We got some big news in the form of a press release today: avastin (bevacizumab) didn't produce a survival benefit in the European AVAiL (AVAstin in Lung Cancer) trial of cisplatin/gemcitabine with or without avastin at either a higher dose (15 mg/kg IV every three weeks) or a lower dose (7.5 mg/kg IV every three weeks):

Since the anti-angiogenic agent avastin (bevacizumab) has been shown to confer a survival benefit in a subset of patients with previously untreated advanced NSCLC (see prior post), we have been struggling with questions of whether the restricted eligibility requirements in the pivotal initial avastin trial were necessary.

I’ve previously described the concept of the “precocious metastasis”, the situation in which a patient presents with early stage NSCLC, except for a single metastasis, most typically in the brain or adrenal gland. Our conventional teaching is that a patient with any metastatic disease almost certainly has additional micrometastatic disease, cancer cells floating in the bloodstream, that will inevitably lead to development of new areas of visible metastatic disease in the future (so having a small amount of metastatic disease would be like being “a little pregnant”).

The epidermal growth factor receptor (EGFR) is a central component of a cell pathway for growth and cell division that is thought to be affected in many cancers, including NSCLC. EGFR inhibitors have been the focus of clinical trials for several years and are now used for many types of cancer.

One of the novel agents being studied in lung cancer is sutent (sunitinib), a multi-targeted oral anti-angiogenic drug that I’ve described in a prior post.

One very important trial that has changed how we treat previously treated patients with advanced NSCLC has been a trial coded JMEI by Lilly, which sponsored this phase III randomized trial that directly compared second line treatment with alimta (pemetrexed) against the only FDA-approved second line treatment at that time, taxotere (docetaxel).

I was reminded of the important topic of occult N2 NSCLC by a comprehensive review that just came out in the Journal of Thoracic Oncology (abstract here) by a friend, thoracic surgeon Frank Detterbeck, who leads the thoracic oncology program at Yale.

Several members have asked about the appropriate dose of avastin (bevacizumab), which is really still a controversial subject. It's worth exploring how we got here and where we are now.

While other doses of avastin have been used with other tumor types, the first study in lung cancer that used avastin tested two different doses, 7.5 mg/kg or 15 mg/kg combined with carboplatin and taxol (paclitaxel). This work was done at Vanderbilt Univ. Cancer Center by Dr. David Johnson and colleagues, and Dr. Laskin worked with them for a couple of years. This study had the following design:

One of the issues we struggle the most with, as oncologists, patients, and families, is how to choose a therapy that won’t make someone feel worse. There are so many things to factor into these decisions: what is the baseline function of the person, what comorbidities (other chronic illnesses) might interact or interfere, what side effects are acceptable or worth the risk, to what degree is the cancer interfering with their functioning and can this be reversed with chemo, and of course what does any individual patient want and expect from chemo?

Just last week I described in a prior post the news that a large trial of Nexavar (sorafenib) had been reported as negative in first line advanced NSCLC, and with some evidence of an increased risk of death on the novel agent in combination with chemo in the subset of patients with squamous cell NSCLC.