Crizotinib - PF 02341066 - ALK / Met Inhibitor

[Fictional]

Hi everyone,

I'm going to add this to 'K''s update, but we just heard that the ASPS tumor that came from the lung and floated up to the left atrium was 40% necrotic. We are very happy with this and will try to use it to ask for a protocol exception. She was kicked out because of the incident discovery of the heart mass.

Criztonib has very tolerable side effects - worst were in the first 1.5 months - diarrhea and a few episodes of vomiting. She normally doesn't vomit at all - and I think vomited maybe 3-5 times in the first month or so. after 2 months - side effects were minimal. She does get migraines and hard to know if these are worse on Crizotinib, but it's been great, she's full time at school and was practicing with volleyball team.

Crizotinib looks very promising for ALK+ non small cell lung cancer, and many people think it will be approved in the middle of next year.

I cannot guarantee that the necrotic heart ASPS met was necrotic due to Crizotinib, but it is implied. Her primary tumor on Sutent x 6 months showed 5% necrosis, and on ARQ197 (met inhibitor), something like 2 out of 17 lung mets were necrotic (40% and 80%) - the fastest growing ones. ARQ197 may be even better as an antimetastatic agent (inhibit the formation of new metastases).

Another nice thing about Crizotinib is that benefit has been seen out to 2 years +. At least in our experience, we had more problems with rebound tumor growth coming off Sutent than the met inhibitor ARQ197. We probably got a little rebound coming off R1507 (IGF inhibitor), but the worst for us was the VEGF inhibitor Sutent.

[Fictional]

p.s. What I meant to add is that one could argue that 40% necrosis is not due to Crizotinib - but that once this nasty met punched through the pulmonary vein, it outgrew its blood supply and began to die. I personally think Crizotinib helped because none of the marker lesions grew at all over 5 months - actually the best result of any med trial we've had - and the fact that ASPS can cause intracardiac and pulmonary vein mets - one case in the literature had solid tumor from the lung via pulmonary vein and into the left atrium.

Anyway, I wanted to add this to the list of possibilities. I especially like the potential antimetastatic effect of met inhibitors. Perhaps the best data from ARQ197 thus far is with NSCLC (lung cancer) that shows ARQ197 reduced the onset of net metastases from 3 months to 11 months. Kgal started ARQ197 when new lung mets were presenting with each new scan. I think within 2 months of starting the drug, we never had a new metastasis. With this latest heart lesion, we are still at risk for mets - but that's why Crizotinib goes to the top of the list for us.

[Bonni Hess]

Is there any information available as to whether or not this promising new met treatment can cross the blood brain barriar? This is a critically important factor especially for ASPS patients with a history of previous or active brain mets. Based on our extensive research and experience, there are unfortunately currently very few ASPS systemic treatments that can cross the blood brain barriar to try to prevent new brain mets or to shrink/destroy existing brain mets, so it would be an especially important addition to the list of limited ASPS treatment options if Crizotonib has this capability like Cediranib does.
Also, are there currently any other ASPS patients being treated with Crizotonib, and if so, is there any data available yet regarding the outcome of their treatment?
We will continue to closely follow the results of this new treatment option with great interest and continued Hope for its success.
Bonni

[Olga]

Bonni - just a short note - Crizotinib is not a treatment but an investigational drug in a trial yet (as is cediranib). The risks/potential side effects and its effect on the OS (overall survival) is only under the investigation now.

[Fictional]

I think it is thought to cross the blood brain barrier. One trial is accepting primary brain tumors. Crizotinib has a relatively small molecular weight - and it is not an antibody. There is also a freaky occasional side effect with vision - that is fine once you recognize it - it comes and goes and usually when you wake up transition from dark to light...probably from a visual cortex effect.

Crizotinib's other name is PF 02341066.

And correction on the path report - our final report says 50% necrosis, so formally a "response". We are asking for an sIND - it needs IRB approval, but apparently the paperwork is going faster than our onc thought...hopefully that is a good thing.

Crizotinib was THE exciting drug at the most recent ASCO meetings and mainly because of the ALK+ NSCLC results. I will attach a pic (this is not ASPS -see how the tumors look different) - but we were interested in the drug because of its high potency at the met receptor. Met is highly expressed in both primary and metastatic ASPS and in K's molecular profiling. And there are many met-positive tumors (not just NSCLC or ASPS) so Pfizer is hoping it is a 'blockbuster' drug. We will see. The practical information for ASPS patients is that it is highly likely to be approved next year - at least if there are no surprises. 85% of Alk positive NSCLC respond, some with complete remission, and the responses are durable (2 years +), and these results are really unheard of. Now it's a big scramble to get the drug esp by ALK+ people. Once FDA approved, at least theoretically Criz can also be combined with drugs like a VEGF inhibitor - no data yet to know for sure.

Another nice thing about met inhibitors is that c-met seems mainly important in early development...like when you're an embryo. Linnea has a blog where she's talked about being on Crizotinib. She was also very kind to us when we asked about side effects, stopping before surgery etc. She was hiking and fractured her ankle while on Crizotinib. They wanted her 2 weeks off the drug, but they petitioned to be on as soon as possible - so she was able to have her ankle surgically pinned and only be off the Crizotinib for 4 days total without any problems. Our heart surgeon wanted her off at least 2 weeks before heart surgery, so that's what we did. We were happy to see that by post heart surgery CT, it looked as if there was no rebound growth being off the drug for 3 weeks. Our surgeon wants us off drug for 2 weeks after surgery, so we are hoping that we might be able to be back on the drug in 1 week. Linnea's blog: http://lifeandbreath.wordpress.com/

[Olga]

Is this the scan of the initial response? I've read her blog before and it was my understanding that she is becoming resistant to this drug. Here is the excerpt from there:
"Since our last visit, Dr. Shaw had reviewed all of the scans from the past twelve months, and at this appointment she placed them side by side for me. Although she feels that my cancer is behaving in a fairly indolent fashion, it is nonetheless persistent. The difference between my most recent scan and that from a year ago is striking. So we talked about the benefits of getting a biopsy now, while I’m still feeling good, rather than later when shortness of breath will likely become more of an issue.

The purpose of this biopsy is not to confirm malignancy, as there is really no doubt that we are looking at metastasis. Rather, it is to gather genetic material in an attempt to ascertain why my ALK mutation has become resistant to the crizotinib."
Can you ask her if her cancer was behaving in a fairly indolent fashion before of crizotinib trial. At least it looks like the accrued resistance does not cause the interval growth for now but just a pick up of the slow growth, in that case it may be bought her 2 years of the life in between.

[Fictional]

Look at the subsequent posts. They thought she was developing progression in a few tumors - but felt that the overall is stability, so she's still on the drug 2+ years out. We've been corresponding off Inspire.

I don't know if she is officially off the trial but she is getting the drug on sIND (single user IND). The onc regulatory head at Pfizer said they have a lot of people on sIND for Crizotinib.

Linnea is waiting until another clinical trial is available. I think her doctors are thinking that this is better than nothing - and although a few grew a little on one scan, the next set of scans were stable so she is not switching.

[Bonni Hess]

Thank you Olga for correcting my terminology of "treatment" as opposed to "investigational drug" in reference to Crizotonib ( as well as Cediranib). It is of course an important distinction to make at this point where both medications are still in the testing stage. Thank you too 'F' for the additional information. It would be a significant factor in the consideration of this drug as a potential ASPS treatment option if it does indeed cross the brain blood barriar given the nature of ASPS to metastasize to the brain in some patients. I will explore this issue further through research and also discussion with Dr. Sawyer to try to assess if Crizotonib has been definitely determined in Clinical study to cross the brain blood barriar, and if so, if it has been able to prevent new brain mets and/or cause necrosis in existing ones in study patients. Aldditionally, I am still not clear from your response as to whether or not you are aware of any other ASPS patients besides 'K' who are currently being treated with Crizotinib, and if so, what the results of their treatment with this drug have been thus far. It will certainly be wonderful to have a possible new ASPS treatment option available through prescription rather than only Clinical Trial if Crizotonib receives FDA approval, although as with other recently approved drugs such as Sutent, it may then concerningly be cost prohibitive if insurance companies refuse coverage.
With appreciation for the shared information, and continued Hope,
Bonni

[Olga]

New article about case of successful use of the crizotinib in another sarcoma was published in a New England J. of Med. here:
Crizotinib in ALK-Rearranged Inflammatory Myofibroblastic Tumor
http://www.nejm.org/doi/full/10.1056/NEJMoa1007056
I do not have an access to its full text article but I found a good commentary here:
http://www.medicalnewstoday.com/articles/206070.php
the point is that the response was related to the ALK protein his tumor expressed and that another patient with no expression did not respond and that there was a accrued resistance few months after the respose when the growth restarted and the tumors were resected with the success. Good information overall as it gives an indication that when the tumor respond well there might be the window of opportunity to resect them if the initial situation was unresectable or resectable with the potential complications that might be avoided if the tumor shrinks.

[Bonni Hess]

Dear Olga,
Thank you for finding and posting this important information. Although the patient was not an ASPS patient, and the patient unfortunately developed resistance to the medication with increased tumor growth after several months of Crizotonib treatment, it is very encouraging that the Crizotonib was able to cause enough shrinkage of the tumors for them to be successfully resected, and that following the tumor resection the patient was allowed to resume taking the Crizotonib and had no new tumors as of September 2010. Perhaps 'K' will be allowed to resume participation in her Crizotonib Trial based on this case which allowed the patient to resume taking Crizotonib following surgery. However, as with all of the other promising new targeted treatments, there discouragingly seems to be an issue of eventual developed resistance to Crizotonib as per the following excerpt from the article:
Geoffrey Shapiro said that even extremely targeted medications, such as crizotinib are vulnerable to resistance from tumors. Co-author Pasi Jänne, MD, PhD studied some of the tumors that had developed resistance and had been surgically removed. The study, published in Cancer Research identified a second mutation in ALK in the patient's tumor which conferred crizotinib resistance.
Hopefully sometime VERY soon researchers will be able to find a way to prevent developed resistance in all of the promising new targeted treatments. In the meantime, the search and the Hope continues.
With deepest gratitude for your faithful sharing, special caring thoughts, and continued Hope,
Bonni

[Ivan]

I think that, based on the current available information regarding targeted inhibitors, the best course of action is shrinking your tumors as much as possible, and then aggressively resecting. This is better than just waiting to develop resistance which almost always eventually happens.