Clinical significance of heterogeneity in response to retreatment with epidermal growth factor receptor tyrosine kinase inhibitors in patients with lung cancer acquiring secondary resistance to the drug.

Background: In patients with lung cancer acquiring resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), an intrapatient heterogeneity in response to retreatment with EGFR-TKIs remains to be elucidated.

Patients And Methods: Records were retrospectively reviewed for 68 patients with advanced non-small-cell lung cancer who received second EGFR-TKIs after systemic progression that followed durable response to the first EGFR-TKIs. All tumor lesions identified on radiologic images before second EGFR-TKIs were categorized into organs. Tumor response to EGFR-TKIs was assessed per patient and per organ. Mixed response (MR) was defined as the coexistence of at least 2 responsive and progressive organs.

Results: Tumor lesions were detected in 244 organs. The response rate (RR) and median time to progression (TTP) to second EGFR-TKIs for patients were 26.5% and 11.6 weeks (95% CI, 8.5-14.7 weeks), and the RR and median TTP for organs were 38.8% and 17.3 weeks (95% CI, 14.8-19.8 weeks). Of 35 patients categorized to progressive disease, 22 (62.8%) showed MR. Among organs, the RR was highest for the central nervous system (CNS) and lowest for the liver (CNS vs. others vs. liver: 77.8%, 36.9%, 17.6%; P < .001). Multivariate analysis confirmed the organ type and prior drug sensitivity at the time of stopping first EGFR-TKIs as predictors for the risk of progression to second EGFR-TKIs in organs.

Conclusions: Intrapatient heterogeneity in response to second EGFR-TKIs is not a rare event. The organ type and prior drug sensitivity at the failure time of first EGFR-TKIs may predict the efficacy of second EGFR-TKIs in individual organs.