Nivolumab + Ipilimumab

Previous trials had already showed high response rates, pCR and EFS with the use of Ipilimumab + Nivolumab, but mostly the use of the reverse dosing with Ipi 1 and Nivo 3 showed a better safety profile, which is quite important when we are dealing with an early stage disease and have a curative intent.

In OpACIN, patients with macroscopic stage III melanoma were randomized to Ipi3+Nivo1 x 4 as adjuvant vs Ipi3+Nivo1 x 2 followed by surgery then by Ipi3+Nivo1 x 2 as adjuvant.

In OpACIN-neo, patients with macroscopic stage III melanoma were randomized to arm A (Ipi3+Nivo1 x 2), arm B (Ipi1+Nivo3 x 2), or arm C (Ipi3+Nivo3 x 2) followed by surgery.

Survival data from both trials of OpACIN and OpACIN-neo was quite remarkable after neoadjuvant combination of checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.

PRADO was an extension cohort of the phase 2 OpACIN-neo study aiming mostly to test response-driven subsequent adjuvant therapy. We gradually got more data regarding the omission of TLND and adjuvant therapy in patients who achieve MPR post neoadjuvant treatment from both PRADO and OpACIN-neo. But this strategy was mainly validated by the recent design of the NADINA trial.

The NADINA trial published in nejm and presented at ASCO 2024 randomized patients to TLND followed by a year of adjuvant Nivo q4w vs NA Ipi80 + Nivo240 x 2 followed by TLND. Patients who achieved MPR did not proceed to adjuvant and those who did not achieve MPR were eligible for adjuvant therapy (TT for BRAFm or Nivo q4w x 11).

This trial did set a new standard of care for resectable, macroscopic stage III melanoma: NA Ipi80+Nivo240 x 2 followed by surgery then a response-driven adjuvant therapy.