Dr. Omid Hamid:
Welcome to The ASCO Post Roundtable Series on Updates in Melanoma. I'm Dr. Omid Hamid, Chief of Translational Research and Immunooncology at The Angeles Clinic and Research Institute, and Co-Director of Cutaneous Malignancies at Cedar Sinai Medical Center. Joining me today are two of my colleagues, Dr. Sapna Patel, and Dr. Ryan Sullivan.
Dr. Sapna Patel:
Hi, I'm Dr. Sapna Patel. I'm a medical oncologist, and Associate professor and Director of the Uveal Melanoma Program at MD Anderson Cancer Center in Houston, Texas.
Dr. Ryan Sullivan:
And I'm Ryan Sullivan. I'm also a medical oncologist, and the Associate Director of the Melanoma Program at the Mass General Cancer Center, and Associate Professor at Harvard Medical School.
Dr. Hamid:
James is a 67-year-old man with a long-standing mole on his right leg that began to change over the last year. He was seen by his dermatologist, and an initial biopsy showed a 2.2-mm melanoma, nonulcerated. Unfortunately, during the physical examination there were the feeling of palpable lymphadenopathy in his inguinal area. He receives a CT scan and a PET scan that showed no evidence of metastatic disease, and he is seen by medical oncology, and an initial consultation with surgical oncology, about plans to move forward. The tumor is BRAF-positive.
At this point, there are many possibilities for a patient like James, and today we'll discuss the neoadjuvant paradigm, as it has entered into our armamentarium for malignant melanoma.
Dr. Sullivan, can you talk about some of the initial thoughts here in the neoadjuvant space for melanoma?
Dr. Sullivan:
Absolutely, Dr. Hamid.
The neoadjuvant space is actually a space that's long been known to be a place of potential efficacious therapy. We've learned a lot about this from our colleagues in breast cancer, who have not only developed neoadjuvant therapy for women with high-risk breast cancer, but also have developed drugs, and developed new drugs in that setting. And so there's not only a paradigm of therapy, but also a paradigm of drug development. Which our colleagues in breast cancer have been at the forefront of.
In melanoma, it was always thought that it might be a little bit different. That the rationale for immunotherapy, which is the mainstay of our treatment, might actually be a bit more justified in the neoadjuvant setting than the adjuvant setting. The concept being that, you probably need a immune microenvironment. Now that could be a microscopic immune microenvironment that you can't see on a scan, but that's developing, and so adjuvant therapy could still be effective. But having a palpable node in delivering immunotherapy, it was thought that maybe just the presence of that lymph node there, and the T cells that have made it there in the early immune attack that's ongoing, that immunotherapy may be even more stimulating in that scenario and lead to better outcomes.
In terms of theory, it's all well and good, but there's actually even a little bit of data that supports that statement, and it came from our colleagues at the Netherlands Cancer Institute and work led by Christian Blank. Which he initially started a trial called the OpACIN trial, which randomized patients to ipilimumab and nivolumab, either receiving all of their therapy after surgery, so in the adjuvant setting, or receiving their four doses of therapy, split. Two before surgery and two after surgery.
While the trial was pretty small, and not large enough to make any claims about which was better for the patients, ultimately. What was interesting is that, there was a lot of immunologic data that was generated out of there, that suggested that neoadjuvant therapy was immunologically better than adjuvant therapy. In particular, there was an increase in tumor-specific T-cell clones in the peripheral blood in patients who received neoadjuvant therapy, to a higher degree than patients who received adjuvant therapy, suggesting that indeed, the presence of that tumor micro-environment was important for the development of a better immune response.
The folks at Netherlands Cancer Institute, again at the forefront of neoadjuvant therapy in melanoma, then decided to try and test what was the best regimen using ipilimumab and nivolumab in the neoadjuvant setting, and did what was called the OpACIN-neo study. Which is now three arms, looking at two doses of the traditional full dose, 3 mg/kg ipilimumab and 1 mg/kg of nivolumab. Or flipping that dose, 1 mg/kg ipilimumab and 3 mg/kg of nivolumab, and then some weird regimen, where they gave two doses of ipilimumab and then two doses of nivolumab and then took them to surgery.
It turns out that, that trial again also wasn't powered to figure out which was better, but what it really showed was that, there was high pathologic response rates in each of those arms. And the toxicity of the flipping dose of ipilimumab and nivolumab was like half as toxic as sort of the full dose, and specifically, grade 3/4 toxicity was 20% in the flip dose of 40% in the full dose. And so it sort of became that the regimen of choice in our minds, without actually having any randomized data to say we should be giving that over adjuvant therapy or even over say, single-agent anti–PD-1 antibody in the neoadjuvant space. And then, one of our esteemed colleagues, who actually happens to be on this panel, presented some amazing data. And so I'll let Dr. Patel talk about her trial.
Dr. Patel:
Well, thank you guys. We designed the SWOG S1801 study to really answer the question that Dr. Sullivan alluded to, is sequencing therapy before surgery, compared to after surgery, is one actually better for patients, in terms of survival? The OpACIN and OpACIN-neo studies were fundamental to our understanding of neoadjuvant therapy. They certainly gave us hypotheses on which to base therapeutic regimens, but we certainly didn't learn, from a power and sample size standpoint, if there was a superior regimen.
So with that in mind, we designed the S1801 study. It's a randomized phase II study of participants with resectable, essentially palpable, lymph node disease, or oligometastatic stage IV disease, that a surgeon said this is resectable. They would go the traditional route, which would be to surgery first, and then get 1 full year of flat dosing of pembrolizumab given every 3 weeks. So that totals 18 doses of pembrolizumab. The comparator arm was neoadjuvant therapy, which was essentially giving 3 of those 18 doses before surgery, then going to surgery, and then finishing with 15 doses in the adjuvant setting.
Importantly in this study, the surgery that was to be done was pre-specified at the time of randomization. So before a patient or a surgeon knew which arm they were randomized to, they had to agree, what would be the standard approach here? Would it be a lymph node dissection? Would it be a metastasectomy plus a lymph node dissection? What would be the optimal surgery? And that would be carried out, regardless of which arm they got randomized to, importantly, that same surgery would be done regardless of response to neoadjuvant therapy. And that left us asking only one question in S1801. Does the sequence matter?
We didn't alter the surgery, so you didn't get the perhaps benefit of deescalating surgery, nor did you get the bias of deescalating surgery. And everybody took adjuvant PD-1. The same number of doses of pembrolizumab were administered, 18 doses in the adjuvant setting, or 3 in the neoadjuvant, and 15 in the adjuvant, again for a total of 18 doses.
And our primary endpoint was something called event-free survival, which measures from the time of randomization, any of the following four events. Failure to proceed to surgery, say there was a toxicity, or there was already progression in somebody randomized to the adjuvant arm before they even made it to surgery. Which by the way, we think happens in about 15% of our melanoma patients. So progression rendering you unable to have surgery, or toxicity rendering you unable to have surgery events 1, events 2. Event 3 would be a melanoma recurrence at any point after surgery. And then, event 4 would be death from any cause. So those four events define event-free survival.
And what we noted at a median follow-up of 14 months was, we hit the number of events needed to trigger the principle analysis. What we see is that the neoadjuvant arm is faring better, in terms of event-free survival, than participants in the adjuvant arm. If you look at the 2-year landmark time point, again, at a median follow up of 14.7 months. So some of this data is immature at 2 years, but an estimated 2-year event-free survival is 72% in the neoadjuvant arm, vs 49% in the adjuvant arm. That's a tremendous hazard ratio. And two-sided P-value benefit of 0.004, hazard ratio of 0.58. And that means there's a 42% improvement in participants receiving neoadjuvant therapy at any time, essentially, from their diagnosis of palpable resectable melanoma.
I feel like I could go on and on about S1801 and tell you all the nuances that we were investigating, but I think we have now answered a very fundamental question. Does sequence matter? And if you move therapy before surgery, are you simply delaying a curative surgery, or are you actually improving their outcomes? I think S1801 says we are improving outcomes. The mechanism behind that has yet to be uncovered. So studying the tumor biopsies, importantly, studying S1801 tissue for pathologic response will be very key, as it seems to emerge as a possible surrogate for radiographic response, or perhaps, it fares just as well as radiographic response, in terms of outcomes.
But now, we want to ask the question about combination neoadjuvant therapies. OpACIN-neo clearly showed there are different ways to sequence combination therapies. And what we know from the metastatic setting is that there are combinations that may be even less toxic than something like a ipilimumab/nivolumab combination.
In a recently published paper in Nature Medicine, a pilot study of neoadjuvant nivolumab plus relatlimab was simply looking to see what is the pathologic response of neoadjuvant nivolumab/relatlimab? That study showed in line with OpACIN-neo, that there's a high rate of neoadjuvant pathologic response to this neoadjuvant combination regiment greater than 50%.
And now what I think we need to answer in a randomized fashion is a number of questions, right? Is combination immunotherapy better than single agent? Combination immunotherapy does have toxicities that can delay surgery. They might lead to steroid use. Steroid use might then augment the T-cell clonality diversity, and it could affect disease recurrence. Certainly, in people that are having an excellent neoadjuvant response to therapy, both radiographically, and perhaps even, on a index node pathologic basis. Can you deescalate the surgery and minimize morbidity associated with surgery? And importantly, in people who have complete pathologic response, can you omit the adjuvant portion of a neoadjuvant regimen? These are all future questions that we hope to answer.
One important point on pathologic response is that, the International Neoadjuvant Melanoma Consortium pooled these neoadjuvant pilot studies that were done as either single arm, single institution, or even small randomized studies, and looked at immunotherapy vs targeted therapy, and what was the value of pathologic responses?
Certainly, patients who have a pathologic response of any sort, in response to immunotherapy, seem to do better than non-responders, and that criteria is defined in a white paper from the International Neoadjuvant Melanoma Consortium. But interestingly, pathologic complete responses to targeted therapy is not carte blanche for lack of relapse. So what that pooled analysis found was that, pathologic complete response patients to targeted therapy, neoadjuvant targeted therapy, still had a portion of those patients with recurrences or relapses after approximately 2 years. So this is suggesting that neoadjuvant targeted therapy may not do the same thing, in terms of T-cell clonality and T-cell diversity, as immunotherapy.
But lots of questions, I think, to answer in the neoadjuvant space. One of the important things of S1404 was that it looked at resectable stage IV. So similar to the IMMUNED study in the sort of stage IV resected setting, these were patients who were stage IV and resectable, and the question was, does neoadjuvant pembrolizumab fare, better than resecting them and giving single-agent pembrolizumab? There were small numbers of these groups of resectable stage IV, but it does appear that a neoadjuvant approach may have a tail, as far as events occurring in short follow up for those patients.
Dr. Hamid:
Thank you so much. As you can see, there's a lot to be taken away from the neoadjuvant paradigm. Not only the fact that it has now become standard in the way we think about our resectable stage III patients, but the ability to identify these patients can give us a better option, and possibly better long-term survival in clinical trials that are upcoming now. We're looking at whether there's an ability to deescalate surgery, or deescalate adjuvant therapy post-surgery. And also, multiple clinical trials with multiple combinations, such as the NADINA trial that's looking at ipilimumab/nivolumab, vs adjuvant PD-1 therapies are upcoming.
So at the end of this case, you can see that neoadjuvant has now firmly rooted itself in melanoma care. Please see the other segments, for further discussion about the latest data in melanoma, or visit ascopost.com.
