ROS1: New Marker of Small Population w/ Apparent Big Benefit

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ROS1: New Marker of Small Population with Apparent Big Benefit with XALKORI

http://blog.lungevity.org/2012/01/07/ro ... -and-criz/

January 7th, 2012 - by Dr. Jack West

A new report just out in the Journal of Clinical Oncology characterizes the frequency and clinical features of a newly identified molecular marker known as a ROS1 rearrangement. This was first identified in 2007 and is similar in structure to an ALK rearrangement. Like the ALK rearrangement, it has also been found to be responsive in preclinical cell lines to ALK inhibitor therapy. Importantly, very early but quite promising work is showing that patients with a ROS1 rearrangement may respond very well to the oral ALK inhibitor XALKORI (crizotinib), as was illustrated by a single dramatic case described in the paper.

This particular report looked at the molecular features of 1073 tumors from patients primarily from Massachusetts General Hospital and Vanderbilt University, noting that 18 (1.7%) had a ROS1 rearrangement and 31 (2.9%) had an ALK rearrangement. Both groups share the same clinical features, specifically skewing toward a much younger median age than the broader NSCLC population (around 50 in both ROS1- and ALK-positive patients, compared with 62 in the larger NSCLC population), is predominantly found in never-smokers (in whom a ROS1 rearrangement was seen in 6% of the total group), and being seen predominantly in patients with an adenocarcinoma (in fact, all of the patients with a ROS1 rearrangement have an adenocarcinoma). Within the category of adenocarcinomas, many different subtypes were seen, tending towards being more poorly differentiated and higher grade (associated with a more aggressive appearance).

Lab-based research on a cell line with a ROS1 rearrangement revealed that these cells were inhibited by an experimental ALK inhibitor (TAE684) and that XALKORI could also inhibit these cells. This led to a patient with a ROS1 rearrangement receiving XALKORI within a clinical trial. As we’ve come to sometimes see with XALKORI given to patients with an ALK rearrangement, the response was dramatic, with near complete resolution of his advanced bronchioloalveolar carcinoma (BAC), as highlighted in the scans below (“before” on the left, “after” on the right):

(Click on the blog link above to view the images)

While the published experience of XALKORI for ROS1-positive NSCLC is limited to one patient, there are about a dozen patients out there right now with a ROS1 rearrangement who have started XALKORI, and I understand that most are doing very well on it. Dr. Shaw relayed to me that she’s seen particularly impressive responses in the patients with BAC who have a ROS1 rearrangement and have received XALKORI (though this observation is based on just a handful of patients).

Others with a ROS1 rearrangement are still awaiting an opportunity to try XALKORI, generally because they’re doing well on their current therapy. I met one such patient in my own clinic this week; she has done remarkably well on Alimta (pemetrexed), which has also been reported to be unusually effective for patients with an ALK rearrangement, with a plan to start XALKORI on clinical trial when a new treatment is needed.

We’ll need a larger experience with XALKORI in ROS1-positive patients over time, but there’s plenty of reason to be very optimistic when the clear majority of the first dozen patients experience a nice response. From there, we need to consider the limited number of patients with a ROS1 rearrangement, which will probably amount to about 2000-3000 patients per year in the US. While relatively few and far between, there are enough that if we can see dramatic and long-lasting responses (though duration of response is still too early to know right now) in the clear majority of these patients, it raises the incentive for testing. For the moment, ROS1 mutation testing is available at just a few centers (I believe only MGH and University of Colorado, but others may be coming on line soon). In the future, though, with a steadily increasing proportion of lung cancer patients getting adequate amounts of tissue for molecular testing, and now a growing collection of markers important to test for, I expect that we’ll soon see new testing platforms developed that will test for a panel of multiple relevant markers all from one sample and all at one time.

Though these smaller and geographically dispersed patient populations lead to new challenges for research and routine clinical practice, the finding of more and more of these targets in small subgroups that receive big benefits from the right targeted therapy just raises the value proposition of crossing the chasm into the world of molecular oncology. We may be chipping away at lung cancer with our improvements by just a few percent at a time, but it’s adding up.