Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study

F Dimitriou; K Namikawa; I L M Reijers; E I Buchbinder; J A Soon; A Zaremba; P Teterycz; M J Mooradian; E Armstrong; Y Nakamura; M G Vitale; L E Tran; X Bai; C Allayous; S Provent-Roy; A Indini; P Bhave; M Farid; K C Kähler; I Mehmi; V Atkinson; O Klein; C J Stonesifer; F Zaman; A Haydon; R D Carvajal; O Hamid; R Dummer; A Hauschild; M S Carlino; M Mandala; C Robert; C Lebbe; J Guo; D B Johnson; P A Ascierto; A N Shoushtari; R J Sullivan; B Cybulska-Stopa; P Rutkowski; L Zimmer; S Sandhu; C U Blank; S N Lo; A M Menzies; G V Long

doi:10.1016/j.annonc.2022.06.004

Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study

Ann Oncol. 2022 Sep;33(9):968-980. doi: 10.1016/j.annonc.2022.06.004. Epub 2022 Jun 16.

Authors

F Dimitriou¹, K Namikawa², I L M Reijers³, E I Buchbinder⁴, J A Soon⁵, A Zaremba⁶, P Teterycz⁷, M J Mooradian⁸, E Armstrong⁹, Y Nakamura¹⁰, M G Vitale¹¹, L E Tran¹², X Bai¹³, C Allayous¹⁴, S Provent-Roy¹⁵, A Indini¹⁶, P Bhave¹⁷, M Farid¹⁸, K C Kähler¹⁹, I Mehmi²⁰, V Atkinson²¹, O Klein²², C J Stonesifer²³, F Zaman²⁴, A Haydon²⁴, R D Carvajal²³, O Hamid²⁰, R Dummer²⁵, A Hauschild¹⁹, M S Carlino²⁶, M Mandala²⁷, C Robert¹⁵, C Lebbe²⁸, J Guo¹³, D B Johnson¹², P A Ascierto¹¹, A N Shoushtari⁹, R J Sullivan⁸, B Cybulska-Stopa²⁹, P Rutkowski⁷, L Zimmer⁶, S Sandhu⁵, C U Blank³, S N Lo³⁰, A M Menzies³¹, G V Long³²

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Department of Dermatology, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
² Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
³ Department of Medical Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁴ Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, USA.
⁵ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
⁶ Department of Dermatology, University Hospital Essen, Essen, Germany.
⁷ Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
⁸ Division of Oncology and Hematology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
⁹ Department of Medicine, Melanoma Service, Memorial Sloan Kettering Cancer Center, New York, USA.
¹⁰ Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama, Japan.
¹¹ Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale', Napoli, Italy.
¹² Department of Medicine, Vanderbilt University Medical Center, Nashville, USA.
¹³ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, Beijing, China.
¹⁴ APHP Hôpital Saint-Louis, Dermatology Department, DMU ICARE, Paris, France.
¹⁵ Dermatology Service, Department of Medicine, Gustave Roussy and Paris-Saclay University, Villejuif, France.
¹⁶ Unit of Medical Oncology, Ospedale di Circolo e Fondazione Macchi, ASST Sette Laghi, Varese, Italy.
¹⁷ Westmead and Blacktown Hospitals, Sydney, Australia.
¹⁸ Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
¹⁹ Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
²⁰ Department of Hematology/Oncology, The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles, USA.
²¹ Princess Alexandra Hospital, Greenslopes Private Hospital, University of Queensland, Queensland, Australia.
²² Department of Medical Oncology, Austin Health, Melbourne, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, Australia.
²³ Columbia University Irving Medical Center, New York City, USA.
²⁴ Alfred Hospital, Melbourne, Australia.
²⁵ Department of Dermatology, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland.
²⁶ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Westmead and Blacktown Hospitals, Sydney, Australia.
²⁷ Unit of Medical Oncology, University of Perugia, Perugia, Italy.
²⁸ Université de Paris, APHP Hôpital Saint-Louis, Dermatology Department, DMU ICARE, INSERM U-976, Paris, France.
²⁹ Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Cracow, Poland.
³⁰ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
³¹ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia.
³² Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia. Electronic address: Georgina.long@sydney.edu.au.

PMID: 35716907
DOI: 10.1016/j.annonc.2022.06.004

Abstract

Background: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race.

Patients and methods: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted.

Results: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01).

Conclusions: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Keywords: anti-PD-1; ethnicity/race; immunotherapy; ipilimumab; mucosal melanoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols
Cohort Studies
Humans
Ipilimumab / therapeutic use
Lung Neoplasms*
Melanoma* / drug therapy
Melanoma* / pathology
Prognosis
Retrospective Studies

Substances

Ipilimumab