Herbst RS, et al. - EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. Researchers presumed that patients most likely to benefit from these drugs combined with chemotherapy can be identified by EGFR copy number by fluorescence in-situ hybridisation (FISH). Additionally, in EGFR FISH-positive patients with advanced NSCLC, the activity of cetuximab with chemotherapy was explored. Despite the failure to meet primary endpoints, this study demonstrated that prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers were encouraging and supported continued assessment of anti-EGFR antibodies in this subpopulation.

Methods

• Researchers carried out this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico.
• Eligible patients with treatment-naive stage IV NSCLC were randomly assigned (1:1) to receive paclitaxel (200 mg/m²; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m² weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm.
• Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population were the co-primary endpoints.
• Clinical outcomes were analyzed with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug.

Results

• Between Aug 13, 2009, and May 30, 2014, a total of 1313 patients were randomly assigned to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population).
• In a total of 976 patients, EGFR FISH was assessable and 400 patients (41%) were found to be EGFRFISH-positive.
• Data reported that 35·2 months was the median follow-up for patients last known to be alive (IQR 22·9–39·9).
• Researchers noted that after 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, there was no difference in the progression-free survival between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75–1·12; p=0·40; median 5·4 months [95% CI 4·5–5·7] vs 4·8 months [3·9–5·5]).
• After 570 and 593 deaths in the cetuximab and control group, respectively, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83–1·04; p=0·22; median 10·9 months [95% CI 9·5–12·0] vs 9·2 months [8·7–10·3]).
• In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, it was evident that overall survival in the cetuximab group was significantly longer as compared with the control group (HR 0·58, 95% CI 0·36–0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46–1·01; p=0·055).
• Findings demonstrated that there was no difference in overall survival and progression-free survival among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78–1·40; p=0·77; and 1·02, 0·77–1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68–1·14; p=0·34; and 0·99, 0·78–1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85–1·17; p=0·97; and 1·03, 0·88–1·20; p=0·69; respectively).
• Decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [<1%]) were documented as the most common grade 3–4 adverse events.
• Severe adverse events were reported in 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group.
• Additionally, occurrence of treatment-related deaths was reported in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group.