Neoadjuvant ipilimumab and nivolumab immunotherapy could become new standard of care for resectable stage III melanoma

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Published: 6 Jun 2022
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Dr Christian U. Blank - The Netherlands Cancer Institute, Amsterdam, Netherlands

Dr Christian Blank speaks to cancer about a phase 2 study, known as PRADO, exploring a personalised response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in resectable stage III melanoma patients.

Dr Blank then summarises that neoadjuvant immunotherapy could become a new standard of care for resectable stage III melanoma and explains the next steps

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



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.