Differential prognostic value of tumor and plasma T790M mutations in EGFR TKI-treated advanced NSCLC

Pi-Hung Tung; Tzu-Hsuan Chiu; Allen Chung-Cheng Huang; Jia-Shiuan Ju; Chi-Hsien Huang; Chin-Chou Wang; How-Wen Ko; Fu-Tsai Chung; Ping-Chih Hsu; Yueh-Fu Fang; Yi-Ke Guo; Chih-Hsi Scott Kuo; Cheng-Ta Yang

doi:10.1177/17588359231222604

Differential prognostic value of tumor and plasma T790M mutations in EGFR TKI-treated advanced NSCLC

Ther Adv Med Oncol. 2024 Jan 19:16:17588359231222604. doi: 10.1177/17588359231222604. eCollection 2024.

Authors

Pi-Hung Tung^{1

2}, Tzu-Hsuan Chiu^{1

2}, Allen Chung-Cheng Huang^{1

2}, Jia-Shiuan Ju^{1

2}, Chi-Hsien Huang^{1

2}, Chin-Chou Wang³, How-Wen Ko^{1

2}, Fu-Tsai Chung^{1

2}, Ping-Chih Hsu^{1

2}, Yueh-Fu Fang^{1

2}, Yi-Ke Guo⁴, Chih-Hsi Scott Kuo^{5

6

4}, Cheng-Ta Yang^{1

2}

Affiliations

¹ Division of Thoracic Oncology, Department of Thoracic Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taipei, Taiwan.
² Thoracic Oncology Unit, Chang Gung Memorial Hospital Cancer Center, Taipei, Taiwan.
³ Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
⁴ Data Science Institute, Department of Computing, Imperial College London, London, UK.
⁵ Division of Thoracic Oncology, Department of Thoracic Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, No. 199, Tun-Hwa North Road, Taipei 333, Taiwan.
⁶ Thoracic Oncology Unit, Chang Gung Memorial Hospital Cancer Center.

Abstract

Background: Substitution of methionine for threonine at codon 790 (T790M) of epidermal growth factor receptor (EGFR) represents the major mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer. We determined the prognostic impact and association of secondary T790M mutations with the outcomes of osimertinib and chemotherapy.

Methods: Patients (n = 460) progressing from first-line EGFR-TKI treatment were assessed. Tissue and/or liquid biopsies were used to determine T790M status; post-progression overall survival (OS) was analyzed.

Results: Overall, 143 (31.1%) patients were T790M positive, 95 (20.7%) were T790M negative, and 222 (48.2%) had unknown T790M status. T790M status [T790M positive versus T790M negative: hazard ratio (HR) 0.48 (95% confidence interval (CI), 0.32-0.70); p < 0.001, T790M unknown versus T790M negative: HR 1.97 (95% CI, 1.47-2.64); p < 0.001] was significantly associated with post-progression OS. T790M positivity rates were similar for tissue (90/168, 53.6%) and liquid (53/90, 58.9%) biopsies (Fisher's exact test, p = 0.433). Tumor T790M-positive patients had significantly longer post-progression OS than tumor T790M-negative patients (34.1 versus 17.1 months; log-rank test, p = 8 × 10^-5). Post-progression OS was similar between plasma T790M-positive and -negative patients (17.4 versus not reached; log-rank test, p = 0.600). In tumor T790M-positive patients, post-progression OS was similar after osimertinib and chemotherapy [34.1 versus 29.1 months; log-rank test, p = 0.900; HR 1.06 (95% CI, 0.44-2.57); p = 0.897].

Conclusion: T790M positivity predicts better post-progression OS than T790M negativity; tumor T790M positivity has a stronger prognostic impact than plasma T790M positivity. Osimertinib and chemotherapy provide similar OS benefits in patients with T790M-positive tumors.

Keywords: EGFR; chemotherapy; osimertinib; plasma T790M; tumor T790M.

Plain language summary

Different prognostic meaning of tumor resistant gene detected from tumor or blood in patients with EGFR-mutant lung cancer The study demonstrates that patients with EGFR-mutant lung cancer who develop resistance due to a secondary T790M mutation, defined by tumor or blood T790M positivity, achieve better survival than patients without secondary T790M mutation; this association was mainly contributed by tumour T790M positivity. Oismertinib and chemotherapy led to similar survival in tumour T790M-positive patients. However, compared to osimertinib, chemotherapy was associated with longer survival in blood T790M-positive patients.