Randomized Trial of First-Line Tyrosine Kinase Inhibitor With or Without Radiotherapy for Synchronous Oligometastatic EGFR-Mutated Non-Small Cell Lung Cancer

Xiao-Shan Wang, Yi-Feng Bai, Vivek Verma, Rui-Lian Yu, Wei Tian, Rui Ao, Ying Deng, Xue-Qiang Zhu, Hao Liu, Hai-Xia Pan, Lan Yang, Han-Song Bai, Xing Luo, Yan Guo, Ming-Xiu Zhou, Yue-Mei Sun, Zi-Can Zhang, Si-Min Li, Xue Cheng, Bang-Xian Tan, Liang-Fu Han, Ying-Yi Liu, Kai Zhang, Fan-Xin Zeng, Lin Jia, Xin-Bao Hao, You-Yu Wang, Gang Feng, Ke Xie, You Lu, Ming Zeng, Xiao-Shan Wang, Yi-Feng Bai, Vivek Verma, Rui-Lian Yu, Wei Tian, Rui Ao, Ying Deng, Xue-Qiang Zhu, Hao Liu, Hai-Xia Pan, Lan Yang, Han-Song Bai, Xing Luo, Yan Guo, Ming-Xiu Zhou, Yue-Mei Sun, Zi-Can Zhang, Si-Min Li, Xue Cheng, Bang-Xian Tan, Liang-Fu Han, Ying-Yi Liu, Kai Zhang, Fan-Xin Zeng, Lin Jia, Xin-Bao Hao, You-Yu Wang, Gang Feng, Ke Xie, You Lu, Ming Zeng

Abstract

Background: Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether these findings translate to epidermal growth factor receptor (EGFR)-mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual.

Methods: Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided.

Results: A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was 17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in the TKI with RT arm. Based on the efficacy results of this prespecified interim analysis, the ethics committee recommended premature cessation of this trial.

Conclusions: As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.

© The Author(s) 2022. Published by Oxford University Press.

Figures

Figure 1.
Figure 1.
CONSORT diagram for the trial. RT = radiation therapy; TKI = tyrosine kinase inhibitor.
Figure 2.
Figure 2.
Kaplan-Meier curves illustrating progression-free survival between arms. RT = radiation therapy; TKI = tyrosine kinase inhibitor.
Figure 3.
Figure 3.
Kaplan-Meier curves illustrating overall survival between arms. RT = radiation therapy; TKI = tyrosine kinase inhibitor.

References

    1. Gomez DR, Tang C, Zhang J, et al.Local consolidative therapy Vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol. 2019;37(18):1558–1565.
    1. Iyengar P, Wardak Z, Gerber DE, et al.Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2018;4(1):e173501.
    1. Palma DA, Olson R, Harrow S, et al.Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial. J Clin Oncol. 2020;38(25):2830–2838.
    1. Mok TS, Wu YL, Thongprasert S, et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–957.
    1. Zhou C, Wu YL, Chen G, et al.Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735–742.
    1. Al-Halabi H, Sayegh K, Digamurthy SR, et al.Pattern of failure analysis in metastatic EGFR-mutant lung cancer treated with tyrosine kinase inhibitors to identify candidates for consolidation stereotactic body radiation therapy. J Thorac Oncol. 2015;10(11):1601–1607.
    1. Patel SH, Rimner A, Foster A, et al.Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib. Lung Cancer. 2017;108:109–114.
    1. Pocock SJ, Simon R.. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31(1):103–115.
    1. Soria JC, Ohe Y, Vansteenkiste J, et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–125.
    1. Hasselle M, Haraf D, Rusthoven KE, et al.Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer. J Thorac Oncol. 2012;7(2):379–381.
    1. Milano MT, Katz AW, Zhang H, Okunieff P.. Oligometastases treated with stereotactic body radiotherapy: long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys. 2012;83(3):878–886.
    1. Engels B, Everaert H, Gevaert T, et al.Phase II study of helical tomotherapy for oligometastatic colorectal cancer. Ann Oncol. 2011;22(2):362–368.
    1. Xu Q, Zhou F, Liu H, et al.Consolidative local ablative therapy improves the survival of patients with synchronous oligometastatic NSCLC harboring EGFR activating mutation treated with first-line EGFR-TKIs. J Thorac Oncol. 2018;13(9):1383–1392.
    1. Donker M, van Tienhoven G, Straver ME, et al.Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014;15(12):1303–1310.
    1. Jia W, Guo H, Jing W, et especially high rate of radiation pneumonitis observed in patients treated with thoracic radiotherapy and simultaneous osimertinib. Radiother Oncol. 2020;152:96–100.
    1. Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH.. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 2014;9(2):195–199.
    1. Magnuson WJ, Lester-Coll NH, Wu A, et al.Management of brain metastases in tyrosine kinase inhibitor-naive epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multi-institutional analysis. J Clin Oncol. 2017;35(10):1070–1077.

Source: PubMed

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