Zactima (Vandetanib) in SCLC: An Argument Against Maintenance Therapy

Howard (Jack) West, MD, Founder and President

There's been several discussions about the potential value of maintenance therapy after the initial chemotherapy for SCLC; I've discussed this subject in a prior post, in which I focused on chemo -- while the results haven't been strong enough to lead to a change in standard practice, at least one trial showed a strong trend in the right direction. On the other hand, other studies, such as one recent large one with thalidomide (described in a prior post), looked quite unfavorable for maintenance therapy, at least with this agent. I've described the drug zactima (vandentanib, or ZD6474, which inhibits both angiogenesis and EGFR) in yet another post, and it has continued through several large trials, which could potentially lead to its approval in lung cancer if one or more of these is positive. But we've already seen the results of one trial of zactima as a maintenance therapy in SCLC. It's fair to say that this trial won't lead to it's FDA approval.

This particular study came out of Canada and was known as the BR.20 trial (the lung trials conducted by the NCI-Canada are numbered BR.__, where BR stands for bronchus). Presented by Arnold and colleagues at ASCO 2007 (abstract here), the study enrolled 107 patients with SCLC, including both limited (about 43%) and extensive disease (57%) who had achieved a complete or partial response to chemo for at least 4 cycles; patients also received chest and/or brain radiation if it was clinically appropriate. Patients were randomized to receive either zactima at 300 mg by mouth daily (a dose that likely inhibits both angiogenesis and the EGFR axis effectively) or a placebo pill as a maintenance therapy after completing chemo (+/- radiation). The focus of the trial was disease-free survival, looking for a delay or prevention of recurrence after treatment.

While zactima was generally well tolerated, there were some side effects that were signficantly increased in the recipients of zactima compared with a placebo, including EKG changes (15% vs. 0%), high blood pressure (21% vs 9%), diarrhea (79% vs. 40%), rash (71% vs. 49%), and abnormal liver tests (46% vs. 15%). Frankly, I'm surprised to see placebo associated with diarrhea in 40% and rash in half of the patients. In both groups, about 55% of patients reported nausea, and about 80% reported fatigue, underscoring the importance of a placebo (because many of us would be concerned about a drug that produces such significant diarrhea, rash, nausea, and fatigue, but perhaps less so if that's almost entirely just the background of the disease), and the problems caused by advanced lung cancer.

Whether you consider the side effects problematic or not, many people would find it worthwhile if the drug is effective. Unfortunately, there was no benefit to zactima as a maintenance treatment, with an equal progression-free survival, and a nearly significantly worse overall survival for the active drug compared with a placebo:

Zactima SCLC results

(Click on image to enlarge)

Although there aren't many positive things to say here, one interesting thing is that zactima may have been more effective in women, when they picked apart the data (they gave no details). With a small study, this kind of subgroup analysis is very limited, but it's interesting that the same subgroup trend has also been seen in advanced NSCLC (although we haven't covered this issue, which is still pretty preliminary, but provocative).

Zactima has looked better in other settings, and maintenance therapy has been more encouraging when chemo was used, so I wouldn't want to throw out the baby with the bathwater. But this trial at least pretty convincingly tells us that this is the wrong drug, wrong disease, and wrong time. We're still looking for just the right combination as a maintenance therapy in SCLC.

 

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