A New Era of Proactive Melanoma Therapy: Hit Hard, Hit Early

L. Haas; T. Wiesner; A. C. Obenauf


The British Journal of Dermatology. 2018;178(4):817-820. 

In This Article


Immunotherapies use a different mode of action and do not target tumour cells themselves, but unleash the patient's immune system to fight cancer. Immunotherapies exploit the genetic instability of tumours, which results in mutated peptides (neoantigens) and reveals the tumour to the immune system. However, tumour cells evade immune destruction by activating and co–opting inhibitory immune checkpoints that normally maintain self–tolerance, prevent autoimmunity and limit collateral tissue damage during antimicrobial immune responses (Figure 1).[11]

Monoclonal antibodies blocking the inhibitory immune checkpoints cytotoxic T–lymphocyte antigen 4 (for example ipilimumab), programmed death–1 (for example nivolumab, pembrolizumab) or programmed death–ligand 1 (for example atezolizumab, avelumab) aim to re–activate tumour–specific cytotoxic T cells and, thereby, elicit potent immune responses against the tumour. In 20–40% of patients with melanoma, immune–activating checkpoint inhibitors have shown encouraging results with durable clinical responses.[12] Compared with targeted therapy, the response rates to checkpoint inhibitors are lower, likely because in a high fraction of patients cytotoxic T cells cannot recognize the tumour or cannot overcome the immunosuppressive barriers of the tumour microenvironment.[13,14]

To increase response rates and overcome resistance, investigators started to combine different types of checkpoint inhibitors. In the CheckMate 067 trial, a randomized, double–blinded, phase III trial of 945 untreated patients with unresectable stage III or IV melanoma, it was shown that the combination of nivolumab plus ipilimumab results in higher response rates and longer progression–free survival, compared with ipilimumab alone.[15] However, at the time of publication in 2015, the survival data were not mature enough to present, and Wolchok et al.[1] have now provided an update on the survival analysis: the 3–year overall survival rate was 58% in the nivolumab plus ipilimumab group, 52% in the nivolumab group and 34% in the ipilimumab group. At a minimum follow–up of 36 months, the median overall survival had not been reached in the nivolumab plus ipilimumab group, was 38 months in the nivolumab group and 20 months in the ipilimumab group.

Despite these encouraging results, it should be noted that the combination of nivolumab plus ipilimumab frequently causes severe adverse events. Treatment–related grade 3 or 4 adverse events occurred in 59% of patients in the nivolumab plus ipilimumab group, but only in 21% in the nivolumab group and 28% in the ipilimumab group.[1] Whether the small clinical benefit of the nivolumab plus ipilimumab combination – compared with nivolumab alone – justifies the increase in adverse events is currently under debate. Modified doses and drug combinations are being evaluated.