Lung Cancer / Mesothelioma
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Loading ...In a recent post, I described the approval of taxotere as a second-line chemotherapy with a modest but survival benefit for patients previously treated with one line of chemo, usually a platinum-based doublet. Two years ago, erlotinib/tarceva, an inhibitor of a target on many NSCLC tumors called the epidermal growth factor receptor, was approved by the FDA as an additional treatment option for previously treated patients with advanced NSCLC, based on a large randomized clinical trial led by the National Cancer Institute of Canada that was published in the New England Journal of Medicine (BR.21 abstract here), demonstrating the importance of the results.
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This trial, known as BR.21 (BR stands for bronchus in the NCI Canada naming system), randomized 731 patients who had received one or two prior lines of chemotherapy to either tarceva at 150 mg by mouth daily for two thirds of patients, vs. placebo daily for the other third of patients. This showed a significant survival benefit of about two months for the recipients of tarceva, and also an improvement in the likelihood of not progressing at various time points (about 40% improvement compared with placebo). The chance of not progressing at 6 months after starting the trial was more than doubled in patients on tarceva vs. placebo. As with even our best chemo for previously treated NSCLC, tarceva showed a response rate (at least 50% shrinkage of the tumor) of 9%. Side effects were generally modest. While 76% of patients developed a rash, it was severe in less than 10% of patients on tarceva. Diarrhea was also seen in just over half of patients, but this was rarely a significant side effect. Overall, 27% had their drug held for a week or more, 19% of patients had dose reductions due to side effects, and 5% stopped tarceva due to side effects. Also interesting is the fact that 2% of patients found a placebo to be intolerably toxic.
So while some nay-sayers were not overwhelmed by the amount of benefit, most people felt that for a usually well-tolerated pill, an approximately two month survival benefit was compelling enough for FDA approval in November of 2004. Interestingly, and somewhat suprisingly, a very similarly designed trial with Iressa (vs. placebo in previously treated patients with advanced NSCLC) was reported preliminarily just a month later, leading the FDA to withdraw Iressa from the market for new prescriptions, limiting it to patients who were already on Iressa and not progressing, or clinical trials with it. So Tarceva became the major EGFR inhibitor for this setting and remains so to this time.
Among the most important questions, still controversial and very relevant to current treatment decisions, is whether the benefits of this class of drugs is broad or narrow. Are the clinical benefits from tarceva limited to and driven by a small subset of patients, whether women, patients with BAC, never-smokers, or those with EGFR mutations, who develop huge benefits while most of the other patients get no benefits. Or are the benefits more modest but better distributed among a broader population of beneficiaries. The next post will discuss the analyses of different patient subsets to help clarify who benefits from tarceva if a targeted drug is given in an “untargeted” way to everybody.
Posted in: Core Concepts, EGFR mutations and other molecular markers, Epidermal growth factor receptor (EGFR)-based therapies, Lung Cancer, Non-Small Cell Lung Cancer (NSCLC), Second-line treatment, Stage IV/Advanced/Metastatic NSCLC, Targeted Therapies, Activity and Side Effects, Targeted therapies, Third-line therapy and beyond, Treatment
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Hi Dr West:
I am a 55 yr old non-smoking female dx in 2005 with Stage IV adeno of the lung (both lungs, spine, hips and liver). (I am in healthcare administration and worked at MD Anderson for 10. I am in Boston and being tx at DFCI). I enrolled in a phase II clinical trial for non-smoking women first line tx with Tarceva. I had a “spectacular” response to Tarceva–the primary tumor (Left lung) shrunk from 5.4 to less than 2 cm; the liver mets (1.6cm)disappeared after 4 months of tx; and the scattered “stuff” disappeared in both lungs (there may be one spot in the rt lung that is still suspicious). I had to have 10 tx of RT before starting the Tarceva as I had spinal cord compression. So, the spine is stable as well.
I am now just almost at 18 mo on Tarceva. The last few CTs show the tumor as sstable. No more shrinkage ( I am not complaining). i am concerned about my bones (I am on Zometa initially every month and now every other month). This drug could work for me for quite a long time. Is it possible my bones can hold up as well? I have read extensively about Tarceva etc and understand that the drug is “cyclical” but I don’t understand what is happening in my bones. This isn’t a real question I guess, but if bone mets can get worse but the tumor they are measuring for the study remains stable, what happens then? (I have the Exon 19 deletion gene mutation BTW - I forgot to mention that).
Thank you so much and this is fantastic to have this website. I am just perusing it for the first time. Thank you for creating it. Carol
carol1978
Carol,
It’s hard to predict how things will change, but tarceva can certainly continue to work against disease progression in your bones along with the other areas outside of your bones. Zometa is certainly an appropriate intervention to minimize the risk of future progression.
Nobody knows yet what is the best approach for a patient who had a great response to an EGFR inhibitor like iressa or tarceva and then has progression, especially very slow progression. Memorial Sloan Kettering looked at a group of patients like that and found that their cancer worsened quickly if they came off of the EGFR inhibitor, even though they were showing some slight progression on it. They also often had worse symptoms when they came off of iressa or tarceva, and actually felt better when they went back on them.
My conclusion is that slow progression is not usually our goal with cancer, but if the alternative is faster progression, it’s probably a better choice, so I’d be inclined to try to stay on EGFR inhibitor as much as possible.
There is some hope that irreversible EGFR inhibitors like the Wyeth drug HKI-272 may be helpful if patients become resistant to our currently available EGFR inhibitors like tarceva, which are reversible. That’s based on preclinical (test tube-based) work, and we don’t know how well drugs like HKI-272 will work in real people; clinical trials are ongoing.
It may also be feasible to add something to Tarceva. The problem is that I am also a believer that there is a detrimental effect from the combination of EGFR inhibitors and concurrent chemo (at least most types of chemo that have been tested thus far). We don’t know for sure, but there are several clues that lead me to NOT recommend chemo and tarceva at the same time. The concepts we’ve been thinking about for a future trial includes adding something like avastin, which has looked promising in combination with tarceva, or erbitux, which also targets EGFR from the outside of a cell.
Sorry we don’t have a lot of answers yet, but with agents like iressa and tarceva just out for a few years, having patients who previously did well and then became resistant is a problem that is only just emerging now. I promise to keep you and others here posted on the latest developments.
I am having stable results from Tareceva with my non-small cell lung cancer. I will repeat my scans Dec. 6. I have been on Tarceva since July 2005. I was diagnosed in Aug. 04 as non small cell lung cancer with brain mets. I had surgery and partial brain radiation 9/04 . My MRI’s have been goods since. I am dealing with diarrea (Imodium) and dry skin (Aveda senstive cream and cleanser and Palmer’s cocoa butter formula dry skin lotion)Prior to the Tarceva I had chemo carboplatin and taxatere which helped at first and then stopped. Then I was put on Tarceva 150 daily. My quarterly ca t scans have been stable with some shrinkage. I hope it will continue. The only problem is I have practically no hair growth. I know I shouldn’t complain as long as nothing else is growing. Is there anything that anybody could suggest for this?
arline bishop
Arline,
I would love for you to both be doing well in terms of the cancer AND have hair growth. Unfortunately, I don’t know of anything that is especially effective for hair growth in this setting, but I’m sure many of us would love to hear if anyone has a useful suggestion.
In the meantime, I hope you continue to do well on treatment!
-Jack
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