Transcript:Robert H.I. Andtbacka, MD, CM: What about the other factor then? Many of these patients, if they’re 50 years old and they’re working, are coming in for infusions every 2 weeks or every 3 weeks—depending on how you do that—versus taking a pill at home. Does that impact on your decision to have one treatment versus the other in terms of practical reasons, Mike?

Michael A. Postow, MD: It’s a very important issue because the immune therapies that we’re talking about, ipilimumab and nivolumab in combination, or single-agent PD-1, these are all intravenous treatments. And all the BRAF/MEK combinations are oral pills. So, one would think that perhaps it might be easier to take pills at home. And I think, initially, perhaps that may be the case: that the patients get the pills, they take it at home, and they come in to see how they’re doing. That may factor into it a little bit. But the other thing that we need to keep in mind, at least with combination ipilimumab and nivolumab, is a lot of patients do discontinue treatment after just a few infusions after achieving response, particularly in the setting of toxicity. And after that response is achieved and the side effects are managed, many of those patients are not on ongoing treatment in the longer term.

And so, yes, it is more involvement with the intravenous immune therapies up front for the first couple of months or, at least, certainly the first few weeks of coming in every 3 weeks. But if they’ve had toxicity that precludes ongoing immune therapy and they’ve achieved a response, once you’ve managed their toxicity and they’re feeling well and they’re in response, they may just be coming back every 3 months getting scans. And those patients continue to work. You’ve gotten them through that acute period, and there is something to be said for that long-term PFS that you can get from that approach with very short durations of treatment in some of these patients.

Robert H.I. Andtbacka, MD, CM: I guess we really don’t have data on that long-term PFS for these patients yet at this point in time.

Michael A. Postow, MD: We are working on that. We have seen that clinically, but that’s exactly right: we don’t exactly have the specific data. We do know that in some of the published randomized trials, including the phase II CheckMate-069 study, only about 40% of patients went on to get any dose of nivolumab maintenance after that first 3-month induction period of combination ipilimumab and nivolumab. So, more than half the patients aren’t going on to the maintenance phase. So, 60% or so of patients are only getting treatment for 3 months. And yes, that is a more involved 3-month period and maybe another month or 2 of side effect management, subsequently. But if you think about the long time that many of those patients would be off treatment, that is also something to consider. It’s not quite so simple, but I do agree that initially, it is easier to start taking pills than coming back for treatment. But we have to think about this in a longer-term setting because, fortunately, we have a lot of patients who are doing well longer term.

Michael A. Davies, MD, PhD: So, just coming back to this question about, again: can we actually figure out for our patient who presents, is there something that tells us that it’s right to start with targeted therapy or right to start with immune therapy? What we’re now observing, as we look at trials and look at clinical features, is this question about: is there overlap of clinical features of patients who do well with targeted therapy, patients who do well with immune therapy? What’s also going on is there are many investigations of molecular and immune markers and their correlations with outcomes. What’s really interesting is that some of the markers that have been looked at with immune therapy, such as mutation burden, they seem to be associated with a higher chance of responding to immune therapy or responding longer. Or as Dr. Ribas was talking about, we are seeing evidence of an anti-tumor immune response with a T-cell infiltration.

Interestingly, there are now early data that those same features also correlate with better outcomes with targeted therapies as well. Again, this overlap of which patients do and don’t benefit may not only be for clinical features, but may actually be for molecular and immune features as well. As we’re moving forward and doing clinical trials and doing research, we’re really starting to take more comprehensive approaches for each of these patients and each of these therapeutic modalities. It’s important to look at both the molecular biology and the immunology when we study both targeted therapies and immune therapies.

Robert H.I. Andtbacka, MD, CM: Mike, I think that those are very important topics for us to understand as we move forward with this, to try to really find the best treatment for the patients with the highest degree of response and the durability of the response with the least amount of toxicity for the patient, though. But practically, right now though, those studies may not be available in the community-at-large. So, are the clinical features that you would look at, in terms of if this patient came in, if they had fatigue, they had bone pain, and they also had what appeared to be very rapidly progressing disease, are you then more likely to choose one treatment over the other and how do you assess that?

Michael A. Davies, MD, PhD: It is the great question. It is that debate of whether the clearest emphasis is on being able to get the disease under control initially. I think that in a BRAF-mutant patient, your highest chance of getting a response is with targeted therapy. It’s for those patients who present with symptomatic disease with threatened organs. The other place that I particularly think about the targeted therapies is when we see patients with brain metastases, where you don’t really have a lot of room for tumor progression before you start getting into very serious problems. We’re just learning now about how well immunotherapy can work in patients with brain metastases. We’ve had data with ipilimumab that showed it actually worked relatively well as long as the patients didn’t require steroids to control cerebral edema. The data that we have with single-agent anti—PD-1 therapy showed that patients with brain metastases could respond. But it was only tested in patients who didn’t require steroids. Many of our patients are requiring steroids to control cerebral edema for brain metastases. In those situations, I think that targeted therapy would then be something I would go to before immune therapy. But, again, brain metastases are also a place where we have a multidisciplinary evaluation of the appropriate initial therapy because there are also options with radiation therapy as well.

Robert H.I. Andtbacka, MD, CM: How do you decide between those then? Are there certain parameters where you would decide for a patient that you should do radiation first? Or do you have some time, some runway for those patients to do either anti—PD-1 therapy or BRAF/MEK combination if they have a mutation? How do you decide that practically?

Michael A. Davies, MD, PhD: Coming back to Tony’s point, we’re all going with the best data that we have. As I think Dr. Postow said, it is really a gestalt. Certainly, I think for a patient who presents with brain metastasis in this setting of widespread clinically significant extracranial disease that’s causing symptoms, the best way to address both of those problems quickly, at the same time, is starting with the targeted therapy. Because, again, it has a very high chance of controlling the brain metastases as well as the extracranial disease. It is an interesting question for those patients with lower burden of CNS involvement of whether or not it’s right to go with that approach.

Transcript Edited for Clarity