In prior posts I've described the idea of combining targeted agents like Tarceva and Avastin, but there are also some single agents that inhibit multiple targets within cancer cells. I've described sorafenib/nexavar in a prior post. Today I'll focus on another multi-targeted agent, known previously as ZD6474, and with a marketing name of Zactima. Similar to the combination of avastin and tarceva, this single oral drug is anti-angiogenic and also blocks EGFR. Although less well studied, it also blocks a protein called RET and can inhibit cell proliferation that way.

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To be more specific, whether Zactima has anti-EGFR activity depends on the dose: it is primarily an anti-angiogenic drug at lower doses, such as 100 mg per day. At higher doses starting around 300 mg, it inhibits EGFR as well.

Studies in test tube models show that Zactima can dose-dependently inhibit tumor cell growth from many different kinds of cancers. It also inhibits cancer development in some animal models. In people, the early dosing studies of Zactima alone showed that the dose-limiting side effects included diarrhea, rash, decreased blood pressure, fatigue, nausea, and decreased appetite, and several patients had asymptomatic changes on their EKG (called a "prolonged QT interval"). The upper limit dose was around 300-400 mg per day. It was encouraging to see that 4 of 9 patients in Japan with advanced NSCLC who were treated on this trial had an objective response (see abstract).

Other trials were done combining zactima with chemo. One interesting one first tested the safety of combining taxotere and zactima at either lower dose (100 mg) or higher dose (300 mg). The study then transitioned to a larger phase II trial testing taxotere, the standard chemo drug for second-line treatment of advanced NSCLC, alone or with either low-dose or higher-dose zactima:

This trial was run and presented by Dr. John Heymach, a friend and general great guy who recently moved from Dana Farber in Boston to MD Anderson in Houston (I always considered him brilliant until he toiled through another Boston winter to move to Houston last July!). He summarized findings (abstract here) for 127 patients assigned to one of those three groups and found that the response rate was lower for the people who received taxotere without any zactima (12%, which is fine for taxotere alone, not unusually low), but it was actually better with the lower dose (26%) than the higher dose (18%). The median (similar to an average) progression-free survival, or time before a patient's CT scans showed evidence of cancer getting worse, was also longer for both groups getting zactima with taxotere, but again was better for the low-dose group, for which the improvement from 12 to 18 weeks was statistically significant. Interestingly, the overall survival did not improve with zactima, and the group that received the higher dose with taxotere seemed to do clearly worse (7 months) than the low-dose taxotere/zactima or taxotere alone (median around 13 months for both). There was a dose-dependent increase in side effects with zactima; about 40% of patients at the lower dose experienced a rash and diarrhea, and it was about 50% of patients at the higher dose. The results are summarized in the table below:

It's interesting that the arm at the higher dose appeared to do worse with every measure than the arm at the lower dose of zactima. One theory is that because the anti-EGFR activity kicks in only at the higher dose, the potential antagonism of chemo and EGFR inhibitor effect (which I've described so often you may consider it my obsession) may be why the taxotere/zactima 300 mg arm does worse than not only the low dose arm, but chemo alone in terms of overall survival. However, this isn't a large trial, so I don't think it's possible to read too much into these preliminary findings.

Where to go from there? To a larger, phase III trial (with the catchy name AstraZeneca trial 0032), with 1240 advanced NSCLC patients being randomized after first-line treatment to taxotere alone or taxotere with zactima 100 mg daily. AstraZeneca is also starting a trial of the other commonly used second-line chemo, Alimta, with or without zactima, and I'll let people know more about that as the story develops. There are also trials of Zactima as a single agent, and I'll describe the available studies and current trials on that subject next.