Refining the Management of Advanced Melanoma - Episode 6
Transcript:Jeffrey S. Weber, MD, PhD: Let’s turn to Jason, because you’ve had a long interest in biomarkers for the efficacy of immunotherapy. So, the question is, do we truly have robust, useful, clinically important biomarkers for the efficacy of any immunotherapy? Obviously, BRAF mutation would be a predictive biomarker. I think we would all agree that we would not treat a patient who’s BRAF wild-type with BRAF/MEK inhibition, but with immunotherapy, it’s a different scenario. Do we have such biomarkers?
Jason J. Luke, MD: The answer is “sort of.” We do have biomarkers that can inform the decision, and I think that there’s going to be a good discussion around what their clinical utility is. I’ll tell you that in my practice, the one immune biomarker that’s readily available is PD-L1 immunohistochemistry, and yet I almost essentially never order it. The reason for that is, when I look at the data of our clinically available therapeutics and CTLA-4 antibodies and PD-1 antibodies, we have multiple ways to do it. You can do one first and then the other, or do them both at the same time or vice versa.
The question is, does doing PD-L1 immunohistochemistry strongly inform that decision-making process? And, in my practice, I find that it does not. So, there’s a high degree of response to PD-1 monotherapy. It’s higher with the combination, but it’s very clear from your trial, CheckMate-064, that there’s substantial benefit to sequencing the drugs. And it’s not entirely clear to me that there is actually any less benefit in doing that than there is in giving the 2 drugs together. It’s an open question, but the data sets that we have at least allow that argument to be entertained.
So, in that context, when I think about which approach I’m going to take, I really look at the patient and I say to myself, “What’s optimal for this patient?” If I think that they’re not going to have the chance to get both drugs, I’m going to give them both drugs together no matter what the PD-L1 status is. Otherwise, I’m going to start with a PD-1 antibody and follow it with ipilimumab—again, not necessarily informed by the PD-L1 immunohistochemistry. So, at the current time for melanoma, I do not use it. I do think it’s important to think about a future landscape where we might have more drugs, and perhaps then we are going to need more useful biomarkers to inform that landscape, although we’re not quite there yet. But I have a sense that other people may use PD-L1 testing slightly differently.
Jeffrey S. Weber, MD, PhD: Mike, does PD-L1 staining of the tumor drive your decision as to how and when to treat in any way?
Michael A. Davies, MD, PhD: Yes. And I have to say, this is something that we talk about amongst ourselves, I think, at all meetings—whether or not institutions offer this, are we using it? I have to say that for all the reasons that PD-L1 staining shouldn’t be helpful, I think it’s really interesting that, consistently across trials, we do see higher response rates with single-agent PD-1 inhibitors in patients who are positive. And in looking at the recently reported data from CheckMate-067 at the AACR Annual Meeting—despite this idea that sequentially, they should potentially work as well as concurrently—when you look at the overall survival data for patients who were PD-L1-positive, where the curves were completely overlapping with the PD-L1-negative population, even though there was the availability of sequential therapy, there was an 11% difference in overall survival at 2 years in the PD-L1-negative population. I personally am ordering PD-L1 testing on my patients. I’m not using it as the only criterion to pick which therapy, but I do have to say in terms of that being a complicated decision, I actually am incorporating that into how I think about using single therapy versus combination therapy.
Jeffrey S. Weber, MD, PhD: Georgina, do you order it routinely?
Georgina Long, MD, PhD: I don’t order it routinely, but I do consider it and call my pathologist when I’ve got borderline cases. So, very much like Jason, if I have a patient who has high kinetics of disease where you need quick control, that’s the advantage of the combination of the 2 checkpoint inhibitors together. It’s a pretty straightforward decision, because I need to get control quickly. I don’t have time to sequence. Also, we don’t know the answer to sequencing—we really don’t. There are trials that are being conducted. So, anti—PD-1 first if you progress and adding anti–CTLA-4.
However, for the borderline cases, one example is a patient who’s in their early to mid-70s, with no comorbidities but lives 2.5 to 3 hours away from the center. They have quite rapidly progressive disease, but I’m just not sure whether or not we should go for the ipilimumab/PD-1, because they have to be able to report toxicity, get treatment urgently, and I would like to manage the toxicity. I don’t like peripheral hospitals not connected to me managing it. So, in that case, I will call my pathologist and say, “Hey, tell me what the PD-L1 status is, but more than that—tell me about the T cells, the CD8-positive T cells.” And this is a real live case. My pathologist said, “Look, they’ve actually got a moderate amount to high amount of TILs, and they’ve got some PD-L1 there.” So, for that patient, I said, “Let’s go with the PD-1 alone.” And sure enough, they had a very rapid response. They were one of those few who had a rapid response to the PD-1. But it’s only in those borderline cases where I’m trying to find a reason to give the extra toxicity.
Jeffrey S. Weber, MD, PhD: And lastly, Robert, do you think that PD-L1 staining should be done in every melanoma patient?
Robert H.I. Andtbacka, MD, CM: I don’t think we have enough data to justify that and also justify the cost for it, especially since we know that even if you’re PD-L1-negative, you can have a very good response to the anti—PD-1 therapy. So, at this point in time, the answer is no. The other thing—I’m bringing this back to the surgical perspective—is that we talk about PD-L1 testing. But what is not necessarily talked about as much is, where do you get that from? Is that from the primary tumor? Is it from a metastases? And if it is from the metastases, when was this taken? We know this is an inducible factor. We know this can change over time, so I think that there’s a lot of uncertainty still about where it is taken from and how it will then determine today what we will do in terms of anti–PD-1 therapy—either monotherapy or combination. Additionally, I think that we still have the challenge that there are a number of antibodies being used, and how do we then reconcile those differences?
We have to look at the percentage of the cutoff that we use. Is it really feasible to say that something is 1% staining versus 5% staining? How do we determine those differences? So, I think the way I look at the PD-L1 testing from that perspective is that either there is staining or there’s no staining. But to grade this on a continuous scale is quite challenging, and also, where is the staining? Is it in the tumor? Is it in the immune cells? So, I think there are still a number of unanswered questions in melanoma to be addressed for us to order this routinely and use it to determine the therapy for our patients.
Jeffrey S. Weber, MD, PhD: I think one of the most telling pieces of data that I’ve seen was shown yesterday. It was perhaps Kurt Schalper from Yale, who had a biomarker talk where he showed a picture from a recent publication by his colleague, David Rimm. There was a large tumor immunohistochemically stained, and they had 1 portion on the top and 1 portion in the bottom, and they cut those out and did immunohistochemistry for PD-L1. One was absolutely negative and 1 was absolutely 3 or more positive, suggesting that even in the same tumor, you might get disparate results. So, that to me is a bit of a problem.
Transcript Edited for Clarity