Best treatment after Tarceva - 1266345

Hello future1,

Dr. West recently outlined the leading options for treatment after acquired resistance to Tarceva:

"There are many ways to manage acquired resistance, but the first branch point is to determine whether progression is just detectable or is clinically significant. That is in the eye of the beholder, but most experts are very comfortable having patients continue on an EGFR TKI beyond the time of earliest detected progression if a patient is tolerating it well and demonstrating only mild progression.

At the point at which clinically significant progression is noted, it’s fair to ask whether it is only in a single location, in which case focal radiation or surgery is sometimes considered, or the more common situation of several areas of (or quite diffuse) progression. If progression is more widespread, many lung cancer specialists would now favor getting tissue to test for the presence of a T790M mutation and, if present, would favor pursuing a trial of either AZD9291 or CO-1686 if one is within reach. Many experts would NOT feel that a trial needs to be a phase 3 clinical trial to be worth pursuing, as all of the patients who have benefited from these agents up to now have benefited from an earlier phase trial, and some have benefited very substantially.

Otherwise, it is always reasonable to transition to chemotherapy after progression on an EGFR TKI has become clinically significant and also multifocal. Cisplatin/Alimta (pemetrexed) is a very strong choice as a regimen in this setting, and we now have evidence that it seems to be preferable to not continue the EGFR inhibitor concurrent with the chemotherapy after acquired resistance has developed, as described here:

http://cancergrace.org/lung/2014/09/30/acquired-resistance-impress-esmo/

[continued]

[continued]

"As for the timing of whether to continue on the same regimen or switch to something new, that’s entirely in the realm of medical judgment, which means it’s something that we can’t answer. I would just reiterate that it is profoundly reasonable to hesitate before moving on if things are more stable than progressive." - http://cancergrace.org/topic/progression-on-iressa-after-15-months#post…

JimC
Forum moderator

Hi Sharon,

Yes, the unimpressive results from Afatinib after acquired resistance make chemo a likely more effective choice.

As far as the trials, each trial has its own exclusions regarding prior lines of treatment. Some may allow prior use of both an EGFR TKI and chemo, some may not. You would need to look at the specific trial to see their requirements. You can search for trials at clinicaltrials.gov .

Alimta can be used as a single agent, but when used as first-line chemo, it is considered more effective in combination with a platinum agent. Carbo/alimta does tend to be one of the most tolerable of those platinum doublet regimens.

JimC
Forum moderator

I really agree with Jim's comments here. There have been several studies that have shown that results with a "platinum doublet" of cisplatin or carboplatin with Alimta (pemetrexed) or another partner drug is superior in efficacy to single agent chemo alone. Yes, a person can reasonably expect to reduce side effects from chemotherapy by pursuing a single agent regimen, but that could shortchange on optimal survival if the pateint is fit enough to tolerate a doublet. As Jim noted, many of these doublets can be very tolerable.

Good luck.

-Dr. West

Hi future1,

Regarding the effectiveness of chemo to treat (or prevent) brain mets, Dr. West has said:

“It’s not very well studied, but the idea that chemotherapy can’t get into the brain because of the blood-brain barrier is oversimplified. There’s actually evidence that the response rate of metastases in the brain is in the same ballpark as that of measured disease outside of the brain:

http://cancergrace.org/lung/2007/10/24/chemo-for-brain-mets/

There have been some vague hints that Alimta (pemetrexed) and Camptosar (irinotecan) may be particularly effective for brain metastases, but frankly I’d say that the amount and quality of that evidence isn’t enough for me to be at all inclined to make clinical decisions on the basis of that work. There’s really no meaningful work to suggest that one lung cancer treatment is significantly more effective against brain metastases compared with others.” – http://cancergrace.org/forums/index.php?topic=11255.msg92631#msg92631

In these two posts, Dr. West has addressed the issue of returning to an EGFR TKI after progression on chemo:

http://cancergrace.org/lung/2012/06/19/chemo-with-or-without-ongoing-eg…
http://cancergrace.org/lung/2012/06/30/re-treatment-with-targeted-rx/

His conclusion is summarized in this statement:

"My personal approach is to recommend continuing the targeted therapy if the progression is relatively slow and the disease burden is less than the person started with, but to discontinue it and consider trying retreatment later if the progression is at a more rapid clip."

JimC
Forum moderator

There is really no meaningful evidence that adding Avastin (bevacizumab) leads to better disease control in the brain, and I think no knowledegable oncologist would suggest this. Use of Avastin for advanced NSCLC has decreased in the US from about 35% of patients 5 years ago to only about 20% now, as most experts and general oncologists alike look t the overall available data and conclude that it's value is very unclear when added to most chemo doublets, or a platinum/Alimta combination specifically. Many experts use it sparingly or less. Overall, I'd say that adding Avastin is an option but definitely not a mandate.

Re-treating with Tarceva tends to be associated with a <10% rate of tumor shrinkage and very short responses that last under 2-3 months when they do occur. You can see them, but they are almost never anything close to the magnitude of the benefit of treatment the first time around.

Good luck.

-Dr. West

Hello Dr. West et al,

With respect to the IMPRESS trial, From the abstract I was not able to determine how the patients who may have developed "flare" after randomization to the placebo arm( and necessarily stopping Iressa) were managed--how frequently did flare occur and did these patients cross over to the Iressa arm?

My wife and I are very, very grateful for all of the superb presentations in Boston last month, and the chance to speak with world class clinicians and researchers.

Thanks in advance,.

Jarthur

wife--68 y/o dx'd Stage IV NSCLC 3/11, now on Tarceva for past 3 1/2 years, and maintanance Alimta/Avastin, following 2 courses of Carbo/avastin/alimta with very slow progression.

That hasn't been reported, to my knowledge, but it wasn't built into the trial and likely happened very rarely, particularly in the setting of a trial that was trying to ask the question of continuing or not continuing the EGFR inhibitor. Had they crossed over, it would have been considered rapid progression, but the study showed no improvement in progression-free survival from continuation of the EGFR TKI.

I spoke with Dr. Riely again this past weekend, and he is rethinking his and his institution's longstanding conviction about continuing the EGFR inhibitor in the face of the compelling results of the IMPRESS trial.

Thanks for your kind comments about the forum in Boston. Dr. Riely mentioned how much he enjoyed it -- we were pleased with what a high energy event it was.

-Dr. West

Hi future1,

We can't really advise what should be done; that's beyond the practical and legal limits of this site. We provide information on which to base your decisions, in consultation with your wife's oncologist. Dr. West has described the limitations of Avastin and the results of the IMPRESS trial, and if there are no trials of second-generation EGFR drugs available in your area, you can use all of that information to make an informed choice.

There's no set time for how long to wait to begin chemo after stopping Tarceva, except that you might want its side effects to lessen before taking on those of chemo. Tarceva has a half-life of just 36 hours, so in a week it should pretty much be out of her system.

Good luck with the new treatment regimen.

JimC
Forum moderator