Gemcitabine and Cisplatin as Treatment of Advanced NSCLC
Background: 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).
Patients and methods: 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/m on days 1 and 8) and cisplatin alone (75 mg/m 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).
Results: 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).
Conclusions: Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.
Platinum-based two-drug chemotherapy is a standard first-line treatment of patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). This therapeutic approach is associated with response rates ranging from 19% to 37%, median survival ranging from 7 to 10 months, and 1-year survival rate of <45%. Addition of bevacizumab or cetuximab to platinum-based chemotherapy has demonstrated modest improvements in overall survival (OS) in patients with NSCLC. More effective therapeutic modalities for patients with newly diagnosed NSCLC are needed.
Toll-like receptor (TLR) agonists stimulate both innate and adaptive immune responses. PF-3512676 is a synthetic oligodeoxynucleotide that binds specifically to TLR9, thereby triggering a cascade of immune reactions that have the potential to promote an effective antitumor immune response. PF-3512676 was active as monotherapy in patients with metastatic melanoma, advanced renal cell carcinoma, and cutaneous T-cell lymphoma; likewise, in the Lewis murine model for lung carcinoma, PF-3512676 plus paclitaxel demonstrated substantially improved survival compared with control therapy. In a randomized phase II study in chemotherapy-naive patients (n = 111) with stage IIIB or IV NSCLC, PF-3512676 combined with platinum-based chemotherapy demonstrated a significantly higher response rate (38% versus 19%; P = 0.043) compared with chemotherapy alone. OS was also prolonged (12.3 versus 6.8 months; P = 0.188), although the difference was not statistically significant.
Based on these data, two randomized phase III studies were initiated in chemotherapy-naive patients with stage IIIB or IV NSCLC. One study examined PF-3512676 combined with paclitaxel and carboplatin, and the study described in this report examined PF-3512676 combined with gemcitabine and cisplatin.
Abstract and Introduction
Abstract
Background: 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).
Patients and methods: 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/m on days 1 and 8) and cisplatin alone (75 mg/m 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).
Results: 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).
Conclusions: Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.
Introduction
Platinum-based two-drug chemotherapy is a standard first-line treatment of patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). This therapeutic approach is associated with response rates ranging from 19% to 37%, median survival ranging from 7 to 10 months, and 1-year survival rate of <45%. Addition of bevacizumab or cetuximab to platinum-based chemotherapy has demonstrated modest improvements in overall survival (OS) in patients with NSCLC. More effective therapeutic modalities for patients with newly diagnosed NSCLC are needed.
Toll-like receptor (TLR) agonists stimulate both innate and adaptive immune responses. PF-3512676 is a synthetic oligodeoxynucleotide that binds specifically to TLR9, thereby triggering a cascade of immune reactions that have the potential to promote an effective antitumor immune response. PF-3512676 was active as monotherapy in patients with metastatic melanoma, advanced renal cell carcinoma, and cutaneous T-cell lymphoma; likewise, in the Lewis murine model for lung carcinoma, PF-3512676 plus paclitaxel demonstrated substantially improved survival compared with control therapy. In a randomized phase II study in chemotherapy-naive patients (n = 111) with stage IIIB or IV NSCLC, PF-3512676 combined with platinum-based chemotherapy demonstrated a significantly higher response rate (38% versus 19%; P = 0.043) compared with chemotherapy alone. OS was also prolonged (12.3 versus 6.8 months; P = 0.188), although the difference was not statistically significant.
Based on these data, two randomized phase III studies were initiated in chemotherapy-naive patients with stage IIIB or IV NSCLC. One study examined PF-3512676 combined with paclitaxel and carboplatin, and the study described in this report examined PF-3512676 combined with gemcitabine and cisplatin.