What Is Clinically Meaningful?

Transcript:Mark A. Socinski, MD: One of the things—and I have been involved in the necitumumab trials and we’ve had the same criticism with these trials—is the magnitude of the benefit. We have ASCO defining what a clinically meaningful benefit is, and both ramucirumab and necitumumab didn’t quite make that milestone, if you will. I like Corey Langer’s statement that these should be aspirations, not guidelines. But, what’s your perspective on the magnitude of the benefit—I also want to get Roy’s perspective in this setting—and just how does this fit in in the lung cancer landscape?

Edward Garon, MD: Well, first—and I know, Roy, you were involved with those guidelines—nivolumab and pembrolizumab, at least nivolumab in its approved indication, did not reach the ASCO goals. Although in all fairness, in the second-line they did, whereas these goals were in a frontline setting. These have not been goals that have been easy to reach. That being said, it has been a criticism that people have had, and I understand that criticism. We want to have tremendous benefit with a new drug that’s approved, and there’s obviously an expense issue as well, which is that these are costly agents. And so, that plays in as well. I think it’s very hard to indicate what a meaningful survival benefit is. I think you need to take things on their totality. What is the additional toxicity? As you pointed out, there weren’t any new terrible safety toxicities. Things like neutropenia were certainly increased, but, again, I think one has to take it on its totality in terms of what are the costs and what are the benefits of the agent.

The other thing that I’ll put in, which does get to something that Roy mentioned earlier about biomarkers, one has to remember that the BR.21 study—which showed a benefit to erlotinib and made erlotinib available—had very similar survival benefit to what was seen with both of these agents. Now, in retrospect, we consider erlotinib to be a very significant drug in the treatment landscape in lung cancer, although it is because we—as a lung cancer community, largely through Tony Mok’s IPASS study—were able to clearly identify a biomarker, and we’re able to select the appropriate populations. And, so certainly, there continues to be hope that there will be something that can be done with that. But, in the end, I think it is helpful for practitioners to have these options and to discuss then with their patients, and to discuss the benefits and the risks of any agent that we’d be looking at.

Mark A. Socinski, MD: Roy, your perspective on the clinically meaningful benefit?

Roy S. Herbst, MD, PhD: About 2, 3 years ago now we sat down at ASCO and looked at, in a number of tumor types—that was done for GI cancers as well—and lung and a few others, what would be a hazard ratio and what would be considered clinically meaningful. And you’re right, Eddy, that was in the frontline setting. And I believe we had a hazard ratio of about 0.75 after looking at a lot of data. Again, you have to look at every trial on its merit. It’s the toxicity in relation to that value that’s going to make a difference. And, again, are there subsets that benefit more. I think as far as the ramucirumab goes, it was a second-line trial. I was impressed. The fact that something could be added to docetaxel, between the three of us…How many trials have we looked at where we couldn’t add docetaxel, and, in fact, that this drug could be added to docetaxel both in non-squamous and squamous cell cancer? So, that I think is good. The hazard ratio, is it a home run? No. Is it incremental progress? Yes. I think the most important thing is we talk about immunotherapy. It’s great, but still in lung cancer, only for a quarter of the patients. What about the rest? This gave us a drug that’s now available to us, those patients who don’t have other options, and it’s a little bit better than the chemotherapy alone. It gives us a drug to now figure out how to use it better.

And, I think one thing we have to do now is as we get more experience with the drug and people are in practice, how can we add this to the immunotherapy, how can we add this to other regimens, how can we develop a biomarker? The hardest thing about the angiogenesis has been that we’re really indirect targeting here. Although, because this is VEGF—mostly on the endothelial cells—certain tumor types do have VEGF receptor on the tumor cells as well, but it works a little bit. We can figure out how to make it work more. We can look at combinations, but we need these small steps and the big steps. Hazard ratio, what was it, 0.84?

Mark A. Socinski, MD: 0.86.

Roy S. Herbst, MD, PhD: 0.86. It’s, again, across the population, but if it’s you, or me, or your family, you want to have something to offer. It’s tough, and we’re in tough times now economically. So, we have to look at all that, but if there’s nothing else left to offer, I think this is reasonable.

Mark A. Socinski, MD: Eddy, I wanted to ask you, there were I think, what, 14% of people who had prior bevacizumab and that didn’t seem to matter. What’s that telling us about these two agents?

Edward Garon, MD: So, as you point out, it was a small subset, and so it’s hard to make definitive conclusions. But what it would indicate is that there’s clearly no data that would say that the benefits are not going to extend to that group of people. Although, one also—based on the data available—can’t definitively say that the benefits would extend to them either. Of course, whenever one looks at a subset analysis in the study, you’re going to get a subset or a smaller group. It makes it more difficult to definitively state that you’re going to have a benefit, but clearly that was a group that was included. And there’s no data to say that that group would not benefit. You’ve already heard much of the data from the GI cancers where continuing this is just part of their established armamentarium of therapy.

Transcript Edited for Clarity