Although it’s only a leak from a “reliable source”, news came yesterday (link here) about a new lung cancer development from a financial source (yet another example of us learning oncology from Wall Streeters). Specifically, we heard that the BMS-099 that I described in a prior post is actually demonstrating a significant benefit in overall survival (OS). To summarize the BMS-099 trial, it’s one that compared standard chemo of carboplatin/taxane (either taxol (paclitaxel) or taxotere (docetaxel) at the physician’s discretion) with or without the EGFR inhibitor Erbitux (cetuximab), which is an IV monoclonal antibody and “targeted therapy” in a population of patients with previously untreated advanced NSCLC. The schema is as shown here.

The initial press release about the BMS-099 trial was less favorable, but overall a little puzzling. As described in my initial post about it back in August of 2007, the trial was large, with 676 patients who were not restricted by EGFR markers like protein expression (by immunohistochemistry, or IHC) or gene amplification (by fluorescence in situ hybridization, or FISH); some trials have restricted enrollment to patients with postivie EGFR IHC or FISH tests, in order to increase the chance of showing good results with an EGFR inhibitor. BMS-099 was designed to look at progression-free survival (PFS) by the investigators but also with an independent radiology review board (IRRB). The preliminary results of that trial, as reported by Dr. Tom Lynch from Massachusetts General Hospital back in September at the World Conference on Lung Cancer in Korea (abstract here), showed that the IRRB did not find a significant improvement in PFS, but the investigators did (PFS and response rate (RR) are examples of “soft endpoints” that may somewhat subjective based on what you want or expect; hence the IRRB that shouldn’t have any biases based on expectations of who received an investigational drug). In contrast, the reverse was true for RR, where investigators found a non-significantly higher RR in chemo/erbitux recipients, but the IRRB noted a statistically significant difference. Here’s a summary of what we learned:

Go figure. So it’s hard to call this a clearly negative trial, even if it didn’t technically meet its primary endpoint.

At the time of the initial presentation by Dr. Lynch, we didn’t have OS results. Now, however, with at least a reliable leak that survival will be significantly better in chemo/erbitux recipients (and survival tends to be a “hard endpoint” with no controversy between investigators and independent reviewers), we’ve got another trial that adds to the “FLEX” trial I’ve described in another post and that we are told also shows a survival benefit for chemo/erbitux vs. chemo alone (this trial, done in Europe, uses cisplatin/navelbine (vinorelbine)). We haven’t received any details about that trial, either, but as a reflection of the importance of a positive large randomized trial in first line treatment of advanced NSCLC, it’s penciled in to be presented at the ASCO Plenary Session, where the most important cancer trials of the meeting are discussed.

There’s no question we need to see the data and not just go by press releases and Wall Street rumors, but it’s reassuring to see multiple trials with different chemo regimens and done in different parts of the world all showing similar results. We now have the FLEX trial with cisplatin/navelbine and done in Europe, the BMS-099 trial with carbo/taxane (taxol or taxotere) and done largely in the US, and finally a trial I described in a prior post with platinum (cisplatin or carboplatin with gemcitabine) that was done largely in Canada, all showing the same finding of superior survival with chemo and concurrent erbitux. This conclusion is particularly interesting to me because it appears that the intravenous monoclonal antibodies can be effective when given concurrently with standard chemo, which is unlike what we’ve generally seen with chemo and the oral small molecule tyrosine kinase inhibitors like tarceva (erlotinib) and iressa (gefitinib).

Coming in the wake of the reported absence of a survival benefit for avastin in the first line AVAiL trial of cisplatin/gemcitabine with avastin (bevacizumab) or placebo, I think it’s quite likely that our views of current “best” treatment, or standard of care, will continue to develop for first line treatment of advanced NSCLC. It’s important also to recognize that many patients are not eligible for avastin because of brain metastases, squamous tumors, blood thinners and other restrictions, so chemo/erbitux may be a clear best choice for these populations, at least until we learn more about the safety of avastin here. But putting it all together, and knowing that we’re still looking for the factors that will help us predict which patients will be the major beneficiaries of erbitux and which ones may get little or no benefit, I’d bet that we’re going to be hashing out new standards of care for advanced NSCLC for a good while.