Osimertinib best after Afatinib ? (with no result from liquid biopsies)

Portal Forums Lung/Thoracic Cancer EGFR Inhibitors Osimertinib best after Afatinib ? (with no result from liquid biopsies)

This topic contains 16 replies, has 4 voices, and was last updated by  onthemark 1 week, 1 day ago.

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July 1, 2018 at 1:44 pm  #1294740    

daxys

My mum (73years,IVstage,small meta in lymph nodes,EGFR+,exon18,G719X), was for 21 months on 1st line Afatinib (first 40% reduction, last three months with slow progression), after that she was on pemetrexed monotherapy for 3 months with quite significant progression (30%). Since finishing on Afatinib 3 liquid biopsies for T790M have been done with no outcome – not even the original mutation showed. Tissue biopsy would be problematic.
Also one month ago, 1 lesion in brain was detected, first considered to be a brain metastasis. Now the doctors say it might rather be meningeom. Still they are not quite sure and want to observe for 1-2 months.

I think there is a really good chance my mum is T790M positive given her long time and slow progression on Afatinib.
As the best next step I see trying osimertinib (even without confirmed T790M mutation). I have already ordered it in the form of Tagrix (which we can afford) . The oncologist suggested erlotinib (which is rather unusual after 1st line afatinib and does not promise much long-term success).
Follow-ups of LUX-Lung trials show that patients who took 1st generation TKI (erlotinib) after afatinib were on this therapy for 4 months. I read results of other studies for osimertinib where patients who were T790M negative had PFS on osimertinib 3-4 months. So it seems there is nothing to lose even if it turned out my mum is T790M negative.
Can anyone give some advice/comments on this, thank you.

July 1, 2018 at 4:14 pm  #1294747    

onthemark

I’m trying again to post this reply. The site has been having problems accepting.

Hi Daxys,

Your Mum has a relatively rare EGFR mutation (exon 18: G719X) that is thought to respond better to second generation TKI’s like afatinib than 1st or 3rd generation. See

“EGFR exon 18 mutations in lung cancer: molecular predictors of augmented
sensitivity to afatinib or neratinib as compared with first or third generation
TKIs”

Exon 18 mutations including G719X, E709X, and
exon 18 deletion were present in 3-4% of all EGFR mutations. Lung cancers
harboring these mutations appeared to have higher sensitivities to second
generation-TKIs, especially afatinib and neratinib, than to first and third
generation-TKIs based on in vitro experiments as well as clinical data. Although the
currently available in vitro diagnostic kits do not detect all exon 18 mutations, lung
cancers harboring exon 18 mutations should not be overlooked in clinical practice
and patients with these tumors can be best treated with afatinib or neratinib.

http://clincancerres.aacrjournals.org/content/clincanres/early/2015/07/23/1078-0432.CCR-15-1046.full.pdf

Also the pattern of resistance in these rare mutations is different than than the usual ones for Exon 19 or 21 and it is not all that likely that your Mum has picked up the T790M mutation.

So it doesn’t seem promising to look to Erlotinib or Osimertinib. I’ll look more in to this and see if I can find anything promising. One option might be the quadruple therapy in the Impower150 trial, but I would try very hard to get a tissue biopsy.


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.

July 1, 2018 at 4:50 pm  #1294748    
JimC Forum Moderator
JimC Forum Moderator

Hi daxys,

In addition to the study referenced by onthemark, there is a comprehensive discussion of the G719X variant which you can read here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364853/

According to the data discussed in that report, G719X-mutated lung cancer intermediately responds to first generation EGFR TKIs such as Erlotinib and Gefitinib, while such cancers tend to respond well to second generation TKIs such as afatinib.

Most of the scholarly discussion of erlotinib and afatinib centers on whether afatinib is superior as a first-line treatment for lung cancer with activating mutations, and whether afatinib is a viable choice after acquired resistance on erlotinib. It seems that the move from afatinib to a first-generation TKI is uncommon.

As far as the particulars of your situation, my first question would be to inquire as to the extent of progression on afatinib. With a well-tolerated TKI, oncologists recommend continuing the TKI unless progression becomes more significant. Another option is to combine afatinib with cetuximab, a regimen that has shown good results, although the toxicity of this combination can be difficult to tolerate.

As onthemark suggests, a new biopsy could be helpful, if there is any way that is possible. That could also provide information on whether there is PD-L1 expression. Although that is not as common among EGFR+ patients, it does happen, making immunotherapy a more attractive option.

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

July 1, 2018 at 9:10 pm  #1294755    

daxys

Thanks for your fast replies! I forgot to mention that we are in the Czech Republic, where our choice of treatment options is quite limited. Oncologists have to stick to guidelines that are updated later than in the US. Due to this patients cannot normally stay on post-progression TKIs such as Afatinib (this treatment would not be covered by insurance companies). Also other options that you mention – neratinib, quadruple combo, adding cetuximab, immunotherapy … would be quite hard to get approved here. But maybe we could finance these options in case they are not too expensive or by buying generic forms of these drugs from Asia.

I have tried to search for acquired resistance following original G719X mutations, but was not able to find anything. Onthemark – where did you please find the information that T790M is not a common mechanism of resistance here ?

July 2, 2018 at 7:24 am  #1294756    

onthemark

Hi Daxys,

To add to Jim’s excellent summary, it’s possible that afatinib with cetuximab is considered a possible option of standard of care in the Czeck Republic after progression on afatinib.

There is some ongoing research about acquired resistance in uncommon EGFR lung cancer driver mutations. One 2017 abstract I found set up the first cell line to study that for G719X:

Abstract 4107: Acquired resistance to EGFR-TKI in an uncommon G719S EGFR mutation

Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC

http://cancerres.aacrjournals.org/content/77/13_Supplement/4107.short

Thus far, the mechanisms underlying the development of EGFR-TKI resistance in uncommon mutations have not been investigated. The newly established G719S-GR cell line could be a useful tool for investigating the mechanism underlying the development of AR in the G719X mutation; the loss PTEN could be one such mechanism. Further experiments are warranted.”

They did not find T790M.

I ran across another paper suggesting alternative resistance patterns but can’t find it at the moment. She may have the T790M but, in my view, it is not all that likely. The only way to find out is to get a reliable biopsy and make sure they are checking the all the possible mutations that might arise in her case. I am a little suspicious that they may not be checking the right mutations in her blood biopsies if after three times they didn’t catch anything, even the original mutation.


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.

July 2, 2018 at 10:10 am  #1294761    

daxys

Thank you, Onthemark.
I am afraid that you could be right with the lower chance of T790M.
My mum has been without any therapy for about 6 weeks (she received last pemetrexed around May20th) and our next appointment with the oncologist is not until next week due to holidays here. I was told she should receive a TKI as soon as possible.
Although they are not great options, we will have to choose between erlotinib, osimertinib (and maybe gefitinib). The question now is which of these would be better. I thought it would be osimertinib because I thought the chance of T790M was pretty good. Also osimertinib has the best BBB penetrability (my mum brain lesion still might be a brain met).
Now I am in doubt. If osimertinib fails, then other TKIs probably won’t work. First and second generation TKIs dont work after osimertinib and I think it would be the case. And we will be without options. Even rechallenge with Afatinib would not probably work.
If we go with Erlotinib, the chance of its working longer after Afatinib is not very high, but maybe.. But we could maybe try gefitinib too and Afatinib rechallenge later.
Could you please give me your thoughts on this- I mean the choice between these.

July 2, 2018 at 10:30 am  #1294762    

onthemark

Hi Daxys,

I’d be circumspect about interpreting clinical trials of EGFR inhibitors since your Mum has a uncommon variant and that variant is known to respond significantly better to second generation TKI therapies like Afatinib than to first or third generation, at least as first line treatment.

This is different than Exon 19 and 21 mutations that respond best to Osimertinib (third generation) as first line. So I would not read too much into the studies that do not focus on your Mum’s initial mutation.

I would also wonder if the brain met (if that is what it is) only arose when your Mum was taken of off Afatinib. Without knowing the mutations she presently has it is hard to make any inferences. My inclination would be to try a rechallenge with Afatinib and see if that changes the rate of growth. If it slows things down at all. Afatinib also penetrates the blood brain barrier. It is noteworthy that your Mum’s rate of progression changed once she was taken off of Afatinib.

Barring using Afatinib either alone or in combination (as Jim suggested in his post) since you already have access to Osimertinib that might be the best course at this point that is available to you.


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.

July 2, 2018 at 11:06 am  #1294763    

daxys

Thanks a lot Onthemark, Im sorry I do not understand exactly what you are suggesting (because of my worse understanding of English). Are you saying that Osimertinib would be a better option now (than Erlotinib)?

Afatinib rechallenge is good suggestion, but in trials they usually do rechallenge after a longer period of time – like 9 months. I guess it might work better after a linger vacation from the drug.
But question is, if we try Osimertinib first – would rechallenge with Afatinib work at all after Osimertinib?

July 2, 2018 at 11:17 am  #1294764    

onthemark

It is not so much a rechallenge but rather it isn’t all that clear that Afatinib isn’t your best option now for slowing the rate of growth of the cancer and then using for instance stereotactic radiation for areas that are not controlled.

There isn’t a lot of information to go on so one cannot be too confident but if Afatinib isn’t an option now then the next best would be Osimertinib, not Erlotinib because it has fewer side effects and penetrates the brain better.


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.

July 6, 2018 at 8:47 am  #1294822    

onthemark

ps About, T790M mutation, it is hard to say one way or the other, my previous comments were to suggest that uncommon mutations may develop TKI resistance in a different fashion than the main EGFR mutations.

With T790M, then osimertinib would be the choice according to the NCCN guidelines, which are easy to download once you sign up. I haven’t gotten nuisance emails from them! You can get the physician guidelines by going to:

https://www.nccn.org/professionals/physician_gls/default.aspx#site

then search for the kind of cancer you are researching.

The only good reason to differ from these guidelines would be unavailability of the medications, particularly for people outside of the US…, or intolerance to the treatment, patient choice, clinical trials or some new information that isn’t in the guidelines yet, but is still convincing.

I word searched the NSCLC nccn physician guidelines for “G719″ andund 2 instances, which unfortunately I am having trouble copying and pasting here. It just says these of uncommon mutations account for about 10% EGFR mutations in total and they also respond to TKIs. So there is not fine grained information about G719 and nothing to say whether you Mum would be more or less likely to have T790M mutations.

Papers suggest 2nd generation TKIs are more effective that 1st or 3rd in the first round for G719X.

The best course to figure out what to do is to get a complete mutation testing if that is possible. Then you will know what is going on at least and be able to do more than guesswork.

Barring that it may make sense to start with Erlotinib as your oncologist suggested and closely monitor to see if it helps or not, then switch to osimertinib at some point. I am not sure what the NCCN guidelines recommend as a second line therapy to afatinib without T790M mutation. But it is possible to find out.


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.

July 6, 2018 at 9:21 am  #1294823    

daxys

Thanks for your comments, Onthemark. Today I found data from AURA study http://www.ahdbonline.com/issues/2016/march-2016-vol-9-seventh-annual-payers-guide/2147-tagrisso-osimertinib-approved-for-patients-with-non-small-cell-lung-cancer-and-the-egfr-t790m-mutation :
In addition, 97% of patients had adenocarcinoma of the lung, and 70% had received ≥2 previous treatments for EGFR mutation metastatic NSCLC. The sites of extrathoracic metastasis included bone (51%), brain (37%), and liver (32%). Somatic EGFR mutations in addition to T790M included exon 19 deletion (71%), L858R (25%), G719X (2%), and S768I (2%).8
So I guess it would mean G719X transforms into T790M (but maybe less frequently than common mutations).

I had my mum take her first pill of osimertinib today. We are seeing her oncologist on Monday, but we cant lose any more time. If she insists on erlotinib, it will take another couple of days to get it approved, maybe even longer as it is summer and time of vacations. My mum has been without any treatment since 16th of May (a really long time for someone experiencing a post-TKI progression) Her oncologist has been on a 3week vacation and her substitute who was supposed to decide about erlotinib earlier did not want to do that. I hope her oncologist approves osimertinib. I dont think we can afford another weak treatment. If we have to stop osimertinib after a couple of days taking it now, it could lower our chances to use this drug for an effective treatment later.

July 6, 2018 at 9:23 am  #1294824    

daxys

Actually my last sentence should have been a question: Do you think if you take a TKI for a couple of days (e.g. 4-12 days) and then stop it and then get back on it e.g. in 4 months the effect would be lower ? I guess so.

July 6, 2018 at 9:39 am  #1294825    

onthemark

Hi daxys, yes that would also be my interpretation of the G719 representation in the study sample, that was 100% tested for T790M. [It could also be more frequently with such small numbers if that is all one has to go on.]

I am sorry to hear of all of the delays and your concern about starting treatment is valid. Resistance is an evolutionary process that takes time to develop. My guess is that taking a TKI for a week or two and then stopping it wouldn’t have a significant effect on response to that TKI later since the mechanisms for resistance take months or years and not days or weeks.

It’s not an ideal situation to be switching, of course.


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.

July 10, 2018 at 10:16 am  #1294854    

daxys

My mums oncologist agreed to my treatment proposal with osimertinib (Tagrix) yesterday. Despite the fact that the actual result of last liquid biopsy was negative (it showed the original G719X mutation, but not T790M mutation). I still tend to think that T790M could be present, but is not expressed in the blood. Because most of the progression happened after stopping Afatinib, I think that the original mutation G719X is responsible for the major part of the progression. My mum has had three liquid biopsies so far. The first two did not show anything and the last one (done after a bigger progression) showed G719X. Is there anything wrong with my reasoning? (thanks for comments)

July 10, 2018 at 11:01 pm  #1294862    
catdander forum moderator
catdander forum moderator

daxys,

TKIs have been shown to be less effective against egfr G719X than egfr 19 deletions or exon 21 L858R mutations and are said to have an intermediate response to TKIs. In the sense this mutation is probably the sole driver of the cancer then it’s also responsible for whatever happens.

It’s very possible the biopsies didn’t pick up a t790m that may be there. I hope your mum does well on tagrix. Chemo tends to be very effective for those with an egfr mutation and alimta can be a rather mild single agent.

All best,
Janine

July 11, 2018 at 8:41 am  #1294865    

onthemark

Hi Daxys,

Janine raises good points. Chemo is a viable option down the road. I am glad to hear your doctor agreed to your treatment plan. I hope the Tagrisso turns out to be effective for a long time. You will know soon if it is controlling the disease.

Since you mentioned that most of the progression happened after stopping Afatinib, and it is known that the G719X responds best to second generation TKI (statistically), then going back to Afatinib it in case Tagrisso doesn’t slow the cancer down is also still a viable option to try, in my mind.

Maybe combined with chemo. There is evidence that combining TKIs with chemo at the same time is more effective for EGFR+ patients, at least in first line.

Dr. West has a video on that here. (I find these things by following Dr. West on twitter at: https://twitter.com/JackWestMD)


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.

July 11, 2018 at 8:55 am  #1294866    

onthemark

I want to add that Dr. West makes the argument in the video that chemo and TKIs kill different cell populations, so that is how you can prolong survival by giving them together rather than sequentially when the illness is first treated.

It makes sense to me this could still be a valid argument for later treatment lines in some cases…


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.

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