There does not appear to be an established third-line (or beyond) treatment option for patients with advanced NSCLC; most patients in practice will receive BSC. 

The Phase III BR.21 study showed that erlotinib was associated with an overall absolute increase in survival of 2.0 months compared to BSC, in the treatment of patients with advanced NSCLC who had received one or two previous lines of therapy.  For those being treated third-line (49%), the difference was 2.2 months (median of 6.8 months in the erlotinib group and 4.6 months in the placebo group; HR of 0.75; 95% CI 0.6-1.0; p=0.02).  Although not powered to detect statistically significant differences in subgroups, exploratory analyses suggested that a number of characteristics may be associated with improved response to erlotinib, including female sex, adenocarcinoma and never having smoked (only the latter was found to be a significant predictor of survival).  Further analyses showed that EGFR mutations were associated with an increased response rate; the difference in overall survival did not however meet statistical significance (HR 0.55; p=0.12).  Only 1% of the study population were treated after receiving three previous lines of therapy (i.e. as fourth-line) and it therefore does not provide any evidence of the use of erlotinib in this setting.

This study was conducted prior to the introduction of new agents for the treatment of NSCLC, and it is unclear how the results would apply to patients who have received previous treatment with such agents, for example gefitinib.  Also would patients who have been previously treated with erlotinib second-line, according to NICE guidance, be eligible for rechallenge in the third-line setting?  

NICE has recommended the use of erlotinib only in the second-line treatment of NSCLC in patients who would otherwise be eligible for docetaxel treatment, and where the costs of providing the treatments are equal (provided on a discounted basis by Roche). It does not consider erlotinib to be a cost-effective use of NHS resources if used as third-line treatment (£54,200 per QALY gained), and compared to BSC.  

As the standard third-line treatment in practice would be BSC, there are no data available on the number of people reaching this stage who would possibly be eligible for treatment with erlotinib.  Based on an estimation of 7 eligible patients per 100,000 population, use of erlotinib as a third-line therapy would be associated with a drug cost of approximately £25,500 per 100,000 population.