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EGFR Inhibitors: Personalization by “Snips”
What we are striving for in cancer care today is personalized medicine. So, if a patient with newly diagnosed NSCLC has an activating epidermal growth factor receptor (EGFR) mutation, we give that patient Tarceva (erlotinib), a tyrosine kinase inhibitor (TKI). Right? Well, yes — but it doesn’t always work (the response rate is in the 70-75% range). Why not? We’re not sure, but it would be nice to learn why we don’t see near a 100% response rate among patients with EGFR mutations, so that we can know to recommend other alternatives. On the other hand, if a patient does not have the mutation, we don’t really expect much in the way of a dramatic response. Again, only partly right. In fact, some studies show a significant minority of patients with normal (“wild type”) EGFR will have at least some response to Iressa (gefitinib) or Tarceva. So, what’s going on here?
A recent study out of China looked at blood rather than tumor in 84 patients with advanced NSCLC who were all treated with Iressa. The analysis looked at naturally occurring single-nucleotide polymorphisms (SNPs, and pronounced “snips”), in the EGFR gene. A polymorphism, which basically means “many forms”, can be thought of as small part of a gene which has a different part (nucleotide) from the general population, but is otherwise normal, as best we can tell. A minority of individuals will have the different nucleotide (polymorphism) while the general population will have the same gene but with a different nucleotide.
In these patients, it was found that having a particular SNP could predict for a better response to Iressa and longer survival than the rest of the group, while different SNP could predict for a poorer response and shorter survival with the drug. Still another SNP could predict for a greater risk of developing a rash, which we know is also associated with a benefit from these TKIs. This has also been seen with Tarceva.
Alimta for Brain Metastases in NSCLC?
Brain metastases from NSCLC is almost a field of its own. This is because of the relatively high frequency with which metastases appear, the fact that they may return, even after treatment with whole brain radiation therapy (WBRT), and that our chemotherapy has long been considered to be ineffective against them. In fact, the extent of them as a problem is reflected in the number of thread questions on this subject in the GRACE forum. At the same time, there has also been work devoted to prophylactic whole brain radiation therapy (WBRT) in selected NSCLC patients considered to be at high risk. For unknown reasons, adenocarcinomas (ADC) seem to be the most likely to appear in the brain, at times the first/only site outside of the lung.
For this reason, a recent study of Alimta, published on-line in Lung Cancer, by Bearz and colleagues from several hospitals in Italy, may be of interest. Of a subset of 22 patients with brain metastases who either recurred after WBRT (11 patients) or had never received radiation (11 patients), and then received Alimta (pemetrexed), a remarkable 68% had what the authors called a “cerebral benefit.” Of the 22, 5 had a partial response, 9 had stable disease, while only 7 had progressive disease.
That being said, the study had several limitations. First, although half of the 22 had prior WBRT, the authors did not say how each of the 2 groups fared. The implication is that some of the 14/22 who benefited from Alimta had prior WBRT. Next, it would have been good to see how those few with squamous cell carcinomas (SCC) responded. In the entire group of 39 patients, only 4 had SCC, a subtype not generally felt to respond well to Alimta. Finally, this was a small study, with presumably a relatively homogeneous population, and the results may not reflect what might happen elsewhere. On the other hand, of the 39 patients with brain mets treated with Alimta, the median survival was 10 months, a pretty encouraging result considering what we had historically expected.
More Evidence from Asia on Where EGFR TKIs Fit into NSCLC Treatment
As more and more oncologists become aware of the importance of testing for at least the EGFR mutation in tumor, and soon, perhaps, in blood, it seems likely that more patients will have their first systemic treatment for advanced non-small cell lung cancer (NSCLC) be an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), usually Tarceva (erlotinib), until Iressa (gefitinib) is re-approved (perhaps). This is because the presence or absence of the mutation seems more important than clinical features in predicting a benefit from the TKI, as Dr. West described in the wake of the evidence from the IPASS trial. In that regard, a recent paper from a group of investigators in Taiwan discusses what second-line treatment should be considered after progresssion following first line Iressa in patients with advanced NSCLC. A total of 195 patients were included in this retrospective analysis, of whom 95 had tissue for testing for the EGFR mutation (61 with a mutation, 34 without). Although these findings may not be directly transferable to a North American or European population who would be receiving the very similar TKI, Tarceva, they are still of some interest.
Those with the EGFR mutation who progressed while on Iressa got a greater survival benefit with Gemzar (gemcitabine) plus a platinum-containing regime than any other regimen, including single-agents Navelbine (vinorelbine), a taxane (such as Taxol (paclitaxel) or Taxotere (docetaxel)), or any of those combined with a platinum, or Tarceva was given in some patients. However, it is of interest that none received an Alimta (pemetrexed)-containing regimen, so this remains an unknown. On the other hand, those patients who did not have an EGFR mutation did just as well with a single chemotherapeutic agent as with a doublet containing a platinum, and no one treatment emerged as especially better than another.
Clinical versus Pathologic Staging of Non-Small Cell Lung Cancer
When oncologists and surgeons talk about staging, we often distinguish between clinical and pathologic staging. Many in the health care field don’t understand or know the difference. Even more, why do we “stage” a cancer (NOT the patient!) at all? These are important questions, because they tell those of us involved in the treatment and care of such patients what is the extent of the disease, what the prognosis might be, and what the treatment plan should entail. That way, the caregivers are all “on the same page”.
It is quite important to know that staging is done, by tradition, ONLY at the discovery of the disease and a tissue diagnosis (by biopsy) obtained, and before the start of treatment. When and if there is a recurrence of the cancer, we do not give the cancer a new stage. It is then just that, a recurrence. Thus, the term “re-staging” is really a misnomer; the process would be better termed a “re-evaluation”. Another common misconception in staging and diagnosis among patients is related to the spread of the cancer from one organ to another: if a lung cancer has spread to the bone or liver, it’s still one process. It isn’t called a bone or liver cancer, but rather, it is lung cancer metastatic to those places.
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