Characteristics of progression to tyrosine kinase inhibitors predict overall survival in patients with advanced non-small cell lung cancer harboring an EGFR mutation

Abstract

Background: Non-small cell lung cancer (NSCLC) harboring EGFR-sensitizing mutations has a distinct biology and heterogeneous clinical behavior. We evaluated the characteristics to progression such as clinical patterns of progression (dramatic, gradual, and local) with the prognosis of NSCLC patients treated with tyrosine kinase inhibitors (TKIs).

Methods: We reviewed 123 advanced-NSCLC patients with an EGFR-sensitizing mutation treated with TKIs (gefitinib, erlotinib and afatinib). We assessed patients according to clinical factors and progression pattern to TKIs at three centers.

Results: For all patients, 58.5%, 31.7% and 9.8% harbored exon19 deletion, exon21 L858R mutation and other-sensitivity mutations, respectively. Median progression-free survival (PFS) was 8.8 months (95% CI: 7.9-9.7). Sixty percent of patients were asymptomatic. Dramatic-progression was the most frequent pattern (50.4%), followed by gradual-progression (32.5%), and local-progression (17.1%). Median overall survival (OS) was 23.1 months (95% CI: 17.4-28.9). In the univariate analysis, factors associated to a longer OS included pattern [gradual-progression (32.1), dramatic (19.5) and local (18.8 months), P=0.008], and the time to progression to TKI [>12 months (38.5), 6-12 months (19.1), <6 months (9.6), P<0.001]. Multivariate analysis showed that only time to progression to TKI was independently associated to OS and PFS.

Conclusions: Factors at TKI progression associated to a longer OS can define a subset of patients who may benefit from continued TKI therapy, as well as from local-ablative therapy in progression sites, especially in patients without T790M or who lack access to third-generation TKI.

Keywords: Lung adenocarcinoma; afatinib; epidermal growth factor receptor (EGFR); exon 19; gefitinib; patterns of progression.

Conflict of interest statement

Conflicts of Interest: AFC has received grants from Roche, Boehringer Ingelheimm, Astra Zeneca and Pfizer, consulting fees from Roche, Boehringer Ingelheimm, Astra Zeneca, Pfizer, Merck Serono Foundation Medicine, MSD, BMS, payment for lectures from Roche, Boehringer Ingelheimm, Astra Zeneca, Pfizer, Merck Serono Foundation Medicine, MSD, BMS, and fees for expert testimony from Roche, Boehringer Ingelheimm, Astra Zeneca, Pfizer, Merck Serono Foundation Medicine, MSD, BMS. LC has participated on advisory boards by Astra Zeneca, and has received honoraria from Astra Zeneca for lectures in scientific meetings. OA has received payment for lectures from Boehringer ingelheim, Astra Zeneca, Merck and Lilly. All other authors have no competing interest to disclose. Preliminary results from this study were previously presented during the 17th World Conference on Lung Cancer–IASLC (4–7 December 2016, Vienna, Austria).

Figures

Figure 1

Clinical patterns of progression to tyrosine kinase inhibitors.

Figure 2

Kaplan-Meier Curves for progression-free survival, according to pattern of progression (A) and symptoms at progression (B) to tyrosine-kinase inhibitors.

Figure 3

Kaplan-Meier curves for overall survival (OS) according to pattern of progression (A), symptoms at progression (B) and time to progression (C) to tyrosine-kinase inhibitors.

Figure 4

Kaplan-Meier curves for subgroup analysis of overall survival, according to pattern of progression to tyrosine-kinase inhibitors and mutation subtype.