3856 - Incidence of T790M in NSCLC patients progressed to gefitinib, erlotinib, and afatinib: a study on circulating tumor DNA

Background

Insights into the mechanism of resistance to first generation EGFR-TKIs may provide important information for further patient management, including the choice of second-line treatments. T790M is a gatekeeper mutation of the ATP binding pocket of the EGFR kinase domain and is the most common mechanism of resistance to first-generation EGFR-TKIs. Owing to its biologic relevance in the response of NSCLC to the selective pressure of treatments, the present study investigated in circulating cell-free DNA (cfDNA) if the occurrence of T790M at progression differed among gefitinib, afatinib, and erlotinib.

Methods

This study included patients with NSCLC bearing EGFR activating mutation, and given gefitinib (G), erlotinib (E) or afatinib (A) as first-line treatment. Plasma samples for the analysis of cfDNA were taken at disease progression (PD) and analyzed by a ddPCR using the ddPCR EGFR Mutation Assay. In selected cases, a rebiopsy was performed to confirm the absence of the T790M in negative plasma.

Results

A total of 83 patients were enrolled; 42 patients received G/E and 41 received A. Patients’ characteristics were comparable across the two groups. Median time to progression (TTP) was 14.4 in G/E vs 10.2 months in A group (p = 0.09). Forty-seven out of 83 patients (56.6%) were positive for the T790M in plasma. There was a higher incidence of the T790M in patients who progressed to G/E than in patients treated with A: 33 (79%) vs 14 (34%), respectively (p = 0.0001). To confirm the absence of the T790M, a rebiopsy was feasible in 7 patients of the G/E group and in 23 of the A group. The analysis of the cytological sample confirmed the absence of the T790M, and PI3K mutation was found in both groups in 1 patient (2%). Three patients (7%) had MET amplification in the A group. Afatinib dosage was reduced in 15 patients to 30 mg; T790M was not correlated with the dose reduction, being detectable in 6 patients who needed the reduction and in 8 who received the full standard dose (p = 0.54).

Conclusions

In conclusion, even though gefitinib, erlotinib, and afatinib belong to the same class of EGFR-TKIs, differences in the appearance of resistance mutation are demonstrated in the present study and this finding may have implications in the choice of 2^nd-line treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.