pf-3512676 and Lung-Neoplasms

After several decades of modest results with nonspecific immune stimulants, immunotherapy has become an exciting approach in the treatment of cancer. Although non-small-cell lung cancer has not been considered an immunogenic disease for very long, a better understanding of tumor immunology and the identification of new targets have led to the development of many clinical trials of immune-based therapies for this neoplasm. Promising results from many clinical trials suggest that immunotherapy could be an effective strategy in the management of advanced non-small-cell lung cancer. Further studies are required to help clinicians in the selection of patients who are more likely to benefit from immunotherapy strategies by the identification of biomarkers and to understand when the combination of immunotherapy with other agents should be recommended.

Topics: Antibodies, Monoclonal; Cancer Vaccines; Carcinoma, Non-Small-Cell Lung; CTLA-4 Antigen; Cytokines; Humans; Immunotherapy; Ipilimumab; Lung Neoplasms; Molecular Targeted Therapy; Nivolumab; Oligodeoxyribonucleotides; Programmed Cell Death 1 Receptor; Toll-Like Receptor 9

This phase 2 study assessed PF-3512676 plus erlotinib in patients with epidermal growth factor receptor-positive advanced non-small cell lung cancer after prior chemotherapy failure. Patients were randomized 1:1 to PF-3512676 (0.20 mg/kg injected subcutaneously once weekly) plus erlotinib (150 mg daily) or erlotinib alone. The primary objective was to estimate progression-free survival (PFS). Patients received PF-3512676 plus erlotinib (n = 18) or erlotinib alone (n = 21). The study was halted because an unplanned interim analysis indicated that large improvement in PFS with addition of PF-3512676 would be unlikely. In the PF-3512676-plus-erlotinib and erlotinib-alone arms, median PFS was 1.6 and 1.7 mo (hazard ratio, 1.00; 95% confidence interval, 0.5-2.0; P = 0.9335), respectively. Salient grade ≥ 3 adverse events in PF-3512676-plus-erlotinib and erlotinib-alone arms were diarrhea (5/0), dyspnea (5/6), fatigue (4/1), other flu-like symptoms (2/0), anemia (2/1), and lymphocytopenia (based on laboratory values, 1/4). Adding PF-3512676 to erlotinib did not show potential for increased progression-free survival over erlotinib alone in patients with advanced recurrent epidermal growth factor receptor-positive non-small cell lung cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms; Male; Middle Aged; Oligodeoxyribonucleotides; Protein Kinase Inhibitors; Quinazolines; Toll-Like Receptor 9

This open-label phase III study assessed the addition of Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 to gemcitabine/cisplatin chemotherapy in patients with non-small-cell lung cancer (NSCLC).. Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomized (1:1) to receive six or fewer 3-week cycles of i.v. gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin alone (75 mg/m2 on day 1, control arm) or combined with s.c. PF-3512676 0.2 mg/kg on days 8 and 15 of each chemotherapy cycle and weekly thereafter until progression or unacceptable toxicity (experimental arm). No crossover was planned. The primary end point was overall survival (OS).. A total of 839 patients were randomized. Baseline demographics were well balanced. Median OS (11.0 versus 10.7 months; P=0.98) and median progression-free survival (PFS) (both 5.1 months) were similar between groups. Grade≥3 hematologic adverse events (AEs), injection-site reactions, and influenza-like symptoms were more frequently reported among patients receiving PF-3512676. At the first-interim analysis, the Data Safety Monitoring Committee recommended study discontinuation. Administration of PF-3512676 was halted based on efficacy futility and increased grade≥3 AEs (experimental arm).. Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Disease-Free Survival; Female; Gemcitabine; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Oligodeoxyribonucleotides; Proportional Hazards Models

This phase III study examined efficacy of the synthetic Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 in combination with standard paclitaxel/carboplatin chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).. Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomly assigned (1:1) to receive up to six courses of paclitaxel/carboplatin (intravenous paclitaxel 200 mg/m(2) and carboplatin at area under the [concentration-time] curve 6 on day 1 of a 3-week cycle) alone (control arm) or in combination with 0.2 mg/kg subcutaneous PF-3512676 on days 8 and 15 (investigational arm). Primary end point was overall survival (OS).. Baseline demographics were similar across arms (N = 828). Most patients (88%) had stage IV disease. Median OS and median progression-free survival (PFS) were similar (OS: investigational arm, 10.0 months v control arm, 9.8 months; P = .56; PFS: investigational arm, 4.8 months v control arm, 4.7 months; P = .79). Most commonly reported PF-3512676-related adverse events (AEs) were mild-to-moderate local injection site reactions, pyrexia, and flu-like symptoms. In the investigational arm, grades 3 to 4 AEs, including neutropenia, thrombocytopenia, and anemia, were more frequent, and more patients had one or more sepsis-related AEs versus controls (17 v 3). At first interim analysis, the Data Safety Monitoring Committee recommended study discontinuation because of lack of incremental efficacy and more sepsis-related serious AEs in the PF-3512676 arm. Administration of PF-3512676, but not chemotherapy, was halted.. Addition of PF-3512676 to paclitaxel/carboplatin did not improve OS or PFS versus paclitaxel/carboplatin alone for first-line treatment of patients with advanced NSCLC but did increase toxicity. This regimen cannot be recommended for treating patients with advanced NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease Progression; Female; Humans; Lung Neoplasms; Male; Middle Aged; Oligodeoxyribonucleotides; Paclitaxel; Toll-Like Receptor 9; Treatment Outcome

This phase I, open-label study investigated the Toll-like receptor 9 agonist, PF-3512676, in combination with carboplatin and paclitaxel in Japanese patients with advanced, non-small-cell lung cancer (NSCLC). Patients (n = 12) with treatment-naive stage IIIB or IV NSCLC received single-agent PF-3512676 subcutaneously once during the first 7 days (monotherapy phase) in three escalating dose levels (0.1, 0.2, and 0.4 mg/kg) followed by a combination phase during which patients received 0.1 or 0.2 mg/kg PF-3512676 subcutaneously on days 8 and 15 of each 3-week cycle of carboplatin (area under the curve, 6 mg x min/mL) and paclitaxel (200 mg/m(2)). Safety and pharmacokinetics of PF-3512676 were assessed during monotherapy and combination therapy phases. PF-3512676 was tolerable as monotherapy or in combination with chemotherapy in patients with NSCLC. Most common treatment-related, non-hematologic adverse events (AEs) throughout the study were injection-site reactions (n = 12, 100%) and flu-like symptoms (n = 11, 91.7%) that were each grade 1 or 2 in all but one patient. All patients experienced neutropenia and leukopenia (>or=grade 3 in 11 [91.7%] and seven [58.3%] patients, respectively). One patient in dose level 2 had a dose-limiting toxicity: grade 3 rash and grade 3 increase in gamma-glutamyltransferase during combination therapy. Mean PF-3512676 half-life ranged from 4.8 to 21.6 h (longer with higher doses). Four (33%) patients had objective responses (one complete response, three partial responses), and seven (58%) patients achieved stable disease. PF-3512676 as monotherapy and in combination with chemotherapy had an acceptable safety profile in Japanese patients with treatment-naive NSCLC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Oligodeoxyribonucleotides; Paclitaxel; Toll-Like Receptor 9

This study assessed the efficacy of the combination of standard taxane plus platinum chemotherapy with the synthetic Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 in patients with non-small-cell lung cancer (NSCLC).. Chemotherapy-naive patients with stage IIIB to IV NSCLC were randomly assigned (one to two ratio) to receive four to six cycles of taxane/platinum chemotherapy alone or with 0.2 mg/kg of subcutaneous PF-3512676 on days 8 and 15 of each 3-week cycle. The primary end point was objective response rate (ORR).. Baseline demographics were similar between treatment arms, although significantly more patients in the PF-3512676 arm had stage IV disease (85% compared with 62% in the chemotherapy-alone arm). The modified intent-to-treat analysis (n = 111) demonstrated a 38% ORR (confirmed and unconfirmed) in the PF-3512676 arm (n = 74) and 19% in the chemotherapy-alone arm (n = 37) by investigator evaluation. Blinded, independent radiologic review for 90 patients showed a similar trend in confirmed response rate (19% and 11%, respectively). Median survival was 12.3 months in the PF-3512676 arm and 6.8 months in the chemotherapy-alone arm, and 1-year survival was 50% and 33%, respectively. Mild to moderate local injection site reactions and flu-like symptoms were the most common PF-3512676-related adverse events, but grade 3/4 neutropenia, thrombocytopenia, and anemia were all reported more commonly for patients in the PF-3512676 arm.. The addition of PF-3512676 to taxane plus platinum chemotherapy for first-line treatment of NSCLC improves objective response and may improve survival. Confirmatory phase III trials are ongoing.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Docetaxel; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Oligodeoxyribonucleotides; Paclitaxel; Taxoids; Toll-Like Receptor 9

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Oligodeoxyribonucleotides