Study Finds Cabozantinib Alone or With Erlotinib Improves Outcome in EGFR Wild-Type NSCLC


Key Points

  • Progression-free survival was significantly prolonged with cabozantinib alone or combined with erlotinib vs erlotinib alone in patients with advanced nonsquamous EGFR wild-type NSCLC.
  • Toxicity was increased with cabozantinib and combination treatment.

Treatment with the multikinase inhibitor cabozantinib (Cabometyx) alone or with erlotinib (Tarceva) improved progression-free survival vs erlotinib alone in second- or third-line treatment of advanced nonsquamous epidermal growth factor receptor (EGFR) wild-type non–small cell lung cancer (NSCLC), according to the phase II ECOG-ACRIN 1512 trial reported by Neal et al in The Lancet Oncology.

Study Details

In the open-label trial, 111 evaluable patients (per-protocol population) from 37 U.S. sites were randomized between February 2013 and July 2014 to receive erlotinib at 150 mg/d (n = 38), cabozantinib at 60 mg/d (n = 38), or erlotinib at 150 mg/d plus cabozantinib at 40 mg/d (n = 35). Imaging was performed every 8 weeks. Patients in either single-agent group had the option to cross over to combination treatment at radiographic disease progression. The primary endpoint was comparison of progression-free survival with erlotinib alone vs cabozantinib alone and combination treatment.

Progression-Free Survival

Median follow-up was 17.0 months. Median progression-free survival was 1.8 months in the erlotinib group vs 4.3 months in the cabozantinib group (hazard ratio [HR] = 0.39, P = .0003) and 4.7 months in the combination group (HR = 0.37, P = .0003). Median overall survival was 5.1 months in the erlotinib group vs 9.2 months in the cabozantinib group (HR = 0.68, P = .071) and 13.3 months in the combination group (HR = 0.51, P = .001).

Adverse Events

The most common grade 3 or 4 adverse events were diarrhea (8% in the erlotinib group vs 8% in the cabozantinib group vs 28% in the combination group), hypertension (0% vs 25% vs 3%), fatigue (13% vs 15% vs 15%), oral mucositis (0% vs 10% vs 3%), and thromboembolic event (0% vs 8% vs 5%). One patient in the cabozantinib group died of respiratory failure considered possibly related to treatment. One patient in the combination group died of pneumonitis considered related to either drug or the combination.

The investigators concluded: “Despite its small sample size, this trial showed that, in patients with EGFR wild-type NSCLC, cabozantinib alone or combined with erlotinib has clinically meaningful, superior efficacy to that of erlotinib alone, with additional toxicity that was generally manageable. Cabozantinib-based regimens are promising for further investigation in this patient population.”

The study was funded by the ECOG-ACRIN Cancer Research Group and the National Cancer Institute.

Joel W. Neal, MD, of Stanford Cancer Institute, is the corresponding author of The Lancet Oncology article.

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