Efficacy of checkpoint inhibition in advanced acral melanoma.
Authors: de Meza Melissa Melanie , van Not Olivier Jules , Blokx Willeke , Bonenkamp Han J. , Blank Christian U. , van den Eertwegh Alfonsus Johannes Maria , Aarts Maureen J.B. , Stevense Marion , van den Berkmortel Franchette , Boers-Sonderen Marye , de Groot Jan Willem , Haanen John B. A. G. , Hospers Geke , Kapiteijn Ellen , Piersma Djura , Van Rijn Rozemarijn , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , Suijkerbuijk Karijn , Wouters Michel W.J.M. 
Published: June 2021

e21527

Background: Recent data in Japanese patients suggest poor outcomes for anti-PD1 in acral melanoma (AM), with no data available on combination treatment. The objective of this study was to analyze the efficacy of anti-PD1 monotherapy and anti-PD1 and anti-CTLA4 combination therapy in these patients. Methods: Our study population consisted of patients registered in the nationwide prospective Dutch Melanoma Treatment Registry between 2014 and 2020. We calculated objective response rate (ORR) in all unresectable stage III and IV AM and nonacral cutaneous melanoma (NAM) patients treated with anti-PD1, and combination anti-PD1 and anti-CTLA4. Progression-free survival (PFS), and overall survival (OS) were estimated for first-line treated patients. A Cox proportional hazard analysis was performed to adjust for potential confounders. Results: Nighty-five AM patients received at least one dose of anti-PD1 monotherapy, of whom 58 (61%) as first-line treatment. ORR was 28% (complete response 11%; partial response 18%). Median PFS and OS in patients with first-line treatment were 5.5 months (95% CI 3.5-8.4) and 14 months (95% CI 9.3-25.0). In patients with NAM (n = 1259) ORR was 48% (complete response 18%; partial response 31%). Six-hundred and eighty-eight (55%) patients received anti-PD1 as first-line treatment. Median PFS was 11.7 months (95% CI 9.1-14.9) and median OS was 24 months (95% CI 20.0-29.3) in these patients. Older age, higher ECOG scores, elevated LDH levels, liver metastasis and brain metastasis were significantly associated with lower OS. After adjustment for covariates, acral subtype remained associated with shorter PFS (Hazard Ratio 1.76, 95% CI 1.25-2.48) and OS (Hazard Ratio 1.70, 95% CI 1.17-2.45). Twenty-four AM patients received at least one dose of anti-PD1 plus anti-CTLA4, of which 15 as first-line treatment. ORR was 25% (complete response 4%; partial response 20%). AM patients treated with first-line combination therapy had a median PFS of 3.8 months (95% CI 2.8-NR) and median OS of 7.63 months (95% CI 6.12-NR). ORR in NAM patients treated with combination therapy (n = 599) was 41% (complete response 8%; partial response 33%). Forty-six percent of these patients were treated in the first-line, with a median PFS of 9.7 months (95% CI 6.6-17.1) and median OS of 21.3 months (95% CI 14.6-36.5). Elevated LDH levels and the presence of BRAF mutation were significantly associated with lower OS. No significant association was found between acral subtype and PFS, or OS after adjustment for covariates. Conclusions: This study shows limited efficacy of anti-PD1 for advanced AM, with clinically relevant lower response rates compared to nonacral melanoma types. Although caution is needed because of relatively small numbers and the observational nature of our study, our data confirm limited efficacy of checkpoint inhibition in AM.