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Neoadjuvant Nivolumab Plus Ipilimumab vs Adjuvant Nivolumab in Stage III Melanoma: NADINA
PracticeUpdate: What results from previous trial prompted the NADINA trial?
Dr. van Akkooi: The NADINA trial is really the culmination of a few neoadjuvant trials we’ve done in sequence so far, starting off with the first OpACIN study. In the OpACIN trial, we examined the dose of ipilimumab 3 mg per kg plus nivolumab at 1 mg per kg, two doses prior to surgery, followed by surgery, followed by two doses after surgery versus adjuvant ipilimumab–nivolumab combination only. We moved forward with the OpACIN-neo study where we examined the flip dose of 1 mg per kg ipilimumab and nivolumab at 3 mg per kg to assess if we could have the same efficacy but reduce the toxicity significantly.
That seemed possible, so we moved that forward with the PRADO study where we expanded our experience on this flip dose of ipilimumab and nivolumab and, again, throughout those three studies, we have seen an overall response rate of around 80% with the major pathologic response rate of around 60%. So, this all forms the premise for the NADINA trial, where we aimed to examine a neoadjuvant combination of ipilimumab and nivolumab followed by a therapeutic lymph node dissection versus a therapeutic lymph node dissection as standard of care followed by adjuvant anti–PD-1 — in the case of the NADINA trial, nivolumab at 480 mg every 4 weeks.
NADINA trial design
PracticeUpdate: What is the design of the NADINA trial, and what are the major endpoints?
Dr. van Akkooi: The design of the NADINA trial is a randomized, controlled phase III trial. So, the control arm of that trial is a therapeutic lymph node dissection followed by a year of adjuvant anti–PD-1, in this case nivolumab at 480 mg every 4 weeks. This is a standard-of-care approach for macroscopic stage III melanoma patients. And then the experimental arm in this case was the combination of ipilimumab and nivolumab at fixed doses, ipilimumab at 80 mg and nivolumab at 240 mg every 3 weeks for two courses prior to surgery, followed by surgery — in this case, a full therapeutic lymph node dissection – and then, based on the pathologic response, adjuvant therapy was decided. For patients who achieved a major pathologic response, there was no adjuvant therapy. For those who had a partial response or a non-response, there was adjuvant therapy, which could be a switch to BRAF/MEK therapy for patients with the BRAF V600 mutation.
Event-free survival as a primary endpoint
A major primary endpoint of this trial was event-free survival, which is a slightly different endpoint than a more common endpoint, which we know as recurrence-free survival. The big difference here is that it also captures all events that happen on the neoadjuvant therapy. So, if there’s any progression on neoadjuvant therapy before surgery, this is also captured in event-free survival. It actually is in favor of the adjuvant arm rather than the neoadjuvant arm in terms of being a valid primary endpoint. So, we think that this is the best endpoint for examining studies that look at neoadjuvant versus adjuvant therapies.
Selection criteria
PracticeUpdate: What patient segment was chosen for this combination study?
Dr. van Akkooi: For the NADINA trial, we chose the population of patients with macroscopic stage III melanoma; so, that included stages IIIB, IIIC, and IIID, where patients had to have a palpable or image-detected lymph node metastasis that could be proven with fine-needle aspiration cytology or a histological biopsy. It did not have to be RECIST-measurable because sometimes in the neck, for example, we have lymph nodes with a small axis of 1 cm that are malignant but then wouldn’t be measurable according to RECIST criteria. So, we allowed those lesions in here as long as they could be proven with a biopsy. Patients could have up to three resectable and transient metastases at time of their diagnosis as well, which is slightly different than many of the previous neoadjuvant trials, which excluded those patients.
Trial results
PracticeUpdate: Can you discuss the results of the NADINA trial?
Dr. van Akkooi: With a median follow-up of only 10 months, 420 patients were randomized — so, more than 200 in each arm — and the primary endpoint was already met of event-free survival at an estimated 1-year rate of 83% for the neoadjuvant group versus 57% for the adjuvant group. So, that is an absolute benefit of 26%, and it had a hazard ratio of 0.32 and was highly statistically significant. So, this is a landslide observation that we have not yet seen from any particular study, at least definitely not a phase III study of neoadjuvant immunotherapy. This is a first in kind to show such a massive benefit.
Advantages to neoadjuvant therapy
PracticeUpdate: Can you share your clinical experience with the outcomes of neoadjuvant therapy in patients with resectable stage III melanoma?
Dr. van Akkooi: The results of patients undergoing a neoadjuvant protocol are, in my experience, really excellent. Both patients as well as we physicians love neoadjuvant therapy because it gives us a good indication of what is happening to a patient. One concern many patients have when they first see you is that they might progress prior to surgery, and that is true, but it is a rare occurrence. It’s about 3%, and I try to reassure them of the fact that the other way around, if I would take them to surgery first and offer them adjuvant therapy thereafter, actually many patients already recur early on after surgery prior to getting the first dose of adjuvant therapy. In all of the phase III adjuvant trials, it was around 20% progression, and, again, here in the NADINA trial we saw that in the first 3 months on the adjuvant arm, 20% of patients already progressed or recurred.
So, it is in their best interest to start with the drug first, not delay that, and then do the surgery later.
Majority achieves a major pathologic response to neoadjuvant therapy
There are also some other advantages to that neoadjuvant approach. One of the most important being that the majority of patients achieves a major pathologic response and that’s around 60%, which, again, we’re seeing here in the NADINA trial as was seen in the previous trials that led up to NADINA. Those patients did not have any further adjuvant therapy after their surgery. So, that means with two doses of the combination of ipilimumab–nivolumab, they were done and they hardly show any recurrences thereafter.
I know it is early days with the median follow-up of only 10 months, but it is very much in line with what we saw before that those patients have an excellent prognosis. This really speaks to the imagination of both patients and physicians that this is a very exciting new avenue to pursue and there are many other opportunities ahead. For example, the de-escalation of surgery that we can validate through the approach that we took in the NADINA and the PRADA trial where we, rather than perform a full therapeutic lymph node dissection on all patients, were able to perform a lesser surgery on those patients with a major pathologic response.
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