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Assessing the association of targeted therapy and intracranial metastatic disease

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Importance — Targeted therapies have been hypothesized to prolong survival in the treatment of patients with intracranial metastatic disease (IMD) but, paradoxically, increase IMD incidence by improving systemic disease control and prolonging survival from the primary tumor. The real-world benefits of targeted therapy in treating patients with IMD are unclear, as clinical trials have excluded patients with IMD and lacked end points that report intracranial outcomes.

Objective — To assess the association of targeted therapy and IMD with patient survival.

Design, Setting, and Participants — This retrospective cohort study included all patients in Ontario, Canada, who received a diagnosis of IMD from April 2005 to January 2018 with primary diagnoses of breast cancer, lung or bronchus cancer, or melanoma and control patients who were matched by primary disease without IMD. The data were analyzed between March and October 2020.

Exposures — EGFR-, ERBB2 (HER2-), or BRAF-targeted therapy or IMD status.

Main Outcomes and Measures — Kaplan-Meier and multivariable Cox regression analyses were performed to compare overall survival (OS) between patient subcohorts divided by primary disease and stratified by targeted therapy receipt or IMD status.

Results — In this cohort of 26 676 patients with IMD and breast cancer, lung and bronchus cancer, or melanoma, 57% of patients were women, and the median age at IMD diagnosis was 64 years (interquartile range, 56-72 years). Post-IMD targeted therapy was associated with prolonged OS in patients with ERBB2-positive breast cancer (hazard ratio [HR], 0.41; 95% CI, 0.33-0.50), EGFR-positive lung cancer (HR, 0.28; 95% CI, 0.23-0.34), and BRAF-positive melanoma (HR, 0.20; 95% CI, 0.14-0.29) compared with those who did not receive post-IMD targeted therapy. The presence of IMD was associated with shorter OS in patients with metastatic ERBB2-positive breast cancer (HR, 1.80; 95% CI, 1.56-2.08) and metastatic EGFR-positive lung cancer (HR, 1.22; 95% CI, 1.08-1.39) but not metastatic BRAF-positive melanoma (HR, 1.11; 95% CI, 0.77-1.61) compared with those without IMD.

Conclusions and Relevance — The findings of this cohort study suggest an association between real-world use of targeted therapies and prolonged OS in patients with IMD in the setting of ERBB2-positive breast cancer, EGFR-positive lung cancer, and BRAF-positive melanoma. Including patients with IMD in clinical trials and using end points that interrogate IMD will be critical to determine the role of targeted therapies in treating patients with IMD.

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Citation

Erickson AW, Habbous S, Wright F, Lofters AK, Jerzak KJ, Das S. JAMA Oncol. 2021; 7(8):1220-4. Epub 2021 Jun 3.

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