This protocol addresses patients with advanced melanoma — either locally unresectable stage III or distant metastatic stage IV — whose tumour is confirmed to be BRAF V600 mutation absent (BRAF wild-type). This molecular status is the pivotal determinant of treatment routing in advanced melanoma, as it excludes the use of targeted BRAF/MEK pathway inhibitors and directs management toward distinct therapeutic strategies.
Patients present with advanced, surgically unresectable melanoma confirmed to lack the BRAF V600 mutation. This sub-population requires a management pathway specifically designed for BRAF wild-type disease, supported by prospective clinical evidence that has established the benefit of dedicated systemic approaches over earlier chemotherapy standards in this molecular group.
The superiority of nivolumab over dacarbazine (DTIC) chemotherapy for the first-line treatment of patients with BRAF-wild-type (WT) melanoma was demonstrated in the prospective randomised CheckMate 066 trial, with an HR for death of 0.42 (99.79% CI 0.25-0.73, P < 0.001) and an HR for death or progression of disease of 0.43 (95% CI 0.34-0.56, P < 0.001).
TIL therapy is an aggressive treatment option for selected patients (young, stage IV M1a-c melanoma, PS 1, LDH <2 ULN and 1-3 prior treatments) who can tolerate its side-effects [II, B; not EMA or FDA approved].
In this trial, patients received a non-myeloablative lymphodepletion regimen, a single infusion of lifileucel and up to six doses of high-dose interleukin-2 (IL-2).
ChT with DTIC, carboplatin-paclitaxel, temozolomide or fotemustine can be discussed.
If clinical trials, ICIs or BRAFis/MEKis are not available, ChT may be administered as later-line therapy [IV, C], with modest activity and no impact on OS.