Real-world Analysis of First-line Afatinib in Patients with -mutant Non-small Cell Lung Cancer and Brain Metastasis: Survival and Prognostic Factors

Overview

Journal Transl Lung Cancer Res

Date 2023 Jul 10

PMID 37425421

Authors

Jehun Kim

Tae Won Jang

Chang Min Choi

Mi Hyun Kim

Sung Yong Lee

Cheol Kyu Park

Yoon Soo Chang

Kye Young Lee

Seung Joon Kim

Sei Hoon Yang

Jeong Seon Ryu

Jeong Eun Lee

Shin Yup Lee

Chan Kwon Park

Sang Hoon Lee

Seung Hun Jang

Seong Hoon Yoon

Affiliations

Soon will be listed here.

Abstract

Background: Overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and brain metastases (BMs) is poor. We aimed to identify prognostic factors and ascertain treatment outcomes of first-line afatinib for patients with epidermal growth factor receptor (EGFR)-mutant NSCLC with BM in a real-world setting.

Methods: This retrospective observational study reviewed electronic records of patients with -mutant NSCLC who received first-line afatinib treatment between October 2014 and October 2019 in 16 hospitals across South Korea. The Kaplan-Meier method estimated time on treatment (TOT) and OS; multivariate analyses were performed using Cox proportional hazards (PH) models.

Results: Among 703 patients who received first-line afatinib, 262 (37.3%) had baseline BM. Of 441 patients without baseline BM, 92 (20.9%) developed central nervous system (CNS) failure. Compared with patients without CNS failure, those with CNS failure during afatinib treatment were younger (P=0.012), had a higher Eastern Cooperative Oncology Group (ECOG) performance status (PS) (P<0.001), increased metastatic site involvement (P<0.001), advanced stage disease (P<0.001), with liver metastasis (P=0.008) and/or bone metastasis (P<0.001) at baseline. Cumulative incidence of CNS failure in years 1, 2 and 3 was 10.1%, 21.5% and 30.0%, respectively. In multivariate analysis, cumulative incidence was significantly higher in patients with ECOG PS ≥2 (P<0.001), uncommon mutations (P=0.001), and no baseline pleural metastasis (P=0.017). Median TOT was 16.0 months (95% CI: 14.8-17.2) and, in patients with CNS failure, without CNS failure, and with baseline BM was 12.2, 18.9, and 14.1 months, respectively (P<0.001). Median OS was 52.9 months (95% CI: 45.4-60.3) and, in patients with CNS failure, without CNS failure, and with baseline BM was 29.1, 67.3 and 48.5 months, respectively (P<0.001).

Conclusions: First-line afatinib in the real-world setting showed clinically meaningful effectiveness in patients with -mutant NSCLC and BM. CNS failure was a poor prognostic factor for TOT and OS correlating with younger age, poor ECOG PS, higher metastatic number, advanced disease stage, uncommon mutations, and baseline liver and/or bone metastases.

Citing Articles

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

Chang A, Piper-Vallillo A, Mak R, Lanuti M, Muzikansky A, Rotow J Oncologist. 2024; 29(7):609-618.

PMID: 38761385 PMC: 11224994. DOI: 10.1093/oncolo/oyae107.

References

Park K, Tan E, OByrne K, Zhang L, Boyer M, Mok T . Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016; 17(5):577-89. DOI: 10.1016/S1470-2045(16)30033-X. View

Schouten L, Rutten J, Huveneers H, Twijnstra A . Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002; 94(10):2698-705. DOI: 10.1002/cncr.10541. View

Lee Y, Choi H, Kim S, Chang J, Moon J, Park I . Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer. Cancer. 2010; 116(5):1336-43. DOI: 10.1002/cncr.24877. View

Soria J, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee K . Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 378(2):113-125. DOI: 10.1056/NEJMoa1713137. View

Sequist L, Yang J, Yamamoto N, OByrne K, Hirsh V, Mok T . Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31(27):3327-34. DOI: 10.1200/JCO.2012.44.2806. View

Oxnard G, Arcila M, Sima C, Riely G, Chmielecki J, Kris M . Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2010; 17(6):1616-22. PMC: 3060283. DOI: 10.1158/1078-0432.CCR-10-2692. View

Heon S, Yeap B, Britt G, Costa D, Rabin M, Jackman D . Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2010; 16(23):5873-82. PMC: 2999638. DOI: 10.1158/1078-0432.CCR-10-1588. View

Passaro A, de Marinis F, Tu H, Laktionov K, Feng J, Poltoratskiy A . Afatinib in EGFR TKI-Naïve Patients with Locally Advanced or Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Pooled Analysis of Three Phase IIIb Studies. Front Oncol. 2021; 11:709877. PMC: 8298067. DOI: 10.3389/fonc.2021.709877. View

He J, Wang X, Xiao R, Zuo W, Zhang W, Yao H . Risk factors for brain metastases from non-small-cell lung cancer: A protocol for observational study. Medicine (Baltimore). 2021; 100(9):e24724. PMC: 7939174. DOI: 10.1097/MD.0000000000024724. View

10.

Lee J, Kim H, Choi C . Recent Trends of Lung Cancer in Korea. Tuberc Respir Dis (Seoul). 2021; 84(2):89-95. PMC: 8010413. DOI: 10.4046/trd.2020.0134. View

11.

Cheng Y, Mok T, Zhou X, Lu S, Zhou Q, Zhou J . Safety and efficacy of first-line dacomitinib in Asian patients with EGFR mutation-positive non-small cell lung cancer: Results from a randomized, open-label, phase 3 trial (ARCHER 1050). Lung Cancer. 2021; 154:176-185. DOI: 10.1016/j.lungcan.2021.02.025. View

12.

Kumarakulasinghe N, van Zanwijk N, Soo R . Molecular targeted therapy in the treatment of advanced stage non-small cell lung cancer (NSCLC). Respirology. 2015; 20(3):370-8. DOI: 10.1111/resp.12490. View

13.

Schuler M, Wu Y, Hirsh V, OByrne K, Yamamoto N, Mok T . First-Line Afatinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. J Thorac Oncol. 2016; 11(3):380-90. DOI: 10.1016/j.jtho.2015.11.014. View

14.

Yong Lee S, Choi C, Chang Y, Lee K, Kim S, Yang S . Real-world experience of afatinib as first-line therapy for advanced mutation-positive non-small cell lung cancer in Korea. Transl Lung Cancer Res. 2022; 10(12):4353-4367. PMC: 8743522. DOI: 10.21037/tlcr-21-501. View

15.

Westover D, Zugazagoitia J, Cho B, Lovly C, Paz-Ares L . Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol. 2018; 29(suppl_1):i10-i19. PMC: 6454547. DOI: 10.1093/annonc/mdx703. View

16.

Yun C, Mengwasser K, Toms A, Woo M, Greulich H, Wong K . The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008; 105(6):2070-5. PMC: 2538882. DOI: 10.1073/pnas.0709662105. View

17.

Mok T, Cheng Y, Zhou X, Lee K, Nakagawa K, Niho S . Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. J Clin Oncol. 2018; 36(22):2244-2250. DOI: 10.1200/JCO.2018.78.7994. View

18.

Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2008; 45(2):228-47. DOI: 10.1016/j.ejca.2008.10.026. View

19.

Ouyang W, Yu J, Zhou Y, Hu J, Huang Z, Zhang J . Risk factors of metachronous brain metastasis in patients with EGFR-mutated advanced non-small cell lung cancer. BMC Cancer. 2020; 20(1):699. PMC: 7390194. DOI: 10.1186/s12885-020-07202-8. View

20.

Ma X, Zhu H, Guo H, Han A, Wang H, Jing W . Risk factors of brain metastasis during the course of EGFR-TKIs therapy for patients with EGFR-mutated advanced lung adenocarcinoma. Oncotarget. 2016; 7(49):81906-81917. PMC: 5348441. DOI: 10.18632/oncotarget.11918. View