Adjuvant therapy with nivolumab combined with ipilimumab vs nivolumab alone in patients with resected stage IIIB-D/IV melanoma
Prof Georgina Long - University of Sydney, Sydney, Australia
I am going to be talking about the phase III Checkmate-915 study which was an adjuvant trial of nivolumab combined with ipilimumab versus our current standard adjuvant treatment, nivolumab alone, in patients with resected stage IIIB, C, D and stage IV melanoma.
In terms of background regarding this trial, we know that nivolumab alone after melanoma is resected for stage IIIB-D and stage IV melanoma improves the relapse free survival significantly compared with ipilimumab, another checkpoint inhibitor, as an adjuvant therapy. We also know that ipilimumab improves the progression of the relapse free survival and overall survival compared with placebo which used to be our standard management paradigm only about five years ago. So for resected stage III or IV melanoma the standard was to resect and then we would watch. So ipilimumab first showed a relapse free survival benefit and then nivolumab in Checkmate-238 so the next study is the Checkmate-915 based on data we see in the metastatic advanced melanoma setting where we know that when we combine nivolumab and ipilimumab we see a numerical improvement in both the progression free survival and overall survival. So naturally we wanted to see what this combination would do for resected stage III and IV melanoma in the adjuvant setting.
In Checkmate-915 which I presented at AACR 2021 we did not see a benefit of the combination over nivolumab alone in resected melanoma. The dosing of the combination in this trial, 915, was very different to what we use in the advanced melanoma setting from Checkmate-067. In this adjuvant trial we used ipilimumab at a 1mg/kg dose every six weeks. Normally in the advanced melanoma setting the dose of ipilimumab combined with nivolumab is 3mg/kg every three weeks for four doses. So it was a bit of a challenge to see that we did not see an improvement in the relapse free survival. In fact the hazard ratio was 0.92, the confidence interval for that hazard ratio crossed 1.0 and the p-value was 0.2 so there was no significant improvement. The landmark two year relapse free survival for the combination nivolumab ipilimumab was 64.6% and 63.2% for nivolumab alone. No subgroups seemed to benefit, there really was no benefit at all for this combination over nivolumab alone.
We looked at whether patients who stopped early because of higher rates of toxicity in the combination arm may have been the reason because they did get less nivolumab overall. So the combination arm, because of the toxicity in the protocol resulted in those patients getting less nivolumab overall. So we looked at whether that was a reason for this lack of improvement but there was only about a 5% difference in the landmark relapse free survival between those who stopped early, less than six months, and those who did not stop due to toxicity at less than six months. So that doesn’t explain these negative results completely. It likely is due to the lower dosing of ipilimumab. We know that ipilimumab does have a dose response in the advanced setting so the more ipilimumab you use the higher the progression free survival and overall survival in advanced disease so it’s probably that but we don’t know. This is worth investigating.
So what does this mean for our field? It means that nivolumab remains a standard anti-PD-1 therapy along with pembrolizumab for resected stage III melanoma and nivolumab for resected stage IV melanoma. This combination has not improved things further. We now need to go back to the drawing board and look at other ways that we can improve the relapse free survival for this patient group and perhaps it’s a dosing issue with the ipilimumab. Thank you.