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.

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There has been quite a lot of discussion recently about the EGFR tyrosine kinase inhibitors (TKIs), erlotinib (Tarceva) and gefitinib (Iressa). Recently however the final results of the FLEX trial were published in The Lancet, bringing attention back to one of the antibodies against EGFR, cetuximab (Erbitux). Dr. West had previously written about the early presentation of results from this trial in a post after the ASCO meeting last year.

As a background, cetuximab is a monoclonal antibody that is given through the vein weekly. It has been shown to prolong life in combination with chemotherapy for patients with head and neck cancers, as well as for patients with colon cancers. The FLEX (First-Line ErbituX in lung cancer) study was a large randomized trial evaluating whether the combination of cetuximab with chemotherapy would prolong life for patients with NSCLC.

This study enrolled patients with NSCLC whose tumors showed staining by immunohistochemistry (IHC) for EGFR, even if it was only one tumor cell. Patients must have incurable NSCLC and could not have previously received chemotherapy. Of 1688 patients with tumors tested, 1442 demonstrated at least one cell positive for EGFR. 1125 patients were ultimately randomized to receive either six cycles of chemotherapy with cisplatin and vinorelbine (Navelbine) or the same chemotherapy with weekly Erbitux. Patients in the Erbitux arm who didn’t show progression after six cycles then continued to receive it weekly until progressive disease or until they experienced toxicity requiring stopping the drug.

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   Those who have followed my writings over time will know that I haven’t been inclined to adopt a reflexive strategy of ordering molecular testing without good evidence that having this information will improve outcomes.  Testing tumors for EGFR mutations is advocated by a vocal minority of lung cancer experts in Boston and New York City, but this hasn’t been advocated by the broader lung cancer community yet, or adopted as routine clinical practice.  Although I’ve felt that we’ll have enough evidence to support broad use of molecular variables to individualize treatment for lung cancer patients in the next few years, I haven’t felt that they have a role yet, but I’ve now seen some results that I believe are enough for me to change that conclusion.

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With last week’s FDA approval of alimta in the first line setting for NSCLC, we’re likely to see a lot of alimta (pemetrexed) use shift from the second and third line setting to first line. Alimta’s been a very popular choice for previously treated patients, based on issues like the relatively convenient schedule of a ten minute infusion one day every three weeks, no hair loss, and typically less of a drop in blood counts than seen with some other regimens. In the last year, we’ve seen a growing amount of data using it in combination with either cisplatin or carboplatin in the first line setting. While the official approval of alimta was with cisplatin and only in patients with non-squamous cancers (see prior post), I suspect that it’ll be the carbo/alimta combination that really makes an impact. Historically, US-based oncologists and their patients have preferred carboplatin for it’s easier side effect profile and greater convenience (cisplatin is usually given with loads of fluids to protect the kidneys, leading to long days in the outpatient infusion center or an overnight hospitalization stay). And based on the responses I saw on a recent audience response system for a case-based lung cancer meeting this weekend, the greater interest will again be with carboplatin instead of cisplatin.

So what data do we have to support this combination in lung cancer? Early safety and efficacy studies were done in Italy (article here) and at MD Anderson Cancer Center in Houston (article here) and were certainly encouraging. A friend of mine at MD Anderson, Dr. Ralph Zinner, led their trial and raved about how well tolerated the regimen was, with some patients continuing without progression for 8 or 10 or even more cycles. With a median overall survival of over 13 months, these results were favorable (we expect most trials from MD Anderson to exceed the numbers seen for trials around the country, due to selection bias in the population who come there), but a special appeal was the tolerability of the regimen.

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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:

 (click to enlarge)

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   Last week, updated information on the AVAiL (AVAstin in Lung cancer) trial (see prior post) of cisplatin/gemcitabine with either placebo or a low or higher (full) dose of avastin was presented in a meeting in Stockholm.  We had previously heard that this trial was positive for a significant improvement in progression-free survival for both the lower and higher doses of avastin with cis/gemcitabine, but there was no overall survival benefit compared with chemo and placebo.

   The presentation last week shed some light on the subject.  The highlight of the presentation, or at least the spin, was that all three groups had an unprecedented median overall survival of over 13 months.  It was actually 13.4 months for the group receiving chemo with avastin at the standard (high) dose of 15 mg/kg IV every 3 weeks, 13.6 months at the avastin dose of 7.5 mg/kg IV every 3 weeks, and 13.1 months in the placebo arm. 

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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:

 (click to enlarge)

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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   Imclone put out a press release yesterday that the previously described, US-based BMS-099 trial of carboplatin-taxane (either taxol (paclitaxel) or taxotere (docetaxel), investigator’s discretion) with or without the EGFR monoclonal antibody erbitux (ceteuximab) has failed to demonstrate a statistically significant improvement in overall survival.  Just over a year ago, we first learned that this trial did not meet its primary endpoint (see prior post): I thought this bode very poorly for the future of erbitux in lung cancer.  Shortly thereafter, though, Imclone put out a press release that the European FLEX trial of cisplatin/navelbine (vinorelbine) with or without erbitux (see prior post), although we had to wait nearly nine months to get more information.   The results of the FLEX trial were ultimately presented at the Plenary Session of ASCO 2008 (summary post here), showing a statistically significant improvement in survival from the addition of erbitux to this chemo regimen, but with an improvement in median survival of only just over a month, many people are left wondering whether this difference is truly clinically significant, especially factoring in the added side effects, weekly ongoing treatment, and expense.

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   As I mentioned in another post, one of the first branch points in the decision tree about what I recommend as treatment for fit patients with previously untreated advanced NSCLC is the question of eligibility for avastin.   Although I do routinely recommend avastin for eligible patients, they aren’t the majority; instead, I would estimate that population ineligible for avastin due to squamous histology, brain metastases (especially now that we routinely look for them with a head MRI), coughing blood, or other factors account for about 60% of my patients. 

   As I’ve described previously (prior post here), the available evidence is pretty definitive that the vast majority of platinum-based doublets are remarkably similar in their overall activity.  There is a little evidence that cisplatin in a little bit more active (see prior post for details), but most oncologists feel that it’s clearly more challenging in terms of side effects, so carboplatin doublets are far more commonly used, including by me.   I’ve historically favored the doublet of carbo/gemcitabine for many patients, because the main side effects are decreases in blood counts with usually very little hair loss, nausea/vomiting, and many other unpleasant side effects.  I generally favor regimens that have mostly “paper toxicities” that you tell the patient about, compared with ones that the patient experiences and tells you about.  But I’ve used several different carbo-based doublet regimens. 

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   As I described in a recent post introducing the concept of the series, “What I really do”, I wanted to provide a summary of how interpret the evidence I show here, how I really approach real life patients.    Some of this will illustrate that the experts don’t agree 100%, and that we all add some interpretation and style to how we manage patients.  What I describe isn’t meant to be a dogmatic  declaration of what everyone should do, but just the way I apply the evidence from trials of somewhat selected patients in the real world.  At the same time, I typically modify plans based on things like a patient’s other medical problems, their aggressiveness vs. aversion to side effects, travel distance to get to me, and other factors.  I don’t have any setting where 90% of patients get the same treatment, because I think many patients need a more individualized approach.  

   That said, let’s start on how I think about a patient presenting with new advanced NSCLC, which is the stage at which about half of the patients with NSCLC are diagnosed, and a higher proportion of my lung cancer patients (because many of the patients with early stage NSCLC, especially stage I, may not need or be feasible candidates for chemo).   

   Performance status is the first indicator.  There’s certainly some correlation with age, but most experts agree that the overall activity level of the patient counts far more than chronologic age.  A 77 year old man who walks his dogs 2 miles per days is a much stronger candidate for aggressive treatment than a 57 year old with severe emphysema who rarely leaves the house because she becomes short of breath making the bed or walking around.   Treating poorer risk patients is a separate issue, so we’ll concentrate on healthier patients who are able to manage their own activities of daily living (ADLs) without assistance and get out and about.  

   Within the healthier population with advanced NSCLC, the question I ask is whether they are a candidate for avastin (bevacizumab), which has been shown to improve survival for a limited subset of patients who don’t have brain metastases, squamous NSCLC, active heart disease,  require full dose blood thinners,  or have a history of coughing up blood (prior post here).  Since that initial approval of avastin for lung cancer, increasing evidence has emerged suggesting that it’s probably pretty safe to give avastin to patients with treated brain metastases (prior post here), and also for patients on blood thinners (prior post here), but right now the FDA approval doesn’t include these groups, and serious or even fatal bleeding  episodes can occur even in well-selected patients receiving the treatment, Avastin added to carbo/taxol, just as it was given in the large trial that led to its approval.  If a bleeding complication occurs in someone treated as Avastin was approved, it’s a terrible thing, but it’s known to happen.  But if, God forbid, a patient on blood thinners bleeds, or someone with a treated brain metastasis has a hemorrhage in their brain, there’s no way to prove it didn’t happen because you treated someone outside of the FDA guidelines.   And some people feel that even if you have a careful discussion with a patient with brain metastases or on blood thinners, and even if you document the risks well, a family member can still come back months after a patient’s unfortunate death and sue their doctor.  I happen to be one of those people, so I use avastin by the book.  And for the sake of completeness, I wouldn’t consider trying it in someone who has coughed up any significant amount of blood (more than slight flecks or streaking), nor someone with squamous NSCLC, since both groups continue to look like they have an unacceptable risk of bleeding complications.

  So if patients are eligible and are inclined to pursue it, I recommend carbo/taxol /avastin for up to six cycles, then maintenance avastin.  I don’t have a real problem with other platinum-based doublets combined with avastin, but no other regimen has shown a survival benefit, and cisplatin/gemctibine has failed to show a survival benefit in the AVAiL trial (prior post here).  This trial also showed that a lower dose looked comparable to the higher dose (but neither was better than placebo).  Putting it all together, I think it’s reasonable to give a lower dose, but I still favor the higher dose that was used in the ECOG trial, the only one that showed a survival benefit, particularly since the side effect profile wasn’t appreciably better with the lower dose. 

   Another point is that the failure of the AVAiL trial to show a survival benefit suggests to me that avastin’s benefit isn’t astounding: I would have hoped to see it significantly improve overall survival with  the cisplatin/gemcitabine regimen  if it were that remarkable (most oncologists have considered the regimen attached to avastin to be pretty much interchangeable, since we presumed that the effect of avastin would be the same for all of these doublets).  One large trial was positive, and another was negative, and I’m not sure that we’d consider it a standard of care if the negative trial had been reported first.  But as it was, US-based oncologists were already conditioned to accept avastin as part of our initial plan, and the AVAiL trial leaves enough unanswered questions that I don’t think it was enough to reverse our practice of giving it.  But it didn’t increase my confidence about how much the avastin was adding.  So I don’t think it’s a crucial mandate that every eligible patient receive avastin.  And it’s something I think about in a patient who is perhaps borderline for eligibility, maybe because of treated stable brain mets or anticoagulation or has had some mild hemoptysis (coughing up blood).  While there is growing experience suggesting that we can be more comfortable giving avastin to patients who may have previously been excluded or are just questionable for it, is it clearly beneficial enough to accept the risk if it didn’t show a benefit in both of the large trials that studied it?

   The other issue is that an analysis of patient age on the ECOG trial showed that elderly patients (defined as 70 and older) didn’t receive the same degree of survival benefit and experienced a significantly higher rate of many side effects compared with younger patients (prior post here).  The trial wasn’t designed to test this, and this remains a debatable point, but I definitely discuss this issue with older patients, and although I wouldn’t hesitate to recommend the triplet to a fit 72 year old, I’d think hard about how to guide a 78 year old.

   That’s more than enough for now.  I would estimate that only about 40% of my patients are eligible for avastin, so another post will cover how I approach healthier patients who aren’t candidates for avastin for one reason or another.