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 study was looking for a significant improvement in overall survival from the early switch to iressa, and it showed a strong trend in that direction, but it wasn't a statistically significant difference:
There was, however, a very significant improvement (over 30%) of progression-free survival with the early transition to iressa:
Interesting, and perhaps worth considering changing practice for appropriate patients. But I wouldn't generalize results from a Japanese study to a non-Asian population: I think it's becoming increasingly clear that lung cancer in Japanese patients is a somewhat different disease than what we tend to see in the US.
The results of a subset analysis of this trial highlight this more clearly. Interestingly, as shown in the following curves (which are small, so click to enlarge and see better), there weren't significant differences in the two trial arms among the never-smokers, although they had a median survival of 21-23 months, compared with the 10-11 month range for smokers, in whom the iressa arm had a significantly longer median survival:
It's perhaps a little puzzling that the smokers had the significant benefit from an early switch to iressa, but my suspicion is that nearly all never-smokers got iressa and most received a major benefit from it, whether they received it earlier or later. Perhaps the smokers were less likely to receive iressa if it wasn't part of the trial but did benefit if they did receive it. But the curves at the bottom of the slide above are also quite interesting, because they show that the smokers with non-adenocarcinomas did better with chemo for six full cycles, while the smokers with adeno NSCLC did better with an early switch to iressa. This same trend held up when all patients on the trial were included:
And the median survival in the adenocarcinoma patients is nearly twice as long as that in the non-adenocarcinoma patients.
As I mentioned above, I don't think these results are generalizable to the world population, but I might consider these findings for my Asian patients. I would emphasize that this trial doesn't say that patients with non-adenocarcinoma NSCLC do worse with an EGFR inhibitor than if they never get one, but it suggests to me that (Asian) patients with adenocarcinomas may benefit from relatively early EGFR inhibitor (or at least a guarantee of getting it), while the patients with non-adenocarcinoma may benefit from more than the three initial cycles of platinum doublet chemo before switching to an EGFR inhibitor.
This study also provides another example of potentially optimized results by individualizing treatments for different subgroups, and the importance of clarifying the NSCLC subtype. It doesn't change my routine treatment approach today, but I think it's the future.
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