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Clinical Trial
. 2021 Jul;26(7):e1110-e1124.
doi: 10.1002/onco.13797. Epub 2021 Jun 5.

Safety and Feasibility of Radiotherapy Plus Camrelizumab for Locally Advanced Esophageal Squamous Cell Carcinoma

Affiliations
Clinical Trial

Safety and Feasibility of Radiotherapy Plus Camrelizumab for Locally Advanced Esophageal Squamous Cell Carcinoma

Wencheng Zhang et al. Oncologist. 2021 Jul.

Abstract

Lessons learned: Radiotherapy plus anti-PD-1 antibody as first-line therapy is safe and feasible in locally advanced esophageal squamous cell carcinoma (ESCC). Tumor-infiltrating and peripheral lymphocytes were associated with patient survival. Further studies combining chemoradiotherapy with immunotherapy in locally advanced ESCC and exploration of predictive biomarkers are warranted.

Background: We conducted a phase Ib study of radiotherapy plus programmed cell death protein 1 (PD-1) monoclonal antibody camrelizumab as first-line treatment for locally advanced esophageal squamous cell carcinoma (ESCC).

Methods: We planned to enroll 20 patients with newly diagnosed locally advanced ESCC. Patients received 60 Gy radiation (2.0 Gy/fraction, 5 fractions/week), with camrelizumab (200 mg every 2 weeks) starting with radiotherapy and continuing for 32 weeks (i.e., for 16 cycles). The primary endpoints were safety and feasibility. Secondary endpoints were rates of radiologic and pathologic response, overall survival (OS), and progression-free survival (PFS). Study data were collected by the week during radiotherapy (RT), every month during the maintenance camrelizumab treatment, and every 3 months after treatment. Tumor microenvironment and peripheral blood were monitored at baseline and after 40 Gy radiation for association with efficacy.

Results: Twenty patients were enrolled and received treatment. One patient (patient 10) was excluded upon discovery of a second tumor in the bladder during treatment, leaving 19 patients for analysis. Toxicity was deemed tolerable. Fourteen (74%) patients had assessed objective response. At a median follow-up time of 31.0 months (95% confidence interval [CI], 27.0-35.1), median OS and PFS times were 16.7 months (95% CI, 5.9-27.9) and 11.7 months (95% CI, 0-30.3), respectively. OS and PFS rates at 24 months were 31.6% and 35.5%, respectively. Kaplan-Meier analysis revealed associations between the following factors and OS/PFS: tumor programmed cell death ligand 1 (PD-L1) expression, PD-1+ CD8+ , PD-1+ CD4+ T cells, and PD-L1+ CD4+ T cells; peripheral blood CD4+ , CD8+ , CD4+ regulatory T cells, and their subsets.

Conclusion: Radiotherapy plus camrelizumab had manageable toxicity and antitumor efficacy for locally advanced ESCC. Several biomarkers were associated with clinical benefit and deserve further study.

Keywords: Camrelizumab; Esophageal cancer; Immunotherapy; PD-1; Radiotherapy.

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Figures

Figure 1
Figure 1
Antitumor efficacy of combining radiotherapy and SHR‐1210. (A): Treatment exposure and response duration. The length of each bar represents the time to the last radiographic assessment according to RECIST version 1.1. Clinical and pathological features (smoking status, drinking history, clinical disease stage, and pathological test for residual tumor cells after 40 Gy) are shown for each patient (per RECIST version 1.1 by investigator review). (B): Overall survival. (C): Progression‐free survival. (D): Local recurrence–free survival. (E): Distant metastasis–free survival. Abbreviations: DMFS, distant metastasis–free survival; LRFS, local recurrence–free survival; OS, overall survival; PD‐L1, programmed cell death ligand 1; PFS, progression‐free survival; Pt, patient.
Figure 2
Figure 2
Consortium diagram and treatment schedule. (A): Consortium diagram. (B): Clinical treatment schedule. Abbreviations: CT, chemotherapy; IF, immunofluorescence; PD‐1, programmed cell death protein 1; Q2W, every 2 weeks; RT, radiotherapy; TME, tumor microenvironment.
Figure 3
Figure 3
Multiplex staining for tumor‐infiltrating T cells in esophageal squamous cell carcinoma tissue sections. Representative images of a patient (patient 3) who had a major pathological response. The PD‐1 and PD‐L1 expression during treatment decreased compared with that before treatment, whereas CD4+ and CD8+ T cells accumulated during treatment. Abbreviations: FOXP3, forkhead box P3; PANCK, pan Cytokeratin; PD1, programmed cell death protein 1; PDL1, programmed cell death ligand 1; PPDDAPIA, DAPI.
Figure 4
Figure 4
Dynamics of tumor‐infiltrating T cells at baseline and during treatment. Pairs of biopsy tumor tissues that were collected before treatment (at baseline) and during treatment after 40 Gy radiotherapy were stained using a multiplex immunofluorescence method. Paired t test was used to evaluate the differences in multiple T‐cell subsets between at baseline and on‐treatment timepoint. p < .05, significant difference. Abbreviations: PD‐1, programmed cell death protein 1; PD‐L1, programmed cell death ligand 1.
Figure 5
Figure 5
Intratumoral T cells were associated with clinical outcomes. Kaplan‐Meier curves for overall survival and progression‐free survival of patients in tumor tissue programmed cell death ligand 1 (PD‐L1) expression (A), programmed cell death protein 1 (PD‐1)+CD8+ T cells (B), PD‐L1+CD4+ T cells (C), and PD‐1+CD4+ T cells (D) at baseline and PD‐1+CD4+ T cells (E) during treatment. Log‐rank p values are reported from an unadjusted analysis. The cutoff values were determined by calculated by the Youden index of the receiver operating characteristic curve. Abbreviations: BL, baseline; CI, confidence interval; OS, overall survival; PFS, progression‐free survival; RT, radiotherapy (during treatment).
Figure 6
Figure 6
Dynamics of peripheral blood T cells at baseline and during treatment. Pairs of EDTA‐anticoagulant peripheral blood specimens were collected at baseline and during treatment after 40 Gy radiotherapy. Flow cytometry was used to identify T‐cell subsets and PD‐1/PD‐L1 expression. Paired t test was used to evaluate the differences in T‐cell subpopulations between at baseline and during treatment timepoint. p < .05, significant difference. Abbreviations: Lym, lymphocyte; PBMC, peripheral blood mononuclear cell; PD‐1, programmed cell death protein 1; PD‐L1, programmed cell death ligand 1; Treg, regulatory T cell.
Figure 7
Figure 7
Kaplan‐Meier estimates of overall survival and progression‐free survival in patients in peripheral blood T‐cell subsets predicting prognosis over time. (A): CD4+ T cells and their subsets at baseline or during treatment were associated with OS and PFS. (B): CD8+ T cells and their subsets at baseline or during treatment were associated with OS and PFS. (C): CD4+CD25+Foxp3+ Treg cells and their subsets during treatment were associated with OS and PFS. The cutoff values were determined by calculated by the Youden index of the receiver operating characteristic curve. Log‐rank p values are reported from an unadjusted analysis. Abbreviations: BL, baseline; CI, confidence interval; CTLA4, cytotoxic T‐lymphocyte–associated protein 4; IFN‐r, Interferon‐gamma; Lymph, lymphocyte; OS, overall survival; PFS, progression‐free survival; RT, radiotherapy (during treatment); Treg, regulatory T cell.

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