In addition to the high proportion of patients with poor baseline prognostic features, a possible explanation to the lack of CRs and shorter median PFS in the patients included in this study may be that the dysregulation of the p16/RB1 or p14ARF/MDM2/p53 pathways sustained by CDKN2A pathogenic mutations, as well as the high tumor mutational load in CDKN2A-mutant melanomas, may limit the chances to obtain a full and lasting inhibition of the oncogenic pathways sustaining tumor cell proliferation. The gene discussed is RB1; the disease is neoplasm.