Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib.
PURPOSE: In patients with epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma, treatment with erlotinib or gefitinib is associated with a 75% radiographic response rate and progression-free survival of approximately 12 months. The most common mechanism of acquired resistance to erlotinib is development of a secondary mutation in EGFR, suggesting that these tumors continue to depend on EGFR signaling. We hypothesized that combined EGFR blockade would overcome acquired resistance to erlotinib in patients with lung adenocarcinoma. To evaluate the toxicity and efficacy of cetuximab and erlotinib in patients with acquired resistance to erlotinib, we conducted this phase I/II clinical trial. EXPERIMENTAL DESIGN: Patients with lung adenocarcinoma and clinically defined acquired resistance to erlotinib were treated with erlotinib 100 mg daily, along with cetuximab every 2 weeks in three escalating dose cohorts (250 mg/m(2), 375 mg/m(2), and 500 mg/m(2)). The recommended phase II dose was then evaluated in a two-stage trial, with a primary end point of objective response rate. RESULTS: A total of 19 patients were enrolled. The most common toxicities for the combination of cetuximab and erlotinib were rash, fatigue, and hypomagnesemia. The recommended phase II dose identified was cetuximab 500 mg/m(2) every 2 weeks and erlotinib 100 mg daily. At this dose and schedule, no radiographic responses were seen (0 of 13, 0%, 95% CI, 0-25). CONCLUSIONS: Combined EGFR inhibition, with cetuximab 500 mg/m(2) every 2 weeks and erlotinib 100 mg daily, had no significant activity in patients with acquired resistance to erlotinib.