Skip to main content
Top
Published in: Journal of Hematology & Oncology 1/2020

01-12-2020 | Hepatocellular Carcinoma | Research

Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial

Authors: Feng Wang, Shukui Qin, Xinchen Sun, Zhenggang Ren, Zhiqiang Meng, Zhendong Chen, Xiaoli Chai, Jianping Xiong, Yuxian Bai, Lin Yang, Hong Zhu, Weijia Fang, Xiaoyan Lin, Xiaoming Chen, Enxiao Li, Linna Wang, Ping Yan, Jianjun Zou

Published in: Journal of Hematology & Oncology | Issue 1/2020

Login to get access

Abstract

Background

Association of immune-related adverse events with tumor response has been reported. Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse event related to camrelizumab, an immune checkpoint inhibitor, but lack of comprehensive analyses. In this study, we conducted comprehensive analyses on RCCEP in advanced hepatocellular carcinoma (HCC) patients treated with camrelizumab monotherapy.

Methods

Data were derived from a Chinese nationwide, multicenter phase 2 trial of camrelizumab in pre-treated advanced HCC. The occurrence, clinicopathological characteristics, and prognostic value of RCCEP were analyzed.

Results

With a median follow-up of 12.5 months, 145 of the 217 camrelizumab-treated patients (66.8%) experienced RCCEP (all grade 1 or 2). RCCEP occurred on the skin surface, mainly on the skin surface of head, face, and trunk. RCCEP could be divided into 5 types including “red-nevus-like,” “pearl-like,” “mulberry-like,” “patch-like,” and “tumor-like,” according to the morphological features. RCCEP biopsy and pathology showed capillary endothelial hyperplasia and capillary hyperplasia in dermis. Significant association between RCCEP occurrence with higher objective response rate was observed (19.3% vs. 5.6%; one-sided p = 0.0044). Compared with those without RCCEP, patients with RCCEP had prolonged progression-free survival (median PFS; 3.2 months vs. 1.9 months; one-sided p < 0.0001) and overall survival (median OS; 17.0 months vs. 5.8 months; one-sided p < 0.0001). In multivariable analyses, the development of RCCEP was significantly associated with prolonged PFS and OS after adjusting for baseline covariates. In addition, the landmark analyses of PFS and OS were consistent with the unadjusted analysis.

Conclusions

RCCEP occurred on the skin surface and was an immune response of skin capillary endothelial cells. RCCEP occurrence positively associated with outcomes of camrelizumab in advanced HCC.
Appendix
Available only for authorised users
Literature
1.
go back to reference Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387:1909–20.CrossRef Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387:1909–20.CrossRef
2.
go back to reference Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374–85.CrossRef Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374–85.CrossRef
3.
go back to reference Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.CrossRef Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.CrossRef
4.
go back to reference Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50.CrossRef Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50.CrossRef
5.
go back to reference Planchard D, Yokoi T, McCleod MJ, Fischer JR, Kim YC, Ballas M, et al. A Phase III Study of Durvalumab (MEDI4736) With or without tremelimumab for previously treated patients with advanced NSCLC: rationale and protocol design of the ARCTIC study. Clin Lung Cancer. 2016;17:232–6.CrossRef Planchard D, Yokoi T, McCleod MJ, Fischer JR, Kim YC, Ballas M, et al. A Phase III Study of Durvalumab (MEDI4736) With or without tremelimumab for previously treated patients with advanced NSCLC: rationale and protocol design of the ARCTIC study. Clin Lung Cancer. 2016;17:232–6.CrossRef
6.
go back to reference Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2016;2:1346–53.CrossRef Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2016;2:1346–53.CrossRef
7.
go back to reference Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal Toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4:1721–8.CrossRef Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal Toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4:1721–8.CrossRef
8.
go back to reference Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5:95.CrossRef Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5:95.CrossRef
9.
go back to reference Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv264–iv6.CrossRef Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv264–iv6.CrossRef
10.
go back to reference Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714–68.CrossRef Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714–68.CrossRef
11.
go back to reference Chinese Society of Clinical Oncology (CSCO). Management of immune checkpoint inhibitor-related toxicity, vol. V1. Beijing: People's Health Publishing House; 2019. Chinese Society of Clinical Oncology (CSCO). Management of immune checkpoint inhibitor-related toxicity, vol. V1. Beijing: People's Health Publishing House; 2019.
12.
go back to reference Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940–52.CrossRef Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940–52.CrossRef
13.
go back to reference El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–502.CrossRef El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–502.CrossRef
14.
go back to reference Qin S, Ren Z, Meng Z, Chen Z, Chai X, Xiong J, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020;21:571–80.CrossRef Qin S, Ren Z, Meng Z, Chen Z, Chai X, Xiong J, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020;21:571–80.CrossRef
15.
go back to reference Finn RS, Ryoo B-Y, Merle P, Kudo M, Bouattour M, Lim H-Y, et al. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). 2019; 37:4004. Finn RS, Ryoo B-Y, Merle P, Kudo M, Bouattour M, Lim H-Y, et al. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). 2019; 37:4004.
16.
go back to reference Yau T, Park JW, Finn RS, Cheng A-L, Mathurin P, Edeline J, et al. LBA38 CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1 L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30:mdz394.029. Yau T, Park JW, Finn RS, Cheng A-L, Mathurin P, Edeline J, et al. LBA38 CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1 L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30:mdz394.029.
17.
go back to reference Cheng AL, Qin S, Ikeda M, Galle P, Ducreux M, Zhu A, et al. LBA3 IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol. 2019;30:mdz446.002. Cheng AL, Qin S, Ikeda M, Galle P, Ducreux M, Zhu A, et al. LBA3 IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol. 2019;30:mdz446.002.
18.
go back to reference Ikeda M, Sung MW, Kudo M, Kobayashi M, Baron AD, Finn RS, et al. 747P a phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results. Ann Oncol. 2019;30:mdz247.073. Ikeda M, Sung MW, Kudo M, Kobayashi M, Baron AD, Finn RS, et al. 747P a phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results. Ann Oncol. 2019;30:mdz247.073.
19.
go back to reference Yau T, Kang Y-K, Kim T-Y, El-Khoueiry AB, Santoro A, Sangro B, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. 2019; 37:4012. Yau T, Kang Y-K, Kim T-Y, El-Khoueiry AB, Santoro A, Sangro B, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. 2019; 37:4012.
20.
go back to reference Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25.CrossRef Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25.CrossRef
21.
go back to reference Huang J, Xu B, Mo H, Zhang W, Chen X, Wu D, et al. Safety, activity, and biomarkers of SHR-1210, an anti-PD-1 antibody, for patients with advanced esophageal carcinoma. Clin Cancer Res. 2018;24:1296–304.CrossRef Huang J, Xu B, Mo H, Zhang W, Chen X, Wu D, et al. Safety, activity, and biomarkers of SHR-1210, an anti-PD-1 antibody, for patients with advanced esophageal carcinoma. Clin Cancer Res. 2018;24:1296–304.CrossRef
22.
go back to reference Fang W, Yang Y, Ma Y, Hong S, Lin L, He X, et al. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol. 2018;19:1338–50.CrossRef Fang W, Yang Y, Ma Y, Hong S, Lin L, He X, et al. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol. 2018;19:1338–50.CrossRef
23.
go back to reference Spratlin JL, Mulder KE, Mackey JR. Ramucirumab (IMC-1121B): a novel attack on angiogenesis. Future Oncol. 2010;6:1085–94.CrossRef Spratlin JL, Mulder KE, Mackey JR. Ramucirumab (IMC-1121B): a novel attack on angiogenesis. Future Oncol. 2010;6:1085–94.CrossRef
24.
go back to reference Lee SJ, Lee SY, Lee WS, Yoo JS, Sun JM, Lee J, et al. Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors. Invest New Drugs. 2017;35:782–90.CrossRef Lee SJ, Lee SY, Lee WS, Yoo JS, Sun JM, Lee J, et al. Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors. Invest New Drugs. 2017;35:782–90.CrossRef
25.
go back to reference Ton NC, Parker GJ, Jackson A, Mullamitha S, Buonaccorsi GA, Roberts C, et al. Phase I evaluation of CDP791, a PEGylated di-Fab' conjugate that binds vascular endothelial growth factor receptor 2. Clin Cancer Res. 2007;13:7113–8.CrossRef Ton NC, Parker GJ, Jackson A, Mullamitha S, Buonaccorsi GA, Roberts C, et al. Phase I evaluation of CDP791, a PEGylated di-Fab' conjugate that binds vascular endothelial growth factor receptor 2. Clin Cancer Res. 2007;13:7113–8.CrossRef
26.
go back to reference Hwang SJ, Carlos G, Wakade D, Byth K, Kong BY, Chou S, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol. 2016;74:455–61.CrossRef Hwang SJ, Carlos G, Wakade D, Byth K, Kong BY, Chou S, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol. 2016;74:455–61.CrossRef
27.
go back to reference Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric Junction Cancer: An Open-label, Dose Escalation and Expansion Study. Clin Cancer Res. 2019;25:515–23.CrossRef Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric Junction Cancer: An Open-label, Dose Escalation and Expansion Study. Clin Cancer Res. 2019;25:515–23.CrossRef
28.
go back to reference Shi VJ, Rodic N, Gettinger S, Leventhal JS, Neckman JP, Girardi M, et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy. JAMA Dermatol. 2016;152:1128–36.CrossRef Shi VJ, Rodic N, Gettinger S, Leventhal JS, Neckman JP, Girardi M, et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy. JAMA Dermatol. 2016;152:1128–36.CrossRef
29.
go back to reference Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152:45–51.CrossRef Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152:45–51.CrossRef
30.
go back to reference Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22:886–94. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22:886–94.
31.
go back to reference Sanlorenzo M, Vujic I, Daud A, Algazi A, Gubens M, Luna SA, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;151:1206–12.CrossRef Sanlorenzo M, Vujic I, Daud A, Algazi A, Gubens M, Luna SA, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;151:1206–12.CrossRef
Metadata
Title
Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial
Authors
Feng Wang
Shukui Qin
Xinchen Sun
Zhenggang Ren
Zhiqiang Meng
Zhendong Chen
Xiaoli Chai
Jianping Xiong
Yuxian Bai
Lin Yang
Hong Zhu
Weijia Fang
Xiaoyan Lin
Xiaoming Chen
Enxiao Li
Linna Wang
Ping Yan
Jianjun Zou
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-020-00886-2

Other articles of this Issue 1/2020

Journal of Hematology & Oncology 1/2020 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine