Cetuximab and First-Line Taxane/Carboplatin Chemotherapy in Advanced Non–Small-Cell Lung Cancer: Results of the Randomized Multicenter Phase III Trial BMS099

Abstract

PURPOSE To evaluate the efficacy of cetuximab plus taxane/carboplatin (TC) as first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This multicenter, open-label, phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or IV NSCLC, without restrictions by histology or epidermal growth factor receptor expression. Patients were randomly assigned to cetuximab/TC or TC. TC consisted of paclitaxel (225 mg/m(2)) or docetaxel (75 mg/m(2)), at the investigator's discretion, and carboplatin (area under the curve = 6) on day 1 every 3 weeks for < or = six cycles; cetuximab (400 mg/m(2) on day 1, 250 mg/m(2) weekly) was administered until progression or unacceptable toxicity. The primary end point was progression-free survival assessed by independent radiologic review committee (PFS-IRRC); overall response rate (ORR), overall survival (OS), quality of life (QoL), and safety were key secondary end points. PFS and ORR assessed by investigators were also evaluated. Results Median PFS-IRRC was 4.40 months with cetuximab/TC versus 4.24 months with TC (hazard ratio [HR] = 0.902; 95% CI, 0.761 to 1.069; P = .236). Median OS was 9.69 months with cetuximab/TC versus 8.38 months with TC (HR = 0.890; 95% CI, 0.754 to 1.051; P = .169). ORR-IRRC was 25.7% with cetuximab/TC versus 17.2% with TC (P = .007). The safety profile of this combination was manageable and consistent with its individual components. CONCLUSION The addition of cetuximab to TC did not significantly improve the primary end point, PFS-IRRC. There was significant improvement in ORR by IRRC. The difference in OS favored cetuximab but did not reach statistical significance.

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“…Cetuximab is a chimeric human-murine monoclonal IgG1 antibody that binds to the extracellular domain of EGFR and inhibits ligand binding, dimerization and ultimately its activation. Cetuximab has shown efficacy in treating HNSCC, mCRC and NSCLC however, several clinical studies have shown that intrinsic and acquired resistances are common (27)(28)(29)(30)(31)(32). Determining why tumors are initially resistant to cetuximab or develop resistance during the course of therapy represents a major clinical challenge.…”

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“…39,40 In the clinical settings, no studies have been conducted using cetuximab as a single agent in previously untreated patients with advanced NSCLC, 41 and the efficacy of cetuximab plus taxane/carboplatin as first-line treatment of advanced NSCLC has been significant but only partial. 42,43 Biomarker studies still yet to define the profile of cetuximab sensitivity and resistancy. 44 These collectively suggest that EGFR signal still survives cetuximab treatment in the tumor populations.…”

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“…Despite a significant benefit in RR, no statistically significant benefit was observed with respect to either PFS (HR, 0.902; 95% CI, 0.761-1.069; p ϭ .236) or OS (HR, 0.890; 95% CI, 0.754 -1.051; p ϭ .169) [34]. Even though the study probably lacked the statistical power to show an OS benefit, the magnitude of the OS benefit was similar in the FLEX and BMS 099 trials.…”

“…In a parallel randomized phase III trial (BMS 099), 676 chemotherapy-naïve patients, without restrictions by histology or EGFR expression, were treated with carboplatin plus a taxane (either paclitaxel or docetaxel depending on investigator preference) with or without cetuximab [34]. Despite a significant benefit in RR, no statistically significant benefit was observed with respect to either PFS (HR, 0.902; 95% CI, 0.761-1.069; p ϭ .236) or OS (HR, 0.890; 95% CI, 0.754 -1.051; p ϭ .169) [34].…”