after loss of t790M as resistant mechanism

Portal Forums Lung/Thoracic Cancer EGFR Inhibitors after loss of t790M as resistant mechanism

This topic contains 18 replies, has 5 voices, and was last updated by  onthemark 2 months, 1 week ago.

Viewing 19 posts - 1 through 19 (of 19 total)
Author Posts   
Author Posts
May 29, 2018 at 4:14 pm  #1294500    

kempten

Hello again

I have been off Alimta maintenance for about 1 1/2 months now and recovered a little from pretty
severe side effects . The chemo lasted me for about 6 months before progression .
Better than nothing .
A recent biopsy shows loss of t790M as my only resistance mechanism .
I’m still on Tagrisso

The next treatment will likely be another chemo. I have had a terrible time on Carbo/Alimta and am
very reluctant to try another one .

Does re-challenging Tarceva ever make sense in such a situation ?
How about adding Avastin to my treatment .

I’d rather try anything else than another chemo.

A single new brain met will be irradiated soon , other that that I have some progression in the lung .

Thank you again for your advice

Kempten

May 30, 2018 at 7:09 am  #1294502    
JimC Forum Moderator
JimC Forum Moderator

Hi Kempten,

I’m glad to hear that you’re feeling at least a bit better. For most people, Alimta doesn’t cause such problems, especially as a single agent for maintenance, and I’m sorry you’re one of the few that really struggle with it. I understand your reluctance to move to another chemo agent, although it’s certainly possible that your body has a particular problem with Alimta in particular, and that other agents might not be anywhere near as toxic for you.

Returning to Tarceva is probably not that attractive an option since you’re already taking Tagrisso and you progressed on Tarceva previously. I don’t see what Tarceva would do that Tagrisso isn’t already doing; cancer cells that seem to be resistant to Tagrisso would likely resist Tarceva as well. In general, there is reluctance to return to a drug on which a patient progressed initially.

There’s not a great deal of evidence to show that Avastin adds much in the maintenance situation, although it is usually pretty well tolerated so you could try it and see if it halts the progression.

As you probably already know, EGFR+ patients have a low response rate to immunotherapy, but if your cancer shows high PD-L1 expression, that could be another option.

In one of your previous threads, the idea of a treatment break was discussed, since the progression at this point appears slow. In your case, that might mean continuing Tagrisso without adding a new agent (assuming that you are tolerating Tagrisso well), or you could go off treatment (even if just for a month or two) and let your body rest from the rigors of anti-cancer treatment. A full treatment break can also help your frame of mind. Of course, close surveillance clinically and with follow-up scans would be necessary in order to detect any change in the pace of progression.

In such a situation, there’s no clear choice; all that can be done is to weigh the options and move forward. I hope you can find an option comfortable for you.

JimC
Forum moderator


Jul 2008 Wife Liz (51/never smoker) Dx Stage IV NSCLC EGFR exon 19
4 cycles Carbo/alimta, 65% shrinkage
Tarceva maintenance
Mar 2010 progression, added Alimta, stable
Sep 2010 multiple brain mets, WBR
Oct 2010 large pericardial effusion, tamponade
Jan 2011 progression, start abraxane
Jun 2011-New liver, brain mets, add Tarceva
Oct 2011-Dx Leptomeningeal carcinomatosis; pulsed Tarceva
At rest Nov 4 2011
Since then: http://cancergrace.org/blog/jim-and-lisa

May 30, 2018 at 12:41 pm  #1294506    

kempten

Thank you Jim for your advice

I will likely not rush right into the next suggested chemo and try to put on some weight first .
Even though dexamethasone is rough on the system , after my upcoming SRT I asked to be put on it for a few days to gain back some weight .
My appetite is at rock bottom and never recovered after chemo . Any thought of food fills me with disgust
and I have to force myself to eat anything .

We can assume I guess that the next chemo will not penetrate the blood brain barrier ?
That’s why I was wondering about avastin . But I heard like you mentioned, that it does not seem to be terribly effective .

Thanks again

Kempten

May 30, 2018 at 5:52 pm  #1294509    
catdander forum moderator
catdander forum moderator

I may be wrong but considering its bleeding issues I don’t think avastin is meant to be penetrate the bbb.
Jim? onthemark?

Have you been able to find a liquid nutrition sub that you can drink? We tried all sorts of products and found Don could take vanilla ensure plus, publix supermarket sold a twin at half the cost but only off and on. Generic magace may help with appetite as long as your tumor burden is relatively low, it worked wonders for Don.

Once you catch your breath gain some weight off chemo a single agent may not be as nasty as you fear it may be (easy for me to say…right?).

Janine

May 31, 2018 at 6:39 am  #1294512    

kempten

Hello Janine

I assumed Avastin might penetrate the bbb because it was approved for glioblastoma , but I heard
from several people now that it is not that effective when added .

thanks for your suggestions on liquid nutrition . The other stuff I’m not familiar with . It’s a man made form
of the hormone progesterone ?

I started drinking high protein Ensure and I force myself to eat albeit with zero joy .

My biopsy came back with a couple of non actionable mutations which both might make my cancer more resistant to therapy .

an excerpt from a study :

” In conclusion, we observed that c-MYC gain was associated with lymphatic invasion, and was an independent poor-prognostic factor for DFS and OS in lung adenocarcinomas, both in full cohort and stage I subgroup, and possibly for DFS in EGFR-mutant subgroup. ”

The other one was a tp53 R273C mutation .

I’m seriously wondering weather doing nothing might give me the better quality of life for now ?

Thanks so much for answering

Kempten

May 31, 2018 at 8:02 am  #1294513    

onthemark

Hi Kempten,

I read the same as you about Avastin being a treatment for gliobastoma and also, if I understood correctly, that it might help other drugs penetrate the blood brain barrier but I haven’t seen anything so far that jumps out for effectiveness in lung cancer brain mets. It does not appear to have an adverse safety profile for patients with brain mets compared to those without.

There is also a thread on inspire about concomitant use of Tagrisso and Avastin in lung cancer here: https://www.inspire.com/groups/american-lung-association-lung-cancer-survivors/discussion/tagrisso-avastin-combo-for-leptomeningial-progression/

Regarding immunotherapy, have you been tested recently for pd-l1 and tumour mutation burden? Even if it is a long shot it might be worth testing for.

There are some other drugs besides dex that have weight gain as a notable side effect and might be less harsh on the system. As well there are appetite stimulants like Janine suggested that can have a positive effect.

I saw on a previous thread you were contemplating a clinical trial. Is that still an option?

You have had a long struggle and I admire your perseverance and courage.

otm


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

May 31, 2018 at 9:07 am  #1294517    

kempten

Hello OTM

Thank you for responding .
I did a tissue biopsy at Mass General in Boston to try to get into a clinical trial for Tagrisso combined
with Savolitinib .
For me to be accepted I had to be MET positive . Unfortunately I was MET negative . So no trial for me .

I’m always wondering when a trial demands a tissue biopsy, how representative this biopsy result is considering
only a single site is biopsied .and other sites with possibly more diverse heterogeneity are missed .

They should always do a companion liquid biopsy and compare tissue to liquid in my humble opinion .

Astrazeneca I think did this just for their own research but the results are kept from trial doctors and patients .
That’s what it said on the forms I had to sigh for consent

My guess is that my mutation load is very low and it would be highly unlikely to make a successful
try with immunotherapy.. I will have to ask my local doctor if PD – l1 was tested tor .
I will see him today.
I will also ask for appetite stimulants . I just know that dexamethasone makes me eat like a horse
and I do have an upcoming SRS of a brain met . We could kill to flies for the price of one

Kempten

June 1, 2018 at 6:55 am  #1294525    

onthemark

Kempten,

I agree with your suggestion that blood biopsies ought to be taken to accompany tissue biopsies due to tumour heterogeneity, and hope there are other clinical trials that open up for you to participate in.

It’s great that dex makes you eat like a horse. That might be enough to put you back into a frame where eating is an enjoyable habit rather than a difficult chore. I hope you have success with your upcoming SRT.

What do you think of the bill that was recently signed into law called “Right to Try”? Are you in the US?

Also, medical marijuana can be a godsend for some cancer patients who want to build up their appetite. I also lost mine after chemotherapy, but find it is better towards the end of the day and in the evening.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

June 1, 2018 at 10:00 am  #1294526    

kempten

Hi OTM

I’m conflicted when it comes to the ” right to try ” legislation

This statement ( not from me ) kind of mirrors how I feel about it :

Michael Becker, a former biotech executive who is dying from cancer, told NPR’s Scott Simon in February that he opposes “right to try.”

“The problem becomes that you have a lot of false hope as a terminal cancer patient. You want to cling to anything that’s going to sound like it’s an opportunity to live longer or have a better quality of life,” he said. “That hope can sometimes cover up the realities of some of the more sinister aspects of getting a drug, which are things go wrong. So I could take a drug that was purported to help me, and it may actually make my condition worse.”

I saw my local onc yesterday . He wants to put me on Taxotere indefinitely. I might decide not to treat any further
at this point, except for the occasional local ablation therapy to relieve symptoms .
I read some patient experiences with this drug that did not seem to increase quality of life as a
4th line therapy .
I might change my mind later but right now I have a better quality of life doing nothing .

Kempten

June 2, 2018 at 7:25 am  #1294531    

onthemark

Hi Kempten,

Dr. West has a detailed talk about some aspects of your situation here.

It’s called

Treatment Options for EGFR T790M Negative Acquired Resistance

It makes sense that you would not want more chemotherapies but I do wonder if other medications might be considered in your situation. It’s almost a half an hour talk and there is more information in it than I can understand at the moment but it may be helpful to you if you haven’t already heard it.

I also have mixed feelings about Right to Try. There will be some patients who will turn out to benefit from it. The question is how many and also how much suffering it might lead to. Hopefully in the law there is at least a way to record the single person trials to build a national database of both positive and negative results.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

  • This reply was modified 2 months, 2 weeks ago by  onthemark.
  • This reply was modified 2 months, 2 weeks ago by  onthemark.
June 3, 2018 at 6:21 pm  #1294536    

kempten

Thank you so much for making me aware of Dr West’s Video

He is stating one of my
dr’s trials in this video . I think it’s from Jan 2016 ? I think my progression would
warrant systemic therapy at this point but I’m just not very good at withstanding it ( chemo ) . The response rate would be around 17% in my case I was told . So pretty low .

I will wait and see what happens . In either case, the brain would remain unprotected and we are still relying
on Tagrisso and SRT for the brain . Not sure how effective Tagrisso is at this point but I hope it’s
better that discontinuing .

Kempten

June 3, 2018 at 7:23 pm  #1294537    

onthemark

I wouldn’t want to go on Taxotere either.

Have you recently been tested for PD-L1? There’s evidence that PD-L1 expression can change when cancer cells develop TKI resistance (see the review paper below). Also, Opdivo can work even with low expression. See for instance:

Nivolumab effective in PD-L1–deficient lung cancers

https://www.mdedge.com/oncologypractice/article/129890/lung-cancer/nivolumab-effective-pd-l1-deficient-lung-cancers

There’s a 2018 review paper:

Osimertinib resistance in non-small cell lung cancer: Mechanisms and therapeutic strategies

that has a ton of detailed information but unfortunately it is behind a publication wall. I could cut and paste and send it to you but I am not sure the best way to go about doing that.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

  • This reply was modified 2 months, 1 week ago by  onthemark.
  • This reply was modified 2 months, 1 week ago by  onthemark.
June 6, 2018 at 2:01 pm  #1294544    

kempten

Hello OTM

thank for the recent opdivo suggestion. I will revisit this again with my oncologist .

I also have a low level of autoimmune disease . I was always afraid opdivo could make this much worse
My immune system is not completely normal . I have chronic fatigue immune dysfunction syndrome,
low grade psoriasis and interstitial cystitis . Non of these diseases have been officially classified as
autoimmune diseases except for psoriasis but I’m very afraid of a major flare up if I try this .
Historically flair ups coincided with allergies, infections, stress , whenever the immune system is up –
regulated .

Interestingly chemo therapy with its immune compromising side effects got me into a partial remission
for all of these immune related diseases .( chronic fatigue better , cystitis better , psoriasis non existent .

I’m also trying to follow the ASCO discussions closely

Thanks again
Kempten

June 6, 2018 at 7:23 pm  #1294547    
JimC Forum Moderator
JimC Forum Moderator

kempten,

Lots of good information here. One thing to remember, though, is that when response rates are quoted, that rate includes only patients who achieved significant tumor shrinkage. Especially for later lines of treatment, that kind of shrinkage is not common. As Dr. West points out in the video, more relevant is the disease control rate, which also includes patients whose cancer remains stable, a result that is quite good for heavily-pretreated patients. In addition, with such patients there is more variability – some patients may have more significant or widespread progression than others, so the results will tend to be more variable as well.

JimC
Forum moderator


Jul 2008 Wife Liz (51/never smoker) Dx Stage IV NSCLC EGFR exon 19
4 cycles Carbo/alimta, 65% shrinkage
Tarceva maintenance
Mar 2010 progression, added Alimta, stable
Sep 2010 multiple brain mets, WBR
Oct 2010 large pericardial effusion, tamponade
Jan 2011 progression, start abraxane
Jun 2011-New liver, brain mets, add Tarceva
Oct 2011-Dx Leptomeningeal carcinomatosis; pulsed Tarceva
At rest Nov 4 2011
Since then: http://cancergrace.org/blog/jim-and-lisa

June 6, 2018 at 7:53 pm  #1294549    

onthemark

Hi Kempten,

Jim’s point is a critical one and I’ll be sure to remember if I ever have to cross that bridge. I’m also trying to follow the ASCO discussions. It would be nice to have a book club to compare notes one day on all the new developments in lung cancer treatment. I also understand your reservations about immunotherapy. Your situation suggests that some may do better with fewer symptoms on chemo and immuno than just immuno… well at least that is a theoretical possibility.

Dr. West has some videos on youtube under the name of “Beacon” which have a lot of useful information in addition to his videos here. Two that I can recommend are


Is immunotherapy ineffective for driver mut-pos. advanced NSCLC? Time to walk that back. (BMIC-027)

” at https://www.youtube.com/watch?v=YrPw5dvq3rc


My Top 5 ASCO 2018 Abstracts in Advanced NSCLC (BMIC-036)

” at https://www.youtube.com/watch?v=R8xyNpgr_mY


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

June 7, 2018 at 2:29 pm  #1294554    
catdander forum moderator
catdander forum moderator

https://twitter.com/lcsmchat is a wonderful twitter feed and abuzz with asco chatter. I wish I spent more time there but you’re all right now is the time of sharing and I’m going to check it tonight. Dr. Pennell and West are both followers/ing. Is the monthly chat discussion still going on? It’s a great tool for open dialogue of lung cancer care.

June 8, 2018 at 9:06 am  #1294556    

scohn

Hi kempten.

I am so sorry to hear about your recent issues in resistance. I too have been a great admirer of your strength and courage.

I wanted to just add a brief thought from the cell biology side. If I understand from what you said above, you have developed a tp53 mutation. This protein is involved in DNA repair and destruction of overly damaged cells. Since carboplatin is an agent that works by damaging the DNA of cancer cells, tp53 mutations often have resistance to carboplatin therapies and others that work on DNA directly. It also seems to sometimes have an effect on the effectiveness of EGFR targeted therapies. See for example:

The role of p53 in cancer drug resistance and targeted chemotherapy

That is most likely why they want to switch to Taxotere, which is a therapy that works by a completely different mechanism, working to physically hinder cancer cells from undergoing cell division by altering cell structure (not the DNA). That is why the effectiveness, and side effects, of Taxotere are often different from the carbo/cis/alimta type treatments (although digestive issues are often a major side effect).

I am certainly not advocating for whether or not you should do the Taxotere treatments, but I just wanted to let you know that the treatments work in a very different way from the chemotherapy you were on.

I wish you all the best as you make your way through the treatment decisions, and for healing of body and spirit.

scohn


Wife, lifelong non-smoker, dx 4/24/15 adeno NSCLC stage IV-2 bone mets, 1 lymph node. HER2 Exon 20 mutation. 6x Carbo/Alimta – >50% reduction in primary tumor, lymph nodes, & bone. Alimta maint. not effective -growth & new liver mets. 11/15 – Opdivo; Not effective-add’l growth. 4/16 – PF-7020- large reduction of tumor and mets. 11/16-mixed results, liver mets stable. 2/17-All Stable. 8/17- Add’l growth-off Pfizer trial, 9/17 Gemzar- reduction/stable 11 mos. 8/18 – TAK-788 Trial.

June 8, 2018 at 10:44 am  #1294558    

kempten

Hello Scohn

Thanks for replying

My recent tissue biopsy showed a c-MYC gain also. Not sure if this makes a forth line chemo even less likely to respond ????

My primary issue is deciding what gives me the better quality of life right now .
Chemo mostly makes people feel worse and sometimes absolutely miserable . There is usually for many
a light at the end of the tunnel . You fight through the chemo and then things get better .
This will not be the case here .
Also what to do with Tagrisso ? Would Tagrisso interfere with the Taxotere ? Would discontinuing the
Tagrisso cause a flare of progression in the brain ??

I remained on Tagrisso during my Carbo/Alimta therapy . Did it make the carbo/alimta less effective ?
I don’t think so.

So many questions .
I’m just happy right now to have a somewhat enjoyable summer without too much pain ( sciatica in both legs )
but some balance problems and slight vertigo ( early lepto ?) Wondering about this too.
Nothing has shown up on MRI jet .
Taking on day at a time

Kempten

June 8, 2018 at 11:21 am  #1294560    

onthemark

Thank you Janine for the twitter feed and scohn for sharing insight on mutations and chemotherapies.

I’d probably do the same as you, Kempten, and stay on Tagrisso. My impression from watching videos of Dr. West and others is that some patients too early abandon targetted treatment where the few places the cancer escapes can be controlled with added local therapy. I don’t recall the specific videos unfortunately.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

Viewing 19 posts - 1 through 19 (of 19 total)

You must be logged in to reply to this topic.