|Year : 2022 | Volume
| Issue : 2 | Page : 545-552
PD-1 inhibitor monotherapy versus combination therapy: A real-world study of patients with recurrent or metastatic advanced esophageal squamous cell carcinoma after first-line chemotherapy
Guanli Yang1, Hongfu Sun1, Chunyang Zhou2, Nini Sun3, Lixia Xu4, Wei Huang1, Baosheng Li1
1 Department of Radiation Oncology, Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University; Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
2 Department of Radiation Oncology, Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
3 Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
4 Department of Radiation Oncology, the Zhangqiu District People's Hospital of Jinan, Shandong, China
|Date of Submission||15-Jan-2022|
|Date of Decision||13-Mar-2022|
|Date of Acceptance||18-Mar-2022|
|Date of Web Publication||20-May-2022|
Department of Radiation Oncology, Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012; and Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan - 250002
Department of Radiation Oncology, Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong - 250012
Source of Support: None, Conflict of Interest: None
Context: Although programmed death 1 (PD-1) inhibitors are a standard second-line treatment for esophageal squamous cell carcinoma (ESCC), their efficacy when used in combination with chemotherapy or anti-angiogenesis targeted therapy is unclear.
Aim: To compare the efficacy and safety of PD-1 inhibitor monotherapy with that of combination therapy.
Setting and Design: A retrospective study was conducted at the Shandong Cancer Hospital.
Materials and Methods: Based on records, patients with advanced ESCC, treated with second-line or above PD-1 inhibitor-containing regimens from August 15, 2019 to April 12, 2021 were divided into combination (PD-1 inhibitors plus chemotherapy or anti-angiogenesis targeted therapy) and monotherapy groups. The primary endpoints were progression-free survival (PFS) and overall survival (OS).
Statistical Analysis Used: The baseline differences between subgroups were assessed using the χ2-test, Fisher's exact test, or Student's t-test. Follow-up period, PFS, OS, median survival, and 95% confidence intervals (CIs) were estimated using Kaplan‒Meier analysis. The log-rank test was used to compare subgroups.
Results: In the 169 patients included, clinical features were well balanced between both groups. The median PFS of the combination group was better than that of the monotherapy group (8.5 months [95%CI 6.3–10.7] vs. 3.2 months [95%CI 0.0–6.5]; hazard ratio (HR) = 0.34 [95%CI 0.13–0.92]; P < 0.001). The median OS showed the same trend (18.9 months [95%CI 14.4–23.3] vs. 9.8 months [95%CI 6.3–13.2]; HR = 0.47 [95%CI 0.21–1.04]; P = 0.010).
Conclusion: Using PD-1 inhibitors in a combination treatment may improve PFS and OS, with acceptable toxicities.
Keywords: Anti-angiogenesis targeted therapy, Chemotherapy, Esophageal squamous cell carcinoma, Immunotherapy
|How to cite this article:|
Yang G, Sun H, Zhou C, Sun N, Xu L, Huang W, Li B. PD-1 inhibitor monotherapy versus combination therapy: A real-world study of patients with recurrent or metastatic advanced esophageal squamous cell carcinoma after first-line chemotherapy. J Can Res Ther 2022;18:545-52
|How to cite this URL:|
Yang G, Sun H, Zhou C, Sun N, Xu L, Huang W, Li B. PD-1 inhibitor monotherapy versus combination therapy: A real-world study of patients with recurrent or metastatic advanced esophageal squamous cell carcinoma after first-line chemotherapy. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:545-52. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/545/345524
Guanli Yang and Hongfu Sun Co.first authors contributed equally.
Wei Huang and Baosheng Li Co.corresponding authors contributed equally.
| > Introduction|| |
Esophageal cancer (EC) is the eighth most common cancer and the sixth leading cause of cancer-related deaths worldwide. The major histological subtypes of EC include squamous cell carcinoma and adenocarcinoma. The prognosis is typically poor in patients with EC with a 5-year survival rate in metastatic cases of <5%., Moreover, 90% of ECs are squamous cell carcinomas.
Fluoropyrimidine and platinum-based duplex chemotherapy are recommended as first-line treatments for advanced EC., When first-line chemotherapy fails, the posterior-line treatment is mainly palliative chemotherapy, including docetaxel, paclitaxel, or irinotecan. Due to adverse events (AEs) and drug resistance, the chemotherapy survival benefit is very limited.
Immunotherapy significantly prolongs survival in advanced esophageal squamous cell carcinoma (ESCC) patients and has become a standard second-line treatment for ESCC, despite its limited absolute survival benefit (progression-free survival [PFS], 2–4 months; median overall survival [OS], 8–10 months).,, Therefore, in the real world, combination therapy is often used to improve patients' survival. However, the survival benefits and toxicity tolerance of this combination therapy are not well established and therefore merit further investigation.
Chemotherapy combined with immunotherapy has been studied in multiple solid tumors, particularly non-small-cell lung cancer, as well as in first-line EC therapy, providing wider treatment options with improved outcomes., Additionally, combination therapy with immune checkpoint inhibitors and anti-angiogenesis targeted therapy has received widespread attention.,
Here, we compared the anti-tumor activity and safety of programmed death 1 (PD-1) inhibitor monotherapy and combination therapy in patients with previously treated, locally advanced, or metastatic ESCC.
| > Materials and Methods|| |
Study population and eligibility criteria
We reviewed the clinical records of patients with recurrent or metastatic ESCC who were treated with immunotherapy at Shandong Cancer Hospital and Institute between August 15, 2019 and April 12, 2021. Inclusion criteria were age >18 years, histopathologically confirmed ESCC, received immunotherapy, and imaging and medical records of disease progression after last-line chemotherapy were available. We judged patients as having a progressive disease (PD) of target or non-target lesions or new lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guideline, based on physical examination, hematological examination, enhanced computed tomography (CT), magnetic resonance imaging (MRI), or positron-emission tomography/CT, including neck, chest, abdomen, and barium-swallow radiography. All patients underwent follow-up every 3‒6 months throughout the last line of chemotherapy. Exclusion criteria were histopathological confirmation of other types of EC, fewer than two courses of immunotherapy, and incomplete medical records. To reduce bias, patients who received first-line immunotherapy were excluded. The approval from the ethics committee was obtained. The date of the approval was on April 11, 2022.
This retrospective study was approved by the institutional review board of Shandong Cancer Hospital. The requirement for obtaining informed patient consent was waived by the board due to the retrospective nature of this study. All methods were performed according to relevant guidelines and regulations. Patient records were anonymized and de-identified before data analysis.
The patients were divided into two groups according to the therapy regimen. Patients receiving PD-1 inhibitor monotherapy were assigned to the monotherapy group, and those receiving combined treatment were assigned to the combination group. Depending on the different combinations of drugs, the latter was subdivided into IT (PD-1 inhibitors plus anti-angiogenesis targeted therapy) and IC (PD-1 inhibitors plus chemotherapy) groups. The primary endpoints were PFS and OS. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and AEs. PFS was calculated from the date of initial treatment until the date of disease progression or death from any cause. OS was calculated as the period between the date of initial treatment and the date of death or until the time of the last follow-up. ORR and DCR were evaluated within 1 month after treatment completion, according to the RECIST version 1.1. AEs, including abnormalities in laboratory tests, were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
We compared baseline differences in patient characteristics between the subgroups using the χ2-test, Fisher's exact test, or Student's t-test. Follow-up period, PFS, OS, median survival, and 95% confidence intervals (CIs) were estimated using Kaplan‒Meier analysis, and the log-rank test was used to compare subgroups. Multivariate Cox proportional hazards modeling was used to determine HRs, including 95%CIs, for PFS and OS. Results were considered significant at P < 0.05. Statistical analysis of all data was performed using R software version 3.6.0 (https://www.r-project.org/) and SPSS 25.0.
| > Results|| |
A total of 169 patients were included in the final analysis (monotherapy: 18 patients; combination: 151 patients, IT: 28 patients; IC: 123 patients). [Table 1] shows the clinical features of the two groups. The last follow-up was on December 15, 2021. The median follow-up periods of the monotherapy and combination groups were 13.9 months (range 9.7–18.2 months) and 14.0 months (range 12.4–15.6 months), respectively.
Patients' characteristics and treatment characteristics
The baseline demographic and disease characteristics between groups were similar [Table 1]. Overall, 28 (16.6%) patients were aged ≥65 years, 145 (85.8%) were men, and 161 (95.3%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. Of 161 patients, recurrent or metastatic advanced disease; 84 (49.7%) had undergone esophagectomy; 126 (74.6%) had a history of radiotherapy for primary or metastatic lesions; and 58 (34.3%) received radiotherapy, either sequentially or concurrently with anti-PD-1 therapy.
Treatment regimens included PD-1 inhibitor monotherapy, PD-1 inhibitors plus anti-angiogenesis targeted therapy, and PD-1 inhibitors plus chemotherapy, and the agents used are listed in [Table 2]. The dosage of all PD-1 inhibitors was as recommended, and in combination therapy, most patients received a standard dosage of chemotherapy and anti-angiogenesis targeted therapy, with only a few patients receiving a reduced dosage.
The proportion of patients who received certain treatment regimens is also shown in [Table 2], and their completion rates are summarized in [Table 3].
Progression-free survival (PFS)
By the time of the primary endpoint analysis (December 15, 2021), 11 (61.1%) and 87 (57.6%) patients in the monotherapy and combination groups, respectively, had disease progression. The 6-month PFS rates were 5.6% and 49.7% in the monotherapy and combination groups, respectively The median PFS was 3.2 (95%CI 0.0–6.5) months and 8.5 (6.3–10.7) months in monotherapy and combination groups, respectively (HR 0.34 [95%CI 0.13–0.92]; P < 0.001; [Figure 1]). This difference remained significant in multivariable analysis (HR 0.33 [95%CI 0.17–0.64]; P = 0.001; [Figure 2]).
|Figure 1: Kaplan–Meier curves for PFS between the mono group and combo group and between the IT group and IC group|
Click here to view
We also compared the survival rates of the IT and IC groups. The median PFS was 10.9 (95%CI 1.9–19.9) months and 8.0 (5.7–10.3) months in the IT and IC groups, respectively (P = 0.711; [Figure 1]). None of the other parameters were significantly associated with PFS [Figure 2].
Overall survival (OS)
At 1 year, 5 (27.8%) patients in the monotherapy group were alive, compared with 60 (39.7%) patients in the combination group (8 [28.6%] and 52 [42.3%] patients in the IT and IC groups, respectively). The median OS was 9.8 (95%CI 6.3–13.2) months and 18.9 (14.4–23.3) months in the monotherapy and combination groups, respectively (HR 0.47 [95%CI 0.21–1.04]; P = 0.010; [Figure 3]). OS was similar between the IT and IC groups (19.3 [95%CI 8.6–30.0] months vs. 18.9 [95%CI 14.0–23.7] months) (HR 0.91 [95%CI 0.47–1.77]; P = 0.768; [Figure 3]). OS was similar between the monotherapy and combination groups in the multivariable analysis (HR 0.53 [95%CI 0.28–1.00]; P = 0.051; [Figure 4]).
|Figure 3: Kaplan–Meier curves for OS between the mono group and combo group and between the IT group and IC group|
Click here to view
Response to immunotherapy in patients
Overall, the ORR was 34.3% among all patients (58/169), with 2 patients having a complete response and 56 patients having a partial response. The ORR was 11.1% (2/18) and 37.1% (56/151) in the monotherapy and combination therapy groups, respectively (χ2-value = 4.81, P value = 0.028). The DCR was 85.8% among all patients (145/169), with no difference between the groups (χ2-value = 0.00, P value = 1.000) [Table 4].
The IC group experienced more AEs related to marrow suppression, gastrointestinal symptoms, reactive cutaneous capillary endothelial proliferation, and pneumonitis. AEs, including high blood pressure, hepatic injury, cardiac dysfunction, and hypothyroidism, were more frequent in the IT group, indicating that the combined regimens were more toxic than monotherapy. Treatment-related AEs occurred in 88.9%, 82.1%, and 99.2% of patients in the monotherapy, IT, and IC groups, respectively. Grade ≥3 treatment-related AEs occurred in 16.7%, 28.6%, and 43.9% of patients in these groups, respectively. Treatment-related AEs that leading to discontinuation were more common in the combination group. No treatment-related deaths occurred in any group. Overall, the frequency of any-grade AEs was slightly higher in the combination group than in the monotherapy group (96.0% vs. 88.9%, P = 0.447). Compared with the monotherapy group, the frequency of grade ≥3 AEs was significantly higher in the combination group (41.1% vs. 16.7%; P = 0.044) [Table 5].
| > Discussion|| |
In recent years, Immune checkpoint inhibitors (ICI) s have changed the therapeutic strategy for advanced solid cancer. Currently, immunotherapy and combination immunotherapy have been the hot topics., Several preclinical studies have found that certain chemotherapeutic agents can eliminate or regulate immunosuppressive cells in the tumor microenvironment (TME). For example, fluorouracil and cisplatin can effectively eliminate bone marrow-derived suppressive cells and thus exert immunostimulatory effects. When the immune checkpoint is suppressed, tumor cells may become more sensitive to cytotoxic drugs after being attacked by T cells. Thus, immunotherapy plus chemotherapy can trigger the host production of long-lasting and effective tumor antigen-specific T lymphocytes and synergistically optimize anti-tumor effects., Moreover, anti-angiogenic drugs can normalize blood vessels in the TME, increasing infiltration of immune effector cells in tumor tissue, thus transforming the inherent immuno-suppressive TME into an immune-promoting microenvironment. In other words, immunotherapy plus anti-angiogenesis targeted therapy can improve therapeutic response by regulating the tumor vasculature and the tumor immune microenvironment.
In this retrospective study, we compared the efficacy and safety of PD-1 inhibitor monotherapy with that of combination therapy in advanced ESCC. The combination treatment yielded a better PFS and OS than did monotherapy. The frequency of grade ≥3 AEs was significantly higher in the combination than in the monotherapy group, but toxicities were acceptable.
Our study had various strengths. First, no previous study had compared the efficacy and safety of PD-1 inhibitor monotherapy and combination therapy with chemotherapy or anti-angiogenesis targeted therapy as second-line or above-line treatments for patients with advanced ESCC. Most of our patients received a standard dose of chemotherapy and anti-angiogenesis targeted therapy. Only a few patients received a reduced dose, mainly due to old age or poor physical fitness, where a discretionary 20% dosage reduction in chemotherapy may be decided by the attending physician. Patients aged ≥ 65 years were not excluded from our study, and the results did not show more serious AEs. In the pre-immune era, the toxicity caused by chemoradiation in elderly patients was that we need to consider, but according to studies, patients with good functional status should not be excluded from therapy based on age alone, which is also the same in the era of immunotherapy.
This study also had several limitations. First, this was a retrospective, single-center study, which might have involved patient selection bias. Second, because the timing and frequency of image evaluation differed across patients, subjective bias could have been present. Nevertheless, all patients were regularly followed-up every 1–2 months at the outpatient clinic and were examined by X-ray, CT, and MRI every 3–6 months. Finally, some AEs were possibly overlooked because they were collected solely from medical records. However, the frequency of AEs did not differ significantly between previous clinical trials and the current study.
In our study, the median PFS was 3.2, 10.9, and 8.0 months, whereas the median OS was 9.8, 19.3, and 18.9 months in the monotherapy, IT, and IC groups, respectively, indicating the superiority of the combination therapy. In previous clinical trials, the PFS and OS with monotherapy was approximately 2–4 and 8–12 months, respectively.,, In our study, the ORR was 11.1% and 37.1% in the monotherapy and combination therapy groups, respectively, while it was approximately 10‒20% in clinical trials of monotherapy.,,
The relationship between ORR, PFS, and OS should be considered when assessing immunotherapy efficacy, as short-term remission and control rates do not necessarily correlate with long-term survival. Immunotherapy has a delayed effect, and some patients may demonstrate false progression. Thus, the time points and methods of efficacy evaluation require further improvement, and the new immune-related RECIST will allow more reasonable evaluation of immunotherapy benefits.
Immune checkpoint inhibitors are associated with a lower incidence of treatment-related AEs than are conventional cytotoxic agents. However, in some cases, serious immune-related AEs, such as pneumonia and myocarditis have been reported. Therefore, the safety of the combination treatment should be considered. Overall, combined therapy did not increase any-grade AEs as compared with monotherapy in our study. The frequency of grades 3‒5 AEs was 16.7%, 28.6%, and 43.9% in the monotherapy, IT, and IC groups, respectively. Similarly, in the KEYNOTE-181 trial, grades 3‒5 treatment-related AEs occurred in 18% of patients in the pembrolizumab group and in 40.9% of patients in the chemotherapy group. In the KEYNOTE-590 trial, pembrolizumab combined with chemotherapy versus chemotherapy for first-line treatment of advanced or metastatic EC found treatment-related AEs of grades 3‒5 in 72% and 68% in the combination therapy and chemotherapy groups, while the incidence of AE-related treatment discontinuation was 19% and 12%, respectively. The higher AE incidence in this study may be related to the application of sufficient cytotoxic drugs in first-line chemotherapy. It was similar in other solid tumors that combination therapies proved to be more effective than either of the individual therapies, although higher grade 3–4 adverse effects were observed than in individual monotherapies. In our study, the incidence of high blood pressure in IT subgroup was 10.7%, which was similar to previous studies. And the treatment discontinuation rate in the combined therapy was approximately 4.6%, and that in monotherapy was 5.6%, comparable with previously reported. It is inevitable that combination therapy would demonstrate more, although acceptable, treatment-related AEs. Therefore, clinicians need to choose the appropriate treatment regimens carefully according to the physical condition of the patient.
In conclusion, the combination therapy resulted in substantial improvements in PFS, OS, and ORR as compared with PD-1 inhibitor monotherapy. Thus, PD-1 inhibitors plus anti-angiogenesis targeted therapy or chemotherapy would be a valid second-line or therapeutic option for patients with advanced ESCC. Although the combination therapy is slightly more toxic, the toxicity levels are acceptable. Further research is critical to design safer and more efficacious combinations and to address biomarker selection to predict the clinical efficacy and prognosis of ICIs in ESCC.
This work was supported by the National Natural Science Foundation of China (grant numbers 81874224 and 81773232) and the Academic Promotion Program of Shandong First Medical University (grant numbers 2019LJ004 and 2020RC002).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]