Merck KgAA, the company developing cetuximab/Erbitux, the monoclonal antibody against EGFR, reviewed here) outside of the US, has announced that their pivotal FLEX trial (for First-Line Trial for patients with EGFR-Expressing Advanced NSCLC) is positive, demonstrating a signficant improvement in overall survival, as indicated here. I mentioned it as an important study to define any role for Erbitux in NSCLC, especially since a recent randomized trial I described in a prior post was reportedly negative.

The press release includes no details, just a glimpse of the trial, with a progress report last presented at ASCO 2006 (abstract here). This is a European phase III randomized trial with just over 1000 patients with previously untreated advanced NSCLC that had to have EGFR protein expression by immunohistochemistry (IHC), which is present on about 60-80% of NSCLC tumors. So there was a modest degree of selection of these patients, but a majority of patients would likely be eligible. All patients received doublet chemo with an "old school" combination of cisplatin and navelbine. This is a fine regimen but not commonly used in advanced NSCLC in the US (but still favored as a very good choice in the post-operative setting, since the majority of the best data in this setting is with cisplatin/navelbine). At the time this trial was developed, European oncologists were most commonly giving cisplatin, often with navelbine and gradually giving way in recent years to gemcitabine.

So all of the patients received the cisplatin/vinorelbine chemo combination, and half also received Erbitux as a weekly treatment with it.

(Click to enlarge)

The only real information in the press release was that the trial showed a significant improvement in overall survival, which was its primary objective. We also know that it included patients with all subtypes of NSCLC, which is particularly important because the subset of patients who are good candidates for Avastin (no squamous cancers, no brain metastases, no history of coughing blood, not on blood thinners...) is probably less than half of the patients out there. However, we don't know how positive this trial really was. The important ECOG 4599 trial that led to Avastin's approval for NSCLC showed a two-month survival benefit, and some even scoff at that. If the Erbitux trial shows a median survival benefit of just 3 weeks, it might be considered statistically signficant but not clinically meaningful, especially if side effects were a very significant issue (rash can be worse than with either Iressa or Tarceva and sometimes very severe). And then there's the fact that the studies with carbo and a taxane (either taxol or taxotere) have looked modestly encouraging at best (reviewed here), with perhaps a hint that some patients, such as those who are positive for EGFR gene amplification by the FISH test, could get major benefit from Erbitux.

We definitely need more information. It's safe to say that US oncologists aren't going to drop carbo/taxol and other much more commonly used regimens to start using cisplatin/navelbine with Erbitux, even though the only encouraging evidence for a survival benefit with Erbitux in lung cancer will be with the cisplatin/navelbine regimen and NOT with a carbo/taxane regimen. However, it's also true that this is the first time we'll have seen any benefit from a combination of an EGFR inhibitor (with a different mechanism than the tyrosine kinase inhibitors Iressa and Tarceva) for a general population in a large phase III advanced NSCLC trial (the INTACT, TALENT, and TRIBUTE trials were all negative, as reviewed here).

We need to learn a lot more about this trial, such as how big the survival benefit was, how the treatment was tolerated, and whether the benefits were seen broadly across many patient types or in more restricted subsets (clinically or molecularly defined). We don't know whether patients who received Erbitux first line ever respond to second lineEGFR tyrosine kinase inhibitors like tarceva. Will there really be a net gain in survival, or was the survival benefit with Erbitux on the FLEX trial only seen because those patients never received an EGFR inhibitor of any type?? Perhaps this is why the US-based trials haven't looked as favorable...

In the meantime, it appears we may have another first line treatment option for patients who are not eligible for Avastin, and a potentially competing targeted therapy option for the subset of first line advanced NSCLC patients who would otherwise receive chemo and Avastin. And because I know what you're thinking, I'll remind you that the Southwest Oncology Group (SWOG) has just completed a feasibility trial called SWOG 0536 that gave chemo (carbo/taxol) with both Avastin and Erbitux:

($$!!)

Like a Rolls Royce, if you have to ask the price for this regimen, you can't afford it).

For now, we await more information. But we may have a new (to lung cancer) agent for advanced NSCLC based on this trial.