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.

There were some very interesting differences between Caucasian and Asian patients. For starters, Asian patients did startlingly better than Causasian ones overall (regardless of assignment to chemo or chemo/erbitux). How much better?? how about a median of 19.5 months for the Asian population vs. 9.6 months for Causasian patients? Asian patients were far more likely to be never-smokers -- 52% (!!) vs. 17% -- and they were very likely to get oral EGFR tyrosine kinase inhibitors such as tarceva (erlotinib) or iressa (gefitinib) than Caucasian patients (61% vs. 17% overall, pooled across chemo and chemo/erbitux). Asian patients didn't receive a significant benefit from erbitux, perhaps because the patients who were assigned chemo alone were much more likely to get a drug like tarceva later (72% vs. 44%). But this point is worth considering: if the survival in Asian patients, including more than 50% never-smokers, was markedly improved because of second or third line oral EGFR inhibitors, they seemed to work after erbitux (median survival 17.6 months for prior erbitux recipients, who as noted above were far less likely to be given tarceva or iressa later than the chemo alone patients, who had a median survival of 20.4 months). If we start using erbitux commonly as a first line therapy, we're going to need to figure out whether and when drugs like tarceva would still have a role, since both agents target the same molecule, although from two different angles.

The survival benefit in Caucasians was about 2 months, so that is arguably in the same range that we've seen and accept as worthy of becoming a new standard of care, in the same ballpark as that with avastin. But some of the lung cancer experts are bothered by the fact that there was no improvement at all in the progression-free survival, which is almost always seen when there is a survival benefit from a new drug (it's hard to understand why patients will live longer if they progress on the new treatment just as quickly as with the old treatment). There was a small increase in the response rate with erbitux, from 29% to 36%. On the downside, erbitux was associated with a rash very similar to tarceva but probably even more of a challenge, and a high rate of fevers with low blood counts (15% with chemo alone, 22% with chemo/erbitux).

Overall, there isn't a clear consensus yet that chemo with erbitux is a standard, and I think many oncologists will think that the survival difference of 1.2 months combined with the added side effects and cost, in the context of another trial that hasn't been declared positive, isn't enough to change practice yet. I suspect most oncologists will continue to use chemo and avastin for avastin-eligible patients, but chemo with erbitux will be a strong consideration and will likely be the approach I use for avastin-ineligible patients, such as those with squamous tumors, and probably those with brain metastases as well. That won't apply to my Asian patients, based on the lack of benefit in that group. And some but probably most oncologists won't be giving erbitux with cisplatin/navelbine, despite the fact that we haven't seen positive results with the trial that gave carbo/taxol or carbo/taxotere with erbitux.

We're going to continue debate what this trial means for a while. I'll have a few concluding thoughts on it in my next post.