OBJECTIVES: EGFR mutations are found in 10-20% of Caucasian patients with NSCLC and patients who initially benefit from targeted therapies develop resistance within 9-13 months of therapy. We systematically reviewed published clinical evidence to assess the effectiveness and safety of available agents in refractory EGFR-mutant NSCLC.

METHODS: Medline, Embase, and Cochrane databases were systematically searched for randomized controlled trials (RCTs) in refractory EGFR-mutant NSCLC published during January 2007-October 2017. 11,708 records were reviewed; 261 full papers screened of which 11 were relevant.

RESULTS: Eleven publications reported data on 10 RCTs in refractory EGFR-mutant NSCLC. Of the 10 RCTs, 3 included patients with ≥1 prior therapy, 4 RCTs with ≥2 prior therapies, and 3 RCTs with 0 to ≥3 prior therapies. Four RCTs focused on addition of tyrosine kinase inhibitors (TKIs; afatinib [1], erlotinib [2], gefitinib [1]) to chemotherapy or another TKI (cabozantinib); four on TKI monotherapy (afatinib [1], dacomitinib [1], osimertinib [2]); two included EGFR-mutant subgroups receiving programmed-death-ligand-1 inhibitors (PD-L1; nivolumab, pembrolizumab). Five of eight studies reporting progression free survival (PFS) showed significant improvement versus comparator: 2.7-10.2 months treatment versus 1.1-5.4 months comparator. In 5 RCTs that reported overall survival (OS), the comparator arm reported higher [4] or the same [1] median OS than the treatment arm: 7.2-14.2 months treatment vs. 7.5-19.5 months comparator. Neutropenia was observed only when TKIs were combined with chemotherapy, with 14% Grade 4 neutropenia noted in erlotinib+pemetrexed group. 30.8% patients receiving erlotinib+cabozantinib reported diarrhea, the highest rate across all selected RCTs. While <1% of patients reported grade ≥3 adverse events in PD-L1 RCTs, an improvement in efficacy versus docetaxel monotherapy was not demonstrated in these patient subsets.

CONCLUSIONS: Although several therapies tested in RCTs showed a significant improvement in PFS, none demonstrated OS benefit versus a chemotherapy comparator in a population with refractory EGFR-mutant NSCLC.