Merrick I Ross, MD: So I’m going to implore the treating clinicians to not jump to resect this disease when a patient recurs after receiving adjuvant therapy. They need to be put on neoadjuvant studies.

Axel Hauschild, MD: That’s a good point.

Merrick I Ross, MD: We shouldn’t be operating on these patients and just saying, “OK, let’s give them an adjuvant therapy even though we have no idea if it’s going to work or not.” That’s a data-free zone. These patients need to be put on a neoadjuvant trial, so you can see what therapies are actually effective in this patient population. So that would be my kind of advertisement for…

Axel Hauschild, MD: But Merrick, you’re a world-known expert not only in surgery but also in translational research. Do you think that the community surgeon is following your guidance and your recommendations?

Merrick I Ross, MD: Yes, but that’s why we’re having this discussion, right?

Axel Hauschild, MD: No, I completely agree with you. This is a perfect scenario for neoadjuvant treatment. Maybe the neoadjuvant treatments are identifying the right candidate for the next line of treatment because you can see that immediately after 4 weeks of treatment, or a maximum of 8 or 12 weeks of treatment, if the patient is responding in the lymph node or in the skin metastases.

So coming to the neoadjuvant arena, there is exciting data from 3 clinical trials out there. One was presented here at ESMO [European Society for Medical Oncology]. It’s a trial on neoadjuvant ipilimumab and nivolumab. Is that exciting data, Caroline?

Caroline Robert, MD, PhD: I think it is. Actually, the first generation of this neoadjuvant trial has just been published this month. It’s online in Nature Medicine. They initially tried the usual regimen of ipilimumab-nivolumab in the adjuvant setting in the first so-called OpACIN trial, and it was quite promising, in terms of a pathologic complete response. It was not exactly what they expected in terms of the transactional research, but still, the neoadjuvant versus the adjuvant gave rise to more clones specific for the tumor in the blood.

But it was highly toxic. It was incredibly toxic. We saw 90% of this very small group of patients with grade 3 or above adverse events that were very severe. So it was not feasible because of the toxicity. But what we heard at this meeting was about another trial called OpACIN-neo. This trial looked at 3 different regimens. One of them is with a reduced dose of ipilimumab of 1 mg instead of 3 mg. And there the toxicity is much better. It’s tolerable. Still, there is this very interesting high rate of pathologic complete response. We don’t know yet if it’s going to be a very good surrogate marker for survival, but it’s extremely encouraging. So yes, this is very exciting data, I would say. I would like to really acknowledge the fact that this team and the others who did this work on the neoadjuvant trial did very sophisticated and very smart immuno-monitoring, and it’s going to be very helpful.

Axel Hauschild, MD: So you mentioned the example, Merrick, of a patient who has received a PD-1 [programmed cell death protein 1] antibody in the adjuvant setting. This patient shows a progressive disease with some growth of lymph node metastases. That would be a good scenario to test dabrafenib and trametinib, in a neoadjuvant setting, and there are data out there on this. Would you like to summarize the current data on neoadjuvant treatment? If the patient is responding either with a complete response pathologically confirmed or with a partial response, is this the ideal candidate to continue after the full resection with an adjuvant treatment?

Merrick I Ross, MD: It’s important to recognize the data that we have available are mature in the neoadjuvant setting. These are all pretty much used for first-line therapy. So these are not patients who have had adjuvant therapy and then relapsed and then were eligible. It’s important to know that the data that are available now would be for the treatment-naive patients. In our trial, they got neoadjuvant therapy for 8 weeks of dabrafenib and trametinib, then had surgery and then had adjuvant therapy. Was it for a year, Mike?

Michael A Davies, MD, PhD: They completed a year of treatment, yes.

Merrick I Ross, MD: So they completed a whole year of therapy for dabrafenib and trametinib depending on the toxicity. A good surrogate marker for outcome has been whether or not the patients received a near complete response or a complete pathologic response. The interesting thing is that our imaging studies probably underestimated the extent of our pathologic complete response. So the patient may have what appears to be residual clinical disease, either on physical exam or on imaging studies. But in many of those cases, the patient actually undergoes a complete pathologic response. So that’s a great marker to show that the therapy is working. Whether they need the additional therapy is a different question. Based on targeted therapies, the mechanisms of response may be different from immunotherapy. Patients who are receiving immunotherapy may not need a whole year of therapy, but we don’t really understand the difference in the mechanisms. So I think for now we would stick to the concept of having the patient receive a year of therapy if they can tolerate it. So, Mike, maybe you have a comment on that.

Michael A Davies, MD, PhD: The pathologic complete-response rate in that trial was 58%, which is much higher than the complete-response rate we see in stage IV patients. And at the time that we published the results, 4 of those patients received neoadjuvant therapy, none of the patients who had achieved a pathologic CR had developed distant metastatic disease. The only distant relapse that happened was in patients who hadn’t achieved a pathologic CR.

So again, it’s clear that adjuvant dabrafenib and trametinib can provide tremendous clinical benefit. The idea that after 8 weeks of therapy you could potentially identify the patients who would continue to do well with this treatment is potentially the paradigm shift that neoadjuvant therapy would offer.

Caroline Robert, MD, PhD: And during this trial you were obliged to stop early because there were 7 patients with no new adjuvant.…At 18 months, I think they were all dead? The 14 patients with neoadjuvant—10 of them were alive at 18 months.

Michael A Davies, MD, PhD: And we had to stop because there was a 60-fold improvement in relapse-free survival with the neoadjuvant...

Merrick I Ross, MD: It wasn’t death. It was relapse-free survival.

Jason J Luke, MD, FACP: Just a quick comment on the practicality. One of the things that comes up is they’re making this tremendous progress in melanoma and in other cancers as well. Many drugs that are coming forward have substantial financial complications as well, especially for other health systems outside the United States.

Axel Hauschild, MD: We call it financial toxicity.

Jason J Luke, MD, FACP: I want to emphasize how important these kinds of studies are to emphasize that there are populations of patients that we can cure. Perhaps they only need shorter windows of therapy. If we could start moving our research toward that, it would actually help with these questions in the metastatic setting and all over, in terms of optimal use of these agents that won’t kill the health system.

Michael A Davies, MD, PhD: And to Caroline’s point, regarding the original OpACIN study, we had a parallel study at [The University of Texas] MD Anderson Cancer Center that randomized neoadjuvant nivolumab versus ipilimumab-nivolumab. As you said, many patients had very significant toxicity and, therefore, received a very short window of treatment—1 or 2 doses of the ipilimumab-nivolumab combination. The interesting part is that in the data that have been presented, none of those patients who achieved response, even with those 2, or 2 doses, has relapsed to this point. And so this question of whether you could do very short-term therapy, even with toxic regimens, may be feasible.

Axel Hauschild, MD: I just have a quick comment before we move to the field of metastatic stage IV disease. There was a third trial that was released at AACR [American Association for Cancer Research] 2018 on adjuvant pembrolizumab. Interestingly, there was 1 infusion of adjuvant pembrolizumab.

Merrick I Ross, MD: Thirty percent.

Michael A Davies, MD, PhD: Neoadjuvant.

Axel Hauschild, MD: Neoadjuvant pembrolizumab leading to 30% of complete or almost-complete responses with less than 10% of viable tumor cells with pathological responses. I think that is also very exciting. It’s just 1 shot. After 3 weeks, the resection was done. So that brings us back to Merrick’s idea of a surgeon who is interested in systemic treatment first, right?

Merrick I Ross, MD: So it’s really interesting. In that trial, the timeline was short. They had surgery after 1 cycle. None of the patients had significant progression to the point where they couldn’t have surgery. In our trial of single-agent nivolumab versus the combination checkpoint-blocking agent, with the single agent, we did have a couple of patients who progressed beyond the point of having surgery. But then again, the therapy was longer. We did 9 or 12 weeks, Mike? Was it 9 weeks?

Michael A Davies, MD, PhD: Yes, 8 or 9 weeks.

Merrick I Ross, MD: So there was more time for a patient to progress. Biologically, you were finding the bad actors because you waited long enough for them to potentially have a recurrence. In the other trial, I think from the University of Pennsylvania, there was only 1 cycle, and they had surgery like after the 1 cycle. So in 3 weeks they had surgery.

Transcript Edited for Clarity