Cited by 175Cancer Immunotherapy and BiomarkersCutaneous Melanoma Detection and ManagementMelanoma and MAPK Pathways

Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G4 Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial

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Sheng, Xinan, Yan, Xieqiao, Chi, Zhihong, Si, Lu, Cui, Chuanliang, Tang, Bixia, Li, Siming, Mao, Lili +14 more·2019·Journal of Clinical Oncology

Abstract

PURPOSE: Metastatic mucosal melanoma responds poorly to anti–programmed cell death-1 (PD-1) monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. The combination of VEGF inhibition and PD-1 blockade provides therapeutic opportunities for patients refractory to either therapy alone. PATIENTS AND METHODS: We conducted a single-center, phase IB trial evaluating the safety and preliminary efficacy of toripalimab, a humanized immunoglobulin G 4 monoclonal antibody against PD-1 in combination with the VEGF receptor inhibitor axitinib in patients with advanced melanoma, including patients with chemotherapy-naïve mucosal melanomas (88%). Patients received toripalimab at 1 or 3 mg/kg via intravenous infusion every 2 weeks, in combination with axitinib 5 mg orally twice a day, in a dose-escalation and cohort-expansion study until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary objective was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and tumor tissue biomarkers. RESULTS: Thirty-three patients were enrolled. No dose-limiting toxicities were observed. Ninety-seven percent of patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were mild (grade 1 or 2) and included diarrhea, proteinuria, hand and foot syndrome, fatigue, AST or ALT elevation, hypertension, hypo- or hyperthyroidism, and rash. Grade 3 or greater TRAEs occurred in 39.4% of patients. By the cutoff date, among 29 patients with chemotherapy-naïve mucosal melanoma, 14 patients (48.3%; 95% CI, 29.4% to 67.5%) achieved objective response, and the median progression-free survival time was 7.5 months (95% CI, 3.7 months to not reached) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CONCLUSION: The combination of toripalimab plus axitinib was tolerable and showed promising antitumor activity in patients with treatment-naïve metastatic mucosal melanoma. Patients enrolled in this study were all Asian, and this combination therapy must be validated in a randomized phase III trial that includes a non-Asian population before it can become a standard of care.

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  • Combination therapies such as sintilimab plus anlotinib, sintilimab plus IBI305, camrelizumab plus apatinib, and toripalimab plus axitinib demonstrated potent antitumor effects in multiple types of cancers.

    “Combination therapies such as sintilimab plus anlotinib, sintilimab plus IBI305 (bevacizumab biosimilar), camrelizumab plus apatinib, and toripalimab plus axitinib demonstrated potent antitumor effects in multiple types of cancers [22, 114–120].”

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  1. [1]Chang AE Karnell LH Menck HR The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade—The American College of Surgeons Commission on Cancer and the American Cancer Society Cancer 83 1664 1678 1998 9781962

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Authors
Sheng, X., Yan, X., Chi, Z., Si, L., Cui, C., Tang, B., Li, S., Mao, L., Lian, B., Wang, X., Bai, X., Zhou, L., Kong, Y., Dai, J., Wang, K., Tang, X., Zhou, H., Wu, H., Feng, H., Yao, S., Flaherty, K. T., & Guo, J.
Affiliations
  • Peking University Cancer Hospital (CN)
  • OrigiMed, Shanghai, People’s Republic of China
  • Junshi Biosciences (China) (CN)
  • Shanghai Junshi Biosciences, Shanghai, People’s Republic of China
  • Massachusetts General Hospital (US)
Corresponding author
Guo, Jun
Venue
Journal of Clinical Oncology
Published
2019-11-10
Volume
37
Issue
32
Pages
2987-2999
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
OpenAlex
W2967113395
Cited by
175
References
40
Citations by year
2026: 13 · 2025: 10 · 2024: 22 · 2023: 30 · 2022: 36 · 2021: 41 · 2020: 21 · 2019: 2
FWCI
10.45
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Clinical Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Greater South Information System
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
axitinib, toripalimab, mucosal melanoma, metastatic melanoma, anti-PD-1 therapy, VEGF inhibition, combination immunotherapy, immune checkpoint inhibitors, treatment-related adverse events, objective response rate, progression-free survival, tumor microenvironment, immunogenicity, pharmacokinetics, pharmacodynamics, Asian patients, dose escalation, hand-foot syndrome, proteinuria
MeSH terms
Exome Sequencing, Axitinib, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Male, Melanoma, Middle Aged, Mucous Membrane, Vascular Endothelial Growth Factor A, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized

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