Clinical Outcomes with Pembrolizumab and Nivolumab in Resected Advanced Melanoma: Real-World Evidence

Background: Cutaneous melanoma (CM) and other skin cancers are prone to respond to immune checkpoint inhibition (ICI), due to a high tumor mutational burden (TMB), mainly caused by ultraviolet radiation (UVR) induced somatic mutations.Acral lentiginous melanoma (ALM) is a clinico-pathological subtype of CM, not linked to exposure to UVR and shows a lower TMB compared to other CM.The existing evidence is not finally settled as to whether these patients would benefit from new ICI therapies.Methods: A total of 160 cases diagnosed with non-resectable stage III/IV metastatic ALM and who received ICI as singe agent anti-PD-1 or in combination with anti-CTLA-4 in first line were evaluated from the EUMelaReg, which is a European initiative combining realworld data on the treatment and outcome of melanoma patients across Europe.1,433 cases with superficial spreading (SSM) or nodal (NMM) subtypes of skin lesions other than acral served as controls.To reduce bias from baseline imbalances a 1:1 matching of both populations was performed for several prognostic covariates using an optimal matching algorithm with Mahalanobis as distance metric.Results: Adjusted outcome parameters showed a significantly lower overall response rate of 31.2% vs 40.6%, shorter median (95% CI) progression-free (5.6 [4.3-8.3]months vs 8.8 [6.7-15.2]months; p=0.0032) and overall survival (20.9 [16.6-31.3]months vs 40.5 [20.6-not reached]; p=0.0014) for ALM patients compared to the control group, respectively.This effect was also observed in a multivariate Cox regression model of the unmatched population, showing that ALM patients had a significantly increased risk of death (HR 1,52; p=0.003) compared to control group, regardless of therapy choice.The OS disadvantage of ALM patients was consistent across all covariates, including treatment regime of anti-PD-1 anti-CTLA-4 in the multivariable analysis.Conclusions: Our study confirms that ALM has a lower response rate to ICI treatment compared with other CM subtypes.Given the fact that treatment alternatives are sparse, in particular since BRAF V600 mutations are rare in ALM, new treatment approaches are urgently needed for patients with advanced ALM underlining importance to include these patients into melanoma trials.