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Brain metastases common during treatment with crizotinib for ROS1-positive NSCLC
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The brain appeared to be a common first site of progression among treatment-naive patients with ROS1-positive non-small-cell lung cancer while on treatment with crizotinib, according to findings from a retrospective review.
Although central nervous system metastases were fairly common among patients with ROS1-positive NSCLC, the incidence did not appear significantly greater than that of different oncogene cohorts.
“Brain metastases and CNS progression remain major challenges for patients receiving crizotinib therapy, largely due to ineffectual CNS penetration by the drug,,” Tejas Patil, MD, oncology fellow at University of Colorado Cancer Center and instructor at University of Colorado School of Medicine, told HemOnc Today. “This study reinforces the initiative taken by many pharmaceutical companies to develop more CNS-penetrant drugs.”
Previous studies have reported conflicting results on the incidence of CNS metastases among patients with stage IV ROS1-positive NSCLC and on the rate of CNS progression during treatment with crizotinib (Xalkori, Pfizer).
Patil and colleagues analyzed incidence of brain metastases among 579 patients with stage IV NSCLC and ROS1, ALK, EGFR, KRAS, BRAF or other mutations. Researchers also measured PFS and time to CNS progression among patients with ROS1 (n = 33) or ALK (n = 115) mutations who received crizotinib.
“Our study was novel in that we compared the incidence of brain metastases in newly diagnosed stage IV ROS1 patients not only with ALK patients, but also with EGFR, KRAS, BRAF and others,” Patil said in a press release.
Overall, researchers did not observe significant differences in incidence of brain metastases across the different oncogene cohorts
Researchers reported an incidence rate of brain metastases of 36% among treatment-naive patients with ROS1-positive disease and 34% among treatment-naive patients with ALK-positive disease. Among ROS1-positive patients, 47% showed progression first and only in the brain compared with 33% of patients with ALK-positive disease.
Researchers did not identify a signal that insinuated patients with ROS1-positive cancer had less likelihood of metasizing to the brain at time of diagnosis.
“Thus, it seems these genes have the same likelihood of brain metastases at time of diagnosis,” Patel said. “The finding implies that ROS1 cancers are no more or less predisposed than other oncogene-driven cancers to metastasize to the brain.”
For the survival analysis, researchers evaluated complete data from 19 patients with ROS1-positive NSCLC and 83 patients with ALK-positive NSCLC. Patients with ROS1-positive disease had a median PFS of 11 months, and patients with ALK-positive disease had a PFS of 8 months.
Patil highlighted the sample size as a potential limitation to the findings, which is attributed to the rarity of ROS1-positive NSCLS.
“Our sample size was not powered to detect differences between ROS1 fusion partners and subsequent brain metastases,” he said. “Additionally, due to the retrospective nature of the study, surveillance brain MRI durations were not standardized and, therefore, we could not provide data on objective response rate or disease control rate.”
Investigators believe the challenge remains that many targeted therapies like crizotinib are too broad to pass through the brain barrier, which prevents the target from reaching the cancer growth within the CNS, according to the press release.
“This reflects poor delivery through blood-brain barrier,” Patil said. – by Melinda Stevens
Disclosures: HemOnc Today could not confirm the authors’ relevant financial disclosures at the time of publication.
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