Dr. Omid Hamid:
Welcome to The ASCO Post Roundtable Series on Updates in Malignant Melanoma. I'm Dr. Omid Hamid, Chief of Translational Research and Immuno-oncology at the Angeles Clinic and Research Institute, and Co-Director of Cutaneous Malignancies at Cedars-Sinai Medical Center. Joining me today are two of my esteemed colleagues, Dr. Sapna Patel and Dr. Ryan Sullivan.
Dr. Sapna Patel:
Hi, I'm Sapna Patel, Associate Professor and medical oncologist, Director of the Uveal Melanoma Program at MD Anderson Cancer Center in Houston, Texas.
Dr. Ryan Sullivan:
And I'm Ryan Sullivan. I'm the Associate Director of the Melanoma Program at the Mass General Cancer Center and Associate Professor at Harvard Medical School.
Dr. Hamid:
Today we'll be discussing recent updates in melanoma and integrating these new developments into four patient case studies. Our first installment will focus on adjuvant therapy.
James is a 67-year-old man with a long-standing mole on his leg that began to change over the last year. He was seen by his dermatologist, and a biopsy showed a 2.2 mm melanoma, nonulcerated with no palpable lymph nodes in the inguinal area. He receives a CT scan and PET scan that show no evidence of metastatic disease. He's seen by surgery and receives a wide excision and sentinel node that is negative. The tumor is BRAF-positive. So Dr. Sullivan, in this patient, what are the options for adjuvant therapy?
Dr. Sullivan:
This is a patient with a T3a tumor, and with absence of nodal involvement, he has stage IIA melanoma. Currently, we don't actually have an approved adjuvant therapy for stage IIA melanoma. Now, if this patient had an ulcerated primary or if that patient's tumor was greater than 4 mm, whether it was ulcerated or not, then this patient would either have stage IIB or IIC melanoma.
There have been two recent randomized trials of anti–PD-1 antibody therapy in this patient population comparing either nivolumab in the CheckMate 76K trial vs placebo or pembrolizumab in the KEYNOTE-716 study, which randomized patients to pembrolizumab vs placebo.
In these two trials, the patients treated with anti–PD-1 antibody therapy had improvement in the primary endpoint, which was for both studies, an improvement in relapse-free survival. If this patient had stage IIB or IIC melanoma, then it would be perfectly reasonable to offer this patient single agent anti–PD-1 antibody therapy.
Now, it's also important to note that there are potential toxicities associated with that, and we often will have very long conversations about the risks and benefits of anti–PD-1 antibody therapy in patients with stage IIB and IIC melanoma. But the options for a patient like that would be single agent anti–PD-1 antibody therapy or very close observation.
Dr. Hamid:
Thank you for that. This is a real new indication, stage II, but let's go into stage III. Dr. Patel, what if his sentinel nodes were microscopically positive or macroscopically positive?
Dr. Patel:
If he had a microscopically positive nodal disease, a sentinel lymph node–positive T3a, N1a or N2a disease, he would map to a stage IIIA in the AJCC staging system. Stage IIIA is unique in that the clinical trials that allowed for these patient populations include the COMBI-AD study, which is adjuvant BRAF/MEK inhibitor, specifically dabrafenib and trametinib vs two matched placebos. There's also the S1404, SWOG-S1404, which allowed this patient population. Then there were other studies that looked for higher stage III disease. But in the IIIA population, we have to remember that the size of the deposit in the lymph node may actually matter. In COMBI-AD you had to have greater than a millimeter deposit in that sentinel lymph node to be eligible. In SWOG-S1404, you had to have two microscopic lymph nodes to be eligible.
Both of these trials showed that intervention was meaningful. So in the COMBI-AD study, participants who took adjuvant BRAF/MEK did better in that same endpoint that Dr. Sullivan mentioned, relapse-free survival compared to placebo. In SWOG-S1404, the IIIA participants who took adjuvant pembrolizumab compared to adjuvant investigator's choice of either ipilimumab or interferon, they seem to fare better with pembrolizumab. But in subset analysis of just the IIIA patients, it's hard to derive a clear benefit. Intervention probably does something, but which intervention not so clear.
In palpable nodal disease, we start to think about after resection of palpable nodal disease studies like the CheckMate 238 study, adjuvant ipilimumab vs adjuvant nivolumab, and then even KEYNOTE-054, which was adjuvant pembrolizumab vs placebo, basically a placebo-controlled arm. These are for essentially higher than IIIA patients. But then of course we start thinking about palpable nodal disease and what we might be able to do for them preoperatively. Maybe that's an interesting thing for us to discuss.
Dr. Hamid:
Yeah, so we'll discuss that in the neoadjuvant portion of this discussion. But new data, not just in stage II adjuvant, stage III adjuvant, but stage IV adjuvant therapy has come out. Dr. Sullivan, can you take us through some of that and IMMUNED study?
Dr. Sullivan:
Absolutely. So the IMMUNED study is a randomized trial in patients who had resectable stage IV disease, underwent resection, and then were randomized to one of three treatment arms: ipilimumab/nivolumab at the standard dosing, which is ipilimumab 3 mg/kg plus nivolumab, 1 mg/kg given every 3 weeks to up to four doses and then followed by nivolumab maintenance for the remainder of a year. The patients could have been randomized to nivolumab; then, the third arm in that study was observation.
What's interesting about this study, it is essentially the resected stage IV version of the CheckMate 067 trial, which was sort of the hallmark trial of metastatic disease, which randomized ipilimumab/nivolumab to nivolumab to ipilimumab, but in the IMMUNED study instead of it, an ipilimumab arm that is the observation arm. What's clear with longer follow-up, which was presented at ESMO this year, is that patients who are treated with ipilimumab/nivolumab have an improved relapse-free survival compared to those who were observed. Patients treated with nivolumab have an improved relapse-free survival vs those who were observed. In an exploratory analysis, there does to appear to be an improvement in for sure relapse-free survival and a trend towards overall survival with the combination of ipilimumab/nivolumab vs nivolumab.
I think this is an important study because in the stage III adjuvant setting, there was a clinical trial that randomized patients to receive nivolumab plus ipilimumab vs nivolumab. That trial ended up failed to meet its primary endpoint. Importantly, that trial incorporated a regimen that was not the regimen in the IMMUNED NED study. That was a regimen of nivolumab standard dosing with every 6 week dosing of ipilimumab at 1 mg/kg. It's a dosing schedule that is used for other diseases but has never been tested in melanoma. It's hard to know, particularly when looking at the IMMUNED NED study, whether that was just a mistake and gave the wrong dose of ipilimumab to a patient population that would've benefited or whether you needed a patient population that had a high enough risk, essentially the metastatic stage, the stage IV resected to NED population that actually benefit from ipilimumab.
Ultimately, in a patient with resected stage IV melanoma, there is clear data to support anti–PD-1 based therapy. It's worth having a conversation about which patients should be offered potentially ipilimumab plus nivolumab. As an aside, I would say not necessarily everybody, but for sure patients who have oligometastatic disease in the brain. The reason I state that, I know we're going to talk about front-line therapy for patients with brain mets at a later point in this conversation, but patients who received either nivolumab or observation and had an oligometastatic lesion in the brain, that was their stage IV, all those patients did pretty poorly. Whereas, the patients who received ipilimumab plus nivolumab actually do quite well and the great majority of those patients remained without relapse.
Dr. Hamid:
Thank you. So lots forthcoming in our other portions of this discussion. As we come to an end on the discussion about adjuvant therapy in malignant melanoma, there are some key clinical takeaways. The first being that at this time we do have options for the adjuvant therapeutics of patients with stage II high risk melanoma, IIB and IIC with immunotherapy. For our patients with stage IIIA and above therapy, an extensive discussion remains important about toxicity and evaluation of their BRAF status and the ability to accrue to either immunotherapy for 1 year neoadjuvant vs targeted therapy for those patients who are BRAF mutant.
As we move forward, the discussion about resected stage IV disease and the IMMUNED NED study, which has shown survival benefit vs just placebo, either in combination anti–PD-1, anti–CTLA-4, or in single agent PD-1 therapy. I think we'll all agree that further information is needed, including more optimal regimens, biomarkers, and the ability to get these is tantamount through clinical trials. The ability to offer our patients adjuvant therapy with known beneficial treatments in the metastatic setting have made it important for us to evaluate newer metastatic regimens.
With that, this brings us to the end of this case. Please see the other segments for further discussion about the latest data in melanoma or visit ascopost.com.
