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.
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):
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.
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.
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. Continue reading →
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