When I first described the developing work with the EGFR monoclonal antibody erbitux (cetuximab) two years ago (see prior post), I described a trial that was just getting started called SWOG 0536. This was a trial testing the safety and feasiblity of a new combination that was moving beyond the triplet therapy of two chemo drugs plus the angiogenesis inhibitor avastin (bevacizumab) to add weekly erbitux to all of these; following 6 cycles of this combination, patients would continue on maintenance avastin (every 3 weeks) and erbitux (weekly). We got the early results from this trial very recently, and they were encouraging enough to move forward with a larger phase III trial that SWOG is about to initiate.

The SWOG 0536 trial was presented by my friend Ed Kim at the recent lung cancer meeting in Chicago (abstracts are all here, but no links to individual abstracts). The trial enrolled 99 eligible and analyzable patients with previously untreated advanced NSCLC, and as is the case with most trials with avastin, patients were excluded if they had a squamous tumor, brain metastases, history of coughing up blood, or required blood thinners. They had a median age of 64, were almost perfectly evenly split between men and women, and 22% of the patients had never smoked. The primary objective of the study was to assess the safety of this regimen, and 2 patients (2%) died from bleeding complications, which is definitely unfortunate but about what was seen in the larger ECOG trial of carbo/taxol/avastin (abstract here). Other common side effects that were moderate to severe included acne (18%), fatigue (19%), neutropenic (very low white blood cell count) fevers (6%), neuropathy (12%), and blood clots (10%). Others following the trial had jokingly said that the treatment limiting side effect of this combination would be cost, since we're talking now about something in the range of $20,000/month. So perhaps they were only half joking.

If the benefits in efficacy are staggering, we can make the argument that this approach is worth the added cost and side effects. And overall, the results appeared favorable, although I don't think most of us would say staggering. The response rate was certainly impressive at 53%. The limitation is that this is still not a large trial, and many trials of 50-100 people have shown response rates in at least the 40-50% range. Both the median progression-free survival of 7 months and median overall survival of 14 months were also quite favorable, better than we expect to see in large studies.

But as I mentioned in a prior post, we need to remember that we generally see more favorable results in smaller studies than we see in larger studies. Some of this is selection bias -- you can imagine that the physicians who were recommending treatment approaches weren't suggesting this four drug regimen to patients who were more marginal candidates, although the data for who actually went on the trial don't show any clear evidence of unusually young, healthy patients. But also recall that the median overall survival for the AVAiL trial of cisplatin/gemcitabine +/- avastin was 13-14 months in all patient groups (see prior post). Several other phase II trials also showed a median overall survival in the 14-15 month range, and we might expect to see unusually good results in any trial that includes only patients with adenocarcinomas and without brain metastases or other significant medical problems.

The results were encouraging enough for SWOG to move forward with a large trial of over 1000 patients that will randomize patients to either carbo/taxol/avastin or carbo/taxol/avastin/erbitux if they're candidates for avastin (and want it), or carbo/taxol vs. carbo/taxol/erbitux if they aren't candidates for avastin. This trial is just getting its final approvals and will be running over the next several years. We'll see how a broader population of patients tolerates the four drug combination and whether it adds significantly to our current standards.