EGFR TKI and acquired resistance - 1245065

Hi graceabchen,

That thread is very long and it doesn't seem that there is a pending question near the end of the thread. So I think if you or anyone else who has posted there or has been reading it has a question, you should go ahead and ask it as a new inquiry, referring to anything from that thread that you find relevant to your question. It would be difficult for GRACE faculty to comb through all those posts to get back up to speed on what was already said in that discussion, so if you can ask a question and specifically refer to what has been discussed, that would make their job much easier.

JimC
Forum Moderator

graceabchen

I wonder if there would be any kind of clinical trial for this drug with TKI since it's an old drug and very cheap and drug companies won't make any $ on it. That's the problem. the time that I can think of that I would try TFP with TKI is if my scan showed very mild progression while I'm on Tarceva - not enough to change therapy yet. then maybe add TFP to current dose of Tarceva and then wait for repeat scan to see if there is any difference. does this make sense? what do the doctors think?

ssflxl

I think that there would still be enough financial incentive for the companies selling EGFR TKIs to do this. Don't forget that if Astelllas/Genentech can restore the activity of Tarceva (erlotinib) for another year, for instance, by finding another drug to restore Tarceva's activity, that's another year of Tarceva sold, even if the manufacturers of TFP aren't interested in funding this work.

AB, I really can't field your questions. I'm not a lab person for the past 15 years, so I really can't judge the rigor of the benchwork described. I have also never, ever given TFP, nor have I even heard of any physician I've ever met using it, nor has a patient I've encountered in my 20 years of being in clinical medicine ever received it, to my knowledge. I personally wouldn't offer it based on preclinical work, but if this research is promising and it leads to enough clinical understanding that we can have some confidence in the probability of activity and good tolerability, I'd certainly be far more receptive.

-Dr. West

I would say that I do prioritize clinical trials, because we can learn from them whether a treatment is effective or not, prohibitively toxic, etc. Having people just do all sorts of creative, untested things outside of a measured setting means that it's really difficult to determine any patterns.

-Dr. West

Hi AB, thanks for initiating this discussion. The treatment of acquired resistance is an uncharted territory. While I believe that the respected main stream oncology is likely bound to follow ethical protocol of evidence based treatments, there seems to be some doctors that are prepared to venture into some unproven, perhaps well thought out, paths. From the perspective of a patient, when best proven ones are generally of less than 5 months median PFS, a new untested but promising one could be more tempting and perhaps a desired calculated move. We could have to make a hard choice one day. Just hope that the day is a long way down the road and better treatment is established then.
NJ

We are living in a very new world when online patient communities can update each other about new side effect and tolerability issues on clinical trial therapies in real time. It's now possible for patients following each other on clinical trials to potentially know more about side effect management than just about any doctor, including investigators for these very trials (who know about their own patients' experiences and some of the more serious adverse issues that get readily reported, but often not as much about nuissance side effects that may fly under the reporting radar).

I think that one key difference between some patients/caregivers and many investigators is that the latter are really more wary about placing much faith on a mechanism of action and scientific theory compared with preliminary clinical results in human patients. We have just seen so, so many promising ideas turn into completely negative actual results that I am very unconvinced that a scientific idea should lead to any clinical recommendations/changes in management outside of a clinical trial. I'm far more impressed when I see genuine results in real human patients.

-Dr. West

Dear Dr West,

I know this might be another individual question, but in general, for a patient who develop AR after 2-3 years stable under first line TKI, what could be your prioritized list of treatments ( chemo, radiation, clinical trials) right now? It seems to me that there are so many out there, up to us to try our luck.

thanks in advance!

I don't mean to be coy, but I think there's a huge amount of nuanced information that isn't conveyed by "AR after 2-3 years stable under first line TKI" that I just can't comment. First, there isn't any evidence to say that one is better than another, and I don't want to just offer speculation. Second, the judgment for me is VERY individualized and based on things like the extent of progression (one or many locations), rate of progression, what treatments have and haven't been tried before, etc. In other words, this is an individual consideration, and not something that I can offer in an online forum with a tiny glimpse of a much more complex big picture.

-Dr. West

graceabchen,

Thank you for re-opening that long-running, wide-ranging, & valuable prior discussion here. Sorry I didn't notice it until now -- I'm still getting my sea-legs with the new topic structures here and haven't found a way to be auto-notified of new discussions I'd want to see.

Re: trifluoperazine hydrochloride (TFP) as an extender of EGFR TKI usefulness, note carefully that while that does seem a simple and cheap thing to try (off-label), the research study only claims to help re-close the PIK3-AKT pathway (at the AKT point), not the two other major pathways of EGFR (RAS-RAF-MEK-ERK and JAK/STAT).

So, if the EGFR TKI resistance happens to be AKT-dependent (e.g., maybe due to MET amp? or CRKL amp?), then one might speculate that TFP might help noticably for a while.

But if, for example, the EGFR TKI resistance is due to blocking the TKI from fitting into the EGFR TKR properly well enough (which I think might be more common), all three of the pathways might be active and shutting down one of three might only slow the cancer. A more complete inhibitor combo might be better if there is one available.

Since we are talking about some pretty early research, these thoughts are just guesses, of course. This does highlight, though, how it can be useful to identify the mechanism of resistance rather than just try things based on subjective judgement.

Best hopes,

Craig

Craig, I so appreciate your fine understanding of the biology behind your cancer. Too I'm thankful you're contributing to others' discussion on the subject. To subscribe or add as a favorite there is an option for either at the first post of any discussion thread.
Good luck and best hopes,
Janine

AB,

As I've said, your questions are very far beyond general management and evidence-based clinical discussions, so the experts here can't guide this, which would be more of a personal discussion of recommendations based on almost complete speculation.

-Dr. West

I understand, and I'm not saying you aren't asking a valid question. I'm saying that the experts are trying to focus on providing assistance to the broadest population in a limited amount of time, and that makes it infeasible to go far down the road of extrapolating basic science to speculate on options for a very limited patient population. As clinical oncologists serving as experts discussing practical management issues, we really need to prioritize human data.

-Dr. West

FWIW, I wouldn't have assumed clinical oncologists would have much to say about biochemistry until biochemists have sorted out their understanding better and translated it into actionable conclusions for clinical research.

re: where other pathways are illustrated, a large variety of EGFR pathway diagrams ranging from simplified to over-my-head-complex are available using google image search:
https://www.google.com/search?site=imghp&tbm=isch&q=EGFR+pathways
After hunting through them, the three pathways I mentioned seemed the most commonly illustrated ones.

Some of these images only illustrate a single pathway that was the subject of a researcher's investigation and others report multiple pathways. I do not have any understanding of the relative importance of different pathways, but am delighted to see that research has already come this far, this deep, this soon. I also get the impression that these pathways seem relevant to other driving mutations (including maybe my own ROS1-driven cancer) even though EGFR may be better understood than the more recently-useful ones.

BTW, a recent anecdote I recently read by a person with an ALK mutation may be an example of "relative importance." She developed resistance that seemed due to EGFR up-regulation and KIT mutation, but had a very good response to LDK378 nonetheless (a strong 2nd gen ALK inhibitor). Maybe that drug has unexpected effects on certain mechanisms of resistance, or maybe simply using a stronger ALK inhibitor was sufficient for the front-runner cancer? I don't think anyone knows and we can only speculate until researchers figure it out.

Best hopes,

Craig in PA
_________________________

P.S. -- Very nice "mechanisms of resistance" citation, graceabchen. Thank you.

I wanted to update this thread with links to some useful recent posts by Dr West, and I have a question arising from them. Their theme is whether to continue a targeted therapy after resistance has set in, perhaps adding chemotherapy or radiation depending on the extent and nature of the progression:
http://cancergrace.org/lung/2012/06/19/chemo-with-or-without-ongoing-eg…
http://cancergrace.org/lung/2012/06/09/ar-local-rx/
http://cancergrace.org/lung/2012/06/30/re-treatment-with-targeted-rx/
My question for Dr West is: suppose you wanted to introduce a fellow-oncologist to the notion that continuing a targeted therapy post-progression was a clinical strategy worth considering, what would you offer them as persuasive evidence? Would it be experience with patients, or research work such as the MSK study cited in the second post? Do you recall what finally convinced you (or colleagues) that the practice of abandoning one therapy for another might not be appropriate in all cases of TKI resistance? Many thanks.

I think it's a combination of factors. Somebody discinclined toward the practice can certainly dismiss the "data" to support it, which is retrospective and not of sufficient quality or quantity to convert someone who is quite resistant. I do think this is an area in which it can sometimes be helpful for an oncologist to know than many of the real leaders in the field, including those at institutions that have done much of the leading research on these targeted agents, continue treatment beyond progression.

Beyond that, I think it's most important to take a step back and examine the principles behind it. It's easy to envision that, when rather limited progression occurs after a great response, only a subset of the cancer cells that have been sensitive to the targeted therapy have now become resistant. Then you match that with the idea that some patients experience rebound progression that is very fast compared with the progression before they stopped the targeted therapy, and that patients can respond a second time if they have been off of the targeted therapy and become resensitized, and it can lead to the conclusion the usual dogma about stopping a treatment on which someone has progressed may not apply.

-Dr. West

OK - many thanks, Dr West. It is daunting when views seem fairly entrenched.

Reading the last 3 posts gave me chills to think of how some of the pracitces of the more dogmatic oncs will play out as treatments continue to change. I'm sure my imagination is more fanciful than real life.

The reality is that different doctors have very different levels of comfort about stepping outside of the evidence-based comfort zone vs. extrapolating based on judgment. I think it's a balance -- I don't want to be completely constrained by what can be dictated by great evidence, but at the same time, I don't want to be so free-thinking that I abandon the principles dictated by limited information. But different doctors fall all along the spectrum of rigidly evidence-based vs. very open to different approaches.

-Dr. West

Of course. I am just trying to think about what might be the tipping point between a doctor feeling that an idea is alien and quixotic, or interesting and worth considering.

An update on the idea of continuing to treat with Tarceva beyond progression (and I should say that I am fortunate enough to be stable at present - this is a question for the future). Attitudes here in the UK seem fairly fixed. So far, everyone I speak to is saying, "Why would we want to do that, when progression proves that the Tarceva isn't working?" In both the hospitals where I am treated, clinical practice is to stop Tarceva on progression, not least because the NHS will not fund it. (My husband and I are trying to work out how we would pay for it privately if that proved necessary.)
Before I try and argue the case with anyone in the NHS who might be willing to listen, can I revert to afatinb, which is available here on a compassionate use basis. Dr West recently presented an interesting post-ASCO Q and A with Drs Neal and Socinski:
http://cancergrace.org/lung/2012/10/01/asco-2012-qa-session/
http://cancergrace.org/lung/files/2012/10/ASCO-2012-LC-Highlights-Q-and…
Both Dr Neal and Dr Socinski said they would be inclined to try afatinib in a patient who had progressed on a first-generation TKI but for whom there was no obvious available clinical trial (p. 5 of the transcript). Yet there seemed to be a consensus among all three doctors that the toxicity is tougher than Tarceva. In such a scenario, would afatinib just function as “something to try”? My recent impression has been that afatinib has not proved particularly effective at combating acquired TKI resistance, especially when used alone. I would appreciate any insights on this - although I can see that it is a context in which there is no "right" answer.

I am personally dubious that afatinib is clearly superior to the other EGFR TKIs, but I do think it would be a practical way to essentially offer a lateral move from continuing the same EGFR TKI if there are practical issues with not doing that (such as a general resistance based on historical bias against the idea). The side effects can be mitigated by lowering the dose as needed, and overall I'd suspect that even if it isn't better than Tarceva, pound for pound, it may well produce the same effect as continuing on it.

I'll also underscore that there is nothing close to consensus that continuing an EGFR TKI in the setting of acquired resistance is the clear way to proceed, and that the historical dogma has long been that you STOP a drug on which someone is progressing. I am just among the growing number of experts who feel that acquired resistance after a prolonged excellent response warrants a separate careful review rather than just reflexively subscribing to dogma.

-Dr. West

Thank you, Dr West. This is hard work!
I found the discussion with Dr Neal and Dr Socinski very useful - I appreciated both the candour of the conversaton and the snapshot of current thinking.

Just updating this thread with a link to Dr West's post about a trial of Nexavar (sorafenib), which was disappointing overall but which appeared to prolong the lives of a subset of EGFR positive patients:
http://cancergrace.org/lung/2012/10/17/mission-trial-neg-egfr-mutn-pos/

(PS: AB, where are you? hope all is well with you)

AB (graceabchen), are you still out there? I have been thinking how I miss your questions about TKI resistance! I see that back in November you were waiting on a clinical trial. Hope it worked out and that things are going OK. All best.

Do note there are various causes for resistance, the T790M mutation, MET, and others. Determining the cause is a first step and it does makes sense to discuss how to get specimens.

Hello everyone. I have been following this thread as a stage IV adenocarcinoma patient on Tarceva. The recent link of Nexavar (Sorafenib) has certainly been an interest to me. Likewise the research on Dacomitinib, AP26113 and co-1686 has me very eager about the future of EGFR Inhibitor treatment. Needless to say, Afatinib's recent approval has good reason to add to optimism. The Afatinib-Cetuximab combo for resistance is by no means the perfect treatment, but it is a step in the right direction. And with the drugs/trials that I mentioned earlier, there may be room for new combination trials to utilize in acquired resistance. As far as Afatinib-Cetuximab, it is a stride to go on and proclaim, "They have done it once, they can do it again!" I realize that research will take time and is often linear in needing to look at a single drug's effect before throwing it into a combination trial. Yet beating cancer and acquired drug resistance in relation to the stem cell mechanisms which drive cell direction, selection. and propagation- trapping and subduing it is like a chess game. You need your queen, rook (and maybe bishop) to trap it. Here's to a future "checkmate". Just a rambling that others may express more to-the-point, Dr. West.

texandave, I like your analogy to chess.
All the best to you and our beloved researchers.

Janine

texandave,

Yes, it is nice to see the research progress on EGFR-driven lung cancer. And since EGFR TKI's have been around for a few years now and there is a lot of EGFR-driven lung cancer out there, there seems more research and farther ahead than for any other lung cancer target.

Just thought I'd add that it might sometimes be important to determine which kind of EGFR drug resistance a person gets when there's progression. That might not matter if you can eliminate easily-targeted spots with targeted radiation, but if it's due to MET amp, a MET inhibitor like MetMAb might be useful, or an inherited BIM gene (e.g., Asians), or if a different mutation or even a different type of lung cancer (even SCLC) has emerged maybe that changes the best-odds choice, too. Some might prefer to first just try a good one with high odds overall (like afatanib+cetuximab) if their oncologist thinks that's a good option to try, but sooner or later I would think it could be good to refresh knowing what you're trying to target so you use the highest-odds treatment for it.

Best hopes,

Craig in PA