PARAMOUNT trial

Abstract: Summary Background Patients with advanced non-squamous non-small-cell lung cancer (NSCLC) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing, non-pemetrexed doublet. The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin. Methods In this double-blind, multicentre, phase 3, randomised placebo-controlled trial, patients with advanced non-squamous NSCLC aged 18 years or older, with no previous systemic chemotherapy for lung cancer, with at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 participated. Before randomisation, patients entered an induction phase which consisted of four cycles of induction pemetrexed (500 mg/m 2 ) plus cisplatin (75 mg/m 2 ) on day 1 of a 21-day cycle. Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 were stratified according to disease stage (IIIB or IV), ECOG performance status (0 or 1), and induction response (complete or partial response, or stable disease), and randomly assigned (2:1 ratio) to receive maintenance therapy with either pemetrexed (500 mg/m 2 every 21 days) plus best supportive care or placebo plus best supportive care until disease progression. Randomisation was done with the Pocock and Simon minimisation method. Patients and investigators were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00789373. Findings Of the 1022 patients enrolled, 939 participated in the induction phase. Of these, 539 patients were randomly assigned to receive continuation maintenance with pemetrexed plus best supportive care (n=359) or with placebo plus best supportive care (n=180). Among the 359 patients randomised to continuation maintenance with pemetrexed, there was a significant reduction in the risk of disease progression over the placebo group (HR 0·62, 95% CI 0·49–0·79; p vs none in the placebo group) and febrile neutropenia (five [1%] vs none). Discontinuations due to drug-related adverse events occurred in 19 (5%) patients in the pemetrexed group and six (3%) patients in the placebo group. Interpretation Continuation maintenance with pemetrexed is an effective and well tolerated treatment option for patients with advanced non-squamous NSCLC with good performance status who have not progressed after induction therapy with pemetrexed plus cisplatin. Funding Eli Lilly and Company.

Abstract: The search for new agents and for innovative strategies is warranted in the treatment of advanced non small cell lung cancer (NSCLC) because the outcomes remain unsatisfactory for most patients. Maintenance treatment with either a chemotherapeutic agent or a molecularly targeted agent after first-line chemotherapy is a very interesting strategy that has been largely investigated in the last years. Maintenance treatment can consist of drugs included in the induction regimen (continuation maintenance) or other non-cross-resistant agents not included in the induction regimen (switch maintenance). The switch maintenance strategy with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor erlotinib (in all the histologies) or with pemetrexed (in non-squamous histologies) have been demonstrated to be two possible effective options versus the classic break from cytotoxic chemotherapy after a fixed course in the treatment of advanced NSCLC. However some biases may have influenced the outcomes of switch maintenance trials as the low rate of patients treated with erlotinib and pemetrexed in the placebo arms. Very recently, a randomized phase III trial named PARAMOUNT has demonstrated a clinically significant benefit in overall survival with a good safety profile versus placebo in favour of continuation maintenance with pemetrexed after four cycles of induction with cisplatin plus pemetrexed. Continuation maintenance can be considered the true maintenance strategy because switch maintenance is an early second-line treatment. Continuation maintenance with pemetrexed after cisplatin plus pemetrexed induction for patients selected for a maintenance strategy is recommended as first-line treatment of advanced non-squamous NSCLC.

Abstract: TO THEEDITOR:Paz-Aresetal 1 reportedintheAugust10issueof Journal of Clinical Oncology the updated survival analysis for the PARAMOUNT trial, which explored continuous maintenance treatment with pemetrexed compared with placebo after platinum-based chemotherapy. The results presented are impressive, with a median overall survival of 16 months and a 3-month significant increase in survival compared with the control. This overall survival result is 4 monthsgreaterthaninthestudybyScagliottietal, 2 atrialthatusedthe same cisplatin/pemetrexed doublet (up to six cycles) in patients with advancedNSCLCandaperformancestatusof0to1,whichisasimilar population to that in the PARAMOUNT trial. In particular, the benefit of pemetrexed maintenance was obtained with only a slight increase in overall toxicity and with no worsening of quality of life. Approximately 70% of randomly assigned patients received secondline therapies after progression of the disease. How should the results of the PARAMOUNT trial be interpreted? Are the results because of pemetrexed or because of a strategy effect? These results were obtained in a setting in which other agents failed to show a survival benefit when used for continuous maintenance therapy (gemcitabine, for example 3,4 ). Subsequently, a metaanalysis of maintenance trials confirmed only a progression-free but not an overall survival advantage with a continuous maintenance strategy. 5 Is it possible that pemetrexed, but not other drugs, could replicate this outcome in any future prospective randomized trial? Another consideration concerns the selection of the enrolled patients.Amongthe939initiallytreatedpatients,68%hadcompleted fourcyclesofinductionchemotherapyandwerenotprogressing;they were therefore randomly assigned to the maintenance phase. In total, 539 patients were effectively randomly assigned to pemetrexed or observation (58% of the total initial population). It is possible that a highly select group of patients with an excellent performance status could lead to this very good outcome. Only 38.3% of the initial population received any salvage therapy after progression (67% of the randomly assigned patients). Is this a natural and favorable selection process that permits some lucky patients to derive the greatest benefit from any form of treatment, including continuous maintenance? Third, in this trial, the authors observed a postprogression survival (calculated from the date of progression until death) of approximately10months.Theoverallsurvivalofpatientswithaperformance