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Brain Metastases in ROS1-Positive Lung Cancer and Treatment With Crizotinib

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Key Points

  • 36% of 33 ROS1-positive patients (compared with 34% of 115 ALK-positive patients) tested positive for brain metastases at the time of diagnosis. When the rate of brain metastases at stage IV disease was compared across ROS1, ALK, EGFR, KRAS, and BRAF mutations, there was no statistically significant difference between the groups.
  • Progression-free survival (PFS) on crizotinib for ROS1-positive patients was 11 months, compared with PFS of 8 months for ALK-positive patients. However, when either of these cancers progressed on crizotinib, it often did so in the brain or central nervous system.
  • In 47% of ROS1-positive patients, the brain was the first and only site of progression.

A study published by Patil et al in the Journal of Thoracic Oncology explores the occurrence and treatment of brain metastases in stage IV ROS1-positive non–small cell lung cancer.

ROS1-Positive Disease vs Other Genetic Mutations

Importantly, and in contrast with the findings of previous groups, brain metastases were found to be fairly common in stage IV ROS1-positive cancers. In this study, 36% of 33 ROS1-positive patients (compared with 34% of 115 ALK-positive patients) tested positive for brain metastases at the time of diagnosis. When the rate of brain metastases at stage IV disease was compared across ROS1, ALK, EGFR, KRAS, and BRAF mutations, there was no statistically significant difference between the groups.

“Our study was novel in that we compared the incidence of brain metastases in newly diagnosed stage IV ROS1-[positive] patients not only with [ALK]-positive patients, but also with [patients with mutations in] EGFR, KRAS, BRAF, and others. When we compared across multiple gene cohorts, we did not find a signal that ROS1 cancers were less likely metastasize to the brain at time of diagnosis,” explained Tejas Patil, MD, oncology fellow at the University of Colorado (CU) Cancer Center and instructor at CU School of Medicine. “Thus, it seems these genes have the same likelihood of brain metastases at time of diagnosis. The finding implies that ROS1 cancers are no more or less predisposed than other oncogene-driven cancers to metastasize to the brain.”

Treatment With Crizotinib

The group also examined the outcomes of patients with ROS1- and ALK-rearranged cancers treated with the ALK and ROS1 inhibitor crizotinib.

Progression-free survival (PFS) on crizotinib for ROS1-positive patients was 11 months, compared with PFS of 8 months for ALK-positive patients. However, when either of these cancers progressed on crizotinib, it often did so in the brain or central nervous system. In 47% of ROS1-positive patients, the brain was the first and only site of progression.

“This reflects poor delivery through blood-brain barrier,” said Dr. Patil.

The challenge is that many targeted therapies including crizotinib are simply too large to pass through the barrier that protects the brain from the rest of the body. “I think this study clarifies the need to develop targeted therapies with brain penetration against these oncogene-addicted lung cancers,” Dr. Patil said.

In fact, new targeted therapies for EGFR- and ALK-positive lung cancers are showing tremendous promise in moving into the brain to target this common location of metastasis. Dr. Patil pointed out that it is everyone’s hope that drug development for ROS1-positive lung cancers will follow a similar trajectory, helping to control cancer not only at its site of first occurrence, but also within the brain, a common site of progression.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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