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.

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    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.

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This past weekend, I had the unenviable task of debating my friend Dr. Nasser Hanna, from Indiana University and a highly respected leader in lung cancer, about maintenance therapy.  He had been the expert discussant of the three key trials on maintenance therapy presented at ASCO this year (the JMEN trial of Alimta (pemetrexed) and the SATURN and ATLAS trials that evaluated Tarceva (erlotinib).   These trials were all “positive”, all showing a significant improvement in progression-free survival, and the JMEN trial showing a significant improvement in overall survival (the SATURN trial was also later reported to show a significant improvement in overall survival, but those results weren’t available at ASCO, the leading oncology meeting of the year.   Each of these trials supported the concept of transitioning immediately from first line therapy to a new therapy after four cycles, or adding a new agent to maintenance Avastin (bevacizumab), but Dr. Hanna added thoughtful commentary and made a convincing argument that the results from these trials weren’t strong enough to make maintenance therapy as standard of care.

So it was likely in the role of the sacrificial lamb that the I was invited by the organizers of the conference to argue the “pro” side in favor of maintenance therapy as the new standard.   Trying to rise to the challenge and ignore the potential of being humiliated by my silver-tongued opponent (so polished that he’s running for Congress in Indiana in the next race), I took the bait.  Though I’d had a good run and won several prior light-hearted debates on controversial topics in lung cancer in the last few years, Dr. Hanna ate my proverbial lunch: the audience, already disinclined toward maintenance therapy prior to the debate (as demonstrated by the pre-debate baseline question), moved further away from the concept after hearing our arguments.  The chairman of the meeting, moderating the discussion that followed, felt a need to publicly note that he felt that my talk was more compelling than the numbers suggested.

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When most oncologists think about the EGFR inhibitor tarceva (erlotinib), they think of the uncommon but very memorable patient who has a spectacular response within a few weeks of starting it, then continues to do well on it for a year or more.   These patients are most commonly never-smokers, often Asian, and almost invariably have an adenocarcinoma.   In contrast, many oncologists perceive there to be little to no value in giving tarceva to patients with squamous tumors, and many don’t even bother to offer it to these patients.   However, it’s worth highlighting the evidence that suggests a meaningful survival benefit, even if it falls short of the “swinging for the fences” idea we have when we give tarceva to some patients.   At the same time, we need to remember that agents like Alimta (pemetrexed) and Avastin (bevacizumab) are not generally indicated or used for patients with squamous NSCLC tumors, due to efficacy or safety concerns, respectively.   Options in advanced NSCLC are limited, but more so for patients with squamous tumors, so we need to ensure that we don’t leave good alternatives unused.

Throughout all of this work it’s important to underscore here the difference between response rate and survival, something that many oncologists still forget when they dismiss a drug for not having a high enough response rate against a certain type of cancer.   But it’s become increasingly clear in the past few years that patients with lung cancer can receive a significant survival benefit in the absence of major tumor shrinkage, and that’s not hard to imagine: if the cancer would otherwise be growing, maintaining stability is a relatively good thing, even if it falls short of major shrinkage.   And to fulfill the clinical trial criteria for even a partial response, a tumor needs to shrink by about 50% of its volume.   When I tell a patient that his or her tumor has shrunk by about 30%, a “minor response” that is still generally considered stable disease in clinical trials, we’re all pretty happy with that and don’t toss that treatment aside just because the tumor didn’t shrink by 50% or more.

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  I just recently wrote a post (here) that describes how I became convinced that under certain circumstances there could be a genuine value in determining whether a particular lung cancer patient has a tumor with an EGFR activating mutation.  While these have seemed to predict that these patients are quite likely to respond with dramatic tumor shrinkage, correct about 70% of the time, I had previously been impressed by how correlated EGFR mutation results were with some other clinical factors, such as being Asian and especially a history of never-smoking.  But recent results that I described in my last post convince me that

1) mutations trump clinical factors

2) patients who receive EGFR inhibitors as first line therapy but don’t carry an EGFR mutation don’t seem to do as well as those who received chemo.

   I also said that this doesn’t mean that patients without mutations don’t benefit from an oral EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) in the second or third line setting (the evidence is far stronger with tarceva, though, showing a survival benefit vs. placebo that hasn’t been shown with iressa).  Member sunnyside then asked about the evidence with regard to EGFR mutations and second/third line treatment.  Here’s what we know.

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One of the central ideas in medical oncology is that if you have two or more anticancer treatments that are active, you test them together to determine whether it’s safe and whether the combination works better than each individually. We’ve been doing this with chemotherapy combinations for decades, but it’s only been in the last few years that we have had more than one targeted therapy in lung cancer with enough activity to move ahead with combination work. Moreover, combinations with new agents is often limited by practical issues like companies needing to cooperative to provide their novel agents to each other if they aren’t commercially available.

The combination of avastin (bevacizumab), an anti-angiogenic drug, with tarceva (erlotinib), an oral epidermal growth factor receptor (EGFR) inhibitor, has been among the best studied targeted therapy combinations. Both agents have been commercially available for several years in oncology, reducing one practical barrier. Secondly, it makes good sense to try to combat the cancer by treating both the cancer cell’s growth and division signaling pathways (with tarceva) and the supporting microenvironment (reducing the tumor blood supply with avastin):

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   Yesterday, as described in a press release, the FDA approved the regimen of cisplatin and alimta as a first line therapy for advanced NSCLC, based on the positive results from a trial called “JMDB” by the sponsor company (Eli Lilly).  I described the highlights in a prior post, also recently published (abstract here).  It compared cisplatin/gemcitabine to cisplatin/alimta (pemetrexed) in 1725 patients with previously untreated advanced NSCLC and found that the overall efficacy was the same between the two regimens, with a little more favorable side effect profile on the alimta arm.  That wasn’t the interesting part. 

   The part that generated interest within the lung cancer community was the fact that the different main subtypes of NSCLC (tumor histology) did better with one chemo regimen or the other.  Patients with squamous NSCLC did better on cisplatin/gemcitabine, while the patients with adenocarcinoma or large cell NSCLC did better on cisplatin/alimta, as shown in both the survival curves and the table below:

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There are two widely tested epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) — iressa (gefitinib) and tarceva (erlotinib). As discussed in my summary of their history (posts here and here), iressa was the first out of the gates, but it failed to demonstrate a significant survival benefit compared with a placebo in previously treated patients with advanced NSCLC, while tarceva did show a benefit. Nevertheless, iressa was approved by the FDA for about a year, based on preliminary promise and no alternatives, before the trial with tarceva became positive. By the time the tarceva trial came out and it was approved by the FDA, gefitinib was relegated to a secondary role in the US, but it has always fared better in Asia, where it continues to be widely used.

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   Another lung cancer trial that received a good deal of attention at the recent European Society for Medical Oncology (ESMO) conference in Stockholm this past week was conducted by the Spanish Lung Cancer Group and led by Dr. Rafael Rosell, who is chief of medical oncology at Catalan Institute of Oncology in Barcelona and one of the true international greats in the field who has made important contributions for a couple of decades now.  His leading interest these days is in refining treatment plans based on molecular characteristics of lung tumors, and this particular study focuses on how patients who have been selected based on EGFR activating mutations do when they receive EGFR inhibitors.  We have a pretty good hint of this from several smaller studies that have already been conducted around the world:

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So while these are smallish trials, the largest being 127 patients who actually had a mutation, they all show response rates in the 55-82% range, and the median time to progression is 9-12 months (with some going far beyond). 

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One of my earliest posts when I started OncTalk was on the use of oral inhibitors of the epidermal growth factor receptor (EGFR), one of the growth signals that is often over-active in cancer cells, against advanced bronchioloalveolar carcinoma (BAC), a unique subtype of lung cancer that tends to grow within the lungs, sometimes slowly, and not progress elsewhere. These EGFR inhbitors like iressa (gefitinib) and tarceva (erlotinib) have certainly been well studied in NSCLC in general, but both of these drugs have been a focus of particular attention as a treatment for BAC. In fact, the largest trial that has yet been conducted in advanced BAC is one that I led, called SWOG 0126, that gave iressa at 500 mg by mouth daily (actually twice the dose that was eventually settled on, but possibly a more effective dose) to 135 eligible patients with advanced BAC. My colleagues and I published the results of this trial a couple of years ago (abstract here), but this year at ASCO I presented the results with longer-term follow up (abstract here), which yielded some interesting findings.

Obviously, the response rates and side effects didn’t change with a couple of years of longer-term follow up. Nor did the median progression-free and overall survival numbers, since those reflect the point at which half of the patients will have demonstrated progression or have died:

It’s worth noting that while this study enrolled both patients who had never been previously treated and some other patients who had received prior chemotherapy, both the chemo-naive and previously treated patients had the same progression-free and overall survival results, as shown in the superimposed curves shown above.

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   I think one of the most important lead stories from ASCO 2008 got buried.  Nobody’s really talking about it yet, but they should. 

   Amidst the results that led to an arguable role for erbitux and more compelling evidence to move second line chemo to bridge first and second line chemo together, we also received what I would consider to be very convincing clinical evidence that we can identify populations of lung cancer patients who are far more or less likely to benefit from alimta (pemetrexed), one of our most commonly used drugs in advanced NSCLC.   Although alimta is considered a conventional chemo and not a targeted therapy, we’re getting increasing evidence of how to target our convention chemo (such as by using ERCC1 levels to predict sensitivity to cisplatin, as discussed in a prior post).  The new data from the JMEN trial of maintnenance alimta vs. placebo provides what I’d consider to be downright convincing evidence that alimta is a quite effective treatment for patients with non-squamous NSCLC and also appears to be far less effective or even simply not effective for patients with squamous cell NSCLC.  

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