Am J Kidney Dis 2011;58(5):817-20. Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations:AEs: adverse events, CSF: colony-stimulating factorsReferences:Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009;374(9699):1432-40. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J ClinOncol 2004;22(9):1589-97.Belani CP, Brodowicz T, Ciuleanu TE, Krzakowski M, Yang SH, Franke F, Cucevic B, Madhavan J, Santoro A, Ramlau R, Liepa AM, Visseren-Grul C, Peterson P, John WJ, Zielinski CC. Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study. Lancet Oncol 2012;13(3):292-9.Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations: EQ-5D: EuroQol 5-dimensional questionnaire, QoL: quality of life, VAS: visual analogue scale, MID: minimally important difference, PS: performance status Key Points:Majority of worsening and least compliance on the questionnaire were observed at the postdiscontinuation visit (ie, at the time of disease progression or toxicity leading to discontinuation from study treatment). At the postdiscontinuation visit, mean changes in the EQ-5D index scores for both pemetrexed and placebo (-0.13 and -0.09, respectively) were clinically relevant according to the MID of 0.08, but not statistically significant.The MIDs for lung cancer determined by Pickard and colleagues were 0.08 for the UK population-based index score and 7 for the VAS score.Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.Reference:Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • Abbreviations: EQ-5D: EuroQol 5-dimensional questionnaire, QoL: quality of life, VAS: visual analogue scale, MID: minimally important difference,PS: performance status Key Points:Majority of worsening and least compliance on the questionnaire were observed at the postdiscontinuation visit (ie, at the time of disease progression or toxicity leading to discontinuation from study treatment). At the postdiscontinuation visit, mean changes in the EQ-5D index scores for both pemetrexed and placebo (-0.13 and -0.09, respectively) were clinically relevant according to the MID of 0.08, but not statistically significant.The MIDs for lung cancer determined by Pickard and colleagues were 0.08 for the UK population-based index score and 7 for the VAS score.Background:This article shows the results of the secondary objectives of PARAMOUNT (a phase III, randomized, double-blind study), which assessed maintenance treatment with pemetrexed after induction with pemetrexed plus cisplatin in patients with advanced non-squamous NSCLC.The secondary objectives of PARAMOUNT included: To assess the prespecified secondary endpoints of safety, resource use, and QoL data from the EQ-5D questionnaire.Reference:Gridelli C, de Marinis F, Pujol J, Reck M, Ramlau R, Parente M, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares L. 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. J Thorac Oncol 2012;7(11):1713-21
  • [Sources: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 1; WCLC_Abstract_JMDB_S124 Indxn final 22Feb2011_Peme-00043776.docx]Reference:Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.Peme00057259Peme00057259
  • [Sources: 3 small bullets Scagliotti GV J ClinOncol 2008. Page 3543 abstract, 2nd diamond Scagliotti Oncologist 2009 Page 257, table 3 ] ]Abbreviations: NSCLC: non-small cell lung cancerReferences:Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. 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(21):3543-51.Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, Simms L, Shepherd FA. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 2009;14(3):253-63.Peme00057259
  • [Sources: Paz-Ares et al Lancet Oncol 2012: Figure 2 and Table 3]Abbreviations: NSCLC: non-small cell lung cancerReference:Paz-Ares LG, De Marinis F, Dediu M, Thomas M, Pujol J, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed SA, John WJ, Chouaki N, Zimmerman A, Visseren Grul CM, Gridelli C. 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(3):247-255.Peme00057259
  • [Source: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 4]Abbreviations: NSCLC: non-small cell lung cancerReference:Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.Peme00057259
  • [Source: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 4]References:Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. 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(21):3543-51.Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, Simms L, Shepherd FA. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 2009;14(3):253-63.Paz-Ares LG, De Marinis F, Dediu M, Thomas M, Pujol J, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed SA, John WJ, Chouaki N, Zimmerman A, Visseren Grul CM, Gridelli C. 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(3):247-255.Peme00057259
  • [Sources: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 6; WCLC_Abstract_JMDB_S124 Indxn final 22Feb2011_Peme-00043776.docx; Scagliotti GV 2008.pdf. Page 3544: column 1, para 1, 2, 5, and 6; column 2, table 1; Paz-Ares-H3E-EW-S124_JCO_ms_revised_24June 2011.docx. Page 7: para 1, 2, 4 (cont. on page 8); page 8: para 1 and 2]Abbreviations: NSCLC: non-small cell lung cancer, ECOG PS: Eastern Cooperative Oncology Group performance statusKey Points:JMDB was a Phase 3, noninferiority trial that randomized 1725 chemonaïve patients with advanced NSCLC of all histologies to either pemetrexed (500 mg/m2,Day 1)/cisplatin (75 mg/m2, Day 1) or gemcitabine (1250 mg/m2, Days 1, 8)/cisplatin (75 mg/m2, Day 1) every 21 days for a maximum of 6 cycles. A total of 1252 patients had nonsquamous histology of which 618 patients were on pemetrexed/cisplatin regimen.PARAMOUNT was a Phase 3, double-blind, placebo-controlled trial that enrolled 939 chemonaïve patients with advanced nonsquamous NSCLC to receive 4 cycles of pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) induction therapy on Day 1 of a 21-day cycle. Patients who did not progress after completing 4 cycles of induction and who had a ECOG PS 0/1) were randomized (2:1) to receive either pemetrexed (500 mg/m2, Day 1 every 21 days) plus best supportive care maintenance therapy or placebo (0.9% NaCl, Day 1 every 21 days) plus best supportive care.In both studies, all patients treated with pemetrexed received oral folic acid (350 to 1000 µg) daily and a vitamin B12 injection (1000 µg) every 9 weeks, beginning 1 to 2 weeks prior to the first dose and continuing until 3 weeks after the last dose of study treatment.Reference:Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.Peme00057259
  • [Source: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 7]Abbreviations: ECOG PS: Eastern Cooperative Oncology Group performance status, NSCLC: non-small cell lung cancerKey Point:Baseline demographics and disease characteristics were similar in both trials, except for the percentage of patients with stage IV NSCLC and a tumor histology of Adenocarcinoma, which was higher in the PARAMOUNT trial. The percentage of patients with a tumor histology of Other/unknown was higher in JMDB.Reference:Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.Peme00057259
  • [Sources: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 8; WCLC_Abstract_JMDB_S124 Indxn final 22Feb2011_Peme-00043776.docx]Abbreviations: SD: standard deviation, NA: not applicableKey Points:Of the 618 patients with nonsquamous histology randomized to pemetrexed/cisplatin in the JMDB trial, 604 patients received study treatment. In the PARAMOUNT trial, all 939 enrolled patients received study treatment.Drug delivery was similar for both trials; however, patients on the JMDB trial received a higher number of cycles due to different study design.Reference:Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.Peme00057259
  • [Sources: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 9; WCLC_Abstract_JMDB_S124 Indxn final 22Feb2011_Peme-00043776.docx]Key Points:Response rates were similar for the JMDB and PARAMOUNT trials (29% vs. 30%). Compared with the JMDB trial, greater percentage of patients on the PARAMOUNT trial had stable disease, thus the disease control rate was also comparably higher (64% vs. 75%).Reference:Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.Peme00057259
  • [Sources: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 10; WCLC_Abstract_JMDB_S124 Indxn final 22Feb2011_Peme-00043776.docx]Abbreviations:SAE: serious adverse event, AE: adverse eventKey Point:Percentages of drug-related deaths and SAEs were comparable between the two trials. Patients on the JMDB trial had 50% more frequent Grade 3/4 toxicities.Reference:Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.Peme00057259
  • [Source: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 11]Key Point:The incidence of Grade 3/4 drug-related laboratory toxicities was low and comparable between the two trials except for the frequency of neutropenia, which was twice as high on the JMDB trial.Reference: Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
  • [Source: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 12]Key Points:The incidence of Grade 3/4 drug-related nonlaboratory toxicities was low on both trials.Compared with the PARAMOUNT Trial, the most frequently experienced nonlaboratory toxicities nausea, fatigue, and vomiting occurred with twice the frequency on the JMDB trial.Reference: Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.Peme00057259
  • [Source: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 13]Abbreviations: G-CSF: granulocyte colony-stimulating factor, GM-CSF: granulocyte-macrophage colony-stimulating factorKey Point:Supportive care was comparable between the two trials except for the usage of antiemetics on the JMDB trial, which was more frequent due to a greater incidence of nausea and vomiting.; and On the PARAMOUNT trial a greater usage of colony-stimulating factors was observed.Reference:Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.Peme00057259
  • [Sources: S124-JMDB WCLC poster slides final draft 23Jun2011.pptx. Slide 14; WCLC_Abstract_JMDB_S124 Indxn final 22Feb2011_Peme-00043776.docx]Abbreviations: NSCLC: non-small cell lung cancer, AE: adverse eventReferences:Scagliotti G, Gridelli C, De Marinis F, Thomas M, Dedui M, Pujol JL, Manegold C, Melemed S, John W, Zimmermann AH, Chouaki N, Melemed A, Visseren-Grul C, Paz Ares L. First line chemotherapy with pemetrexed plus cisplatin in advanced nonsquamous non-small cell lung cancer (NSCLC): A comparison of two phase III trials. J Thorac Oncol 2011;6(6 Suppl 2):S1160.Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. 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(21):3543-51.Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21(14):2636-44.Peme00057259

Transcript

  • 1. Paz-Ares LG, J Clin Oncol 2013 Aug 8;31(23):2895–902
  • 2. PARAMOUNT
  • 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. 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. • 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. 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. 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. 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. 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. “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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Annals of Oncology, 25 de marzo de 2014