This post will be a little different from most of the expert posts on GRACE. I’m not an expert. I’m not an oncologist. In fact, I’m not a physician. I’m a patient with a social science background, and I’ve followed the work on the drug I’m writing about for some time.
I’ve been interested in Zactima (vandetanib) for two reasons. First, I thought the early trials looked promising, and it might eventually be a drug that could help me. Second (and this is going to drive Dr. West crazy), the four large phase III trials of Zactima have really catchy acronyms (see below).
I’m no expert on the biology, but it appears that Zactima is a cross between Tarceva (erlotinib) and Avastin (bevacizumab). It is taken as a pill, once a day at home (also appealing to me). Phase II trials were promising enough that Zactima progressed to four phase III trials (large, double-blind and randomized trials that attempt to compare it with other established treatments). Let’s look at those.
ZEST: This trial was for patients who had had one or two previous lines of chemotherapy, and it included all histologies of non-small cell. Patients were randomized between receiving the approved treatment of Tarceva at its standard dose of 150 mg. per day and receiving Zactima at 300 mg. per day (which appears to be the standard dose coming out of earlier trials). The key results are that there was no difference in progression-free survival (the designated primary endpoint of the study) in the two arms. However, side effects were somewhat more numerous in the Zactima arm than in the Tarceva arm.
So is this good news or bad news? On the one hand, Zactima performed as well as an established treatment that is considered something of a breakthrough for many patients. Since Tarceva is one of three approved second-line treatments (and just one of two for squamous cell), being as good as Tarceva is not bad.
On the other hand, if Zactima helps the same patients as Tarceva but with greater side effects, one would always prefer to do Tarceva first (and the question then arises as to whether Zactima benefits people who have already had Tarceva; see below). Thus, the question of who benefits from Zactima is very important. Thus far, no identifiable subgroups have been shown to benefit from Zactima more than other groups.
I would argue that this in itself supports the use of Zactima. First, since we know that Tarceva is more beneficial to some subgroups (never-smokers, people with adenocarcinoma, Asians, and, arguably, women) than to others, and even more so that Tarceva is likely to provide its greatest benefit to those with a particular type of mutation, we know that the group getting response from Tarceva and the group getting response from Zactima are not the same. Further, since progression-free survival (as a median) is the same for both Zactima and Tarceva, and since we can identify groups where it is greater than the median for Tarceva, that implies that for those not in those groups, Zactima is actually a more effective choice. One could envision a protocol where patients are routinely tested for the EGFR mutation. Those with the mutation would be given Tarceva; those without it would get Zactima. Mathematically, that protocol should produce a higher median progression-free survival than just giving everyone Tarceva.
Again, however, the key question remains what happens if you give people Tarceva first and then Zactima. More on that when we look at the ZEPHYR study below.
ZEAL: This trial was for second-line patients. Half received Alimta (pemetrexed) every three weeks (the standard interval) at the standard dose, plus a placebo. The other half received Alimta plus 100 mg. per day of Zactima. Presumably, the lower dose was because it was being offered in combination with chemotherapy. Again, the primary endpoint of the study was progression-free survival. However, overall survival and response rate were also compared. In both progression-free survival and overall survival, there was a trend toward better results for those who were getting both Alimta and Zactima. However, the results did not meet the standard for statistical significance. In most research, researchers only make claims when they are 95% sure that they are not due to random differences. In this instance, the researchers could only conclude with 90% certainty that Alimta/Zactima led to longer progression-free survival than Alimta/placebo, and they were only 80% sure that it led to longer overall survival. Two other items are worthy of note. First, the Alimta/Zactima combination produced a 19% response rate versus 8% for Alimta/placebo (the latter is in line with other Alimta studies). I can’t tell from the abstract whether this difference is statistically significant. Secondly, the Alimta/Zactima combo, while increasing some side effects (rash, diarrhea, and hypertension), actually seemed to reduce some other side effects (including anemia, nausea, and vomiting). More on this study in a minute.
ZODIAC: This one is similar to ZEAL, except that it employed a different approved second-line drug, along with Zactima. This one used Taxotere (docetaxel) at its normal dose and interval, together with 100 mg. per day of Zactima, versus Taxotere plus placebo. The results here were pretty similar to the results in the ZEAL trial, with one (perhaps) important difference. Again, the Zactima plus chemo arm did better than the placebo plus chemo arm in progression-free survival, overall survival, and response rate. This time, the difference in progression-free survival was statistically significant. Again, the advantage in overall survival did not reach statistical significance (the researchers could again only be 80% sure that those in the Zactima arm survived longer than those in the placebo arm). The difference in response rate was 17% (Taxotere plus Zactima) versus 10% (Taxotere plus placebo). Again, I’m unclear as to whether the response rate difference was statistically significant. Again, adding Zactima increased some side effects and decreased others; the breakdown on which was which was similar to that in ZEAL.
So what are we to make of the ZEAL and ZODIAC trials? I think the conclusion to be reached is that Zactima is fairly promising when added to standard second-line chemotherapy. When used in combination with either Alimta or Taxotere, it shows a trend toward increasing overall survival (while in neither case can we conclude with 95% certainty that it increases overall survival). In one case, it shows a statistically significant advantage in progression-free survival, and, in the other, it shows a trend in that direction. And, finally, it shows (in both cases) an increase in response rate, though again I’m not sure about statistical significance. It also shows a change in the side effect profile that appears to be basically neutral (increasing some side effects, decreasing others). Finally, it’s worthy of note that the dose of Zactima used (100 mg.) in these two trials was much less than the standard monotherapy dose (300 mg.). Perhaps increasing the dose of Zactima used in these combinations would strengthen the results (or perhaps it would just increase side effects).
While some (mostly careful oncologists) may say that none of the three studies have shown a statistically significant increase in overall survival, I (perhaps because I’m a metastatic lung cancer patient, which basically means I’m an impatient patient) would view the evidence differently, I would conclude that:
Zactima appears to be as effective as Tarceva (a well-established treatment), and the group of patients it appears to help most does not overlap totally with the group of patients that Tarceva helps most (the ZEST trial).
Concurrent Zactima appears to improve the results of two different kinds of second-line chemotherapy. While most of the individual results do not pass muster at the strict altar of statistical significance, the chances of getting all the positive trends that appear in the ZEAL and ZODIAC trials (without an increase in overall side effects) are less than 5% (and thus, combined, we can say with 95% certainty that Zactima appears to potentiate second-line chemotherapy).
This is particularly striking when we remember that most experts, including Dr. West, have concluded that adding Tarceva to standard chemotherapy is a bad idea.
Thus, if I were the FDA, I would approve Zactima immediately, as it provides another bullet in the all-too-small arsenal against non-small cell lung cancer. I’m not sure how often it will be used, but I do know of several people who have written to Dr. West on GRACE about themselves or loved ones who are still doing reasonably well but are out of approved treatments. As someone who could be in that boat as early as my next scan, I’m more than satisfied that the weight of the evidence supports Zactima.
That said, all of this is likely to be settled fairly easily by the remaining phase III trial of Zactima, the ZEPHYR trial, the results of which are due in the second half of this year. That trial compares Zactima plus best supportive care with placebo plus best supportive care for patients who have already progressed on Tarceva (a very similar design to the study that cleared the way for Tarceva). If that study shows a statistically significant survival benefit, it will be clear that Zactima is not just Tarceva with more side effects. In the meantime, I would argue that the overall weight of the evidence (and the relative lack of alternatives) should give the presumption to Zactima unless and until proven otherwise.
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