Tarceva did not work! Need help! - 1251395

Hallo, needinfo. It is very unfair but it does happen - your mother is not alone. We have had several GRACE members in this situation. I am linking to a thread where one of them, Mark G, discusses this problem with the doctors. In a post at the foot of the first page, Dr Weiss explains that he tends to use chemotherapy for first-line treatment (so your mother is on the right track now):
http://cancergrace.org/forums/index.php?topic=9877.0;wap2
Dr Weiss also says that he saves Tarceva for later, hoping that it will have the same effect as it might in a patient without the mutation.
May I ask, are you sure that the Tarceva was not working after just a month - was there actual evidence of progression? My understanding is that some exon 20 mutations confer resistance and some don't.
It's an interesting question as to whether Afatinib would act differently on an exon 20 mutation, and hopefully one of the doctors will have an answer to that.
MarkG's wife did really well on chemotherapy, so please don't despair. all best.

needinfo,

This situation is uncommon but not incredibly rare. Unfortunately, it's uncommon enough that it's not possible to offer any expectation of what the best approach should be. I don't think there's good reason to expect that a different EGFR inhibitor like afatinib would produce far better results, but in truth, nobody has any answers (if they do, don't trust them, because they're not based on any real substance). There are no studies of this situation, people with a combination of mutations are all somewhat unique cases, so we're left just using our best judgment.

I'm sorry there's no actual information out there to guide us here.

-Dr. West

I just wanted to offer the conclusions of a recent article (Yasuda et al in Lancet Oncology, January 2012, vol 13), which looked at the available research on exon 20. What the authors concluded is that patients with exon 20 mutations "should be treated with conventional systemic therapies that are available for EGFR wild-type tumours". In other words, best to forget about the EGFR dimension and treat the patient as your mother is being treated now, with chemotherapy. I hope she will do very well. All best.

The abstract essentially says that some of the uncommon mutations or combinations of common mutations with an exon 20 mutation respond or at least demonstrate prolonged stable disease on afatinib, but the report essentially acknowledges that these are such unusual situations that they only provide the experience of a stray patient or two at a time, rather than any clear conclusions.

I appreciate the reference to the Yamada paper, which I'll need to review. I would make a distinction between an exon 20 mutation as the only mutation present in a person (which is not one of the consistently activating EGFR mutations) and the very different situation of someone who has an activating mutation on exon 19 or exon 21 while also having an exon 20 mutation that could have an inhibitory effect. In the case of an exon 20 mutation alone, there typically isn't any factor leading to a strong response, whereas a combination of two mutations with opposing effects can lead to more of a tug of war between the two mutations...and quite varied outcomes from EGFR-based therapies. I have one patient with both an exon 19 and an exon 20 mutation, in whom we decided to start on chemotherapy, saw a modest but not stellar response, and then a very nice response to Tarceva, which came quickly after that. I've started others in this situation on Tarceva, never seeing a phenomenal response in these patients, but seeing fairly prolonged minor responses or at least stable disease in others.

My own inconsistency here is based on my careful discussions with each patient about the options, along with the lack of any substantial data or consensus of expert opinion about how best to proceed.

-Dr. West

Hi Needinfo,
Just wondering if you've sought a second opinion at an academic center? L861Q is an activating mutation but the S7681 exon 20 mutation is uncommon and infrequently discussed with regard to treatments. I wonder if the targeted therapy CO-1686 would overcome that exon 20 mutation as it does T790m (also in exon 20, but is acquired)? Your Mom is early in her treatment so hopefully chemo will give you time to research further.

Univ. of Colorado has a remote 2nd opinion program, whereby a patient would send their records and pathology samples. After reviewing the materials, the oncologist would call the patient and discuss their recommendations. I bring this up only as I was made aware of it by my oncologist there, Dr. Camidge. Perhaps other academic centers offer this service if there isn't one near you.

Best of luck to you and your Mom,
Jazz

needinfo,

Although the mechanism is not necessarily understood or identified, it does appear that cancer cells mutate further in response to treatments, making those cells resistant to that particular therapy.

But if you're thinking that her cancer cells could mutate to develop an ALK rearrangement or KRAS mutation, allowing use of a drug that targets those mutations, that's really not the way it works. Mutations are what cause cancer cells to develop, and the only thing good about the presence of a particular mutation is the fact that those cancer cells may respond well to a particular drug targeting that mutation. But you don't really want more mutations at this point.

That's different than discovering another mutation that was already there, which might be good if it suggests the use of a targeted therapy effective against cancer cells with that mutation, a mutation that was simply not picked up in prior testing.

JimC
Forum moderator
.

Right -- it's really the evolutionary pressure of cancer treatments that leads mutations to develop that almost always lead to increasing resistance of the cancer to previously effective treatments. It would be extremely unusual to see the spontaneous development of a driver mutation that wasn't there previously. At the present time, the only time that mutation testing is considered standard of care (for patients with a non-squamous NSCLC) is at the time of initial workup and planned first line treatment of the cancer.

-Dr. West