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Fibroblast growth factor—the next molecular target in lung cancer?
What is FGF?
FGF is a type of receptor tyrosine kinase. What, you might ask, is a receptor tyrosine kinase? Well, since you were so kind as to ask, and since I’m a bit of a nerd at heart, I’ll tell you. Receptor tyrosine kinases are a part of the machinery of a cell; they have a role in signaling to the rest of the cell what it should do.
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Lesser Known Lung Cancer Mutations Part 1: HER2, a promising therapeutic target?
By now, most patients (and hopefully, all oncologists!) are familiar with the significance of EGFR mutations in non-small cell lung cancer (NSCLC). The discovery of ALK mutations and the successful use of crizotinib in this setting has also been big news in the lung cancer world. I’d like to bring everyone up to date on two lesser known abnormalities that can occur in non-small cell lung cancer: HER2 and BRAF mutations. This post will cover HER2 mutations in NSCLC, and I will cover BRAF in a companion post to follow shortly. Dr. West alluded to these mutations in his recent post on the Lung Cancer Mutation Consortium study, and you can see in the figure he previously presented the relatively low frequencies of these mutations compared to more common mutations such as EGFR and KRAS.
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Heterogeneity in Population of NSCLC Patients with Acquired Resistance to EGFR Inhibitors: T790M is Key Predictor
Over the past several years, probably the biggest development in the field of NSCLC has been the recognition of the importance of molecularly-defined subgroups that help define the clinical patterns of how patients are likely to do with various treatments. We’ve seen this clearly illustrated with EGFR mutations vs. EGFR wild type (no mutation), and more recently with the very uncommon but clinically important ALK rearrangements.
One newly defined clinical setting that has emerged has been the group of patients who experience a very good response to an oral EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib) or Iressa (gefitinib), generally but not necessarily those with an activating EGFR mutation (most typically on exon 19 or 21, as described in this great summary by Dr. Nate Pennell) who respond for a period of months or years and then develop resistance. Why does it happen, and what are the leading options for managing this situation?
Early work on this problem of acquired resistance (as opposed to primary resistance, which is the situation in which a person starts out by not being very responsive to an EGFR TKI), largely out of the Harvard hospitals in Boston and Memorial Sloan-Kettering Cancer Center in New York City, have shown that about half or slightly more develop a resistance mutation called T790M on exon 20 (and a minority of people with an activating EGFR mutation also have this from the beginning, likely helping to explain why the response rate with one is not 100% but more like 70-75%). Another 10-20% or so are found to have over-expression of c-MET (targeted by agents like ARQ-197), reflecting a pathway that can bypass the EGFR signaling cascade as a mechanism for resistance.
Are There Significant Differences Among EGFR Mutations?
Since we’ve come to appreciate the presence of distinct activating EGFR mutations associated with a very high probability of responding to an oral EGFR inhibitor, the question has emerged about whether there are significant differences in outcomes between the two most common ones, which are a deletion in exon 19 and a “point mutation” in exon 21. Some retrospective work in smaller aggregated series has suggested that patients with an exon 19 deletion tend to do best, but other work has suggested no difference between these two most common mutations. The recently reported trio of prospective trials of patients with an EGFR mutation receiving first line chemo or an EGFR inhibitor provide a good opportunity to evaluate this question.
The studies are actually pretty consistent in conveying that there is a modest trend toward the most favorable progression-free survival (PFS) in people with an exon 19 vs. an exon 21 mutation, but the differences aren’t great. Here are the PFS curves directly comparing the two main types of mutations in the Japanese trials with Iressa (gefitinib):
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So while the curve for exon 19 deletion is on top by a small margin, both activating mutations appear to follow a very similar trajectory overall, with no significant difference.
TITAN Trial: Comparison of Chemo and Tarceva in Patients Who Progressed Early on First Line Chemo for Advanced NSCLC
One of the trials presented at the Chicago Multidisciplinary Symposium in Thoracic Oncology last month was the TITAN trial, one of a pair of studies conducted in Europe to test the oral EGFR inhibitor Tarceva (erlotinib) in patients with chemotherapy pre-treated advanced NSCLC. The other trial, SATURN, was designed to test Tarceva as a maintenance therapy vs. placebo in patients who had shown a response or stable disease after four cycles of first line chemotherapy (without the VEGF inhibitor Avastin (bevacizumab)) has been summarized previously and ultimately led to the approval of Tarceva as a maintenance therapy in this patient population. But what happened to the significant fraction of patients who progressed by the time of the repeat imaging after four cycles of first line platinum-based doublet chemotherapy? They were directed to the TITAN trial, which was a head to head comparison of Tarceva vs. either Taxotere (docetaxel) or Alimta (pemetrexed), both well studied and commonly used second line agents for advanced NSCLC. The trial looked for an improvement in overall survival with Tarceva.
The trial closed earlier than planned, due to slow enrollment, with just 424 patients, which leaves it quite underpowered to detect a difference even if there really is one between the two treatment approach. Still, there may be some conclusions that can be drawn from what they saw, even if limited by smaller numbers than needed to say anything definitive.
Adding EGFR Inhibitor Therapy to Radiation or Chemo/Radiation for Locally Advanced NSCLC
We’ve recently received a series of questions on the question of whether it makes sense to give an oral EGFR inhibitor like Tarceva (erlotinib) or Iressa (gefitinib) concurrently with radiation. This is really a poorly studied question, but a paper just published in the Journal of Thoracic Oncology describes a clinical trial that helps to address this question. Unfortunately, for reasons that aren’t very clear, the results didn’t look very favorable overall. But let’s explore this in more detail.
The Cancer And Leukemia Group B (CALGB), one of the three main cancer cooperative groups in the US, noted that EGFR inhibitors were apparently active for at least some patients with NSCLC and with often modest side effects, most typically rash and a tendency toward diarrhea. The investigators from CALGB started trial 30106 to ask a slightly different question in two different clinical populations:
1) For patients with a good performance status (PS) and unresectable stage III NSCLC, does adding daily Iressa to initial chemo followed by concurrent chemo/radiation lead to more favorable results than would be expected from this approach without Iressa?
2) For patients with a marginal PS and unresectable stage III NSCLC, does adding daily Iressa to initial chemo, giving Iressa with radiation instead of chemo/radiation lead to favorable results?
Is lymph node involvement by direct extension more favorable than “separate” nodal involvement?
The staging of lung cancer makes the distinction of whether there are any lymph nodes involved with cancer, and if so, whether they are within the lung that houses the primary cancer or outside of it; if the latter, a distinction is made among mid-chest nodes on the same side as the main tumor (N2), mid-chest nodes on the opposite side from the main tumor (N3), or above the collarbone (N3). This staging is described in more detail in a summary chapter in the lung cancer reference library on initial workup and staging of lung cancer.
But there may also be useful distinctions to be made. I’ve previously described some investigational work suggesting that the number of lymph nodes involved may have prognostic value. Another concept that is commonly accepted is that the risk of recurrence is lower if a patient has a lymph node involved just by direct extension of the cancer into an adjacent lymph node, as opposed to spread to lymph nodes that are some distance away from the primary tumor and therefore presumed to have spread through lymphatic channels. A Japanese study reviewed results in patients with resected early stage NSCLC and N1 nodal disease in order to address this question.
A prior publication by the same group from earlier this year looked at outcomes from just patients with squamous NSCLC who underwent surgery and had N1 disease as their highest stage. Among the 120 patients with N1 nodal disease, the 5-year survival was 67.7% in those with just direct extension, compared with the significantly inferior 5-year survival of 32.4% in those with distant spread, a result that was comparable to that seen in patients with N2 nodal involvement. The current effort looked at a much larger group of 324 consecutive patients with pathologically confirmed N1 nodal involvement, including patients with both squamous and adenocarcinoma histologies. They compared these results to those of 1524 patients with node-negative disease, and 330 others with N2 nodal disease (N3 nodal involvement is generally considered to not be best managed with surgery). The investigators reviewed whether there were differences in the overall NSCLC population and also looking specifically at the histology of the NSCLC tumor, as squamous tumors have a tendency toward more local spread and adenocarcinomas tend toward earlier spread to distant sites, although these are only general tendencies.
Lung Cancer Screening Saves Lives!
For years and years, lung cancer advocates have often aggressively championed screening for lung cancer, while many in the medical “establishment” and policy-makers expressed reservations that, while there were encouraging indicators of benefit, there was not evidence that lung cancer screening saves lives, so we really couldn’t make a blanket statement encouraging lung cancer screening. That has now changed, as the NCI-sponsored National Lung Screening Trial (NLST) has now been reported to demonstrate a 20% improvement in lung cancer-specific survival. A preliminary but detailed manuscript describing the trial itself is published in the journal Radiology and is available at no charge.
The trial was started in 2002 and randomized over 53,000 patients who were 55-75 and had at least a 30 pack-year smoking history (pack-years being the product of average number of packs of cigarettes smoked per day x number of years smoking) to either annual low-dose spiral CT scans for three consecutive years or a chest x-ray on the same interval. These screening CT scans are done without IV contrast and are done within a single breath hold (up to 15 seconds) but can fully view the lung fields.
The Data Safety Monitoring Committee that regualrly reviews the trial results over the course of a study’s ongoing conduct recently reviewed the most current results and noted a statistically significant improvement in the lung cancer-specific survival of people were were randomized to screening CT scans. Specifically, there were 354 deaths from lung cancer on the CT arm, vs. 442 deaths from lung cancer on the arm assigned to chest x-rays, a 20.3% reduction. In addition, the CT screened patients had a 7% reduction in “all cause mortality” (not just lung cancer, but deaths for any reason), with only 25% of the deaths in the overall trial due to lung cancer. This was likely due to detection of issues such as cardiovascular disease and other incidental but significant medical problems with CT but not chest x-ray screening.
Introduction to Lung Cancer in Never-Smokers
The following is the edited transcript and figures from a webinar presentation made by Dr. Heather Wakelee, medical oncologist and Associate Professor at Stanford Cancer Center, on Never-Smokers and Gender Differences in Lung Cancer.
I’ll start with the association of lung cancer with smoking.
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There is no doubt that smoking remains the biggest risk of lung cancer, and what this slide is showing in the green is cigarette consumption and how that started off in the 1900s, gradually increasing until the 1960s ,when the public first became aware of the health risks and as that dropped, lung cancer deaths also started to drop but obviously trailed that.
The gray line is the men, showing that men led early smoking cessation efforts and stopped, and so the death rates in men dropped as the cigarette smoking dropped. Unfortunately for women, we were a little slower to hear that message about health risks from smoking, and we’re only now starting to see a tapering off of lung cancer in women. Still a little bit lower than men, but a real risk.
Rising to the Challenge of Narrowed Patient Subgroups
Only a few years ago, oncologists saw lung cancer as divisible into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with very little relevance to any division beyond that point. We knew that patients with NSCLC could be categorized into having adenocarcinoma (including the subset of that larger group, bronchioloalveolar carcinoma (BAC), squamous, large cell and large cell neuroendocrine carcinoma, and into those with and without a significant smoking history, and other demographic variables, but they weren’t a primary focus when we didn’t perceive that these differences had clinical significance in our treatment recommendations. And at that time, most people received remarkably similar treatments, with first line trials in advanced NSCLC incredibly commonly designed as carbo/Taxol (paclitaxel) +/- new drug, and second line trials of Taxotere (docetaxel) +/- new drug, or a direct comparison to placebo in previously treated patients.
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