The improvement in median survival of 1.2 months with the monoclonal antibody to EGFR erbitux (cetuximab) in the FLEX trial that I’ve previously described was statistically significant, but there’s plenty of room to debate whether it’s really clinically significant (see prior post).  What If we could add some way to refine our predictions of who will benefit from the addition of erbitux?

   At the Chicago Lung Cancer meeting in November 2008, Dr. Ulrich Gatzemeier presented results of a planned subset analysis of the FLEX trial, in which the results compared the outcomes of patients randomized to receive cetuximab by whether they developed an acne-like rash within three weeks of starting this treatment.  This was based on a growing and rather consistent experience that patients who receive EGFR inhibitors, whether oral tyrosine kinase inhibitors or IV antibodies, generally show a a strong trend or significantly better survival than patients who develop no rash (see prior post).  The investigators found that there was a very significant difference in efficacy with cetuximab among the patients who developed a rash (of any severity) after two weeks (56%) compared with those who didn’t (44%).  The difference in median survival was a near doubling: 15.0 months for the patients with any rash, compared with 8.8 months for those who didn’t:

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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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An interesting trial presented at ASCO 2008 came out of Japan, asking the question of whether there is an advantage to continuing first line platinum-based doublet chemo for up to six cycles or whether it might be better to give just three cycles and then switch from chemo right to the EGFR inhibitor iressa in Japanese patients with advanced NSCLC (abstract here). I haven’t mentioned it before because the trial, although interesting and with some provocative findings, didn’t clearly provide conclusions that would lead to obvious management changes.

For trial 0203, the West Japan Thoracic Oncology Group (WJTOG) enrolled 600 patients with previously untreated advanced NSCLC, with asymptomatic brain metastases permitted. Unlike North American NSCLC patients, among whom 10-15% are never-smokers, 31% of the patients in this Japanese trial were never-smokers; about 78% had adenocarcinomas (a higher proportion than in North America or Europe). They were randomized to receive chemo for six cycles vs. three followed by Iressa. The chemo could be carbo/taxol or cisplatin with gemcitabine, taxotere, navelbine, or irinotecan, all comparable in activity.

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     The European Society for Medical Oncology (ESMO) Congress, similar to ASCO but based in Europe, has been going on in Stockholm, where the results of a study called the First Line Iressa versus Carboplatin/Paclitaxel in Asia Study (taking some liberties to force it into the acronym ”IPASS”) was presented in the Presidential Symposium by my friend and Hong Kong-based colleague Tony Mok.   This study, as shown in the schema below, randomized 1217 Asian patients with advanced NSCLC who had not received prior systemic therapy to either the oral EGFR inhibitor iressa (gefitinib) or the standard chemotherapy carboplatin/taxol (paclitaxel):

 (click to enlarge)

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  We’re recognizing more and more that lung cancer in never-smokers (LCINS) is a distinct disease, with different patterns of who gets it, how the cancer behaves, and it responds  to treatments.  But this recognition is still a work in progress, coming from a background in which the party line has been that NSCLC is treated the same regardless of the histologic type (squamous, adenocarcinoma, large cell, or other), smoking history, or other factors.   In fact, it’s fair to say that it’s still appropriate to treat never-smoking patients with the same approach that I described in other posts about NSCLC patients in general.  But I do think of never-smokers a little differently because of its apparently distinct biology, and this does modify my practice recommendations. 

   To me, the guiding point, based on what we know right now, is that never-smokers have a high likelihood of receiving a significant benefit from oral EGFR tyrosine kinase Inhibitors (TKIs) like tarceva and iressa (see prior post).   While the LCINS population isn’t as likely to have a significant response to EGFR TKIs as a population defined  by the presence of an EGFR gene mutation (around 30-50% for never-smokers vs. 60-80% for EGFR mutation-positive patients) , they are a readily identifiable group of patients who consistently have a higher magnitude of benefit with EGFR inhibitors than we’re used to seeing with chemo.   But there are absolutely other factors, since some studies corroborate my own clinical observations treating the LCINS population really demonstrates that Asian never-smoking women are clearly more likely to respond than some other groups, such as Caucasian never-smoking men.

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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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   One of the initial appeals of targeted therapies like tarceva (erlotinib) was that they may have fewer side effects and emerge as an alternative to standard chemo for some people.   And one of the most appealing areas for offering a good alternative to standard chemo has been in the setting of older patients, who may be more wary of side effects and/or have additional medical problems than younger patients.  

   A theme that has emerged very consistently in studies of elderly patients in lung cancer, and largely in oncology in general, is that fit older patients without many medical problems are very likely to do every bit as well as younger patients.  Although studies of older patients with lung cancer have largely paired the elderly and “poor risk”/frailer patients (performance status of 2, corresponding to being symptomatic, a little limited in activities, but spending more than half of the day in bed or a chair) in pooled trials.  More recently, though, we’ve come to recognize that these are overlapping but definititely distinct groups.   We also learned in a prior post that unselected patients (not singled out by things like having never smoked, or having an EGFR mutation, for instance), with a marginal performance status who receive tarceva instead of standard chemo clearly do less well than patients who get standard chemo.  But how well do older patients do with tarceva, independent of performance status?  This is an important question now that more than half of all newly diagnosed lung cancer patients are over 70.  A couple of trials help shape our thinking here.

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   Within the lung cancer community, the biggest story from the ASCO meeting was the long-awaited plenary session presentation (abstract here) of the FLEX trial of chemo with or without the EGFR monoclonal antibody Erbitux (cetuximab) that we knew was statistically significantly positive for an overall survival benefit as far back as September of last year (see prior post for details of trial and that initial press release). However, we had received no further information since that time but knew that if it showed a survival benefit, erbitux would have earned a place as a player in our considerations for treatent of lung cancer, at least first line treatment of advanced NSCLC. But we really needed to see more details to determine how to integrate it our current strategies.

  FLEX was a European trial that enrolled 1125 previously untreated patients with advanced NSCLC who were all screened and found to have expression of the EGFR protein on their tumors (because that’s what the monoclonal antibody binds to). There are various levels of stringency for the amount of protein expression, but this trial was as lenient as you could get, with evidence of the protein by immunohistochemistry (IHC) on just one single cell being considered enough to get waved into the trial. A total of 15% of patients who were screened didn’t have any EGFR expression by IHC, which may be a reason why this trial was positive for a survival benefit but the results from the BMS-099 trial have been less clearly favorable (a rumor last month of it being positive for survival was wrong and based on miscommunication — we don’t have any survival data yet for that).

   Regardless, the FLEX trial randomized patients to either cisplatin/navelbine alone or the same chemo with erbitux weekly, and patients who didn’t progress after 6 cycles would receive erbitux weekly as a maintenance therapy until progression or serious problematic toxicity. It was reported in the plenary session because it was only the second trial that has shown a significant survival benefit from adding a targeted agent to chemo (the first being avastin), and this is the first that applies to a much broader patient population, since it included patients with a marginal performance status and didn’t exclude patients with squamous tumors, on blood thinners, unlike the trial of avastin (although the FLEX trial also excluded patients with brain metastases). But the overall difference in median survival was only 1.2 months, or 5 weeks — 10.1 months in the chemo alone arm, compared with 11.3 months with erbitux. There was only a 5% difference in one-year survival between the two groups, although both groups did better than we’ve seen in older studies (42% vs. 47%). The trial just barely met the pre-defined criteria for what would be considered a statistically significant improvement in survival, and many in the audience, both general oncologists and also the lung cancer specialists, were largely left struggling with the question of whether the difference was really large enough to be considered clinically meaningful. Read the rest of this entry »

   As I’ve described in a prior post, there is some evidence that patients who develop a rash on tarceva (erlotinib) have an improved survival compared to patients who experience no skin toxicity on tarceva.  The key question is whether this is an issue of under-dosing some patients, or if it’s just a correlate of overall immune function or constitution in a person, in which case increasing the dose won’t improve the outcome.

   The best evidence we have to address this issue is a trial by the Eastern Cooperative Oncology Group, ECOG 3503 (abstract here), in which 137 patients (118 eligible) with previously untreated advanced NSCLC were treated with first line tarceva, starting at the typical dose of 150 mg daily.  But the dose was then escalated by 25 mg every two weeks until patients developed either grade 2 rash (scattered bumps or spots or general skin redness with itching or other symptoms) or significant other side effects that precluded dosing up to a maximum of 250 mg per day.  

    Only half of the patients (60 of 118) ended up pursuing the dose escalation, presumably because the other half already had enough of a rash or other side effects that increasing tarceva dose wasn’t feasible.  Only 15 (13%) were escalated up to 250 mg daily.   The overall response rate was only 7% (8/112, with one complete response), and the overall survival wasn’t any better than you’d expect. 

    This trial was actually presented at ASCO last year, but it’s one that we heard almost nothing about.  It hasn’t been published as a full manuscript (that’s not unusual, as it can easily take many months or a year or more to get a full paper drafted and accepted in a journal), but I suspect that this information hasn’t gotten out there into the world because the results were pretty disappointing.

   But they do make an important point.  So to recap, this trial showed that with aggressive dose escalation of tarceva, the response rate was less than was seen in the larger trial with 150 mg and then dose reduction as needed (abstract here); survival was also no better than you’d expect.  So this really suggests that there isn’t any incremental benefit to escalating dose.  Patients who don’t benefit on tarceva don’t appear to be underdosed.  The standard dose of 150 mg per day seems to be adequate, and there doesn’t seem to be an incentive to increasing side effects.   This isn’t especially surprising for me, since I see that some of the patients who do very well on tarceva also do it on a reduced ongoing dose of 100 mg or sometimes lower when they’re experiencing toxicity.  You don’t need to experience pain to receive the gain.     

   In a recent issue of the Journal of Clinical Oncology, Dr. Vince Miller and colleagues published the results of an important trial of the EGFR inhibitor tarceva (erlotinib) in the unusual NSCLC subtype bronchioloalveolar carcinoma, or BAC (abstract here).   This work was predicated on the observation, also by Dr. Miller and his colleagues at Memorial Sloan Kettering Cancer Center in NYC, that EGFR inhibitors, and specifically gefitinib in the earliest clinical experience, appeared to be most associated with great responses in patients with adenocarcinoma and particularly BAC, and also in never-smokers (abstract here).    Over the past several years, much of our greatest interest in drugs like iressa and tarceva has focused on BAC, including a trial with iressa that I led with the Southwest Oncology Group (SWOG) and subsequently published (abstract here), and also the trial with tarceva that Dr. Miller ran with collaborators at Vanderbilt-Ingram Cancer Center in Nashville and MD Anderson Cancer Center in Houston.   

   Over several years, these investigators enrolled 101 patients, most of whom had adeno/BAC and not the pure form of BAC (see prior post for discussion of this spectrum), which is representative of the eligibility of most or all of our current trials that we say are for “BAC”: the majority, and sometimes the vast majority, are BAC mixed with some invasive adenocarcinoma.  In truth, different pathologists, even great ones, differ in their definitions of what is BAC, what is adenocarcinoma with BAC features, and what is BAC with focal invasive adenocarcinoma. Read the rest of this entry »