Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 as first line treatment of advanced non-small cell lung cancer (NSCLC).

8016 Background: Paclitaxel/carboplatin (PC) is standard first line therapy for patients (pts) with Stage IIIB/IV NSCLC. PF- 3512676 (PF-676) is an oligodeoxynucleotide toll-like receptor 9 (TLR9) agonist. In a randomized phase 2 trial, addition of PF-676 to first line taxane/platinum chemotherapy produced a higher objective response rate and a trend toward improved overall survival (OS) in pts with advanced NSCLC. Confirmatory phase 3 trials were subsequently conducted.,Chemotherapy naive pts with Stage IIIB (pleural effusion) or Stage IV NSCLC, ECOG PS 0 or 1, measurable disease, adequate bone marrow, renal and hepatic function, no pre-existing autoimmune disease, no brain metastases and no chronic systemic corticosteroid therapy were included. All pts received P (200 mg/m) and C (AUC 6) IV on D1 of each 21 day cycle (max 6 cycles). In the investigational arm pts also received PF-676 (0.2 mg/kg) SC on D 8 and 15 of each chemotherapy cycle and weekly thereafter until progression. The primary endpoint was OS.,828 pts were randomized (409 PC + PF-676, 419 PC) from Dec '05 to April '07. Interim data reviewed by an external DSMC is reported. No increment in OS (98 deaths on PC + PF-676, 99 on PC [HR 0.971 95 % CI 0.76, 1.26]) or PFS (Median 4.6 mos on PC+PF-676, 4.4 mos on PC) was noted for the addition of PF-676. Many pts in the PF-676 arm experienced mild/moderate injection site reactions (65% [4 % G3/4]) or flu-like symptoms (50% [3 % G3/4]). G3/4/5 neutropenia and thrombocytopenia and septic episodes were reported more commonly in pts receiving PF-676 (63% vs 52%; 14% vs 6%; 4% vs 0.5%). The DSMC recommended termination of the trial due to lack of incremental efficacy and added toxicity. PF-676 administration was discontinued in all pts but collection of follow-up data continues. Updated results will be reported.,Addition of PF-676 to PC did not improve the outcome of pts with advanced NSCLC. Alternative development opportunities are being explored for TLR-9 agonists in the treatment of cancer. [Table: see text].