EGFR Tyrosine Kinase Inhibitors in Advanced BAC

H. Jack West, MD, Founder, President and CEO

As we established several years ago that it is indeed possible to do clinical trials with more than 50 or even 100 patients with advanced BAC, we were also seeing that those first forays into advanced BAC with standard chemotherapy were somewhat disappoingting (described further in another post). Fortunately, as it became clearer that we needed other options for advanced BAC, we started to see the first cases of patients with BAC who received Iressa on clinical trials who would sometimes have rapid and profound responses to this drug (below showing a difference after just 5 days):

BAC pre and post iressa

The lung cancer physicians at Memorial Sloan Kettering Cancer Center (MSKCC) reviewed the results from 139 patients who received the EGFR tyrosine kinase inhibitor (TKI) Iressa (gefitinib) as a single agent over a 5 year period and found that a diagnosis of BAC was among the strongest predictors for having a response to Iressa (abstract here).

I wrote and led the SWOG trial that we launched in 2001 to study Iressa at 500 mg daily in advanced BAC, and this is the largest prospective trial in advanced BAC that has ever been conducted (SWOG 0126 abstract here). This trial included two patient groups, one who had not received any chemotherapy and another previously treated with conventional chemotherapy; a total of 138 eligible patients were enrolled from around the US. We saw responses in about 1 in 6 patients, a bit more commonly in patients who hadn’t received any prior treatment. Nearly half of the patients at least didn’t have progression of their disease for several years. While the patient population as whole did about the same as we saw in the prior trial with taxol, several patient groups did better than others on the Iressa trial, including women, patients who developed a rash, never-smokers, and patients who were healthier to begin with Importantly, patients with pure BAC weren’t the only ones to do well with Iressa. Patients with tumors that were adenocarcinoma mixed with BAC did well, and patients with non-mucinous pure BAC did better than those with mucinous BAC.
A smaller trial, led by MSKCC, has treated approximately 100 patients with advanced BAC with Tarceva (erlotinib) at 150 mg daily. As in the SWOG trial, one quarter of the patients had been previously treated with chemotherapy. The results of this trial have only been published as an abstract thus far (preliminary results here), but approximately 24% exhibited a response, and those responses have lasted about a year on average. They also found a greater likelihood of response among lifelong non-smokers than former smokers or current smokers, and saw no responses were seen among patients who did not develop a rash on erlotinib. Responses were not restricted to patients with pure BAC and in fact were more commonly seen in tumors that demonstrated adenocarcinoma with BAC than in pure BAC.
Taken together, the evidence from these two trials clarify the utility of EGFR TKIs in the treatment of BAC, either in the front-line or salvage setting, although it appears that there remain distinct subsets that will benefit more or less from these agents. It is certainly reasonable to treat BAC with chemotherapy, with or without Avastin, as other types of NSCLC are managed, but EGFR TKIs are generally used early, either as first treatment or as a leading choice shortly thereafter.
Right now, I’m leading a trial through SWOG that gives patients with BAC the combination of Tarceva and the anti-angiogenenic agent Avastin (SWOG 0635), since the combination appears to be well tolerated and may be more active than Tarceva alone. Since BAC is generally treated with Tarceva now as an approach of choice, the question is whether we can improve on that with Avastin added, as adding Avastin to carboplatin/taxol has been shown to improve survival in non-squamous advanced NSCLC in general. Other interesting clinical trials of BAC are studying drugs like Alimta (pemetrexed), Velcade (bortezomib), Nexavar (sorafenib), Sutent (Sunitinib), and Erbitux(cetuximab). It is encouraging to see that the interest in BAC is steadily increasing in the lung cancer community, since this may lead to ongoing improvements in treatments for patients with BAC, as well as a better understanding of the disease.

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