EGFR mutation - p.747_P753delinsS(exon19) - current treatment Osimertinib (Tagrisso)

Hi Clark,

Welcome to Grace.  We do put a hold on new threads to help weed out spam and bots.  But adding posts to threads shouldn't be a problem. 

I'm very sorry to know you're dealing with lung cancer.  It sounds as if you're doing very well on tagrisso. Congratulations!  And hopefully, it will continue to work for a long long time.  It's known that the exon 19 deletion responds well to TKIs but the specific subtypes such as your p.747_P753delinsS haven't been studied enough to have any effects on treatment choice or even to tell us much on what to expect.  From a search on clinicaltrials.gov I didn't see any trials related to those subtypes.  Maybe by the time you need a change there maybe something more known about them or a trial to consider. 

When you look at info on the subject you'll want to look for Exon 19 deletions and exon 21 L858R substitution (or exon 19 and 21)(or just egfr).

We have lots of information on lung cancer in general and egfr mutations.  Our older forums have a plethora of info of a supportive nature.  Look for videos on our youtube channel or ask for help here.  Dr. West, Grace's president and creator also has a site, beaconmedic.com. 

Grace is set up to answer and comment on specific issues but doesn't have a large posting support community.  Forums such as Lungevity and Inspire have large support networks that you might try. 

I have not had cancer but my husband did and I have only guessed at what that must feel like.  It's good to know you're responding so well (responders respond) and know that you have options should you need them. 

I hope you do well.  Don't hesitate to ask when you need to or please do keep us posted.  You never know when your questions, experiences, and comments will help someone else. :)

Janine

Dear Clark,

my name is Martina, I am writing from Germany.

I am still looking for further patients who suffer adeno lung carcinoma stade IV, treated with Tagrisso 80mg. But it seems that in Germany only few patients exist and they don´t write in any forums.

I had a check after taking Tagrisso for three months and my CT showed a regression of the tumour and as well of the lymphangiosis, covering my whole lung before.

I would be happy to read about your experience and of course I hope that you are feeling well.

Many greetings,

Martina

Hi Martina and Martha,

Welcome to Grace.  It's great that you both are doing well on tagrisso.  It's comforting and helpful to have others who are going through the same thing to talk to.  Martha, I hope you get nothing but good news today.  Keep us posted.

And if either of you have questions don't hesitate to ask.  I will always call on Dr. West or another of our faculty for input.

Take care,

Janine

Hello !!! I need some information too !! My brother has malignant melanoma and we need Osimertinib. The doctor definitely recommended it, having the T790M mutation ... it's urgent. Do you know anyone who has taken or is taking this medicine? Maybe someone (who took it and now doesn't need it anymore) can donate a box for a start ... it's not settled and it's very expensive.

Hello, 

my mother is suffering from the same mutation. She had a primary lung tumor, two lymph nodes on the same side and a 1.2cm brain lesion. She was given srt for the brain lesion and was put on tarceva. Two months later she did a pet scan and the brain lesion has not shown up, the lymph nodes have reduced in size and the primary tumor is 'not showing activity' said her doctor. 

However her new oncologist has changed her medication to tagrisso (5 days ago) saying its better than tarceva and there is only a 50% chance of tagrisso working after tarceva. I am worried that this might be a mistake. Ive read some "GioTag" study saying afatinib followed tagrisso allows for the longest overall survival on targeted drugs for egfr+ exon 19 deletion patients.

Can someone please advise me whether sequential afatinib and tagrisso is better for long term survival? Apparently there are no options after progression on tagrisso besides chemo. Immunotherapy doesnt seem to work for egfr patients according to the doctor. 

Regards

Hi Rowan,

Welcome to Grace.  I'm very sorry to hear about your mother's diagnosis.  Today the standard of care would be front-line tagrisso instead of tarceva.  One of the benefits of tagrisso is its ability to reach the brain.  However, there are unknowns about tagrisso following tarceva because at some point tagrisso only benefits those who picked up a T790mutation from using a prior tki (tarceva).   I don't know why her oncologist made the decision to change before your mother progresses, which is the norm.  It could be she hopes your mother hasn't been on tarceva long enough to matter about T790m and instead will get the benefit as if she had started with tagrisso. 

Published here almost 3 months ago, Dr. Melissa Johnson describes the FLAURA trial that won tagrisso the front-line setting for those with egfr mutation.  As for the subtypes of exon 19 deletions, I'm not aware of news since my first post on this thread, which is unfortunately nothing.  If you've found something else please let me know in case I need to contact one of our faculty for input.

I hope your mom does well for long long time.

Best of luck,

Janine

Dear Janine, 

please let me know about the study below its called the GioTag study. This drug sequence apparently allows patients the most amount of time on targeted drugs. I recently spoke to another molecular oncologist and he recommends afatinib first. I really dont know what to believe. We got alarmed after her new oncologist changed her onto tagrisso and said if there is progression there is nothing much they can do except chemo. 
 

regards

https://www.futuremedicine.com/doi/10.2217/fon-2020-0740

Rowan, to play devils advocate, the first thing that jumps out at me about this trial is to be included you must aready be 10 months into tagrisso.  That means they benefited then progressed on afatanib and are now responding to tagrisso for at least 10 months.  That already assumes a lot about how someone in your mother's current position would ultimately be compared to those in the trial.  Another consideration to think about is that the trial was/is a review of records, so parameters on how the patients' treatment evolved weren't stringently controlled as if it were a trial such as flaura or lux. 

Consider that your mother has already started 2 different tki drugs.  We don't know how that would effect the trajectory of the coarse, especially considering 'sequencing' is the question being asked in the gio trial.  There are many promising trials studying drugs/combos/sequencings that could be appropriate for your mother that she could be excluded from if she has taken this or that treatment.  Maybe the most important consideration is about side effects with afatinib.  They can be pretty bad.  On the other hand side effects from chemotherapy, especially alimta, can be very mild, has high efficacy for efgr exon 19, and can be effective for long period of time. 

 Tagrisso has a good side effect profile, it has good penetration into the brain and has been shown to improve OS with data from a well recognized study.

I know how much you want to get this right.  I've been there (it's why I'm here now).  One of the toughest things about this is there are so many unknowns and it depends.  In the scheme of things using tagrisso front line in someone with your mother's broad profile makes good sense.  Talking to the oncologist personally can help you understand the thought process. 

I hope she does well.  Keep us posted.

Janine

Essentially, I would say that people shouldn't be duped by the GioTag "study". It was an analysis done by the company that sells afatinib. People should understand that these analyses are essentially marketing efforts with a thin veneer of actual research. It was not an actual "prospective" study looking at how people at the start of treatment do. It was a retrospective look back that started with people who happened to have all of the best things happen -- exon 19 is the most favorable mutation,  started on afatinib, and these patients were fortunate enough to have a T790M mutation at progression and get Tagrisso (osimertinib).  This is NOT a look at people who started out with a new or recent diagnosis and are having treatment decisions made prospectively. All of the people who happened to do deviate from the most favorable path were winnowed off the study and weren't included in this favorable analysis for afatinib, but these patients still exist.

In addition, it's worth remembering that in the history of drugs and medicine, I don't think there has ever been a pharma company sponsored retrospective study that was published showing a result that didn't support the conclusion that people should use more of their drug. This is "economically motivated research" that more discriminating physicians and scientists rightfully view with skepticism.

Practically speaking, afatinib is generally less well tolerated than first generation EGFR inhibitors (Iressa (gefitinib) and Tarceva (erlotinib)) and way less well tolerated than Tagrisso.  This is quite important when people are taking treatment for what we hope will be years. And the evidence from an actual prospective randomized trial showed that patients who started on Tagrisso did significantly better in terms of overall survival than patients who started on Iressa or Tarceva, even though the patients who started on Iressa or Tarceva could cross over to Tagrisso if they had an EGFR T790M mutation at progression -- and many did.  

It's fair to say that afatinib is a second generation EGFR inhibitor that hasn't been proven to be inferior to Tagrisso in the same way Iressa and Tarceva have, but there isn't a scintilla of prospective evidence to support the idea of sequential afatinib followed by Tagrisso. One critical issue is that Tagrisso has very good activity in the brain, to treat existing brain metastases and prevent new disease in the brain, which is a major risk over time in patients with EGFR mutation-positive NSCLC. Iressa and Tarceva have some, but much less. Afatinib may be more than Iressa and Tarceva, but not necessarily -- trials with afatinib have not focused on brain metastases, and that's likely because they aren't that confident it's in the same league for activity in the brain as Tagrisso. If you develop very symptomatic brain metastases on a less effective EGFR inhibitor, you may never get the chance to benefit from Tagrisso later.

Overall, there's a reason almost nobody is talking about the GioTag study -- I suspect it's not an exaggeration to say that no health care professional who isn't paid by Boehringer-Ingelheim as an employee or paid consultant does.  There is a very strong consensus among lung cancer experts that front line Tagrisso is the preferred option for advanced EGFR mutation-positive NSCLC.

Good luck.

-Dr. West

Thank you Dr West and Janine for educating me. That cleared up a lot of misconception. We are also fearful that she will run out of options after tagrisso progression. Worst case end up having to undergo chemotherapy. Does egfr positive lung cancer respond well to chemotherapy? And how does treatment generally work? Are patients kept on a maintenance dose till nearing the end? 
 

Rowan,

Going into the cancer center and having an IV infusion every 2 or4 or 6 weeks may be the worst of typical chemotherapy.  It's true chemotherapy can be difficult to impossible to manage but that's no longer the experience most people have.  Normally side effects can be mitigated with drugs given with the chemo and other prescriptions and otc drugs and other tricks.   Many people breeze through chemo with few or even no side effects. 

People with egfr mutation tend to respond better than others.  Alimta in particular has a mild side effect profile.  Usually chemo starts with a doublet meaning a platinum drug probably carboplatin plus another agent like alimta.  after 4 or 6 rounds of this the platinum is dropped and alimta is continued for as long as it's beneficial. 

Progression free survival with tagrisso was recently recorded in the FLAURA trial with median PFS around 19 months.  And if I'm reading this right, "Treatment beyond disease progression was permitted in the setting of continued clinical benefit.", the time someone continues to take tagrisso after 'Progression' isn't counted.  And people can do very well with slow progression on tki for months or more.  It's not a stretch to say that by the time your mom needs another treatment a new drug could be available.

Anticancer treatment can be continued until it is no longer benefiting the patient.  That could mean no treatments are controlling cancer or that treatment is causing more harm than good.  It can be a delicate balance on which your mother and her cancer team will need to agree.

All best,

Janine

Dear Janine, 

this is just an update on my mother's progress. After switiching to tagrisso from tarceva on nov 23rd/2020 her chest ct on dec 29th showed almost a complete response to TKI therapy. She is happier on tagrisso due to milder side effects so far. Also her brain mri showed no new mets. We would like to know from your experience do patients who respond so well to TKI therapy have a longer PFS than otherwise? Her oncologist is so far satisfied with her progress. Furthermore He has also prescribed megestrol for her to get her appetite back. Is this common practice for lung cancer patients because from what we understand its given for breast cancer patients. Thanking you in advance.
 

Best regards

Rowan

Hi Rowan,

That's terrific news, and thanks for sharing it with us! Great to hear that the side effects are more manageable as well.

Although you can't make a definitive statement on expected progression free survival (PFS) in this situtation, in general the better the response, especially to a line of therapy subsequent to the initial regimen, the more likely that response may last longer. 

Megestrol (Megace) is commonly prescribed for cancer patients in general, including lung cancer patients, to help stimulate appetite. Hopefully, the combination of megestrol and response to treatment will help your mother regain her appetite.

Please let us know if you have any further questions. We look forward to your next positive update!

Jim C Forum Moderator

Hi Rowan,

That's beyond terrific!  I don't have anything to add to Jim's response.  I know you both are taking a well-deserved breath.

Magace may work very well since your mother has close to no tumor burden.  The more cancer there is the less effective magace tends to be.  My husband did very well with it.  

Don't forget, you can get the generic version if you need to a deep cut in its cost.

Another reason to enjoy the good news, there's a saying in cancer care, 'responders respond'.  People who respond tend to respond to other treatments. 

Take care,

Janine

Thank you for the encouraging replies. Also just to be clear. She did not progress on tarceva. Her new oncologist changed it due to the harsh side effects and also because he said there was only a 50% chance of tagrriso working after tarceva failure. She had already responded quite well to tarceva after two months. I will write an update after a few months again. 
 

thank and regards 

Right, I did forget she quit tarceva before giving it a chance to lose efficacy for it and possibly tagrisso.  I hope she's feeling better already and enjoying some good food.

Take care and stay safe

Hello Janine, 

are lung cancer patients on tagrisso allowed to take supplements? My mother likes to take fish oil and certain herbal supplements such as ginseng and we are wondering if there are any drug interactions from your experience. She stopped taking the megace because it bloated up her face. She is trying to regain her appetite by other means now. 
 

also she did a pet scan on feb 6th which showed a complete reponse to tagrisso. How often do patients need to have pet scans from now on? Her oncologist thinks every 6 months but we are worried that when it relapses we might not catch it early enough 
 

Best regards 

Hi Rowen,

So good to know your mother is NED (no evidence of disease).  That's great, she's a responder.  I just accidentally erased my reply instead of sending it, grr.  So I'll be short tonight and add tomorrow.  Always talk to the onc or their support staff before taking supplements and otc anytime she changes treatment, there could be individual issues. 

I want to check about the scans.

I hope your mother is feeling better.

Janine

Hey Rowan,  I'm sorry about the delay.  When we talk about a pet scan we mean a combination pet/ct.  Dr. West has often commented on its use in follow up during treatment because many oncs still use it even though it's not warranted. It gets the job done but is very expensive, includes radioactive dye that takes an hour wait to circulate before the scan can begin, and has now been determined not to be of added benefit. Here Dr. West states "I'd really say that PET/CT scans for following advanced disease are rarely needed and have been identified as a leading area of unnecessary expense compared with a CT. You're really looking for a clear signal of progression, so you shouldn't need a PET/CT to identify that. With only very rare exceptions, if the change isn't visible on CT, it's not a clinically relevant change. And there isn't a clear value in heaping on more treatment in this situation when there isn't clear progression." 

My husband's oncologist used pet/ct to follow his cancer for a while.  I often questioned this to no avail and I didn't find it worth the precious time we had with his oncologist on a deeper discussion (you know, "choose your battles"). 

So whether pet/ct or ct is used I've got a request for comment into faculty.  Seems like 6 months may be fine with complete response to tagrisso.  But let's see.

Again so good to know about the complete response and I hope it lasts a good long time.

Janine

Hi Rowan,

Great news on your mother's response to treatment. To add just a bit to Janine's comments on the question of PET vs. CT for follow up, I'll just add that there are two methods used by oncologists to monitor for recurrence. Most patients understand the importance of scans, but just as critical is regular clinical evaluation, including blood work and a physical exam. As far as scans, the NCCN (National Comprehensive Cancer Network) guidelines state that PET/CT is "not routinely indicated" for follow up, and that CT is the usual choice. As Janine pointed out, there is significant extra cost for a PET/CT, and the CT portion of such a scan does not tend to be as high in resolution as a standalone CT. In addition, a PET scan can "light up" as a result of other abnormalities not related to cancer, which can result in increased anxiety and possibly risky and costly invasive diagnostic procedures such as biopsies. The suggested follow up when there is no evidence of disease is a CT (with and without contrast) every 3-6 months for the first 3 years, then every 6 months for 2 years, followed by an annual, low-dose chest CT. It is important to note that there is room for individualization in the recommendations of the treating physician, based on clinical and other factors, so if you think it might help perhaps you could ask your mother's doctor to explain his reasoning for choosing a PET/CT and the particular interval.

Jim C Forum Moderator

Hello Jim, 

thank you for the valuable advice. Should she do a CT Scan only for the chest and brain each time? Her brain lesion was discovered via CT Scan, they later did a brain MRI to confirm. Do relapses begin in the lungs again? 
 

regards

Typically CT for the chest and MRI for the brain.

Hello all, I am Ruken from Istanbul, Turkey. My mother had been diagnosed with Non-small-cell lung carcinoma (NSCLC) at October with EGFR and L858R mutation. She had her one lung removed in November and unfortunately, 1 month ago she was diagnosed with brain metastasis and later started the treatment with Tagrisso. It all happened very fast, when she was diagnosed 4 months ago it was stage 2. The treatment had good improvement on her syndromes and regression at tumours was found. So we had a huge hope on that. Later Tagrisso had to be stopped because it caused QTc interval at heart even after the decrease in the dosage, 80mg to 40 mg. I kindly would like to ask if anybody had this kind of side effect and have any knowledge on this matter, if there has been any improvement.

This treatment was very beneficial compared to radiotherapy which has many side effects, especially on the brain. I would like to know if Tagrisso can be used with any other cardiac treatment? I would be very happy if you can spare time.

Hi rukenk, I'm so sorry your mother has this side effect of tagrisso.  The website states if there is qtc along with signs or symptoms the drug should be permanently discontinued.  That's such a loss.  I've asked our oncology pharmacist if she has some insight on other tki's. 

I can't copy-paste this quote legibly but it's on the first page top of second column here under warnings and precautions.  Note that it states to withhold then restart at lower dose.  I wonder if there is a certain amount of time to withhold before restarting. 

Hoping for the best for you and your mother,

Janine

Edit to add from the 2nd paragraph, "Heart rate-corrected QT (QTc) interval prolongation occurred in TAGRISSO-treated patients. Of the 1479 TAGRISSO-treated patients in clinical trials, 0.8% were found to have a QTc >500 msec, and 3.1% of patients had an increase from baseline QTc >60 msec. No QTc-related arrhythmias were reported. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia"

There appear to be caveats such as signs and symptoms of arrhythmia and withholding then restarting at lowered dose.

You're very welcome.  If we can be of help even if it's to agree on treatment decisions and lending an ear then that's great.  I remember how much Grace helped sometimes by just agreeing that a certain treatment was appropriate.  As far as local pharmacists are concerned I have a weekly relationship with our locals and I admire their willingness to spend time answering my questions.  However the pharmacist I've asked for input is an oncology pharmacist who is a professor at the medical school at Univ of S Florida and is doing cutting-edge research in personalized treatments like the tki's your mother was taking.  So I thought she might have some insight we aren't privy to.  But it does sound like your mother is unfortunately not able to take tki's.  I am so so sorry.

I don't think there are studies on this but oncologists believe they see better response to chemotherapies especially alimta in people who have egfr mutations and with fewer side effects than other chemo drugs. 

I hope she does very well,

Janine

I just heard from Dr. Walko.  She apologized for not getting to our questions straight away but is quite busy and will get to it asap. 

I know there is way too much to take in in such a short amount of time so no question is too small, we've all been there.  TKI are a type of targeted therapy pill that works on specific mutations like your mother's egfr mutation.  Tagrisso is one and all the other egfr pills as well. 

Alimta is a relatively new chemotherapy that is given via IV not a tki.  But again it's often considered quite mild. 

We can discuss the brain mets in the other thread post #12 if it turns out she has lepto disease. 

Janine

Hi Rukenk and Janine,

 As you described above, the prolonged QTc interval has been well described with osimertinib (Tagrisso).   This may be more specific to this drug rather than the whole class however. 

Afatinib (Gilotrif) does not appear to commonly result in this effect.  Specifically, the package labeling states that in a large, single-arm trial of afatinib 50 mg daily, "no large changes in the mean QTc interval (i.e. > 20 ms) were detected in the study".  I can find one case report of a patient who received afatinib at 40 mg daily who had a significant QTc prolongation after 7 weeks of treatment (PMID 32505368).  It appears that afatinib may have a lower risk of QTc prolongation than erlotinib, for which it has been previously reported more commonly. 

Best wishes,

Dr. Walko

Dear Janine and Dr. Walko,

I hope everything is going well with you and your health. Thank you for your comment previously, regarding to that I have passed this info to our medical oncologist which she also made her research about that and agreed on the treatment with Afatinib (Giotrif here), she had started to the medications at last Thursday after her WBRT, and she had an ECG at last Monday and her QTc interval was fine around 430ms, today, after the use of Afatinib only for 5 days she had QTc interval around 507ms and this is our last hope basically.. She was additionally using Kordexa for around 10 days which is a Corticosteroid drug with Dexamethasone, I have called the drug pharmacy of this if this was the reason because according to their prospectus both of these drugs don`t seem to have this kind of side effect which as Dr.Walko you mentioned, there was one case known.

At the moment I kindly would like to ask if you could recommend me to do anything? Thank you in advance for your time and interest!

Best Regards

Hi Ruken,  If further tki is out then chemotherapy is the next option.  Alimta with carboplatin or even alimta alone can be beneficial.  Normally a combination of carboplatin and alimta or carbo and a taxan is given for 4 to 6 cycles then the platinum is stopped and alimta or taxan is continued.  Alimta is usually milder than a taxan but also more expensive.  Sometimes bevacizumab is added to the combo. 

Remember many people find chemo quite manageable and can be beneficial for a long time.

I'm so sorry she isn't responding better.  Keep us posted and take care.

Janine

Hi everyone,

My dad was diagnosed with stage 4 NSCLC in January of this year. He's been on Tagrisso for 4 months and according to his recent scans the tumors in his lungs and other parts of his body appear to be stable. However, his oncologist was concerned with a part of his brain (I think they said the brain lining) where the tumors appear to be more prominent than before (his other brain tumors appeared stable). Apparently, Tagrisso is generally quite effective on tumors in the brain but it is said to be less effective on the brain lining. The radiation oncologist recommended Dad undergo a whole brain radiation for two weeks and asked him to stop taking Tagrisso during this time to avoid any collateral effects. Once Dad is done with radiation therapy, and if the scans show that his brain mestases are stable he can go back on Tagrisso. The radiation oncologist said that because there were tumors in Dad's brain lining he was worried that there could be tumors also in his spinal fluid so he asked Dad to do a full spine MRI to make sure they didn't miss anything. I'm wondering if there are other alternatives to whole brain radiation as I'm concerned with the side effects (in particular cognitive decline) and whether it is safe to stop Tagrisso for two weeks? Should Dad increase his intake of Tagrisso from 80mg per day to 160mg? Will that work better on the tumors in his brain lining or just increase or make his side effects worse? Should we wait until we receive the results of his full spine MRI before we decide whether or not Dad should undergo radiation therapy in case it changes his treatment? I also just learnt about lepto yesterday. If a patient has cancer in the brain lining, how likely would he or she have lepto?

Thanks so much for reading.

Liqiao

Hi Liqiao,

Welcome to Grace.  I'm so sorry your dad has lepto.  Unfortunately, once cancer cells have entered the lining it's a matter of time before it develops tumors.  Fortunately, it sounds like tagrisso is working.  Leptocarcinoma is very difficult to treat and the treatments often cause a lot of side effects and can take a long time from which to recover.  The bright side is that tagrisso has shown to be very effective.  Taking more tagrisso is very likely to amp up the side effects but even those are likely to be less severe than WBR plus the dose can be lowered or raised and otherwise managed. 

From this thread, Dr. West responded in an email to my question on the matter,  "To the question, are oncologists pulsing tagrisso he states, "No. I'm sure someone has done it, but Tagrisso is effective in the brain, so we mostly would consider increasing dose from 80 to 160 mg daily, but pulsed dosing is not an approach that has been used and reported with any meaningful frequency.""

I hope your dad does well with his treatment.  Please do let us know how he proceeds from here.

All the best,

Janine