Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study)

Y Nakamura; K Namikawa; S Yoshikawa; Y Kiniwa; T Maekawa; O Yamasaki; T Isei; S Matsushita; M Nomura; Y Nakai; S Fukushima; S Saito; T Takenouchi; R Tanaka; H Kato; A Otsuka; T Matsuya; N Baba; K Nagase; T Inozume; N Fujimoto; Y Kuwatsuka; M Onishi; T Kaneko; T Onuma; Y Umeda; D Ogata; A Takahashi; M Otsuka; Y Teramoto; N Yamazaki

doi:10.1016/j.esmoop.2021.100325

Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study)

ESMO Open. 2021 Dec;6(6):100325. doi: 10.1016/j.esmoop.2021.100325. Epub 2021 Nov 25.

Authors

Y Nakamura¹, K Namikawa², S Yoshikawa³, Y Kiniwa⁴, T Maekawa⁵, O Yamasaki⁶, T Isei⁷, S Matsushita⁸, M Nomura⁹, Y Nakai¹⁰, S Fukushima¹¹, S Saito¹², T Takenouchi¹³, R Tanaka¹⁴, H Kato¹⁵, A Otsuka¹⁶, T Matsuya¹⁷, N Baba¹⁸, K Nagase¹⁹, T Inozume²⁰, N Fujimoto²¹, Y Kuwatsuka²², M Onishi²³, T Kaneko²⁴, T Onuma²⁵, Y Umeda²⁶, D Ogata², A Takahashi², M Otsuka³, Y Teramoto²⁷, N Yamazaki²

Affiliations

¹ Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama, Japan. Electronic address: ynakamur@saitama-med.ac.jp.
² Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
³ Department of Dermatology, Shizuoka Cancer Center, Shizuoka, Japan.
⁴ Department of Dermatology, Shinshu University, Matsumoto, Japan.
⁵ Department of Dermatology, Jichi Medical University, Tochigi, Japan.
⁶ Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
⁷ Department of Dermatologic Oncology, Osaka International Cancer Institute, Osaka, Japan.
⁸ Department of Dermato-Oncology/Dermatology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan.
⁹ Department of Clinical Oncology, Kyoto University, Kyoto, Japan.
¹⁰ Department of Dermatology, Mie University, Tsu, Japan.
¹¹ Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
¹² Department of Dermatology, Gunma University, Maebashi, Japan.
¹³ Department of Dermatology, Niigata Cancer Center, Niigata, Japan.
¹⁴ Department of Dermatology, Kawasaki Medical School, Kurashiki, Japan.
¹⁵ Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
¹⁶ Department of Dermatology, Kyoto University, Kyoto, Japan.
¹⁷ Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
¹⁸ Department of Dermatology, Fukui University, Fukui, Japan.
¹⁹ Division of Dermatology, Department of Internal Medicine, Saga University, Saga, Japan.
²⁰ Department of Dermatology, Chiba University, Chiba, Japan.
²¹ Department of Dermatology, Shiga University of Medical Science, Otsu, Japan.
²² Department of Dermatology, Nagasaki University, Nagasaki, Japan.
²³ Department of Dermatology, Iwate Medical University, Morioka, Japan.
²⁴ Department of Dermatology, Juntendo University Urayasu Hospital, Urayasu, Japan.
²⁵ Department of Dermatology, Yamanashi University, Kofu, Japan.
²⁶ Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama, Japan; Department of Dermatology, Kawasaki Medical School, Kurashiki, Japan.
²⁷ Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama, Japan.

Abstract

Background: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients.

Patients and methods: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4.

Results: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001).

Conclusions: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.

Keywords: anti-CTLA-4 antibody; anti-PD-1 antibody; ipilimumab; mucosal melanoma; nivolumab; pembrolizumab.

Publication types

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

MeSH terms

Aged
CTLA-4 Antigen
Humans
Immunotherapy / methods
Japan
Melanoma* / drug therapy
Retrospective Studies
Skin Neoplasms*

Substances

CTLA-4 Antigen