The antibody to the epidermal growth factor receptor erbitux (cetuximab) (introductory post here) has been used as an effective treatment for colon and also head and neck cancer for several years, but its role in lung cancer has yet to be defined. Early work in lung cancer was not especially impressive (prior post here), but in September, 2007, a press release reported that the FLEX trial, a European randomized study for first line advanced NSCLC that gave cisplatin/navelbine with or without erbitux, was positive with a statistical survival benefit (prior post here). Several months later, we've got no more information than that press release, but we do know that the trial was designed to require a survival benefit of at least 20-25% (I've never gotten a firm answer on this) from chemo/erbitux compared with chemo alone to be positive, so presumably it achieved a pretty impressive result that should be clinically relevant, offering a survival benefit in the same range as adding avastin to chemo for first line advanced NSCLC.

In the setting of mixed results and unreported positive trials, additional signals that can validate positive results are particularly helpful. A randomized phase II trial by Dr. Charles Butts and colleagues that enrolled first-line advanced NSCLC patients to receive either platinum-based chemo alone or with erbitux was presented at ASCO this year (abstract here), and the results were provocative, but the trial was small, with just 131 patients, and in the absence of a larger trial demonstrating the benefit of erbitux, it didn't blow me away.

The full manuscript was just published in the Journal of Clinical Oncology (abstract here), and while it's still a small study that won't change the world, it now corroborates the positive FLEX trial and therefore has a new significance, to my eye. The schema was that previously untreated patients would be randomized to receive platinum (cisplatin or carboplatin) with gemcitabine on three week cycles, either alone or with weekly erbitux:

(Click on image to enlarge)

It was actually originally designed to be a larger trial, with 300 patients, but the company decided to focus on FLEX and the BMS 099 trial (described in this post) and reduce this trial to about 120 patients.

Although technically you can't compare the two arms of a randomized phase II trial, it's remarkably hard not to, especially when people present the results next to or on top of each other. And the results of this trial, while favorable, certainly aren't enough to change practice. But the response rate was 28% for the recipients of erbitux with chemo, vs. 18% for chemo alone, and the progression-free and overall survival results both appear notably superior on the erbitux arm:

The side effects of erbitux weren't surprising in light of the significant clinical experience with this agent in oncology over the past several years. Rash/skin toxicity (worse than the EGFR tyrosine kinase inhibitors like iressa and tarceva, overall), low blood magnesium levels, diarrhea, and fatigue were the leading issues with erbitux compared with chemo alone.

With just 131 patients, this isn't the definitive answer, but it makes the positive FLEX trial seem much less like the outlier and suggests that erbitux may also be beneficial with a range of chemotherapy regimens. There were also some signals of favorable results in other erbitux trials as well, albeit less striking. One other open question is whether there is a much greater benefit from erbitux in patients who have tumors positive for EGFR by fluorescence in situ hybridization, or FISH, as was suggested by preliminary work by the Southwest Oncology Group (see post here), remains an open question. In the meantime, even without being able to select a subset of patients who do especially well with erbitux, the FLEX trial no longer stands alone as a positive trial. Significantly, it also appears that erbitux can be effectively combined with chemo in a way that I don't think applies for EGFR tyrosine kinase inhibitors with concurrent chemo (as discussed in prior post).

We'll get more information on the FLEX trial and other work with erbitux in lung cancer in coming months, but I'm becoming increasingly convinced that it will have a real place in treating NSCLC in the (near) future.