In terms of the subgroup of BRAF mutant patients with Stage IVd melanoma, whether immunotherapy should be used second-line after initial RAF-MEK inhibitor treatment, or in the first-line setting or perhaps concurrently with targeted therapy, remains uncertain, in view of the very small number of patients with brain metastases in the DREAMSeq and SECOMBIT trials. The gene discussed is BRAF; the disease is melanoma.