Japanese alk dosage option - 1290983

Hi me53,

There is always room to individualize treatment choices based on particular factors unique to any given patient, and your need to avoid liver toxicity is certainly such a factor. The standard dosage of any drug is the "maximum tolerated dose" as determined in early-phase clinical trials, rather than the minimum effective dose. In response to a question of dose reduction, Dr. West has said:

"The dose you describe as "100%" isn't the right dose for everybody. It's a starting point that is typically the "maximum tolerated dose", and it is completely appropriate to decrease the dose based on the parameters of how low the blood counts get and how well or poorly a patient tolerates treatment in terms of the symptoms of chemo that they experience." - http://cancergrace.org/forums/index.php?topic=1699.msg9977#msg9977

Though the results of the J-Alex trial are encouraging with regard to the lower dose, as Dr. West points out "there may well be racial differences in how different cancer drugs are metabolized". - http://cancergrace.org/lung/2016/06/24/j-alex-asco-2016/ These differences may go beyond typical physical dimensions and diet.

The only risk would be that you do not get as good a response from the lower dose than you would have gotten at the standard dose, and you might never know whether that has happened. In other words, you may get a good response, but it might have been better.

JimC
Forum moderator

Hi me53,

Jim touched on the reason for the higher dosage in his post above. All clinical trials for new drugs are set up to first find the highest safe dose of a drug before testing efficacy. This way the drug gets the best possible chance of showing whether or not it will work in the manner for which it's being tested. Then the drug is tested at this dose and if the efficacy is significant and the toxicity profile is not so bad, statistically, then the drug may be approved by the government agency that controls drugs (In the US it's FDA). Once FDA approved the drug goes to market and the drug company has little reason to spend millions of dollars to test for a lower dose that may in turn lead to less income. At that point the doctors and patients can manipulate the dosage if individual circumstances arise. I think all doctors and patients would agree that finding the least dosage needed would be a great thing to know but that's a difficult point to find for the masses. I keep hope is alive for figuring that one out.

Circumstances require doctors to fiddle with doses so their patients are able to try treatments without excessive possibility of severe adverse events.

No one but your oncologist can say why your oncologist didn't get a baseline MRI. One question you can ask yourself is, how would an MRI change your treatment plan. Until now there were no systemic anticancer treatments that would treat brain mets. So doing an MRI before beginning systemic treatment was common in case one needed brain radiation before beginning systemic treatment. Today, alectinib would be a first option for ALK + nsclc with non symptomatic brain mets. So if you do have non symptomatic brain mets alectinib would be an excellent first choice, thus an MRI wouldn't change treatment plans for now or later. I get wanting to know but I also get needing to cut medical cost to a minimum without changing treatment options.

I hope some of this is helpful.
All best,
Janine

Hi me53,

Jim touched on the reason for the higher dosage in his post above. All clinical trials for new drugs are set up to first find the highest safe dose of a drug before testing efficacy. This way the drug gets the best possible chance of showing whether or not it will work in the manner for which it's being tested. Then the drug is tested at this dose and if the efficacy is significant and the toxicity profile is not so bad, statistically, then the drug may be approved by the government agency that controls drugs (In the US it's FDA). Once FDA approved the drug goes to market and the drug company has little reason to spend millions of dollars to test for a lower dose that may in turn lead to less income. At that point the doctors and patients can manipulate the dosage if individual circumstances arise. I think all doctors and patients would agree that finding the least dosage needed would be a great thing to know but that's a difficult point to find for the masses. I keep hope is alive for figuring that one out.

Circumstances require doctors to fiddle with doses so their patients are able to try treatments without excessive possibility of severe adverse events.

No one but your oncologist can say why your oncologist didn't get a baseline MRI. One question you can ask yourself is, how would an MRI change your treatment plan. Until now there were no systemic anticancer treatments that would treat brain mets. So doing an MRI before beginning systemic treatment was common in case one needed brain radiation before beginning systemic treatment. Today, alectinib would be a first option for ALK + nsclc with non symptomatic brain mets. So if you do have non symptomatic brain mets alectinib would be an excellent first choice, thus an MRI wouldn't change treatment plans for now or later. I get wanting to know but I also get needing to cut medical cost to a minimum without changing treatment options.

I hope some of this is helpful.
All best,
Janine

Hi me53,

Jim touched on the reason for the higher dosage in his post above. All clinical trials for new drugs are set up to first find the highest safe dose of a drug before testing efficacy. This way the drug gets the best possible chance of showing whether or not it will work in the manner for which it's being tested. Then the drug is tested at this dose and if the efficacy is significant and the toxicity profile is not so bad, statistically, then the drug may be approved by the government agency that controls drugs (In the US it's FDA). Once FDA approved the drug goes to market and the drug company has little reason to spend millions of dollars to test for a lower dose that may in turn lead to less income. At that point the doctors and patients can manipulate the dosage if individual circumstances arise. I think all doctors and patients would agree that finding the least dosage needed would be a great thing to know but that's a difficult point to find for the masses. I keep hope is alive for figuring that one out.

Circumstances require doctors to fiddle with doses so their patients are able to try treatments without excessive possibility of severe adverse events.

No one but your oncologist can say why your oncologist didn't get a baseline MRI. One question you can ask yourself is, how would an MRI change your treatment plan. Until now there were no systemic anticancer treatments that would treat brain mets. So doing an MRI before beginning systemic treatment was common in case one needed brain radiation before beginning systemic treatment. Today, alectinib would be a first option for ALK + nsclc with non symptomatic brain mets. So if you do have non symptomatic brain mets alectinib would be an excellent first choice, thus an MRI wouldn't change treatment plans for now or later. I get wanting to know but I also get needing to cut medical cost to a minimum without changing treatment options.

I hope some of this is helpful.
All best,
Janine

Hi me53,

Jim touched on the reason for the higher dosage in his post above. All clinical trials for new drugs are set up to first find the highest safe dose of a drug before testing efficacy. This way the drug gets the best possible chance of showing whether or not it will work in the manner for which it's being tested. Then the drug is tested at this dose and if the efficacy is significant and the toxicity profile is not so bad, statistically, then the drug may be approved by the government agency that controls drugs (In the US it's FDA). Once FDA approved the drug goes to market and the drug company has little reason to spend millions of dollars to test for a lower dose that may in turn lead to less income. At that point the doctors and patients can manipulate the dosage if individual circumstances arise. I think all doctors and patients would agree that finding the least dosage needed would be a great thing to know but that's a difficult point to find for the masses. I keep hope is alive for figuring that one out.

Circumstances require doctors to fiddle with doses so their patients are able to try treatments without excessive possibility of severe adverse events.

No one but your oncologist can say why your oncologist didn't get a baseline MRI. One question you can ask yourself is, how would an MRI change your treatment plan. Until now there were no systemic anticancer treatments that would treat brain mets. So doing an MRI before beginning systemic treatment was common in case one needed brain radiation before beginning systemic treatment. Today, alectinib would be a first option for ALK + nsclc with non symptomatic brain mets. So if you do have non symptomatic brain mets alectinib would be an excellent first choice, thus an MRI wouldn't change treatment plans for now or later. I get wanting to know but I also get needing to cut medical cost to a minimum without changing treatment options.

I hope some of this is helpful.
All best,
Janine

Hi me53,

Jim touched on the reason for the higher dosage in his post above. All clinical trials for new drugs are set up to first find the highest safe dose of a drug before testing efficacy. This way the drug gets the best possible chance of showing whether or not it will work in the manner for which it's being tested. Then the drug is tested at this dose and if the efficacy is significant and the toxicity profile is not so bad, statistically, then the drug may be approved by the government agency that controls drugs (In the US it's FDA). Once FDA approved the drug goes to market and the drug company has little reason to spend millions of dollars to test for a lower dose that may in turn lead to less income. At that point the doctors and patients can manipulate the dosage if individual circumstances arise. I think all doctors and patients would agree that finding the least dosage needed would be a great thing to know but that's a difficult point to find for the masses. I keep hope is alive for figuring that one out.

Circumstances require doctors to fiddle with doses so their patients are able to try treatments without excessive possibility of severe adverse events.

No one but your oncologist can say why your oncologist didn't get a baseline MRI. One question you can ask yourself is, how would an MRI change your treatment plan. Until now there were no systemic anticancer treatments that would treat brain mets. So doing an MRI before beginning systemic treatment was common in case one needed brain radiation before beginning systemic treatment. Today, alectinib would be a first option for ALK + nsclc with non symptomatic brain mets. So if you do have non symptomatic brain mets alectinib would be an excellent first choice, thus an MRI wouldn't change treatment plans for now or later. I get wanting to know but I also get needing to cut medical cost to a minimum without changing treatment options.

I hope some of this is helpful.
All best,
Janine

Hi me53,

Jim touched on the reason for the higher dosage in his post above. All clinical trials for new drugs are set up to first find the highest safe dose of a drug before testing efficacy. This way the drug gets the best possible chance of showing whether or not it will work in the manner for which it's being tested. Then the drug is tested at this dose and if the efficacy is significant and the toxicity profile is not so bad, statistically, then the drug may be approved by the government agency that controls drugs (In the US it's FDA). Once FDA approved the drug goes to market and the drug company has little reason to spend millions of dollars to test for a lower dose that may in turn lead to less income. At that point the doctors and patients can manipulate the dosage if individual circumstances arise. I think all doctors and patients would agree that finding the least dosage needed would be a great thing to know but that's a difficult point to find for the masses. I keep hope is alive for figuring that one out.

Circumstances require doctors to fiddle with doses so their patients are able to try treatments without excessive possibility of severe adverse events.

No one but your oncologist can say why your oncologist didn't get a baseline MRI. One question you can ask yourself is, how would an MRI change your treatment plan. Until now there were no systemic anticancer treatments that would treat brain mets. So doing an MRI before beginning systemic treatment was common in case one needed brain radiation before beginning systemic treatment. Today, alectinib would be a first option for ALK + nsclc with non symptomatic brain mets. So if you do have non symptomatic brain mets alectinib would be an excellent first choice, thus an MRI wouldn't change treatment plans for now or later. I get wanting to know but I also get needing to cut medical cost to a minimum without changing treatment options.

I hope some of this is helpful.
All best,
Janin

Hi me53,

Jim touched on the reason for the higher dosage in his post above. All clinical trials for new drugs are set up to first find the highest safe dose of a drug before testing efficacy. This way the drug gets the best possible chance of showing whether or not it will work in the manner for which it's being tested. Then the drug is tested at this dose and if the efficacy is significant and the toxicity profile is not so bad, statistically, then the drug may be approved by the government agency that controls drugs (In the US it's FDA). Once FDA approved the drug goes to market and the drug company has little reason to spend millions of dollars to test for a lower dose that may in turn lead to less income. At that point the doctors and patients can manipulate the dosage if individual circumstances arise. I think all doctors and patients would agree that finding the least dosage needed would be a great thing to know but that's a difficult point to find for the masses. I keep hope is alive for figuring that one out.

Circumstances require doctors to fiddle with doses so their patients are able to try treatments without excessive possibility of severe adverse events.

No one but your oncologist can say why your oncologist didn't get a baseline MRI. One question you can ask yourself is, how would an MRI change your treatment plan. Until now there were no systemic anticancer treatments that would treat brain mets. So doing an MRI before beginning systemic treatment was common in case one needed brain radiation before beginning systemic treatment. Today, alectinib would be a first option for ALK + nsclc with non symptomatic brain mets. So if you do have non symptomatic brain mets alectinib would be an excellent first choice, thus an MRI wouldn't change treatment plans for now or later. I get wanting to know but I also get needing to cut medical cost to a minimum without changing treatment options.

I hope some of this is helpful.
All best,
Janin

Hi me53,

I'm sorry that your doctor is not as accessible as you would like. Apparently he or she has decided, on the basis of the J-Alex trial results and your own situation, that you should begin at the lower dosage. This is a judgment call based on full information about you but limited trial data. As Janine pointed out, it is unlikely that further trials of the lower dosage, using a general population, will be performed. And as Dr. West stated in the above quote, it is perfectly reasonable to use a lower dosage in order to avoid toxicity issues. As in any situation in which a dose is reduced to make a therapy more tolerable, there is no trial evidence to indicate whether that lower dose will produce fewer side effects and be as effective as the standard dose. The J-Alex trial provides more evidence than most patients have in this situation, with the caveat that it is based on a limited population.

If you had more time before starting treatment and have questions not being answered by your doctor, the typical suggestion would be to obtain a second opinion from an academic oncologist, after providing him or her with all of your medical records. Dr. West cannot provide that second opinion. He does not have access to all of your medical data, and it is beyond the scope of this site for him to tell you what to do or second-guess the decision of your local doctor, based on the limited information he would have. As the GRACE forum guidelines state:

"Please don’t ask what you “should” do. We can provide general information, and we’re delighted to do it, but we can’t provide medical advice to people who aren’t our patients. We could get into legal trouble, and we don’t want to try to replace the local team that has access to more relevant details, such as scans, labs, and the ability to evaluate a person directly. “Should” is the one word on the forum that is a trigger that we’re crossing a line." - http://cancergrace.org/grace-discussion-forums#guidelines

Continued

Continued from previous post

Again, I'm sorry that your doctor is not answering you questions. I suspect that some of these questions have no answers, as is often the case when individualized treatment choices are made. They are usually made on the basis of informed assumptions; in this case, that a lower dosage will reduce the chance of liver toxicity yet be just as effective. There is an art to the practice of oncology, in addition to the science, but as long as the assumptions are well reasoned and based as much as possible on extrapolations of currently available data, that's the best that can be expected. In your case, your doctor has based the decision on a desire to avoid toxicity, based on the J-Alex results. It's the kind of decision that is often made in the real-world practice of oncology, and many patients quite reasonably are uneasy about an unproven course of action. We wish that there were always clear courses of action for every situation, but unfortunately there are not.

Best wishes for good results from your treatment, both in terms of response and tolerability.

JimC
Forum moderator

I'm sorry that I have misunderstood. It seems to me that you have done good research and analyzed your situation as well as can be. In the J-Alex trial you have found the relevant data, while being aware of the limitations of extrapolating that data to a general population. Oncologists often make the perfectly reasonable assumption that a lower dose will reduce the likelihood and severity of side effects, and you understand that your response may not be as good as it would be at the higher dose. I think all of these are the relevant factors to consider, and if you choose the lower dose you are making an informed choice.

You will probably want to re-scan after a relatively short interval (although too short an interval may not be enough to show true response), and if the response is less than you might expect or if there is progression, it may make sense to consider switching to the higher dose. That would also depend on how you are tolerating the low dose.

All this being said, if your oncologist strenuously opposes starting at the lower dose, I would press him or her for the specific reasons for their recommendation.

Again, best wishes for a good response.

JimC
Forum moderator

I know that you certainly can get responses at 450 mg twice daily, but it's not as well studied as the FDA approved dose. I don't think eating Japanese food makes a difference, and thus far neither does patient size.

While it is true that the J-ALEX trial showed great efficacy for the lower dose of 300 mg twice daily in Japanese patients, we know that there are many instances of significant racial differences in metabolism of various anticancer therapies. The larger, global ALEX study used 600 mg twice daily, and that is the dose I and likely most or all experts favor as initial treatment for the vast majority of patients. In someone who has difficulty tolerating it, I would not hesitate to lower the dose to 450 mg or even down to 300 mg, knowing that this dose can be effective at least in some patients, based on the Japanese experience, I would not be inclined to presume that a lower dose is as effective as the best studied dose, at least not in a non-Asian patient. My starting dose would be the 600 mg twice daily dose.

Good luck.
-Dr. West