JCO precision oncology · 2026
Determining the Causal Effect of Neurotrophic Tropomyosin Receptor Kinase Gene Fusions on Survival Prognosis for Adult Patients With Advanced Cancers.
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Krebs Emanuel, Tamvada Nirupama, Weymann Deirdre, Lim Howard J, Chia Stephen, Ho Cheryl, Regier Dean A
Аннотация
PURPOSE: Uncertainty about the prognostic significance of neurotrophic tropomyosin receptor kinase (NTRK) fusions complicates clinical decisions and interpretation of survival outcomes in oncology care. Drawing on the largest cohort of NTRK fusion-positive (NTRK+) patients, we establish the prognostic effect of NTRK fusions in adults with advanced cancers.
METHODS: We used a large real-world clinicogenomic research database from the United States to emulate a pragmatic randomized trial that determines the causal effect of harboring an NTRK gene fusion (NTRK+) on survival prognosis for adult patients with advanced solid tumors. We 1:1 matched NTRK+ patients to patients with no identified NTRK genomic alterations (NTRK-) using a machine learning matching approach. Excluding patients who received TRK inhibitors, we conducted stratified matching within common tumor groups. We used Kaplan-Meier and Weibull regression survival analyses and estimated the difference in restricted mean survival time (RMST) over 1-, 2-, 3-, and 5-year study periods.
RESULTS: We included 68,145 NTRK- patients for matching to 73 NTRK+ patients within seven tumor groups, including colorectal (n = 22), non-small cell lung (n = 13), sarcoma (n = 13), breast (n = 10), head and neck (n = 7), neuroendocrine (n = 4), and prostate (n = 4), and 14 NTRK+ patients representing eight other cancers. The difference in overall survival over 1 year was statistically significant using the Kaplan-Meier estimate (P = .008), Weibull regression (hazard ratio, 2.105 [95% CI, 1.207 to 3.673]), and RMST (-50 days [95% CI, -96 to -5]; P = .029). Differences were also statistically different at 2 years and 3 years. At 5 years, no survival differences were statistically significant.
CONCLUSION: In this large real-world target trial emulation, NTRK gene fusions were associated with clinically meaningful reductions in overall survival among adults with advanced cancers not treated with TRK inhibitors. These findings clarify the prognostic role of NTRK fusions and inform clinical interpretation of outcomes in routine oncology.
METHODS: We used a large real-world clinicogenomic research database from the United States to emulate a pragmatic randomized trial that determines the causal effect of harboring an NTRK gene fusion (NTRK+) on survival prognosis for adult patients with advanced solid tumors. We 1:1 matched NTRK+ patients to patients with no identified NTRK genomic alterations (NTRK-) using a machine learning matching approach. Excluding patients who received TRK inhibitors, we conducted stratified matching within common tumor groups. We used Kaplan-Meier and Weibull regression survival analyses and estimated the difference in restricted mean survival time (RMST) over 1-, 2-, 3-, and 5-year study periods.
RESULTS: We included 68,145 NTRK- patients for matching to 73 NTRK+ patients within seven tumor groups, including colorectal (n = 22), non-small cell lung (n = 13), sarcoma (n = 13), breast (n = 10), head and neck (n = 7), neuroendocrine (n = 4), and prostate (n = 4), and 14 NTRK+ patients representing eight other cancers. The difference in overall survival over 1 year was statistically significant using the Kaplan-Meier estimate (P = .008), Weibull regression (hazard ratio, 2.105 [95% CI, 1.207 to 3.673]), and RMST (-50 days [95% CI, -96 to -5]; P = .029). Differences were also statistically different at 2 years and 3 years. At 5 years, no survival differences were statistically significant.
CONCLUSION: In this large real-world target trial emulation, NTRK gene fusions were associated with clinically meaningful reductions in overall survival among adults with advanced cancers not treated with TRK inhibitors. These findings clarify the prognostic role of NTRK fusions and inform clinical interpretation of outcomes in routine oncology.