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Is Rash a Good Thing with EGFR Inhibitors?
An acne-like rash or dry skin is a very common side effect of the drugs that target the epidermal growth factor receptor, with approximately 3/4 of patients who receive the EGFR tyrosine kinase inhbitor tarceva/erlotinib experiencing skin toxicity. Similar skin toxicities are also seen, but a bit less commonly, with the very similar drug iressa/gefitinib, and also frequently with erbitux/cetuximab, a monoclonal antibody that is less well studied in lung cancer. But since the earliest clinical trials of these agents, there have been questions of whether the rash is something more than just a potentially problematic side effect, but rather a marker of someone likely to do well with these agents.
Never-Smokers, Part II: Different Responses to Treatment
I reviewed some of the differences in the biology and clinical behavior of never-smoker lung cancers vs. the much more common lung cancer seen in current or former smokers. The main reason it is worth discussing is that there appear to be important differences in how never-smokers with NSCLC respond to some treatments, particularly EGFR tyrosine inhibitors like Tarceva, or Iressa previously. Among the first reports of this came from Memorial Sloan Kettering Cancer Center in NYC, which reviewed their experience with single-agent iressa several years ago and found that never-smokers were much more likely to demonstrate a significant response to iressa than current or former smokers (36% vs. 8% response rate, shrinking the cancer by 50% or more of the total measured volume). Along with bronchioloalveolar carcinoma histology, smoking status was among the most important variables in predicting response to iressa (abstract here).
As we learned about EGFR receptor mutations, first described in 2004 and associated with a high likelihood of response to EGFR inhibitors, we got some explanation for why never-smokers seemed to do well. In fact, the initial report by Dr. Lynch in the New England Journal of Medicine described 9 patients with excellent responses to gefitinib, of whom 6 were never-smokers. A study of tumor tissue out of Memorial Sloan Kettering showed that 7 of 15 lung tumors from never-smokers carried an EGFR mutation, compared with only 4 of 81 from smokers. Another study of patients who had surgery for early stage lung cancer in Japan showed that among 154 resected tumors (36% were from never-smokers, really highlighting how common never-smoker lung cancer is in Japan!). Since then, multiple trials have shown that never-smokers are significantly more likely to have EGFR mutations than smokers, and are also significantly less likely to have mutations in the gene k-ras (rhymes with mass) that in study after study are associated with no benefit from EGFR inhibitors. There are many controversial issues in lung cancer, but this is not one of them. From all over the world, the studies all show the same thing. Continue reading
Avastin Studies Beyond its Current FDA Approval
As mentioned in prior posts, the anti-angiogenic monoclonal antibody Avastin (bevacizumab) is now approved in first-line treatment of advanced NSCLC in combination with carboplatin/paclitaxel chemotherapy. Among the very interesting questions is whether Avastin should be added with other active drugs for NSCLC. Most of us in the field strongly suspect that the survival benefit from Avastin will also be the case with other types of therapy, but we’re only starting to get the evidence to address this. Continue reading
Are EGFR Inhibitors Only Useful in Certain Patient Groups?
Since the earliest clinical trials of EGFR inhibitors in NSCLC, certain clinically defined patient subsets became identified as more likely to show a benefit than others. Such studies suggested that women, patients with adenocarcinomas rather than squamous cell carcinomas, Asian patients, and never-smokers compared with current or former smokers were the patients who would do well with EGFR tyrosine kinase inhibitors like gefitinib (Iressa) or erlotinib (Tarceva). Since that time, we have been debating whether these targeted therapies should be used primarily or exclusively in selected populations or whether they should be used in general lung cancer populations. The correlation of rash with better outcomes is another interesting issue that is a big enough topic I’ll discuss it separately in the near future. Since it’s not something you know about before you start treatment, unlike patient sex race or subtype of lung cancer, it’s a different issue.
Erlotinib (Tarceva) in Previously Treated NSCLC
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.
(Click to enlarge picture)
Treatment after Initial Chemo in Advanced NSCLC: Second Line and Beyond
Although we are all frustrated by the relatively slow pace of progress in lung cancer, there are times when we can look back and feel that we have made a real impact. Six years ago there were no treatments that were FDA approved and appeared to benefit patients who had previously been treated with first-line chemo for NSCLC. Now there are several. Continue reading
Clinical Trial Focus: RADIANT Trial in Adjuvant NSCLC
As described in a prior post, chemotherapy after surgery is often recommended after surgery, at least for a subset of patients with stage IB to IIIA (without mediastinal lymph node involvement) NSCLC, based on a potential to increase cure long-term survival compared to surgery alone. At this point, two forms of targeted therapy (erlotinib, or Tarceva, as a single agent in second- and third-line advanced NSCLC, and bevacizumab, or Avastin, combined with carboplatin and paclitaxel for first-line treatment of advanced NSCLC) have been approved by the FDA for advanced NSCLC because they have demonstrated an improvement in survival. At this point, however, we don’t know whether adding targeted therapies as a strategy in earlier stage NSCLC can increase cure rates. But one key trial that is evaluating this possibility is the RADIANT trial.
RADIANT Trial; click to enlarge.
RADIANT is an acronym for Randomized, Double-Blind Trial in Adjuvant NSCLC with Tarceva. This will be an international trial designed to enroll 945 patients who have undergone surgery, with no residual cancer left behind, for stage IB, II, or stage IIIA NSCLC. Patients may have received up to four cycles of chemotherapy after surgery, but patients who received no chemo are still eligible. Patients are then randomized to receive either tarceva or a placebo, with two-thirds of patients receiving the active drug and one-third receiving placebo. Because it is a double-blinded study, neither patients nor their treating doctor know who is getting tarceva or a placebo. This is appropriate because we don’t know whether Tarceva is going to be better, the same, or actually worse, with side effects of treatment but no added benefit.
Importantly, although Tarceva is approved by the FDA for all patients with previously treated advanced NSCLC, regardless of whether their tumor has high levels of EGFR, the target of Tarceva, or amplification of the EGFR gene in tumor cells. We still debate whether Tarceva works best, or perhaps only works at all, in patients with EGFR protein expression as detected by a test called immunohistochemistry (or IHC) or amplification (excess copies) of the EGFR gene by a test called fluorescence in situ hybridization (or FISH). Many trials that are investigating the future role for Tarceva are using more selected populations based on clinical characteristics such as never-smoking or BAC, or molecular characteristics such as EGFR overexpression by IHC, gene amplification by FISH, or presence of an EGFR mutation detected by gene sequencing. Perhaps the benefits of Tarceva can be found to be more pronounced and more consistent if we can identify and treat those patients most likely to do well with it, rather than use a “targeted therapy” unselectively.
Further information about eligibility details and participating centers can be found here.
EGFR Tyrosine Kinase Inhibitors in Advanced BAC
As we established several years ago that it is indeed possible to do clinical trials with more than 50 or even 100 patients with advanced BAC, we were also seeing that those first forays into advanced BAC with standard chemotherapy were somewhat disappoingting (described further in another post). Fortunately, as it became clearer that we needed other options for advanced BAC, we started to see the first cases of patients with BAC who received Iressa on clinical trials who would sometimes have rapid and profound responses to this drug (below showing a difference after just 5 days):
The lung cancer physicians at Memorial Sloan Kettering Cancer Center (MSKCC) reviewed the results from 139 patients who received the EGFR tyrosine kinase inhibitor (TKI) Iressa (gefitinib) as a single agent over a 5 year period and found that a diagnosis of BAC was among the strongest predictors for having a response to Iressa (abstract here).
Continue reading
EGFR Mutations and Acquired Resistance After Responding
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.
Continue reading
Where do we go from here with Avastin?
Although Avastin has been approved for first-line treatment of advanced NSCLC, at this point it cannot be universally employed. Patients with squamous cancers account for something in the range of 30% of patients, while patients with brain metastases amount to about 10-15% of patients. Another 5-10% may have hemoptysis, or the symptom of coughing up blood, and many others are on therapeutic blood thinners for a history of blood clots or atrial fibrillation. The trial of Avastin in lung cancer (called ECOG 4599) also did not include patients who had a marginal performance status, defined as being able to care for oneself but not able to work, and patients moderately limited in how active they can be, whether due to fatigue or shortness of breath or other issues, account for a lot of patients in the real world. We also still have trouble predicting which patients will have bleeding complications that can be serious or even fatal, even if only patients who meet the eligibility criteria are given Avastin. We are somewhat concerned about the risk of bleeding in patients with cavitary lesions (with an empty space in the middle, shown below)
and those with central cancers near major blood vessels, but those patients would be eligible for Avastin according to the trial and the approval guidelines. Finally, while most oncologists expect that Avastin would give similar benefits if added to different chemo regimens, we don’t have proof of that yet, nor do we know with certainty that it is safe when combined with other chemo agents.
So trials are now being done to clarify whether Avastin can be given safely to patients with hemoptysis who have received radiation to treat that issue, and to patients who have squamous cancers who may have received prior treatment with radiation to minimize bleeding risk. Other trials are evaluating Avastin in patients with treated brain metastases. Multiple trials are carefully assessing whether the patients with central cancers or cavitating tumors are at significantly greater risk for bleeding, and also will clarify whether women show a benefit with Avastin outside of the ECOG trial. Multiple ongoing trials are combining Avastin with other chemo drugs to ensure that it is safe in other regimens.
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