DR GOVINDAN: I was involved in the study for a very simple reason. This is not a genomic study. This is not a scientifically appealing study, but it actually asks a very practical question. You use paclitaxel/carbo/bev in practice. The doctors are very comfortable using pemetrexed and carboplatin. So can we compare the two? So it’s a very straightforward, 2 regimens, commonly used, and asking, can we spare the patients from the side effects of bevacizumab? Can we use that?
That I agree. The endpoint is you could have said simply progression-free survival, but the decision was made to look at this composite endpoint. So this is where it gets a little bit complicated. So the primary endpoint is not your straightforward progression-free survival. It’s a Grade IV progression-free survival. What does it mean? Your progression is defined if you have one or the other, if you either have Grade IV toxicities, adverse events, not anything less than that, or disease progression — obviously, whichever comes first. So that’s as simple as that.
You can quibble with that kind of a thing, but it’s kind of loaded toward a favorable regimen that probably also has a better efficacy. But the important point to highlight here is that this is not a noninferiority study. This is a superiority study. So going on the hypothesis that pemetrexed/carboplatin would be superior to paclitaxel/carbo/bev in terms of the Grade IV PFS, that is, either Grade IV toxicities or progression-free survival. So that’s the outline of the study.
Four hundred fifty patients or so were screened, and essentially 360 or 370 patients got enrolled in the study. And the bottom line is that the study did not meet the primary endpoint of showing that pem/carbo is better in terms of Grade IV PFS, than paclitaxel/carboplatin and bevacizumab. And, in fact, if you look at the numbers, the Grade IV PFS as was defined was about 4.5 months with pem/carbo, 5.5 months with paclitaxel/carbo/bevacizumab. Overall survival, once again, statistically not different, but the pemetrexed/carboplatin was about 10 and a half months, paclitaxel/carbo/bev about 11 and a half months. So numerically superior with the ECOG regimen, paclitaxel/carbo/bev. So this study did not meet the primary endpoint, but you do get a sense of what the patients got when you randomized them in terms of progression-free survival and overall survival. So for those physicians who are using pemetrexed and carbo over paclitaxel/carbo/bev, this is probably the first comparison, head to head, of what happens when you randomize a group of patients.
Based on these results, could you say that you should use pem/carbo or paclitaxel/carbo/bev? The answer is no. If you really don’t want to use bevacizumab for one reason or the other, you want to get a sense of what pem/carbo does in this population, this is the only piece of data that’s out there.
DR LOVE: And if the patient, let’s say — we keep talking about the astute patient — says to you, “Okay. Is the benefit that I might receive from these 2 regimens, the carbo/paclitaxel/bev versus carbo/pem, is the benefit going to be the same?”
DR GOVINDAN: So that’s a technical answer. That is a practical answer. Technically correct answer is that the study was designed to show superiority in terms of PFS. When you don’t show superiority, it doesn’t mean they are equivalent or — you cannot say that. In terms of practical things, the benefit from bevacizumab in these patients is modest. That’s the best you can say from all the studies, and that stands. So in other words, looking at the data, I don’t feel bad in giving somebody pem/carbo alone, if I decide not to give bevacizumab. That’s the take-home message.
DR LOVE: That was actually the initial thought I had, was it was a little bit comforting to people who are not bev eligible, that there’s, in fact, a regimen. But then what I saw is people kind of taking the thought, “Even though” — it’s funny because it was a negative trial, and yet looking at this as potentially equivalent and “Do I really need to give bev?” John, how did you see this?
DR HEYMACH: Yes. I think factually, everything that Govindan said, I have no choice but to agree with. But taking a bit more of a cynical eye to this, while there is a practical nature, one expects that this trial was designed to show some way that carboplatin and pemetrexed could be found to be superior to the ECOG 4599 regimen. And I think the expectation was the toxicity would end up being favorable. And if you actually look at it, really, I think some people may be surprised that in terms of overall toxicity, there isn’t a clear advantage to my eye with the pemetrexed regimen.
I think there’s an expectation, for example, in the elderly study looking above age 75, that pemetrexed would be a gentler regimen. But consistently we’re seeing higher anemia, higher thrombocytopenia. We’re seeing more fatigue, typically, in those regimens. Now, clearly we have alopecia and neuropathy and a little higher F&N in the paclitaxel-containing regimens. But one of the take-homes here actually may have been the lack of toxicity advantage for the pemetrexed regimen here, that it was clearly, I think, the reason the study was done, if one took a more cynical view.
DR GOVINDAN: I couldn’t — I agree with —
DR SOCINSKI: Yes, I — actually, I agree with many of the points John made. And I don’t think we should put too much emphasis on the secondary endpoints.
DR GOVINDAN: Right.
DR SOCINSKI: This was a really underpowered trial, only 360 patients. You can’t draw conclusions about PFS and OS and all those sorts of things. So I think this was more of a plot to show the different toxicity that frankly failed. And it really — I actually don’t know how this should influence your practice and, in fact, I think it shouldn’t influence your practice in any way.