Thus far, the vast majority of patients who have an initial response to EGFR tyrosine kinase inhibitors like Iressa and Tarceva will eventually become resistant to them. At this year’s ASCO, our huge annual US-based oncology conference, a report was made by the group at Memorial Sloan Kettering Cancer Center (Riely abstract here) on a small series of patients who had progressed after a prolonged period of responding to Iressa or Tarceva. They found that patients who had slow progression, generally without symptoms, and then came off of their EGFR TKI therapy would often experience a rapid worsening of symptoms.
In general, we don’t continue drugs on which patients are showing progression, because we consider the drug ineffective at that point, but in this case it could just be a less effective set of brakes that is still better than not having them. In some cases in oncology, we do routinely continue drugs after patients have shown progression, such as men who initially responded to hromone therapy for prostate cancer and then continue on hormore therapy, or women with breast cancer who progress on chemo with Herceptin and are then often put on another chemo approach with Herceptin. We really don’t know the best way to manage situations like this.
The early evidence suggests that approximately half of the patients with an initial response to EGFR TKIs who then progress seem to develop a defined mutation, called T790M, that makes drugs like Tarceva no longer fit as well as it previously did to the EGFR target protein. At this point, it is not clear if there is a way to reverse that process and have patients respond again to EGFR inhibitors. In lab models, some “irreversible” inhibitors of EGFR, such as a drug made by WYeth that goes by the catchy name HKI-272, seems to have encouraging activity in the test tube models. It is being tested in patients at a few centers around the country right now. The new agent Tykerb (lapatinib), which blocks both EGFR and another receptor in the same family known as HER-2 and has demonstrated activity in patients with breast cancer who have been previously treated, may bind to EGFR anfter it develops the secondary mutation. Still, at this point we haven’t seen how these and other potentially helpful drugs perform in real people who have stopped responding to drugs like Tarceva or Iressa. A further complicating factor is the evidence thus far that adding chemo and drugs like Iressa or Tarceva at the same time may lead to antagonism of each other, which would make it problematic to just add new chemo while keeping the EGFR TKI therapy ongoing. Perhaps adding the anti-angiogenesis agent Avastin or another agent targeting EGFR like cetuximab (an IV monoclonal antibody against EGFR) can be combined with EGFR TKIs and improve results, but at this point nobody has a clear answer of a best way to proceed in these cases.
posted by admin @ 4:33 pm link to this post
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January 3rd, 2007 at 12:28 am
T79OM..how and when is it found?
January 3rd, 2007 at 10:42 am
This test is done only at specialized labs (placed like Memorial Sloan Kettering), very few, from tissue obtained from a biopsy. It is not a routine test and is not established in its clinical utility yet.
January 13th, 2007 at 8:27 pm
Dr. West,
About how long does it take on average for someone who has responded to Tarceva to show signs of resistance? I have been on Tarceva for 16 months without any evidence of disease. BWS
January 13th, 2007 at 8:41 pm
The median duration of response on tarceva is about 8 months. That means that half of the responses are longer, and half shorter. There are definitely people who have gone 2+ years and are still going, but Tarceva was only approved in 11/04, so very few people have had the opportunity to respond longer than two years. I suspect that eventually nearly all lung cancers will develop resistance, but a fortunate minority will go for 2 or 3 years before that happens.
-Dr. West
February 25th, 2007 at 6:02 pm
When is no progression of the cancer not good?
At the last consultatation (21st Feb 2007) my mother’s oncologist said that as my mother showed no improvement (but was stable - no progression) we would have to think about discontinuing teatment with Tarceva. This was after her first month with Tarceva. I was a bit shocked, as I thought no progression was good. I do not know what the next line of treatment would be. Any ideas? Could she go back toher previous conventional chemo treatment ie Gemcitabine/ Carboplatin? She only had 3 cycles of this and it seemed to suit her quite well (it even seemed to stop her rheumatoid arthritis flaring up).
If not this then what? She has lost a lot of weight (14 lbs) whilst on the Tarceva and seems fatigued, but this could just be from the bad rheumatoid arthritis attack which she got 5 days after starting the Tarceva. Is there any known relationship between Rheumatios Arthritis and Lung Cancer and/or Tarceva?
February 25th, 2007 at 8:05 pm
I don’t know of a relationship of RA and tarceva, or lung cancer in general. I would not be inclined to stop tarceva or many other therapies when a patient is showing stable disease IF the treatment is well tolerated and the patient is not declining. However, with the weight loss and other problems, I would be less inclined to press on and assume everything’s fine. If no progression from first-line treatment, it’s certainly possible to go back, but we usually stop first-line therapy after 4-6 cycles and don’t feel that more is very helpful. Otherwise, based on the available evidence, both taxotere and alimta have been approved by the FDA and are probably among the chemo agents most likely to provide some additional survival benefit.
-Dr. West