Addition of Linifanib to Carboplatin-Paclitaxel Increases Progression-Free Survival and Toxicity in Advanced Nonsquamous NSCLC


Key Points

  • The addition of linifanib significantly increased progression-free survival in the linifanib 7.5-mg group.
  • Linifanib treatment was associated with greater toxicity.

In a phase II trial reported in Journal of Clinical Oncology, Ramalingam et al found that the addition of the VEGFR and PDGFR inhibitor linifanib to carboplatin-paclitaxel increased progression-free survival in patients with advanced nonsquamous non–small cell lung cancer (NSCLC). The addition of linifanib resulted in greater toxicity.

Study Details

In the study, 138 patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned between September 2009 and December 2010 to receive 3-week cycles of carboplatin (AUC 6) and paclitaxel (200 mg/m2) plus daily placebo (n = 47), linifanib 7.5 mg (n = 44), or linifanib 12.5 mg (n = 47). Patients had a median age of 61 years, 57% were male, and 84% were smokers; 92% to 96% had metastatic disease. The primary endpoint was progression-free survival.

Progression-Free Survival

Median progression-free survival was 5.4 months (95% confidence interval [CI] = 4.2–5.7 months) in the placebo group, 8.3 months (95% CI = 4.2–10.8 months) in the lower-dose linifanib group (hazard ratio [HR] = 0.51, P = .022, vs placebo), and 7.3 months (95% CI = 4.6–10.8 months) in the higher-dose linifanib group (HR = 0.64, P = .118, vs placebo). Median overall survival was 11.3, 11.4 (HR = 1.08, P = .779), and 13.0 months (HR = 0.88, P = .650). A baseline CEA/CYFRA 21-1 biomarker signature was associated with improved progression-free survival in the linifanib 7.5-mg group (HR = 0.49, P = .049) and 12.5-mg group (HR = 0.38, P = .029).

Adverse Events

Adverse events occurring in ≥ 10% of patients that were significantly more common with linifanib treatment (P < .05) were diarrhea, anemia, hypertension, dysphonia, decreased weight, and palmar-plantar erythrodysesthesia. Grade 3 or 4 adverse events occurred in 57% of the placebo group, 86% of the linifanib 7.5-mg group, and 72% of the linifanib 12.5-mg group, and serious adverse events occurred in 34%, 59%, and 53%.

Thrombocytopenia was the only grade 3 or 4 event that was significantly more common in linifanib patients (2%, 17%, and 30%) and was the most common reason for treatment interruption or dose reduction of carboplatin and paclitaxel. Thrombocytopenia, diarrhea, and palmar-plantar erythrodysesthesia were the most common causes of linifanib interruption or dose reduction. Adverse events leading to death were considered possibly related to linifanib in one patient receiving 7.5 mg (respiratory failure) and one receiving 12.5 mg (neutropenic sepsis).

The investigators concluded: “Addition of linifanib to chemotherapy significantly improved [progression-free survival] ([linifanib 7.5 mg group]), with a modest trend for survival benefit ([linifanib 12.5 mg group]) and increased toxicity reflective of known VEGF/PDGF inhibitory effects.”

Suresh S. Ramalingam, MD, of Winship Cancer Institute of Emory University, is the  corresponding author for the Journal of Clinical Oncology article.

The study was supported by AbbVie. For full disclosures of the study authors, visit

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