Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma.

2022-07

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

CTLA-4 Antigen

Immunotherapy

Melanoma

Programmed Cell Death 1 Receptor

Journal Article

http://orcid.org/0000-0001-9084-8467

http://orcid.org/0000-0001-5092-5544

http://orcid.org/0000-0002-8065-4412

http://orcid.org/0000-0002-9060-4961

http://orcid.org/0000-0001-8990-5380

http://orcid.org/0000-0002-8289-8015

http://orcid.org/0000-0003-0022-9553

http://orcid.org/0000-0002-8322-475X

http://orcid.org/0000-0003-0658-5903

http://orcid.org/0000-0001-5344-6645

10.1136/jitc-2022-004668

Acral 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. Patients 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). In 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. While 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.

link

Journal for immunotherapy of cancer 2022; 10(7): e004668

Journal for immunotherapy of cancer