Transcript:Jeffrey S. Weber, MD, PhD: Georgina, are you looking forward to seeing results of PD-1 inhibitors? Will that be the next best adjuvant therapy? Will that be better than ipilimumab?

Georgina Long, MD, PhD: I can’t answer the question as to whether or not it will be better than ipilimumab, but I am very excited to see the results for sure. We know that anti-PD-1 therapies work better than ipilimumab in stage 4 disease, but we can’t necessarily say the same thing will happen in stage 3. The way that anti-PD-1 therapies work is different than anti—CTLA-4. Anti–CTLA-4 therapy works in earlier stages in the immune cycle, and perhaps the PD-1 antibodies require tumor bulk to have their greatest activity. But what I’m suggesting is that we should wait for the data. I’m hopeful, and I’m pretty happy that we may see better results, but we just don’t know.

Jeffrey S. Weber, MD, PhD: Jason, what about ipilimumab-nivolumab? Is there a place for concurrent combination therapy as adjuvant therapy?

Jason J. Luke, MD: Well, that’s an open question that will be answered by an ongoing trial. I have to say that from my perspective, I’m not sure as to whether or not there really is a role there. I base that off of what we see in the metastatic setting where there is an improvement in survival, but that it is quite modest. So, if you then extrapolate that backwards, it is the amount of toxicity in the adjuvant setting we’re talking about in patients who don’t have cancer. Can that really be justified based on what we now know in the metastatic setting of a statistically significant but clinically questionable amount of difference in terms of overall survival?

Jeffrey S. Weber, MD, PhD: Which relates to a question that came up at the melanoma session. You have to have a different tolerance for toxicity in the adjuvant mode, when half of your patients may be cured just sitting there in your office, versus the metastatic mode, where if you don’t treat them, they’re going to die. So, I would agree. It’s a different scenario.

Georgina Long, MD, PhD: There’s one more point to make on that, though. In the metastatic setting, we did not see any deaths in the CheckMate-067 trial with the combination of ipilimumab and nivolumab. That’s presumably because we’re much more experienced in dealing with immunotherapy toxicities, whereas a very high rate of deaths with 10 mg/kg of ipilimumab may be a reflection of experience in that these trials were conducted earlier.

Jeffrey S. Weber, MD, PhD: Yes, I would agree. So, we also heard about the adjuvant bevacizumab trial. Mike, is there any reason why we should be thinking about angiogenesis inhibitors as adjuvant therapy? I was a little surprised to hear about this trial.

Michael A. Davies, MD, PhD: I don’t think so. What happened was that we got the final report with at least 5 years of follow-up on a randomized study on adjuvant bevacizumab versus just surveillance. The results showed that there was a statistically significant improvement in relapse-free survival, but not in distant metastases-free survival or overall survival. And so, I don’t think at this time, particularly with the data that we have with ipilimumab, that there’s really a role for that.

Jeffrey S. Weber, MD, PhD: This is the last point in thinking about locoregional therapy. Robert, do you routinely do any type of neoadjuvant therapy, whether it be immunotherapy or targeted therapy, in patients to render them resectable?

Robert H. I. Andtbacka, MD, CM: We do. We usually do this on clinical trials, if at all possible. We have a number of clinical trials that we have actually conducted internationally, one of them being with oncolytic viruses such as talimogene laherparepvec, also known as T-VEC. We had a randomized study in which patients received surgery upfront for resectable disease versus 3 months of T-VEC and then having surgery. The primary endpoint for this is recurrence-free survival. So, that study has closed, and we should have data coming out within the next year and a half, we hope. There are also other neoadjuvant studies that have been performed, both with immunotherapies and checkpoint inhibitors, including the PD-1 inhibitors and also BRAF/MEK inhibitor combinations, both in Australia as well as in the United States. I think that those studies have shown us that we can use neoadjuvant therapies to decrease the tumor burden prior to surgical resection, which, especially in patients who have borderline-resectable tumors, can be beneficial.

In addition, we also hope with these patients that we will decrease the risk of recurrence once we’ve used this to try to activate the immune system prior to surgical resection. Now, whether or not that will hold true in larger studies, we have to see—but that’s something that’s being investigated at the moment. In some patients, especially patients who have BRAF mutations or V600E and V600K mutations, if they have large, bulky disease, we often use that—not necessarily in a trial perspective, but we try to use it to decrease the tumor burden before we do the surgical resection. I think that is something that can be quite beneficial in these patients, because these are patients who are marginally resectable or unresectable, but we can potentially surgically resect them after it.

Jeffrey S. Weber, MD, PhD: You mentioned BRAF testing. That’s a nice segue into thinking about who we should be genetically profiling.

Transcript Edited to Clarity