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Expert Discusses Potential Breakthroughs in ROS1+ and BRAF+ NSCLC

Angelica Welch
Published: Monday, Jun 25, 2018

Dr. Sai-Hong Ignatius Ou

Sai-Hong Ignatius Ou, MD, PhD

The treatment of patients with non–small cell lung cancer (NSCLC) was revolutionized with the discovery of targetable mutations more than a decade ago. Although many agents have been approved in the ALK-positive NSCLC landscape since then, other targets, such as ROS1 and BRAF, are under investigation in a new age of targeted therapies, said Sai-Hong Ignatius Ou, MD, PhD.

In a presentation during the 2018 OncLive® State of the Science Summit™ on Non–Small Cell Lung Cancer, Ou, professor, Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, broke down the current landscapes of ROS1-positive and BRAF-mutant NSCLC.

Approximately 2% of all patients with NSCLC have a ROS1 alteration, and about 1% to 3% of patients are positive for the BRAF V600E mutation. Historically, each of these subtypes have been considered to have a poor prognosis.

Currently, the only FDA-approved next-generation sequencing (NGS) test to detect both ROS1 and BRAF mutations is the Oncomine Dx Target Test. This assay was approved in June 2017 for detection of BRAF, EGFR, and ROS1 alterations. Although it is a 23-gene panel, it can only be used to test for these 3 alterations, based on the FDA’s indication, explained Ou.

ROS1-Rearranged NSCLC

The ROS1-rearrangement was discovered in lung cancer around the same time as ALK in 2007. This receptor tyrosine kinase fusion is also seen in other tumor types such as brain, breast, soft tissue, skin, stomach, and ovarian cancer. All receptor tyrosine kinase fusions have fusion partners, said Ou, adding that there are about 13 fusions partners established for ROS1.

“We all figured that not all [of] the fusion partners will be the same; they locate differently in the cells and they may have different functions. It is a heterogeneous disease, and in the next decade, through NGS, we can understand the fusion partners much closer than just calling it ROS1-positive NSCLC,” said Ou.

ROS1 can be targeted through a few inhibitors. The agents that have been tested in phase II clinical trials include ropotrectinib (TPX-0005), lorlatinib, DS-6051b, entrectinib, crizotinib (Xalkori), and ceritinib (Zykadia). Cabozantinib (Cabometyx) and brigatinib (Alunbrig) have been evaluated in phase I studies. Crizotinib is the only ROS1 kinase inhibitor that is FDA approved for this population.

Crizotinib was approved in March 2016 based on data from a 50-patient experience. Findings of this phase I study demonstrated on overall response rate (ORR) of 72%, with more than a 17-month median duration of response, as determined by independent review.1

Ou explained that patients with ROS1-rearranged lung cancer do very well on crizotinib compared with patients who have ALK-positive NSCLC.

ROS1 is a very good prognostic biomarker, but eventually patients do progress. We do not have as many inhibitors for ROS1 as there are for ALK, in terms of second- and third-generation [agents]. However, [they are] coming in a few years,” Ou said. Although crizotinib is currently the only FDA-approved agent for the treatment of patients with ROS1-positive NSCLC, there are several drugs under evaluation, with data coming out later this year.

In data presented at the 2018 ASCO Annual Meeting, ropotrectinib, a next-generation ROS1 inhibitor, was found to be well tolerated and exhibited both intra- and extracranial clinical activity in tyrosine kinase inhibitor-refractory ROS1-positive and NTRK-positive patients with solvent front mutation– containing tumors.2

Additionally, there is a cohort of patients with ROS1-positive disease in a trial of lorlatinib, and both ceritinib and brigatinib have data impending. Ou noted that entrectinib may be approaching FDA approval as well.

Lorlatinib data were presented at the 2017 IASLC World Conference on Lung Cancer. There were 47 patients enrolled in the ROS1 cohort. Regardless of prior treatment, the ORR for ROS1-positive patients was 36% (17/47; 95% CI, 23%-52%) and the intracranial ORR was 56% (14/25; 95% CI, 35%-76%).3

Ou said that the problems with this study are that it was only in 47 patients and the agent does not have a fast track designation. “We will see what the path of getting lorlatinib is when its approved; it will probably be an off-label use.”

Ceritinib is another inhibitor under investigation in this patient population. In a Korean study of 30 TKI-naïve patients, there was a promising response rate (62%), with a median progressionfree survival of 19.3 months.4 Ou said that since this study was smaller, he is unsure if it will be enough data for an FDA approval.


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Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Key Questions for the Use of Immunotherapy Throughout the Disease Continuum for NSCLC in an Era of Rapid DevelopmentSep 29, 20181.5
Community Practice Connections™: 18th Annual International Lung Cancer Congress®Oct 31, 20181.5
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