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Multicenter Study
. 2018 Oct;13(10):1595-1601.
doi: 10.1016/j.jtho.2018.07.004. Epub 2018 Jul 11.

Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET-Rearranged Lung Cancers

Alexander Drilon  1 , Jessica J Lin  2 , Thomas Filleron  3 , Ai Ni  4 , Julie Milia  5 , Isabella Bergagnini  4 , Vaios Hatzoglou  4 , Vamsidhar Velcheti  6 , Michael Offin  7 , Bob Li  7 , David P Carbone  8 , Benjamin Besse  9 , Tony Mok  10 , Mark M Awad  11 , Jurgen Wolf  12 , Dwight Owen  8 , D Ross Camidge  13 , Gregory J Riely  7 , Nir Peled  14 , Mark G Kris  7 , Julien Mazieres  3 , Justin F Gainor  2 , Oliver Gautschi  15
Affiliations
Multicenter Study

Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET-Rearranged Lung Cancers

Alexander Drilon et al. J Thorac Oncol. 2018 Oct.

Abstract

Introduction: In ret proto-oncogene (RET)-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized.

Methods: A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined.

Results: The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)-rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3-2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0-4.9 months).

Conclusions: Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.

Keywords: RET fusion; RET rearrangement; brain metastases; lung cancer cabozantinib; vandetanib multikinase inhibitor.

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Conflict of interest statement

DISCLOSURES

No Conflicts of interest were reported for: Jessica J. Lin, Thomas Filleron, Ai Ni, Julie Milia, Isabella Bergagnini, Vaios Hatzoglou, Vamsidhar Velcheti, Michael Offin, Julien Mazieres, David P. Carbone, Benjamin Besse, Tony Mok, Mark M. Awad, Dwight Owen, Ross Camidge, Nir Peled and Oliver Gautschi.

Figures

Figure 1.
Figure 1.. Brain metastases in RET-rearranged lung cancers.
In Figure 1A, the frequency of brain metastases at the time of diagnosis of stage IV disease is shown on the left. The lifetime prevalence of brain metastases in stage IV disease, including brain metastases at diagnosis, is shown on the right. In Figure 1B, the cumulative incidence of brain metastases in RET-rearranged lung cancers is compared to ALK- and ROS1-rearranged lung cancers for patients without known brain metastases at diagnosis.
Figure 2.
Figure 2.. Survival with multikinase inhibition in RET-rearranged lung cancers with intracranial disease.
Kaplan-Meier progression-free survival (PFS) and overall survival (OS) curves of patients with stage IV, RFT-rearranged lung cancers treated with multikinase inhibitors are shown. The PFS and OS of patients with brain metastases prior to tyrosine kinase inhibitor (TKI) therapy were compared to patients without baseline brain metastases.
See this image and copyright information in PMC

References

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