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. 2017 Sep 13;8(44):77897-77914.
doi: 10.18632/oncotarget.20857. eCollection 2017 Sep 29.

Oncogenic driver mutations, treatment, and EGFR-TKI resistance in a Caucasian population with non-small cell lung cancer: survival in clinical practice

Martin Faehling  1 , Birgit Schwenk  1 , Sebastian Kramberg  1 , Robert Eckert  2 , Anna-Lena Volckmar  3 , Albrecht Stenzinger #  3 , Jörn Sträter #  4
Affiliations

Oncogenic driver mutations, treatment, and EGFR-TKI resistance in a Caucasian population with non-small cell lung cancer: survival in clinical practice

Martin Faehling et al. Oncotarget. .

Abstract

Introduction: Oncogenic driver mutations activating EGFR, ALK, or BRAF in NSCLC predict sensitivity to specific tyrosine-kinase inhibitors (TKIs). We provide data on prevalence, treatment and survival of driver-mutation positive NSCLC in a predominantly Caucasian population in routine clinical practice.

Patients and methods: NSCLC patients diagnosed from 2006-2015 with an EGFR-test result were included (n=265). Testing for EGFR, ALK, or BRAF was performed if specific TKI therapy was considered. Case-control analyses of overall survival (OS) comparing driver-mutation positive and negative patients were performed.

Results: 44 sensitizing EGFR mutations (17%), 8 ALK translocations (7%, n=111) and 3 BRAF mutations (8%, n=39) were detected in adenocarcinoma or adenosquamous carcinoma. We did not find mutations in tumors without an adenocarcinoma-component. More than 90% of inoperable driver-mutation positive patients received TKI-therapy. Case-control analysis revealed improved OS of driver-mutation positive patients (39.6 vs. 19.4 months, HR 0.51). OS was improved in stage IV patients but not in stage I-III patients.OS of EGFR-TKI treated patients was similar for 1st and 2nd-line EGFR-TKI treatment. Patients not treated with EGFR-TKI had no benefit in OS. Re-biopsies obtained at progression revealed an EGFR-T790M mutation in 73% (n=11). These patients responded to the 3rd-generation EGFR-TKI osimertinib.

Discussion: Testing guided by predictive clinical parameters resulted in twice as high rates of mutation-positive patients than expected, and TKI treatment resulted in a strong long-term OS advantage.

Conclusion: Testing for driver mutations is feasible in routine clinical practice, and identifies patients who benefit from TKI-therapy. OS compares favorably with OS in clinical studies.

Keywords: ALK; BRAF; EGFR; NSCLC; overall survival.

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Conflict of interest statement

CONFLICTS OF INTEREST None of the authors has declared a conflict of interest.

Figures

Figure 1
Figure 1. Oncogenic-driver mutation: distribution
(A) Distribution of oncogenic driver mutations in AC patients with EGFR-test result. (B) Distribution of EGFR mutations.
Figure 2
Figure 2. Oncogenic-driver mutation: overall survival
(A) Unselected patients: Kaplan-Meier curves for OS of driver-mutation positive patients compared to patients with no driver mutation detected. Clinical characteristics are given in Table 1. (B-D) Case-control analysis: Patients were matched for gender, clinical stage, performance status, smoking status, and age. Clinical characteristics are given in Table 1. (B) Kaplan-Meier curves for OS of driver-mutation positive patients compared to patients with no driver mutation detected. (C) Kaplan-Meier curves for OS of driver-mutation positive patients stage I-III compared to patients with no driver mutation detected. (D) Kaplan-Meier curves for OS of driver-mutation positive patients stage IV compared to patients with no driver mutation detected.
Figure 3
Figure 3. Oncogenic-driver mutation: overall survival by specific mutation
(A-C) Kaplan-Meier curves for OS of driver-mutation positive patients compared to patients with no driver mutation detected (case-control analysis). Patients were matched for gender, clinical stage, performance status, smoking status, and age. (A) EGFR-positive patients. (B) ALK-positive patients. (C) BRAF-positive patients.
Figure 4
Figure 4. Oncogenic driver mutation-positive patients: treatment course
Swimmer plot showing the sequence of treatment lines in patients who received at least one line of targeted therapy. Bars start from begin of palliative treatment. Arrows signify ongoing therapy. Green: EGFR TKIs. Red: ALK TKIs. Blue: BRAF TKIs. Dark gray: Chemotherapy.
Figure 5
Figure 5. EGFR-positive patients: subgroup analysis of overall survival
Forrest plot showing HR and CI of subgroups of the case-control population in Figure 3A. I-III: UICC stage I-III, IV: UICC stage IV. p-values are given for comparison with matched EGFR-negative controls.
Figure 6
Figure 6. EGFR-positive patients: overall survival by TKI-therapy
Case-control analysis of EGFR-positive and negative patients matched for gender, clinical stage, performance status, smoking status, and age. For patient characteristics and type of EGFR mutation cp. Table 3. (A) EGFR-mutation positive patients who received EGFR-TKI therapy. (B) EGFR-positive patients who did not receive EGFR-TKI therapy. (C) EGFR-positive patients who received 1st line EGFR-TKI therapy. (D) EGFR-positive patients who received 2nd line EGFR-TKI therapy.
Figure 7
Figure 7. HE stains of endobronchial biopsies of patient 7 (Figure 4)
(A) EGFR-positive adenocarcinoma. (B) Transformation into small-cell lung cancer. Magnification 400 fold.
See this image and copyright information in PMC

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