Mets to brain during CO-1686 - 1270599

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hain
Mets to brain during CO-1686 - 1270599

Hello everyone, I have a question for you all:

Mom just finished cycle 6 on CO-1686 and just had CT scans done this week. The results showed that there is continued stability in her lungs, abdomen, pelvis, and neck. However, there seems to be indications of NEW metastasis to her brain (multiple spots in her frontal, occipital, temporal lobes, and basal ganglia; currently small and ranging from 5-7mm). We are currently waiting for an appointment for a brain MRI to more clearly see these new spots. The onc has mentioned that the Clovis med although works well to control disease in the lungs, it does not seem to cross the blood brain barrier. If indeed these new spots are due to metastasis, they would proceed to brain radiation (either spot radiation or whole brain depending on how numerous) and she can still continue on the trial med.

My question is: do you guys think brain radiation and continued trial med is the best way to control disease, especially given the new possible brain mets? Would standard chemotherapy or some other treatment for cancer work better to control brain mets?

We are not sure if we should stay on this trial med or if there are other treatments out there that is better at controlling disease that has progressed to the brain. Thanks for the replies in advance guys.

-Hain

JimC
Hello Hain,

Hello Hain,

It's good to hear that CO-1686 has been effective in the rest of the body. Although there are claims that some drugs penetrate the blood brain barrier well enough to prevent or even treat brain mets, systemic therapy in general does not tend to be that effective in that context. Radiation is the preferred treatment and WBR is the typical choice when there are more than 3-4 brain mets.

It is possible that there were micrometastases present in the brain even before starting CO-1686, which have only now progressed to the point of becoming visible lesions. If that's the case, that would be a strong argument in favor of continuing with CO-1686 after whole brain radiation, since the current therapy seems to be controlling the disease well. It would be good to get all the benefit you can from CO-1686 before moving on to another therapy.

Good luck with radiation.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

hain
Hi Jim, thank you for your

Hi Jim, thank you for your response. It sounds to me like there aren't much that we can do currently with brain Mets besides radiation. You mentioned not many drugs cross the BBB, in that case, just wondering if there are any select few drugs that u know of that actually treats lung cancer and also crosses this barrier? (I'm wondering if first generation TKIs like iressa or tarceva can cross since mom was on iressa for 1.5 years without brain mets and have only been on clovis for 5 months and now seems to have developed multiple brain mets). I'm afraid radiation may hold off cancer growth for a short time only to experience uncontrolled and continued growth soon after. Any advice and personal experience on anyone who had brain Mets and still successfully fighting it off would be appreciated. Thanks.

JimC
Hi hain,

Hi hain,

Actually many drugs do cross the BBB, it's just that they don't tend to cross it in a sufficient concentration to treat active brain mets. That's why in many instances the first progression noted after a good response to an EGFR inhibitor tends to be in the CNS, which acts as a "sanctuary site" for the disease, probably because not enough of the TKI is present in that location. That's why pulsed Tarceva is at times attempted to treat CNS metastases, in an effort to get a high enough concentration of the drug across the BBB.

Although it was not true for my wife, in most cases whole brain radiation effectively "sweeps the brain clean" of cancer cells, providing an extended period free from metastases, especially when the disease is well-controlled in the rest of the body.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

njliu
Hi Hain, just to share

Hi Hain, just to share experience, my wife experienced multiple brain mets 2 1/2 years ago while on half dose of Iressa. She underwent Whole Brain Radiation then and reverted back to full dose Iressa immediately. She has been relatively stable and has good quality of life. Brain mets have been detected on MRI again for the last one year but no symptom. We elect to keep close watch only while on Afatinib + cetuximab. Everyone is responding to treatment differently and in my wife's case, full dose iressa and whole brain radiation seems to have worked until recent signs of progression.
Hope this sharing can be of help to you.
NJ

hain
Hi Jim and NJ,

Hi Jim and NJ,

Thanks for your responses.

Jim: I'm sorry to hear about your wife. It really seems like radiation is hit and miss and it may work well for some but not great for others - at least from the experiences from others I've been reading.

NJ: Thanks for sharing your experience with us. I told my mom your wife's story and that helped to cheer her up a bit :) Just curious, would you mind sharing how extensive your wife's mets to brain were/are? My mom's scans showed mutliple small mets 5-7mm to both her frontal, occipital, temporal lobes, and basal ganglia - sounds very scary. Do you feel that Iressa kept the cancer at bay or is it the WBR? I'm just wondering if staying on clovis is a good idea if it doesn't seem to work in the brain too well. But if radiation can keep the cancer at bay while Clovis can control cancer elsewhere in body that might be our best option.

njliu
Hi Hain, there were 5 brain

Hi Hain, there were 5 brain mets upto the size of 1cm but asymptomatic when she went for whole brain radiation. They remained visible but more or less stable thereafter. They appeared to be growing very slowly again in the last one year. However, as she had no symptom we were no longer as fearful and elected to just closely watch. Here is the latest: 6 weeks ago, her MRI showed increases in size and number of brain mets after she had 2 episodes of transient partial vision loss, while there were evidence of progression in the lung too. We decided to switch to Afatinib + Cetuximab. Last Friday MRI showed the largest mets is down to 8 mm from 1 cm and the rest are stable and less visible. To me, this is a clear sign that Afatinib does get to the brain.
Solely based on our experience, (1) both Iressa and Afatinib do get to the brain, but perhaps at a lesser amount. Therefore the challenge is to find the highest dose tolerable. (2) whole brain radiation works generally with significant risk of serious after effect for some.
NJ

hain
Hi NJ thanks for the reply

Hi NJ thanks for the reply and sorry for my late one. Mom just had a brain MRI few days ago, haven't had any reports yet so still waiting. In the meantime I've been reading lots of this brain met issue and there doesn't seem to be a one best treatment option available.

Just wondering, how come you opted for Afatinib + Cetuximab, rather than other possible options, such as: pursuing AZD9291 drug, trying pulsed Tarvceva, or trying traditional IV chemo?

I am trying to research which of the above options (including the one you and your wife has chosen with Afatinib) would be the best next course for mom. She is very similar is age as your wife and has also only been on Iressa, and currently co-1686 for her stage 4 cancer diagnosed in June 2013.

njliu
Hi Hain,

Hi Hain,
Here is my non-professional understanding.
Why Afatinib+Cetuximab: The plan was to switch to Carboplatin+Alimta upon progression on Iressa. However, the discovery of some progression in the brain led the oncologist to recommend Afatinib+Cetuximab instead as it was considered having a better chance of reaching the brain.

Why not AZD9291 or CO1686: They are not FDA approved and not readily available to us. They are considered the next option when Afatinib + Cetuximab runs its course.

Pulsed Tarceva: It is a "desperate choice" for Leptomeningeal Carcinomatis. Although there appeared to be some leptomeningeal enhancement on MRI Scan prior to Whole Brain Radiation, this was rendered unnecessary as it disappeared after the radiation.

Of course, immunotherapies like Opdivo and Keytruda are the other viable options down the road.

Hope this help.
NJ

hain
Hi guys,

Hi guys,

NJ thanks for the reply and providing your reasoning. We are meeting with the radiation oncologist Tuesday and a follow up with her primary lung onc the next day to discuss options. It sounds like mom will most likely need a course of WBRT as the recent MRI reported multiple mets throughout the brain roughly over 2 dozens in number and sized 1-11 mm. She is still asymptomatic, however.

Mom was told to stop the CO-1686 medication today, wait for WBRT, then she can re-start the trial medication after the course of radiation to the brain is complete. I am anticipating 1-2 weeks course of radiation.

I would like to ask Dr. West or another doctor on this site what your thoughts of are in terms of continuing CO-1686 (as it seems to be controlling the primary lung tumor well, just not the brain; please see below for mom's brief medical history), OR seeking another line of treatment, such as AZD9291 - as this has been claimed to be able to cross the blood brain barrier and can potentially treat the lung and brain together.

Our other options we are considering include:
- Afatinib + Cetuximab
- traditional IV chemo

Like Jim mentioned earlier, it might be a good idea to treat with brain rads, then continue on CO-1686 to maximize its benefits before moving on to another line of treatment. But my concern is that if the systemic treatment isn't controlling the brain mets, would her condition progress so quickly that later down the road pursuing AZD9291 would be too late? Very confused and demoralized, hoping to get some guidance and opinions in this critical juncture. Thanks in advance.

Mom's medical history:
- 57 year old, exon 21 L858R mutation, T790m positive
- June 2009-2013 stage Ib adenocarcinoma NSCLC, LUL Lobectomy
- June 2013 to February 2015 (Stage IV lung cancer + mets to bone, treated with Gefitinib)
- February 2015 to present (progression in lung and bone mets, started CO-1686)
- Scan in July 2015 => new mets to brain

JimC
Hi hain,

Hi hain,

In response to the question "Any idea if the new generation TKIs like Afatinib in combination with Cetuximab, CO1686 or AZD9291, as well as Anti PD1/PDL1 hold better promise?" Dr. West stated simply:

"Unknown/unpublished/unreported, on all fronts. None of these approaches is being advertised as a treatment for disease in the CNS." - http://cancergrace.org/topic/blood-brain-barrier-penetration-on-egfr-mut...

If you read the earlier part of the discussion in that thread, you'll see that there are anecdotal reports of various chemo agents successfully crossing the blood brain barrier, but no solid evidence that any single agent in particular is significantly better than others.

In that regard, I'd be inclined to get the maximum benefit from CO-1686 after WBR.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

hain
Hello Jim,

Hello Jim,

Thank you for the reply. I found a youtube video of Dr. West a couple years ago (https://www.youtube.com/watch?v=XGGCsjt1Xxg), speaking about the possibility of delaying WBRT and trying out targeted therapy that can cross the brain more easily (e.g., Tarceva or Gefitinib at the time), which has the potential to control disease in lung as well as brain. The main advantage is the chance to delay WBRT because of the possible cognitive decline side effect from radiation.

My question is whether this is still a relevant notion today, but instead of Tarceva, it would be with a newer agent like AZD9291 (since mom has already used Gefitinib and progressed in the lungs, no brain mets at the time however).

There's article that hints that AZD9291 is better at penetrating the BBB compared to Gefitinib 10 fold:

" Quantitative whole-body autoradiography (QWBA) studies in rat brain with [14C]AZD9291 have indicated that AZD9291 had a brain-to-blood ratio of up to 2 over the first 24 hours, suggesting the potential of AZD9291 to penetrate the brain. This is in contrast with [14C]gefitinib, which had a maximum brain-to-blood ratio of only 0.2"

http://cancerdiscovery.aacrjournals.org/content/early/2014/06/05/2159-82...

Interested in anyone's thoughts on this matter. Thank you.

catdander
The biggest question is often

The biggest question is often whether or not the brain mets are symptomatic. Since brain mets have the worst symptom profile they are usually targeted with the most relevant treatment (cyber knife type or wbr) asap if they are symptomatic. Another question is whether or not someone is able to get a 3 gen tki like azd9291.

hain
Hi Catdander,

Hi Catdander,

Thanks for replying. My mom is currently asymptomatic. Her brain mets were found end of July during a routine 2 month CT scan while on the Clovis trial. An MRI done last week confirmed the mets and indicated numerous mets throughout the brain sized 1-11mm. We are meeting with the rad onc tomorrow to discuss radiation and her lung oncologist (from the Clovis trial) the next day to discuss plan.

On the other hand, I am in contact with someone in the US, who is reaching out to the sponser at astrazeneca to see whether or not we are able to access AZD9291 in Canada somehow. Still waiting for response at the moment.

So nothing is set in stones right now, but just wondering from a doctor on this site for an opinion first, prior to meeting with her primary onc in a day or two, in order to make an informed decision about final plans once we meet with the onc, to not delay treatment. In an ideal world if AZD9291 is available to us, and so is WBRT + continuing CO-1686 - what would the sensible thing to do be? (I understand there isn't a right or wrong answer here, just wanted to get more minds on this topic if possible).

Thanks,
Hain

catdander
Hain,

Hain,

I hope you understand our faculty aren't able to address every eventuality. The video you've referred to is about a woman who was on chemo but had egfr mutation. There was more to the decision than just moving from a treatment that was working well with the one exception of the brain mets. She wasn't on the best standard of treatment to begin with which was tarceva. It made since in that situation. That's different than leaving a trial drug that's otherwise working to seek out a drug that if you can get it it hasn't been proven to benefit a person better systemically than what's she on, not to mention the cost would likely be prohibitive.

Please let us know how your mom's appointments went.

All best,
Janine

dr. weiss
In general, the two major

In general, the two major options for treating small asymptomatic brain mets are to either do whole brain radiation or to observe carefully. Note that "observe carefully" is the not the same as doing nothing--it means close interval MRI brain imaging and monitoring for symptoms. The judgement on which makes more sense is very situation dependent. The rules of the trial will also be relevant--CO1686, like the other 3rd gen TKIs is sufficiently active against systemic disease that you likely want to avoid doing (or not doing) anything that would result in loss of access to the drug. In general, when systemic therapy is working but a patient has isolated brain progression, I don't tend to consider switching drugs in an attempt to get better brain penetration because there really aren't any at this time that are so promising for the brain that I'd give up good systemic control. The judgment regarding whole brain vs. observation is one that really needs to be personalized to your specific situation. Some relevant variables are the timing of prior MRIs, growth rate in the brain, location of mets (relative to dangerous areas), extent of systemic response, tolerance to ongoing drug, and your values. If your'e at a center large enough to have access to the Clovis trial, I am hopeful that your docs will have this conversation with you.

hain
Hello Janine and Dr. Weiss,

Hello Janine and Dr. Weiss,

Thank you for your replies. We met with the radiation oncologist as planned and was advised to proceed with WBRT (as there were too many small mets in order to pursue SRS). Unfortunately we were not allowed to pursue temozolomide (as per trial protocol because of unknown interactions), as well as memantine (because the radiation oncologist mentioned it is still experimental). Mom had 3 of 5 WBRT sessions already and is tolerating it fairly well, besides having occasional headaches and slight dizziness. Hope these symptoms improve.

The meeting with the primary oncologist resulted in us deciding to continue CO-1686 after WBRT as per the onc's recommendations. The systemic response to CO-1686 is great so far (~60% tumor reduction initially, followed by stability thereafter); however, we are a bit disappointed in the recent brain mets development and hearing that it is probably due to the poor penetration of the med through the blood brain barrier.

Any further advice would be much appreciated. Thanks again everyone for all the helpful replies.

Best,
Hain

catdander
The only thing I can think of

The only thing I can think of is to hope for a drug that shows good penetration into the brain that compares to wbr and srs.

I so glad your mom is doing well on co 1686 and hope it continues to keep her stable for a long long time.

Janine

cards7up
FWIW, many people have great

FWIW, many people have great response to their treatment but get brain mets anyway. There is no definite drug proven to cross the BBB. Some may have done so for a couple of people here and there, but it's not at a point of using it instead of brain radiation. Brain mets are not something you want left to chance. Wishing your Mom the best outcome. Take care, Judy

njliu
Great to learn from Dr. Weiss

Great to learn from Dr. Weiss that two major options of treating asymptomatic brain mets are WBR and Observe Carefully. These are exactly what we did with my wife's multiple brain mets for the last 2 years and 8 months. May I just take this opportunity to ask if it is not uncommon that some may have multiple small brain mets but is generally stable for months and even years under "Observe Carefully" with only systemic treatment? As we have been living with high anxiety under such condition.
NJ

hain
Hello NJ,

Hello NJ,

I don't have an answer to your question but also interested in hearing what others have to say on this matter. My guess would be that everyone's cancer is different and that it may choose to become more aggressive or more dormant based on factors that are difficult to predict clinically. It's at least good to know that your wife's cancer seems to be more of the former characteristics.

Mom just completed 5 sessions of WBRT and will be meeting with onc in a few days to hopefully restart trial med. Just wondering what the dosage of WBRT your wife had? (my mom had 20 grays in 5 sessions)

Just wanted to ask you a question actually. Just wondering if your wife was or is on any supplements in addition to conventional treatments? My mom's been on several naturopathic supplements since 2013 diagnosis but this recent brain mets issue is new so we aren't sure if supplements is still in our best interest to continue. She's on: Cucrumin (300mg, twice daily), fish oil (2g EPA/DHA daily), vitamin D (3000IU), melatonin (20mg nightly). We were thinking of possibly trying out reishi mushroom as a tea to see if it might be beneficial in any way.

Looking forward to hearing back.

-hain

njliu
Hain, glad to know that your

Hain, glad to know that your mom is responding well to WBR and I believe we can remain hopeful of long term response. My wife was given a total of 30 grays in 10 sessions. She is not, nor has she been, on any supplements other than prescriptions given by the doctor. She is especially wary of any unknown interaction of supplements with the cancer drugs. When I told her that Dr. West did caution the use of hair dye, she immediately stopped.
NJ

hain
NJ, great to hear your wife

NJ, great to hear your wife has responded well to conventional treatments without need to supplement with other complementary treatments.

Just curious is your wife being monitored for brain disease via MRI scans or CT scans of brain? and how often is she being monitored?

We had a meeting today and were told that mom will be followed-up with CT of brain every 2 months while continuing with the trial med (CO-1686), which restarted today. When I asked about how come an MRI was not ordered instead, the nurse answered because we have a previous CT scan so we will use the previous one to compare (despite us actually also having a more recent brain MRI prior to WBRT; I didn't express my thoughts at the time due to fear of sounding too pushy). My guess would be due to cost and convenience? I can't think of any other reasons why not order MRI to followup on brain disease especially if MRI is more sensitive and specific in picking up lesions within the brain and an MRI would need to be ordered anyways when a CT scan shows abnormal growth or progression between scans.

Does anyone have any ideas? Is this the conventional diagnostic test ordered for brain disease? Just hope mom is getting the best and timely care possible. Thanks for replies in advance guys!

-hain

njliu
Hi Hain, since the Whole

Hi Hain, since the Whole Brain Radiation 2 3/4 years ago, she has been on Brain MRI surveillance in the intervals of between 6 weeks to 15 weeks.
NJ

JimC
Hi hain,

Hi hain,

Although CT scans can be used, the preference is usually for an MRI. As far as the difference between CT and MRI for detecting brain lesions, Dr. West has said:

“There is little to no question that head MRIs are superior to CT scans in detecting brain metastases. MRI scans detect a greater number of lesions and defines the location more readily, and they are also better at detecting spread to the meninges, the lining around the brain (and spinal cord).”http://cancergrace.org/lung/2007/04/05/intro-to-brain-mets/

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

dr. weiss
Hi all! I have a two points

Hi all! I have a two points to add, if I may.

*While textbooks may say that chemo doesn't penetrate the brain, this is not always true. When systemic agents work elsewhere in the body, they sometimes help in the brain too. However, in my practice, I rely on them less. That is to say that if I'm truly scared of the mets hurting my patient, I favor radiation of some kind. If they're small and not threatening my patient immediately and we together choose observation, I image regularly.

*Choice of imaging modality matters. In my opinion, using CT of the brain to look for mets is like looking around your attic for something with a flashlight with half dead batteries. MRI is like turning the lights on.

catdander
Hi Dr. Weiss,

Hi Dr. Weiss,

Thanks so much for dropping in with always wise words. Hope to see you around. :)

Janine

hain
Hello everyone,

Hello everyone,

Thank you NJ, Jim, and Dr. Weiss for your helpful replies!

I just spoke to the nurse to clarify the plan with CT vs. MRI of brain and was told that actually we will CT scan brain to followup the first month, and then possibly follow up with MRI moving forward.

Dr. Weiss, thank you for the added point on chemo and its potential to penetrate the BBB. I hope somehow after WBRT, the BBB is made more permeable to the CO-1686 med and mom can enjoy stability for longer time until another line of therapy is needed.

-hain