In previous studies we have shown that neoadjuvant immunotherapy, and especially ipilimumab plus
nivolumab, gives a high pathologic response rate in the 70-80%. If patients achieve a pathologic
response then they have an almost flat line relapse free survival of hardly any patients relapsing. This
is a pooled analysis from the International Myeloma Consortium. In PRADO we now addressed the
question, first, because these were only small trials, whether with now a larger cohort of about 100
patients whether we confirm this high pathologic response rate from neoadjuvant ipilimumab plus
nivolumab. We wanted to address also the questions can we decrease the extent of surgery and omit
the adjuvant therapy in patients achieving a deep response, a major pathologic response, after
neoadjuvant ipilimumab nivolumab. While if we increased the treatment e.g. by giving a large surgery
and an adjuvant therapy plus synchronous radiotherapy in the non-responders whether we can then
improve the outcomes of these patients. Because in previous trials they have about two-thirds
relapse, the non-responders.
So to address this question we designed PRADO in that way that patients up front neoadjuvant
immunotherapy got placed a marker into the largest lymph node, the so-called index lymph node
procedure, which is well known in the breast cancer world but it’s not very well known in the
melanoma world. Then the patients were treated with the two courses of ipilimumab nivolumab and
then only the largest lymph node, or this marked lymph node, was removed. The pathologist
addressed the pathologic response in this one lymph node and if we had a major pathologic response
these patients were not treated with therapeutic lymph node dissection anymore and did also not
have any adjuvant therapy. If they had a partial response the patients still received the therapeutic
lymph node dissection but no adjuvant therapy. If they had no response we escalated and then
therapeutic lymph node dissection, adjuvant therapy, BRAF wild-type adjuvant nivolumab, BRAF
mutated adjuvant dabrafenib trametinib plus synchronous radiotherapy. This was the design of the
trial.
Now the results: we present here at ASCO for the first time the two-year relapse free survival data.
For the whole cohort it was two-year relapse free survival of 85% with a distant metastasis free
survival of 89%. The pathologic response was 71%; major pathologic response 62%. So these 62% of
the patients were not treated with any extensive surgery nor adjuvant therapy. So now comes the
question what was the relapse free survival for this group? It was 93% relapse free survival and 98%
distant metastasis free survival, clearly showing that you can really omit in more than 50% of the
patients this extensive surgery, which translated into a way better quality of life, statistically significant.
For example, also for fatigue even ongoing now up to two years follow-up.
Wise words, and now comes the question is the extensive treatment now improving the outcome of
the non-responders. I remind you, normally you had only relapse free survival in 36%, now with this
extensive therapeutic lymph node dissection, adjuvant therapy and synchronous radiotherapy we
have now 71% relapse free survival at two years and 76% distant metastasis free survival at two
years. So clearly both goals, on the one side to improve the outcome of the non-responders but also
omitting the surgery in the major responders we achieve a good outcome in distant metastasis free
survival for these patients.
We are now at the event that neoadjuvant therapy will become soon standard therapy. We have the
SWOG trial, the S1801, that will read out at the end of this year. We have the NADINA trial comparing
neoadjuvant ipilimumab nivolumab personalised adjuvant therapy versus adjuvant nivolumab. We
hopefully will read out at the end of next year. But we are now coming to the point that after a long
journey of small trials becoming bigger and bigger, neoadjuvant therapy might become standard after
these two randomised trials.
