Although osimertinib has been approved as first-line therapy, 1st or 2nd generation EGFR TKIs are still being used as first-line therapy. Although T790M acquired resistance occurs 30 to 40% after the treatment of the 1st- or 2nd-generation EGFR TKIs, most cases of T790M mutation-negative patients undergo cytotoxic chemotherapy or other supportive treatment. There are several reports that EGFR TKI re-administration may be helpful in T790M-negative patients. We did prospectively undergo EGFR TKIs retreatment trial as a third or later line treatment.
The enrolled patients were resistant to 1st or 2nd generation EGFR-TKI as a 1st-line treatment and then treated with chemotherapy for more than 4 cycles because of T790M-negative at 2nd biopsy. The primary endpoint was objective response rate (RR), and the secondary endpoints were progression free survival (PFS), overall survival (OS), and safety.
In total, 63 patients retreated with gefitinib (n = 34) or erlotinib (n = 29) after the progression of 2nd or more line chemotherapy. The median age was 65. The best RR and disease control rate were 14 and 51%, respectively. The median duration of treatment was 65 days (gefitinib 56 days vs. erlotinib 90 days). The median PFS was 2.8 months (gefitinib 1.8 vs. erlotinib 3.5 months), median OS was 8.5 months (gefitinib 8.3 vs. erlotinib 9.0 months). The development rate of T790M after the retreatment of EGFR TKIs was 32% (20/63). Acquired T790M mutation developed in 13 of 20 patients (65%) who had exon 19 del. The median duration from the start of EGFR TKI retreatment to the date of the T790M mutation development was 5.2 months. There was a statistical difference in OS between T790M-negative and induced patients (5.4 vs. 28.9 months, P < 0.001). The most common adverse events were diarrhea and skin toxicities.
Retreatment with EGFR-TKIs can be considered an option after the failure of chemotherapy for patients who were previously controlled by EGFR-TKI. The 1st generation EGFR TKIs retreatment may induce T790M mutation (32%) in patients who had not previously T790M mutation, leading to 3rd generation EGFR TKI sequential treatment and eventually prolong OS.
NCT03382795.
The authors.
Chong Kun Dang Pharmaceutical Company.
All authors have declared no conflicts of interest.