A new mutation on the block: ROS1

There is a newly identified oncogenic mutation in NSCLC, ROS1. Although present in but a small percentage of patients, its discovery represents an additional breakthrough in understanding what ‘drives’ individual cancers. Better yet, crizotinib (Xalkori) would appear to be a potent inhibitor of ROS1.

My friend Craig, who, if he wasn’t so busy being a lung cancer patient would make a fine medical researcher, has the ROS1 mutation and is a veritable encyclopedia of knowledge on all things ROS1. Craig has made it his mission to educate as many people as possible on the importance of being tested for ROS1 in the absence of other identifiable mutations, with numerous postings on both INSPIRE and GRACE. I asked Craig if he would be willing to recant his experience yet again, and he has obliged with an information filled guest blog. Should you have any questions about ROS1, I am certain Craig would be happy to respond.


“The first mutation-targeted miracle drug Linnea successfully used was Xalkori (crizotinib). Crizotinib was remarkable because it was a designer drug, not just a discovery, originally designed to inhibit a lung cancer “driving mutation” called c-MET, but it soon became apparent that it worked dramatically well for ALK-driven cancer. Well, back in January 2012 research was finally published by my favorite superdoc Dr. Alice Shaw and her colleagues at MGH showing that crizotinib seemed to have a similarly dramatic effect on ROS1-driven cancer, a mutation that occurs in about 1% or so of non-small cell lung cancers (NSCLC) vs. about 4% for ALK.

I want to bring you up to speed on this second breakthrough discovery about Xalkori (crizotinib). That January article (http://www.ncbi.nlm.nih.gov/pubmed/22215748) described pre-clinical laboratory research and a dramatic near-complete response in one patient. That work was from last year and in the meanwhile Pfizer’s phase 1 trial of crizotinib for ALK was expanded to add patients with cancer driven by ROS1.

By April 2012 fourteen ROS1 patients were enrolled in that trial and Dr. Shaw presented some data results for them at the ASCO conference early this month. (That ASCO conference is the big annual 5-day event for over 30,000 oncologists and cancer experts where they showcase their research in presentations, educational sessions, and a science fair-like exhibition hall with about 500 exhibitor experiment posters at a time that change each morning and evening.)

As you can see in the graph shown in the article at http://chicago2012.asco.org/ASCODailyNews/Abstract7508.aspx , the responses of the patients to crizotinib was pretty dramatic. In fact, every ROS1 patient had some benefit from the drug, not counting one patient whose test result was ambiguous and probably didn’t really have the ROS1 rearrangement mutation, and one who had to drop out early due to a bowel problem but later had 60% shrinkage from crizotinib. A drug that benefits 100% of patients (including me) is truly remarkable in oncology research. We’ll have to wait to find more of those rare ROS1 patients before we can know if this success rate will hold up and before we’ll know if the duration of benefit is similar to that for ALK or longer.

What is ROS1? It’s a gene that makes a receptor tyrosine kinase (RTK) type of protein which sits on the surface of a cell like a hairpin with the points stuck through to the inside. When certain chemicals come in contact with it this RTK, those points come together and align certain chemicals together inside the cells so they can react and become activated (energized or phosphorylated). That, in turn, begins a cascade of reactions that cause cell behaviors like growth and stubborn survival. In the case of a cancer-causing ROS1 rearrangement, the RTK is misshaped so that it runs amuck, locked into an “on” position that activates chemicals continually whenever they come near.

Fortunately, the normal ROS1 gene isn’t used much in adults, so it isn’t very harmful to try to shut it down when it runs amuck. Even though the ROS1 and ALK genes are located on different chromosomes, they are similar and the RTKs they create fold into a similar molecular shape. That is why crizotinib can inhibit both of them similarly. But they are a little different, and we don’t yet know if the differences will confirm greater odds of benefit from crizotinib, differences in shrinkage, duration, or mechanisms of resistance, or which 2nd generation drugs would work best or longest, but it does seem like they might be similar or analogous.

The first challenge for this research is finding enough ROS1 patients for the clinical trials and research, not just in lung cancer but possibly in other cancers. At about 1% or so of NSCLC, you have to pick through tons of proverbial hay to find those needles. But the odds of ROS1 improve a lot once testing has ruled out the more common driving mutations EGFR, ALK, and KRAS, especially in never-smoker adenocarcinoma. So if you know someone with NSCLC, probably adenocarcinoma in particular, who claims to not have any of the mutations, have them ask their oncologist about ROS1 testing.

I believe knowing the driving mutation of one’s cancer is very valuable. Even if there’s no drug for it yet, there could be a new discovery tomorrow morning. That’s how I felt when I asked my local oncologist where I could get further testing beyond the common ones. He recommended Dr. Shaw 250 miles away in Boston. Until then, the prospects for my kind of cancer seemed grim; I was expected to live only a couple of years or so if nothing worked, and that felt likely. But Dr. Shaw guessed I might have ROS1 and confirmed it with the reliable FISH test for ROS1. With her trial already underway, crizotinib was just waiting for me to show up. My cancer symptoms pretty much vanished within a day or so of starting the trial, my cancer shrank and became a lot less dense, the side effects have been minimal, and it’s been smooth sailing for several months so far. To other NSCLC patients who don’t have any of the more common driving mutations, I hope they will follow my example to find out if there might be a miracle drug waiting for them in Boston, too.”

Craig in PA
June 2012

15 responses to “A new mutation on the block: ROS1

  1. cheryl shields

    As usual you are a wealth of information and have an army of friends who demonstrate the same trait. Glad you got to go on all those vacations and see family and dear friends.

  2. Thank you, Linnea, for helping to spread the word about ROS1. I hope all people with adenocarcinoma NSCLC without any of the common driving mutations will be tested for ROS1, especially if they fit the profile of those who have it.

    Best hopes,

    • Hi Craig. My name Katie and my mom (50s, non-smoker) was recently diagnosed with the ROS1 genetic mutation and has started Crizotinib as her form of treatment. Myself and my parents would love to have a conversation with you about your personal experience, knowledge, etc. that you may have gained through this experience to better inform ourselves. This diagnoses came as a shock to myself, my mom and my family and we are trying to hold it together as best as we can by gaining information.

      I hope to speak with you soon.

  3. This was so interesting, even though so much of it was completely foreign to me. It is inspiring to me when people take such effort to inform and help — both for their own benefit and sharing it with others. What a team you make together and I know there are many others who are part of your larger team.

  4. I do not have the EGFR, ALK, and KRAS mutations. I was diagnosed with NSCLC adenocarcinoma in January 2009. My oncologist requested that I be tested for the ROS1 mutation about 2 weeks ago. I know the likelihood of testing positive for the ROS1 mutation is very small, but I’m hoping for the best. I have never smoked in my life.

    Thank you for sharing information about ROS1. Jean

  5. I’ve got my fingers crossed for you, Jean.

  6. Craig, Thank you for your good wishes. I appreciate it very much. Still have not heard back from the pathology dpt. I’ll post a comment when I find out. Jean

  7. I am a nonsmoker that was diagnosed with NSCLC in Sept 2011. I have been undergoing chemo therapy every 3 weeks since then with positive benefits. Scans should shrinking tumors or stable results. I just learned that I have the ROS1 mutation. I have been advised to stay on the chemo for as long as it stays effective before changing to crizotinib. I’d like to hear any thoughts about this.

    • Barry, my friend Craig (the author of the guest blog and a fellow ROS1 mutant) tried to post a reply but wasn’t able to for some reason, so here is a copy of his response:

      Barry, I’m delighted to “meet” you, another rare ROS1’er.

      I not sure what the answer is because for similar cases with Xalkori (crizotinib) for ALK and Tarceva for EGFR I’ve heard examples of both — either jumping to the targeted drug mid-treatment (and coming back to it later) or making sure you get as much out of the chemo that works you can before switching, despite the side effects.

      It’s not an easy choice and I’m not sure what I’d have done if I were in your shoes, but I do know that I’d want to hear the opinion of the #1 expert in the world on ROS1 — Dr. Alice Shaw at MGH in Boston. If you are nearby, I’d recommend a consultation. In any case either Linnea or I would be glad to give you Alice’s email address privately (or you could google it) so you could ask your question and she’d probably answer.

      Where are you located? Near a crizotinib-for-ROS1 trial location? Where was your ROS1 test done — at MGH in Boston?

      On 2nd thought, maybe a discussion of details are best left to a private messaging discussion. You can reach me here:
      and/or you can join the discussion about ROS1 here:

      Best hopes,


  8. Linnea,
    Thank you for passing the message along. I also just joined Inspire, user name BarryD.

  9. Thanks for the assist, Linnea. It seems to be working for me again right now (if you see this).

    Barry — I’ll look forward to talking details with you.

    Best hopes,


  10. harold kirstein

    Hi I just got a ROS 1 diagnosis (Stage 1B 3.6cm adenocarcinoma). Is there any recommended treatment at this point that you can advise? Thanks Harold

  11. Hendro Widjaya

    Craig, my dad was diagnosed adenocarcinoma stage IV lung cancer. He has malignant bilateral pleural effusion and his tumour size is very big (according to his CT scan). Once we found out that he had ROS1 mutation, we immediately gave him Xalkori. He has been taking Xalkori for 2 months now and is doing great. His latest CT scan does not show any tumour and made the doctor confused and advised him to redo CT scan next month.

    My question is, I heard a lot of stories saying that Xalkori is good. However, it does not last long. So what’s next?

    Thank you
    Hendro Widjaya

    • Hendro, that is great that your father had such a good scan. I know several people with the ROS-1 mutation who show no evidence of disease now and have maintained that status for fifteen months or more. I got almost three years out of Xalkori and know others with ALK mutations who have been on drug even longer. I doubt the clear scan reflects an error—I think your father is more likely one of the lucky ones who has responded. Fingers crossed that his response will continue but there should in fact be more options—thus far the therapies that are effective for ALK mutations seem to have a similar effect for ROS-1 mutations and there are several in various stages of development.


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