Tetracyclines increase the survival of NSCLC patients treated with EGFR TKIs: a retrospective nationwide registry study

BACKGROUND: With the first and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), clinical benefit and rash correlate together. EGFR TKI-induced rash can be alleviated with tetracyclines, but it is unknown whether the use of tetracyclines can increase the survival of non-small-cell lung cancer (NSCLC) patients treated with EGFR TKIs. METHODS: We collected all the patients (n=1271) who had reimbursement for EGFR TKIs (gefitinib, erlotinib and afatinib) in Finland 2011–2016, had purchased TKIs, and had data available at nationwide cancer registry. The survival was analysed from the first EGFR TKI purchase to death or end-of follow-up, and patients were stratified according to TKIs, purchases of antibiotics, their ATC class and timing. RESULTS: 802 (63.1%) patients had antibiotic purchases −14 to +200 days from the first EGFR TKI purchase, 447 of these tetracyclines. 322 (25.3%) had had purchased antibiotics −14 to +14 days (prophylaxis) from the first EGFR TKI purchase, 188 of these tetracyclines. Purchase of antibiotics was associated with improved survival (HR 0.80, 95% CI 0.71 to 0.91), which limited to tetracycline purchases only (HR 0.72, 95% CI 0.64 to 0.82). The largest survival benefit was seen with the prophylactic use of tetracyclines (HR 0.74, 95% CI 0.62 to 0.88). The benefit from tetracyclines was limited to erlotinib only (HR 0.68, 95% CI 0.58 to 0.78) which was retained in multivariate analysis. Prophylactic use of tetracyclines was associated with a longer erlotinib treatment duration (HR 0.81, 95% CI 0.61 to 0.96) but not with dose reductions or treatment breaks. CONCLUSIONS: Tetracyclines improve the survival of NSCLC patients treated with the first and second-generation EGFR TKIs and they should be considered as a prophylaxis when initiating EGFR TKIs with high incidence of rash.