Phase III study comparing maintenance pemetrexed therapy with observation followed by pemetrexed therapy at progression in advanced NSCLC

The aim of the study was to investigate whether maintenance pemetrexed therapy prolongs survival for patients with advanced non-small-cell lung cancer (NSCLC). Until recently, standard therapy has been 3-4 courses of chemotherapy followed by observation and more chemotherapy at relapse. Two studies have demonstrated a survival benefit of maintenance pemetrexed therapy in advanced NSCLC, but there are important limitations to these studies, and the treatment regimens is debated: Few patients on the control-arms received pemetrexed at progression (pemetrexes is more effective than other chemotherapies in this setting), few elderly (> 70 years of age) and none with poor performance status (PS 2) were allowed. Median age at diagnosis of lung cancer is 70 years, and approximately 1/3 of patients have PS 2. Thus, we do not know whether maintenance therapy benefits a large proportion of lung cancer patients. Aims: (1) To investigate whether maintenance pemetrexed therapy prolongs survival compared with observation followed by second-line pemetrexed therapy at progression (2) Investigate whether elderly (> 70 years) and PS 2 patients tolerate and benefit from maintenance therapy (3) Compare health-related quality of life between treatment arms (4) Investigate what characterizes the patients who tolerate and benefit the most from maintenance therapy. In addition to patient reported outcomes, blood samples for analyses of circulating biomarkers are being collected for this part of the project. Patients with advanced NSCLC is a large and resource demanding group of patients with a limited prognosis. Thus, it is important to investigate whether new treatment prolongs survival and reduces symptom burden. We planned to enroll approximately 600 patients, but due to the introduction of immunotherapy for these patients, inclusion stopped at 250 patients. We will perform the planned analyses, but will have much lower statistical power for the primary endpoint than planned.

Chemonaive patients with stage IIB/IV non-squamous non-small-cell lung cancer are eligible provided PS 0-2; age > 18 years; measurable disease according to RECIST 1.1; adequate kidney, liver and bone marrow function; no activating EGFR-mutation or ALK-tra nslocation. Patients with non-progression after 4 courses of chemotherapy (carboplatin/vinorelbine) will be randomized to immediate pemetrexed maintenance therapy until progression (A -experimental arm) OR observation followed by second-line pemetrexed t herapy at progression (B - control arm). Pemetrexed will continue until progression (both arms). A CT scan will be performed before and after induction chemotherapy and then every 9 weeks during the observation period (Arm B) and during pemetrexed therap y (both arms) until progression. To show a difference in median overall survival (MOS) of 2 months (from 8 [A] to 6 [B] months), 198 patients are required on each arm. We expect to complete enrollment at 25 hospital in Norway in 30 months. Patients will report health-related quality of life before and after induction chemotherapy; then every 2 months until 2 years after randomization or (death) - enabling us to do cost-benefit analyses and assess patients' functional levels during maintenance therapy. Blood samples for translational research will be collected before and after induction chemotherapy; 2 months after randomization (both arms) and when patients progress during pemetrexed therapy. The study is an investigator-initated trial by the Norwegia n Lung Cancer Study Group - which consists of physicians and researchers from all medical disciplines and most hospitals involved in diagnosis, staging and treatment of lung cancer - including all university hospitals in Norway. This ensures that the resu lts of the study will have impact on future guidelines for treatment of advanced NSCLC.