Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma
Authors: Bhave Prachi , Ahmed Tasnia , Lo Serigne N , Shoushtari Alexander , Zaremba Anne , Versluis Judith M , Mangana Joanna , Weichenthal Michael , Si Lu , Lesimple Thierry , Robert Caroline , Trojanello Claudia , Wicky Alexandre , Heywood Richard , Tran Lena , Batty Kathleen , Dimitriou Florentia , Stansfeld Anna , Allayous Clara , Schwarze Julia K , Mooradian Meghan J , Klein Oliver , Mehmi Inderjit , Roberts-Thomson Rachel , Maurichi Andrea , Yeoh Hui-Ling , Khattak Adnan , Zimmer Lisa , Blank Christian U , Ramelyte Egle , Kähler Katharina C , Roy Severine , Ascierto Paolo A , Michielin Olivier , Lorigan Paul C , Johnson Douglas B , Plummer Ruth , Lebbe Celeste , Neyns Bart , Sullivan Ryan , Hamid Omid , Santinami Mario , McArthur Grant A , Haydon Andrew M , Long Georgina V , Menzies Alexander M , Carlino Matteo S 
Published: July 2022

BackgroundAcral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.MethodsPatients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).ResultsIn total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.ConclusionWhile the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.