Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common immune-related adverse event associated with camrelizumab and has been linked to favorable outcomes. We conducted a pooled analysis of two phase III randomized trials, ESCORT (NCT03099382) and ESCORT-1st (NCT03691090), to evaluate the clinical characteristics and prognostic relevance of RCCEP in patients with advanced esophageal squamous cell carcinoma (ESCC) receiving camrelizumab-based therapy. A total of 526 patients treated with camrelizumab, either alone or in combination with chemotherapy, were included. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared according to RCCEP status. Inverse probability of treatment weighting (IPTW) was applied to adjust for baseline imbalances, and a 2-month landmark analysis was performed to reduce lead-time bias. Overall, 420 patients (79.8%) developed RCCEP, mostly grade 1–2 (99.0%), with no RCCEP-related treatment discontinuations. The median onset was 1.18 months, and the duration was 3.12 months. RCCEP-positive patients showed a higher ORR (52.4% vs. 26.4%), longer PFS (5.55 vs. 1.94 months; HR = 0.45), and OS (13.40 vs. 6.11 months; HR = 0.47), consistent after landmark analysis. These findings suggested that RCCEP was frequent yet manageable and may serve as a potential on-treatment biomarker of camrelizumab benefit in ESCC.
| [1] |
F. Bray, M. Laversanne, H. Sung, et al., “Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 74, no. 3 (2024): 229–263.
|
| [2] |
E. Morgan, I. Soerjomataram, H. Rumgay, et al., “The Global Landscape of Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma Incidence and Mortality in 2020 and Projections to 2040: New Estimates from GLOBOCAN 2020,” Gastroenterology 163, no. 3 (2022): 649–658.e2.
|
| [3] |
H. Yang, F. Wang, C. L. Hallemeier, T. Lerut, and J. Fu, “Oesophageal Cancer,” Lancet 404, no. 10466 (2024): 1991–2005.
|
| [4] |
N. Deboever, C. M. Jones, K. Yamashita, J. A. Ajani, and W. L. Hofstetter, “Advances in Diagnosis and Management of Cancer of the Esophagus,” BMJ 385 (2024): e074962.
|
| [5] |
J. Huang, J. Xu, Y. Chen, et al., “Camrelizumab Versus Investigator's Choice of Chemotherapy as Second-Line Therapy for Advanced or Metastatic Oesophageal Squamous Cell Carcinoma (ESCORT): A Multicentre, Randomised, Open-Label, Phase 3 Study,” Lancet Oncology 21, no. 6 (2020): 832–842.
|
| [6] |
H. Luo, J. Lu, Y. Bai, et al., “Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial,” JAMA 326, no. 10 (2021): 916–925.
|
| [7] |
M. Ramos-Casals, J. R. Brahmer, M. K. Callahan, et al., “Immune-Related Adverse Events of Checkpoint Inhibitors,” Nature Reviews Disease Primers 6, no. 1 (2020): 38.
|
| [8] |
K. P. M. Suijkerbuijk, M. J. M. van Eijs, F. van Wijk, and A. M. M. Eggermont, “Clinical and Translational Attributes of Immune-Related Adverse Events,” Nature Reviews Cancer 5, no. 4 (2024): 557–571.
|
| [9] |
V. R. Belum, B. Benhuri, M. A. Postow, et al., “Characterisation and Management of Dermatologic Adverse Events to Agents Targeting the PD-1 Receptor,” European Journal of Cancer 60 (2016): 12–25.
|
| [10] |
X. Chen, L. Ma, X. Wang, et al., “Reactive Capillary Hemangiomas: A Novel Dermatologic Toxicity Following Anti-PD-1 Treatment With SHR-1210,” Cancer Biology & Medicine 16, no. 1 (2019): 173–181.
|
| [11] |
Y. Yang, S. Qu, J. Li, et al., “Camrelizumab Versus Placebo in Combination With Gemcitabine and Cisplatin as First-Line Treatment for Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN-1st): A Multicentre, Randomised, Double-Blind, Phase 3 Trial,” Lancet Oncology 22, no. 8 (2021): 1162–1174.
|
| [12] |
S. Qin, S. L. Chan, S. Gu, et al., “Camrelizumab Plus Rivoceranib Versus Sorafenib as First-Line Therapy for Unresectable Hepatocellular Carcinoma (CARES-310): A Randomised, Open-Label, International Phase 3 Study,” Lancet 402, no. 10408 (2023): 1133–1146.
|
| [13] |
S. Ren, J. Chen, X. Xu, et al., “Camrelizumab Plus Carboplatin and Paclitaxel as First-Line Treatment for Advanced Squamous NSCLC (CameL-Sq): A Phase 3 Trial,” Journal of Thoracic Oncology 17, no. 4 (2022): 544–557.
|
| [14] |
F. Wang, S. Qin, X. Sun, et al., “Reactive Cutaneous Capillary Endothelial Proliferation in Advanced Hepatocellular Carcinoma Patients Treated With Camrelizumab: Data Derived From a Multicenter Phase 2 Trial,” Journal of Hematology & Oncology 13, no. 1 (2020): 47.
|
| [15] |
K. Haratani, H. Hayashi, Y. Chiba, et al., “Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer,” JAMA Oncology 4, no. 3 (2018): 374–378.
|
| [16] |
M. Freeman-Keller, Y. Kim, H. Cronin, A. Richards, G. Gibney, and J. S. Weber, “Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association With Outcomes,” Clinical Cancer Research 22, no. 4 (2016): 886–894.
|
| [17] |
Q. Ding, Y. Liu, H. Ju, et al., “Reactive Cutaneous Capillary Endothelial Proliferation Predicted the Efficacy of Camrelizumab in Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma,” Medicina Oral, Patología Oral, Cirugía Bucal 28, no. 6 (2023): e525–e529.
|
| [18] |
W. Qu, F. Wang, S. Qin, Y. Sun, and C. Huang, “Reactive Cutaneous Capillary Endothelial Proliferation Following Camrelizumab Monotherapy or Combination Therapy for Multi-Cancers: A Large-Scale Pooled Analysis of 10 Studies in China,” Therapeutic Advances in Medical Oncology 16 (2024): 17588359241242607.
|
| [19] |
Y. Song, J. Wu, X. Chen, et al., “A Single-Arm, Multicenter, Phase II Study of Camrelizumab in Relapsed or Refractory Classical Hodgkin Lymphoma,” Clinical Cancer Research 25, no. 24 (2019): 7363–7369.
|
| [20] |
M. A. Postow, R. Sidlow, and M. D. Hellmann, “Immune-Related Adverse Events Associated With Immune Checkpoint Blockade,” New England Journal of Medicine 378, no. 2 (2018): 158–168.
|
| [21] |
B. Shankar, J. Zhang, A. R. Naqash, et al., “Multisystem Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors for Treatment of Non-Small Cell Lung Cancer,” JAMA Oncology 6, no. 12 (2020): 1952–1956.
|
| [22] |
C. Hua, L. Boussemart, C. Mateus, et al., “Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab,” JAMA Dermatology 152, no. 1 (2016): 45–51.
|
| [23] |
T. Fukushima, M. Morimoto, S. Kobayashi, et al., “Association Between Immune-Related Adverse Events and Survival in Patients With Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab,” Oncologist 28, no. 7 (2023): e526–e533.
|
| [24] |
W. Qin, L. Yang, B. Fan, et al., “Association Between Immune-Related Adverse Events and the Efficacy of PD-1 Inhibitors in Advanced Esophageal Cancer,” Frontiers in Immunology 13 (2022): 931429.
|
| [25] |
R. Cao, C. Wu, Y. Lv, et al., “Correlation Between Immune-Related Adverse Events and Treatment Efficacy of Anti-PD1 Immunotherapy in Patients With Esophageal Squamous Cell Carcinoma,” Oncology Letters 25, no. 2 (2023): 55.
|
| [26] |
C. Luchini, F. Bibeau, M. J. L. Ligtenberg, et al., “ESMO Recommendations on Microsatellite Instability Testing for Immunotherapy in Cancer, and Its Relationship With PD-1/PD-L1 Expression and Tumour Mutational Burden: A Systematic Review-Based Approach,” Annals of Oncology 30, no. 8 (2019): 1232–1243.
|
| [27] |
High TMB Predicts Immunotherapy Benefit. Cancer discovery 2018; 8(6): 668.
|
| [28] |
A. Gault, A. E. Anderson, R. Plummer, C. Stewart, A. G. Pratt, and N. Rajan, “Cutaneous Immune-Related Adverse Events in Patients With Melanoma Treated With Checkpoint Inhibitors,” British Journal of Dermatology 185, no. 2 (2021): 263–271.
|
| [29] |
D. Ostroumov, N. Fekete-Drimusz, M. Saborowski, F. Kuhnel, and N. Woller, “CD4 and CD8 T Lymphocyte Interplay in Controlling Tumor Growth,” Cellular and Molecular Life Sciences 75, no. 4 (2018): 689–713.
|
| [30] |
S. J. Hwang, G. Carlos, D. Wakade, et al., “Cutaneous Adverse Events (AEs) of Anti-Programmed Cell Death (PD)-1 Therapy in Patients With Metastatic Melanoma: A Single-Institution Cohort,” Journal of the American Academy of Dermatology 74, no. 3 (2016): 455–461.e1.
|
| [31] |
W. J. J. Finlay, J. E. Coleman, J. S. Edwards, and K. S. Johnson, “Anti-PD1 ‘SHR-1210’ Aberrantly Targets Pro-Angiogenic Receptors and This Polyspecificity Can be Ablated by Paratope Refinement,” mAbs 11, no. 1 (2019): 26–44.
|
| [32] |
G. Micevic, A. Daniels, and R. A. Flavell, “New Insights Into Programmed Cell Death Protein 1 Blockade-Associated Cutaneous Immune-Related Adverse Events,” British Journal of Dermatology 189, no. 4 (2023): 355–357.
|
| [33] |
C. Zhou, Y. Wang, J. Zhao, et al., “Efficacy and Biomarker Analysis of Camrelizumab in Combination With Apatinib in Patients With Advanced Nonsquamous NSCLC Previously Treated With Chemotherapy,” Clinical Cancer Research 27, no. 5 (2021): 1296–1304.
|
| [34] |
C. Lan, J. Shen, Y. Wang, et al., “Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial,” Journal of Clinical Oncology 38, no. 34 (2020): 4095–4106.
|
| [35] |
Y. Liu, T. Chen, C. Zhang, and W. Pan, “Emerging Treatments for Reactive Cutaneous Capillary Endothelial Proliferation,” Indian Journal of Dermatology 68, no. 1 (2023): 85–90.
|
| [36] |
G. Song, F. F. Zhang, and H. D. Cheng, “Thalidomide for Prevention of Camrelizumab-Induced Reactive Cutaneous Capillary Endothelial Proliferation,” Australasian Journal of Dermatology 63, no. 2 (2022): 217–221.
|
| [37] |
C. J. Morgan, “Landmark Analysis: A Primer,” Journal of Nuclear Cardiology 26, no. 2 (2019): 391–393.
|
| [38] |
P. C. Austin and E. A. Stuart, “Moving Towards Best Practice When Using Inverse Probability of Treatment Weighting (IPTW) Using the Propensity Score to Estimate Causal Treatment Effects in Observational Studies,” Statistics in Medicine 34, no. 28 (2015): 3661–3679.
|
Rights & permissions
2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.
PDF
(1236KB)
