Neoadjuvant ipilimumab added to nivolumab improves outcomes in resectable advanced melanoma

Dr Minke W. Lucas - The Netherlands Cancer Institute, Amsterdam, Netherlands

At ESMO 2024 we have presented the NADINA trial. It’s the second presentation about NADINA, this time we provided an update of the event free survival and for the very first time we presented the distant metastasis free survival.

The NADINA trial is a phase III trial that randomises between a neoadjuvant arm with immunotherapy and an adjuvant arm with immunotherapy in resectable macroscopic stage 3 melanoma. So patients that could be included were patients with at least one macroscopic lymph node metastasis and a maximum of three additional in-transit metastases and they all had to be resectable.

We randomised patients to the neoadjuvant arm or an adjuvant arm to give them in the neoadjuvant arm two cycles with ipilimumab 80mg plus nivolmab 240mg followed by surgery and then followed by a response driven adjuvant strategy in which patients with a partial immune response would receive up to one year of adjuvant treatment and patients with a major pathologic response, meaning a maximum of 10% viable tumour cells, would not receive any adjuvant treatment. In the adjuvant arm patients would undergo up-front therapeutic lymph node dissection, so this is the exact same surgery as in the neoadjuvant arm, and then would receive 12 cycles of adjuvant nivolumab, which is one of the standard of care treatments of the past decade.

Previously we had already demonstrated that the primary endpoint, event free survival, was highly significant in favour of the neoadjuvant arm with a hazard ratio of 0.32. It was already significant with our first interim analysis, meaning that we had a rather short follow-up when we presented this data at ASCO 2024. At ESMO we have now presented the data with a median follow-up of 15.4 months and event free survival was very much in line with previously. So we again found a hazard ratio of 0.32, highly statistically significant although not corrected for multiplicity testing, and we found then an estimated 18 month event free survival for the neoadjuvant arm of 80.8% and in the adjuvant arm of 53.9%.

Importantly, we now also showed for the first time the distant metastasis free survival data. Again we saw a significant benefit for the neoadjuvant arm with a hazard ratio of 0.37 and estimated 18 month distant metastasis free survival for the neoadjuvant arm of 85.7% and for the adjuvant arm with 62.4%.

Furthermore, we looked into various subgroups, for example stage 3b and stage 3c melanoma, to see whether recurrence free survival for these subgroups was similar. Although there were of course differences, as expected, we noted that the benefit was very much consistent between the groups and neoadjuvant treatment seemed to be better for both patient subgroups.

Lastly, we gave a final update of the major pathological response rate and radiological response rate as now all patients in the neoadjuvant arm had undergone their surgery and had their six weeks minimum follow-up which was not entirely the case at the first data cutoff for the interim analysis. The final major pathological response rate, meaning the proportion of patients that had a maximum of 10% viable tumour cells in their resection material, was 60.8% and the radiological response rate was 37.2%. So even though that is very nice, it’s still much smaller than the major pathological response rate. Both outcomes were correlating with recurrence free survival but, as said, because the proportion of patients that had a major pathological response rate was so large and the outcomes were so favourable we think this is a really good biomarker to further tailor the adjuvant strategy and maybe even surgery in the future, based on this pathological response rate.

I think it’s important to note that for the complete pathological response that is around 50% of patients, the distant metastasis free survival at 18 months was 98%. So this is really impressive results of our trial.

So, to conclude, we think this data really supports our conclusion from the previous reports and that’s that neoadjuvant ipilimumab plus nivolumab should be considered the new standard of care treatment for resectable stage 3 melanoma. We think that patients that have a major pathologic response rate can omit any adjuvant treatment after surgery. We hope that this template that we have been testing for neoadjuvant treatment can also be applied in all the other cancer types because we see now a lot of neoadjuvant trials with immunotherapy, basically in any immune responsive cancer. We see very often that adjuvant treatment is still given after surgery to all patients and we think it would be great to tailor it down. Of course, each group has to look for themselves but it would great to see that a bit more also in other cancer types.

Previously we also showed data about safety. At this ESMO we didn’t, but to be complete on that we saw that in the neoadjuvant arm 30% of patients had a grade 3 or 4 adverse event and in the adjuvant arm this was 15%. So there is a difference there but it was completely expected as in the neoadjuvant arm we give combination treatment with ipilimumab plus nivolumab and in our phase II trials we already saw indeed a 30% adverse event rate. So it was very much in line with previous reports and we have also seen previously in a very first look at the quality of life data that we collected in the NADINA trial that it does not really seem to impact quality of life to that extent. It seems to be foremost extensive surgery that we are performing that gives a drop in quality of life but that’s seen in both arms and actually maybe in favour of the neoadjuvant arm because we hope in future with more data that we can even reduce surgery to smaller operations.