Improved survival from early combined radiotherapy: A phase II clinical study and underlying mechanisms of delaying EGFR-TKI acquired resistance in patients with advanced lung cancer.

Authors

null

Li Zhang

Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, China

Li Zhang , Ping Peng , Juejun Gong , Yujie Zhang , Qian Chu , Shu Xia , Rui Meng , Yongshun Chen , Guang Han , Peng Zhang , Lu Zhang , Yuan Chen

Organizations

Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, China, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wu, China, Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China, Tongji Hospital Tongji Medical College Huazhong University of Science and Tech, Wuhan, China, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, Department of Clinical Oncology, Renmin Hospital of Wuhan University, Wuhan, China, Hubei Cancer hospital, Department of Radiation Oncology, Wuhan, China, Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China

Research Funding

Other

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have a significant therapeutic effect in the treatment of advanced non-small-cell lung cancer (NSCLC). However, patients treated with EGFR-TKIs had a median progression-free survival (PFS) of only 8 to 18 months. The occurrence of acquired resistance greatly limits the survival benefit of TKI for NSCLC patients. Extensive efforts have been paid to find a well-tolerated drug or treatment that works before acquired resistance to EGFR-TKI with low toxicity. Focusing on clinical trials of targeted combination radiotherapy, we observed some encouraging results. Methods: Stage IV NSCLC patients with EGFR sensitive mutation (19DEL or 21L858R) have received first-line EGFR TKIs treatment and achieved stable disease or partial response have been enrolled in this prospective, multicenter, randomized controlled, phaseⅡstudy. Recruited from 4 hospitals in China, patients were divided into two groups: Stereotactic Body Radiation Therapy (SBRT) combined with TKIs group as the experimental and TKIs treatment group as an active comparator. The primary endpoint is PFS, and the secondary endpoint aims to overall survival (OS) and safety. To further confirmed these clinical observations in patients, xenograft experiments in nude mice were conducted. To examine the specific mechanism, transcriptome sequencing analysis was performed. Results: Between Mar 2015 and Mar 2018, A total of 61 patients who met the inclusion criteria were randomized to the TKI group and SBRT combined group. The median PFS of the TKI group and SBRT combined group were 9.0 vs 17.6 months (p = 0.016). Meanwhile, the median OS were 23.2 vs 33.6 months (p = 0.026). The total number of patients with T790m was 30(49.1%), and the incidence of T790M did not differ between the two groups. Toxicity data and subgroup analyses including different radiation sites will be presented at the conference. As for the xenograft experiments, data on tumor regression and time of drug resistance of early radiotherapy group was clearly superior to others. Transcriptome sequencing analysis found expression of c-Fos was the key point that led to the phenomena. Conclusions: The addition of SBRT significantly delayed the onset of EGFR TKIs acquired resistance and prolonged the PFS and OS of patients. Radiotherapy for the primary site alone might be superior to metastatic sites. Treatment-related adverse events were generally safe and controllable. The oncogenic role of c-Fos in the effect of radiotherapy on gefitinib resistance and promoting the proliferation of NSCLC cells is confirmed. Clinical trial information: NCT03595644.

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Abstract Details

Meeting

2022 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Lung Cancer—Non-Small Cell Metastatic

Track

Lung Cancer

Sub Track

Metastatic Non–Small Cell Lung Cancer

Clinical Trial Registration Number

NCT03595644

Citation

J Clin Oncol 40, 2022 (suppl 16; abstr 9114)

DOI

10.1200/JCO.2022.40.16_suppl.9114

Abstract #

9114

Poster Bd #

100

Abstract Disclosures