Overall survival (OS) results from PARAMOUNT study of maintenance plus best supportive care (BSC) versus plus BSC, immediately after induction with - Cisplatin, in patients with advanced Nonsquamous Non-small Cell Lung Cancer (NS-NSCLC) J. Corral 1, 2 L. Paz-Ares 1, 2, F. De Marinis 3, M. Dediu 4, M. Thomas 5, J. L. Pujol 6, P. Bidoli 7, O. Molinier 8, T. P. Sahoo 9, C. Gridelli 10 et al* 1 Instituto de Biomedicina de Sevilla, 2 University Hospital Virgen del Rocío, Seville, Spain; 3 San Camillo Forlanini Hospital, Rome, Italy; 4 Institute of Oncology Bucharest, Bucharest, Romania; 5 Thoraxklinik, University of Heidelberg, Heidelberg, Germany; 6 Montpellier CHRU Academic Hospital, Montpellier, France; 7 Medical Oncology Unit, S. Gerardo Hospital, Monza, Italy; 8 Le Mans Regional Hospital, Le Mans, France; 9 Jawaharlal Nehru Cancer Hospital and Research Center, Bhopal, India; 10 San Giuseppe Moscati Hospital, Avellino, Italy *M. Reck (Hospital Grosshansdorf, Grosshansdorf, Germany), E. Laack (University Medical Center Hamburg-Eppendorf, Hamburg, Germany), S. A. Melemed, W. J. John, A. Zimmermann (Eli Lilly and Company, Indianapolis, IN, USA), N. Chouaki (Eli Lilly and Company, Suresnes, Hauts de Seine, France), and C. M. Visseren-Grul (Eli Lilly and Company, Houten, The Netherlands) have participated as co-authors.
Background Most patients have stage IIIB/IV NSCLC when diagnosed 1 Platinum-based combinations are recommended for first-line treatment 2 has demonstrated efficacy in advanced nonsquamous NSCLC (NS-NSCLC): in combination with cisplatin as first-line doublet 3 as maintenance agent following non-pemetrexed platinum doublet 4 PARAMOUNT evaluated pemetrexed maintenance after pemetrexed + cisplatin induction: Primary endpoint was met: pemetrexed reduced risk of disease progression over placebo (HR: 0.62 [0.49-0.79], Wald P<0.0001) 5 Final survival analysis occurred after 390 deaths; log-rank test compared OS between arms, with α level of 0.0498 1 http://seer.cancer.gov/statfacts/html/lungb.html; 2 Azzoli CG et al. J Clin Oncol. 2009; 3 Scagliotti GV et al. J Clin Oncol. 2008; 4 Ciuleanu T et al. Lancet 2009; 5 Paz-Ares L et al. Lancet Oncol. 2012.
PARAMOUNT: Study Design Randomized, placebo-controlled, double-blind phase III study 500 mg/m 2 ; Cisplatin 75 mg/m 2 Folic acid and vitamin B 12 administered to both arms Induction Therapy 4 cycles, q21d Continuation Maintenance Therapy q21d until PD Previously untreated PS 0/1 Stage IIIB-IV NS-NSCLC + Cisplatin CR/PR/SD per RECIST R 2:1 + BSC + BSC Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD)
PARAMOUNT: Patient Disposition 1022 Patients Screened 400 Patients Not Randomized 217 Progressive Disease 62 Adverse Event 56 Death 29 Study Disease 15 AE 11 Drug-Related AE 1 Procedure-Related AE 65 Other Reasons 939 Patients Enrolled 539 Patients Randomized (2:1 Randomization) 83 Patients Failed Screening Induction Phase Maintenance Phase 548 Patients Eligible for Maint 8 Discontinued Pt Decision 1 Discontinued Phys Decision Arm N=359 Arm N=180 OS Endpoint 256 (71%) Pts with events at data cut off 350 (97%) Pts discontinued treatment 141 (78%) Pts with events at data cut off 178 (99%) Pts discontinued treatment
PARAMOUNT: Patient Characteristics Age *Protocol violations. (N=359) (N=180) Median Age, yrs 61 62 < 65 yrs, % 66 62 Male, % 56 62 Caucasian, % 94 95 Smoker, % Ever Smoker 76 80 Never Smoker 23 19 ECOG PS, % 0 32 33 1 68 66 2/3* 0.3 1
PARAMOUNT: Disease Characteristics (N=359) % (N=180) % Disease stage IV* 91 90 Histology Adenocarcinoma 86 89 Large cell 7 7 Other Nonsquamous 7 4 Induction Response CR/PR 44 42 SD 53 53 PD/Unknown 3 6 * TNM Staging System for Lung Cancer, 5 th edition. Protocol violations.
PARAMOUNT: Drug Administration Maintenance Phase (N=359) (N=180) Patients Treated* 357 178 Number of Cycles/Patient Median 4 4 Range 1 44 1 38 Mean 7.9 5.0 Patients Completing > 6 Cycles 37% 18% Dose Intensity of Planned Mean Dose 93.7% NA Median Follow-up, months (95% CI) For all Patients 12.5 (11.1 13.7) For all Alive Patients 24.3 (23.2 25.1) *Two patients on each arm were randomized but did not receive treatment.
PARAMOUNT: Patient Discontinuation Reasons for Discontinuation (N=359) % (N=180) % Progressive Disease 69 84 Adverse Event 18 7 Subject Decision 6 4 Investigator Decision 1 1 Death 2 2 Study Disease 0.8 0.6 Adverse Event/Toxicity 1 2
Survival Probability PARAMOUNT: Final OS from Randomization Pem 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Log-rank P = 0.0195 Unadjusted HR: 0.78 (95% CI: 0.64 0.96) OS Median (mo) 13.9 11.0 (95% CI) (12.8-16.0) (10.0-12.5) Censoring (%) 28.7 21.7 Survival Rate (%) (95% CI) 1-year 58 (53-63) 45 (38-53) 2-year 32 (27-37) 21 (15-28) 0 3 6 9 12 15 18 21 24 27 30 33 36 Time from Randomization (Months) Patients at Risk Pem + BSC 359 333 272 235 200 166 138 105 79 43 15 2 0 + BSC 180 169 131 103 78 65 49 35 23 12 8 3 0
Survival Probability PARAMOUNT: Final OS from Induction 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median OS =16.9 mos (95% CI: 15.8 19.0) Median OS =14.0 mos (95% CI: 12.9 15.5) Log-rank P=0.0191 HR=0.78 (95% CI: 0.64 0.96) 0 3 6 9 12 15 18 21 24 27 30 33 36 Time from Induction (Months) Patients at Risk Pem + BSC 359 335 276 234 200 164 138 106 77 42 15 2 0 + BSC 180 168 132 103 78 63 49 35 23 12 8 3 0
PARAMOUNT: Subgroup OS Hazard Ratios Hazard Ratio All Randomized Patients (N=539) Stage IV (n=490) Stage IIIB (n=49) Induction Response CR/PR (n=234) Induction Response SD (n=285) Pre-randomization ECOG PS 1 (n=363) Pre-randomization ECOG PS 0 (n=173) Non-smoker (n=117) Smoker (n=418) Male (n=313) Female (n=226) Age < 70 (n=447) Age 70 (n=92) Age < 65 (n=350) Age 65 (n=189) Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471) 0.78 0.79 0.82 0.81 0.76 0.82 0.70 0.75 0.83 0.82 0.73 0.75 0.89 0.82 0.71 0.81 0.44 0.80 0.0 0.5 1.0 1.5 2.0 2.5 Treatment Hazard Ratio (95% CI) Favors Favors The survival results were internally consistent; benefit was seen across all subgroups
Survival probability Survival probability PARAMOUNT: Induction Response Subgroups OS Hazard Ratios All Randomized Patients (N=539) Stage IV (n=490) Stage IIIB (n=49) Induction Response CR/PR (n=234) Induction Response SD (n=285) Pre-randomization ECOG PS 1 (n=363) Pre-randomization ECOG PS 0 (n=173) Non-smoker (n=117) Smoker )n=418) Male (n=313) Female (n=226) Age < 70 (n=447) Age > 70 (n=92) Age < 65 (n=350) Age > 65 (n=189( Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471) Hazard Ratio 0.78 0.79 0.82 0.81 0.76 0.82 0.70 0.75 0.83 0.82 0.73 0.75 0.89 0.82 0.71 0.81 0.44 0.80 CR/PR HR = 0.81 0 9 18 27 36 SD HR = 0.76 0.0 0.5 1.0 1.5 2.0 Treatment Hazard Ratio (95%% CI) 0 9 18 27 36 Time from Randomization (Months) Favors Favors The survival results were consistent across both induction response subgroups
Survival Probability PARAMOUNT: PFS from Randomization PFS: Primary Efficacy Endpoint PFS: Reassessed at Time of Final OS Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Unadjusted HR: 0.62 (0.49-0.79) 0.0 0 3 6 9 12 15 Time (Months) Patients at Risk Pem + BSC 359 132 57 21 4 0 Plac+ BSC 180 52 15 5 0 0 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 Unadjusted HR: 0.60 (0.50-0.73) 0 3 6 9 12 15 18 21 24 27 30 33 Time (Months) Pem +BSC 359 215 139 97 67 47 32 22 16 10 5 0 Plac + BSC 180 75 33 16 9 7 6 4 2 0 0 0
PARAMOUNT: Post-discontinuation Therapy (N=359) %* (N=180) %* Patients Receiving Post Discontinuation Therapy 64 72 Erlotinib 40 43 Docetaxel 32 43 Gemcitabine 10 8 Vinorelbine 8 6 Investigational drug 6 4 Carboplatin 5 4 Paclitaxel 3 3 2 4 Cisplatin 1 2 *Data expressed as % of randomized patients. Systemic therapies used in 2% of patients in either arm are shown. Only docetaxel usage differed significantly between arms (P=0.013).
PARAMOUNT: Possible Drug-related CTCAEs* Maintenance safety similar to known profile of single-agent pemetrexed 1,2 (N=359) Grade 1/2 % Grade 3/4 % (N=180) Grade 1/2 % Grade 3/4 % Fatigue 17.5 4.7 10.6 1.1 Nausea 13.4 0.6 2.2 0 Anemia 11.7 6.4 4.4 0.6 Vomiting 7.5 0.3 1.1 0 Mucositis/stomatitis 5.8 0.6 2.2 0 Neuropathy/sensory 5.3 0.3 6.1 0.6 Neutropenia 5.0 5.8 0.6 0 Leukopenia 2.8 2.2 0 0 ALT (SGPT) 2.5 0.3 0.6 0 * Data derived from the March 2011 safety update. Toxicities of any grade, occurring in 5% of patients in either arm, are listed, along with some select toxicities. P<0.05 Fisher s exact test of Gr 3/4 toxicities. Combined term. 1 Hanna N, et al. J Clin Oncol. 2004; 2 Ciuleanu T, et al. Lancet 2009
PARAMOUNT: Conclusions These final results show that survival is significantly improved when patients are treated with pemetrexed continuation maintenance therapy compared with placebo (HR=0.78) The survival results were internally consistent across all subgroups, including response to induction (complete/partial response versus stable disease) PARAMOUNT is the first study to show continuation maintenance has an impact on the disease course of advanced NSCLC (including PFS and OS), supporting a change in the treatment paradigm in this setting
Acknowledgements We thank all of the patients and their caregivers for participating in this trial. We also thank all the Investigators and their support staff who generously participated in this work with a special mention to the Spanish Investigators: D. Isla (Hospital Clínico Universitario Lozano Blesa, Zaragoza, España) Y. García (Hospital Universitari Parc Tauli, Sabadell, España) D. Almenar (Hospital Universitario Dr. Peset, Valencia, España) R. Bernabé (Hospital Universitario de Valme, Sevilla, España) M. Domenech (Hospital Althaia de Manresa, Barcelona, España)