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

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

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.

onthemark
I'm trying again to post this

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/2015/07/2...

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.

daxys
Thank you, Onthemark.

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.

onthemark
Hi Daxys,

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.

daxys
Thanks a lot Onthemark, Im

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?

onthemark
It is not so much a

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.

onthemark
ps About, T790M mutation, it

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.

daxys
Thanks for your comments,

Thanks for your comments, Onthemark. Today I found data from AURA study http://www.ahdbonline.com/issues/2016/march-2016-vol-9-seventh-annual-pa... :
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.

daxys
My mums oncologist agreed to

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)