Predictive biomarkers in LCNS are particularly relevant given the high rates of EGFR activating mutations and AKT rearrangements in this population. In general, the presence and number of EGFR copies are predictive for survival with EGFR TKI therapy regardless of smoking status.22,23,32  Similarly, presence of the EML4-ALK fusion gene predicts response to crizotinib.22,26,28 Testing for each of these mutations is relevant to treatment choice and recommended for LCNS patients presenting with adenocarcinomas.22  

Treatment of NSCLC in Never-Smokers

There is little prospective data for chemotherapy outcomes based on smoking status.10 In a retrospective trial from MD Anderson Cancer Center, never smokers had a higher response rate after platinum-based chemotherapy or chemoradiation compared with current and former smokers, although never-smoking status significantly correlated with longer OS only in the chemotherapy group.10,33 In a cohort study, NSCLC patients with EGFR mutations (of whom 68% were never-smokers) had a higher response to chemotherapy than those with ALK rearrangement or wild-type genes.26 


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In analyses of response to gefitinib or erlotinib in the second-line setting, never-smokers have higher response rates than smokers and derive greater benefit from EGFR TKI therapy.10,23,34 The presence of EGFR exon 19 deletion conveys a particular survival benefit with TKI therapy in the second-line setting.24 In the ISEL study, which prospectively evaluated smoking status, previously treated never-smokers had better survival with gefitinib than placebo (P=0.012), but smokers derived no survival benefit from treatment (P=0.242). A greater treatment effect, as measured by time to treatment failure, was seen among never-smokers than among smokers.35 Erlotinib versus placebo in the second-line setting was evaluated in the BR.21 study, which prospectively evaluated smoking status. In this North American trial, erlotinib response was higher among never smokers than smokers.36  

Never-smokers also benefit from EGFR TKI treatment in the first-line setting. First-line gefitinib was compared with carboplatin/paclitaxel (C/P) in nonsmokers with advanced adenocarcinoma in IPASS, a study conducted across Asia (N=1217). In this study, 12-month progression-free survival was 24.9% with gefitinib and 6.7% with C/P (P<0.001); the benefit was highly dependent on the presence of EGFR mutations.37 The CALGB 30406 study evaluated erlotinib alone or combined with C/P in never or light former smokers with advanced lung adenocarcinoma patients in the United States (N=182). In EGFR-positive patients, erlotinib monotherapy had efficacy similar to the combination, but was less toxic. Both regimens significantly prolonged PFS and OS in EGFR-positive patients versus EGFR-negative patients.38

Crizotinib, an ALK inhibitor, was evaluated in previously treated NSCLC patients who were screened for the ALK rearrangement. Most were never-smokers (76%), had adenocarcinomas (96%), were not Asian (65%), and had received two or more previous therapies (59%).28  The overall response rate was 57%, and further analysis demonstrated that treatment with crizotinib improved survival in EML4-ALK–positive patients.28,39