The efficacy and safety analysis of immunotherapy combined with chemotherapy with or without targeted therapy versus chemotherapy alone as second-line treatment for advanced biliary tract malignant tumors

doi:10.21203/rs.3.rs-4897017/v1

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Research Article

The efficacy and safety analysis of immunotherapy combined with chemotherapy with or without targeted therapy versus chemotherapy alone as second-line treatment for advanced biliary tract malignant tumors

https://doi.org/10.21203/rs.3.rs-4897017/v1

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Objective

The treatment of biliary tract cancer (BTC) keep still limited, especially after the progress of first-line treatment. Immune checkpoint inhibitors (ICIs) have been proved effects in various of solid tumors, so as BTC. But their efficacy and safety in patients with advanced BTC are still need further exploration.

Methods

The clinical information of 126 patients diagnosed with advanced BTC between 2014 and 2024 who received the first-line therapy or neoadjuvant therapy but assessing progress or intolerance were retrospectively reviewed. All patients were treated with chemotherapy, while 57 of them were treated with ICIs in combination targeted therapy or not, the other 69 of them were not. Therefore, we divided the patients into two groups, SC (simple chemotherapy) and CT (combined treatment), then we analyzed the benefit of adding ICIs with or without targeted therapy according to efficacy, adverse events, progression-free survival (PFS), overall survival (OS), progressive disease (PD), and the influence of various factors and effectiveness.

Results

The mean PFS was 4.68 months for CT group and 3.50 months for SC group. And the mean OS was 30.26 months for CT group and 17.14 months for SC group. The PFS and OS were prolonged by 1.18 months and 13.12 months with ICIs with or without targeted therapy respectively, and the difference were statistically significant (p = 0.0012; p < 0.001). The objective response rate (ORR) was 5.26% (3/57) for the CT group versus 1.45% (1/69) for the SC group, and the disease control rate (DCR) was 54.39% (31/57) versus 33.33% (23/69), respectively. Regression analysis demonstrated that factors such as TNM stage, T stage, histological grade, whether CA199 decreased, and therapeutic evaluation grade were related to OS (p < 0.05). For the treatment-related adverse events (TRAEs), the highest grade 3–4 adverse effects was hemoglobin count decreased (29.37%).

Conclusion

Our study showed that ICIs combined with chemotherapy with or without targeted therapy exhibited good antitumor activity with acceptable safety and could be recommended as second-line treatment for patients with advanced BTC.

advanced biliary cancer

chemotherapy

immunotherapy

efficacy

safety

second-line treatment

Biliary tract cancer (BTC) accounts for approximately 3% of digestive malignancies and is a rare tumor with high malignancy, rapid progression, and extremely poor prognosis^{[1, 2]}, less than 20% of patients with advanced BTC have the opportunity for surgery and the 5-year postoperative survival rate is approximately 7%-20%^{[3, 4]}. Once a patient is diagnosed with advanced BTC, there are fewer effective therapies available, primarily gemcitabine-based chemotherapy^[5], but it may not significantly improve patient survival and it will progress soon. However, the efficacy of back-line is limited. Targeted therapies including targets such as human epidermal growth factor receptor 2 (HER2; NCT04722133)^[6], fibroblast growth factor receptor 2 (FGFR2; NCT02052778, NCT02924376)^{[7, 8]}, and isocitrate dehydrogenase 1 (IDH1; NCT02989857)^[9] have been testing in several large-scale clinical trials. Unfortunately, only a few number of patients are eligible to be applied.

In recent years, immunotherapy has been used in solid tumors and achieved great efficacy^[10–12], it has also shown in certain potential in BTC^[13]. In TOPAZ-1 trial^[14], the mOS and mPFS of patients treated with durvalumab in combination with chemotherapy were 12.8 months and 7.2 months, which demonstrated better efficacy than chemotherapy alone. The KEYNOTE-028 clinical trial^[15] shown that the mOS and mPFS for patients treated with pembrolizumab were 5.7 months and 1.8 months. The similar result also shown in the KEYNOTE-158 clinical trial^[16], the mOS and mPFS were 7.4 months and 2.0 months. Although these aforementioned clinical trials are almost phase I/II^[15–17], it can still be found that patients with advanced BTC may benefit from single-agent immunotherapy. However, in several clinical trials using distinct immune checkpoint inhibitors (ICIs) for subsequent treatments in patients with advanced BTC after first-line treatment failure, ICIs did not demonstrate superior efficacy.

Given the fact that ICI combined with chemotherapy has shown good efficacy in second-line treatment of various solid tumors, but there is still a lack of evidence to support the combination in second-line treatment of patients with advanced BTC, considering several clinical trials shown limited positive results. Therefore, we carried out this retrospective study to explore the practical value of ICI in the second-line treatment of patients with advanced BTC, the primary goal is to provide clinical evidences to support the use of ICI in combination with chemotherapy with or without targeted therapy as second-line therapy for patients with advanced BTC.

2.1 The inclusion and exclusion criterion

Our study included patients with advanced BTC who were treated at Harbin Medical University Cancer Hospital from 2014 to 2024. The inclusion criteria were as follows: (1) pathologically diagnosis as BTC, including ICCA, HCCA, DCCA ,VPC and GCA; (2) patients with advanced BTC with measurable target lesions on the basis of response evaluation criteria in solid tumours (RECIST) 1.1; (3) receiving the first-line therapy or neoadjuvant therapy but assessing progress or intolerance; (4) receiving the second-line therapy at least two single regimen cycles, had at least one efficacy evaluation; (5) Eastern Cooperative Oncology Group (ECOG) Score: 0–2 points. The exclusion criteria were as follows: (1) had no measurable target lesions; (2) pathologically diagnosis confirmed the presence of other tumors; (3) missing or incomplete clinical data; (4) had no complete follow-up information.

2.2 Therapeutic regimen

Combined treatment group (chemotherapy in combined with immunotherapy with or without target therapy, experimental group): patients received statistical chemotherapy regimens of the second-line (GP, GS and GEMOX) + ICIs. The single chemotherapy group (control group): standard chemotherapy regimens of the second-line alone. The treatment plan is based on the Chinese Society of Clinical Oncology (CSCO) guidelines.

2.3 Research Methods

2.3.1 Clinical information

The clinical information includes patients’ name, gender, age, height, weight, history of tobacco and alcohol, the time of pathological diagnosis, the primary site of tumors, degree of histological differentiation, degree of TNM, ECOG score, combined with hepatic or other site metastases or not, have been treated for surgery or not, whether neoadjuvant or adjuvant therapy or not, combined with radiotherapy or not, combined with ablation treatment or not, combined with hepatic arterial perfusion chemotherapy or not, with additional ICIs treatment or not, different types of ICIs, with additional target therapy or not, different types of target drug, efficacy evaluation, the time to disease progression, the cause of disease progression, results of the hematological examination, imaging examination findings, genetic test results, treatment-related adverse events (TRAEs), survival status up to the last follow-up visit, time of death, the cause of death, etc.

Follow-up data included visits to hospital case data, readmissions, and telephone contacts. The most recent follow-up visit took place in May 2024. Progression-free survival(PFS) was defined as the time from the start of the first course of treatment until the patients’ progression or death, OS(not yet reached OS) is the time from the start of the course of treatment until death(for any reasons).

Ethical statement: The retrospective study was approved by the Ethics Committee of Harbin Medical University Cancer Hospital prior to conducting the study(approve number is: KY2023-22)

2.3.2 Response evaluation criteria

The effectiveness of both group was assessed using the Response Evaluation Criteria in solid tumors(RECIST1.1), which can be further divided into complete response(CR), partial response(PR), stable disease(SD), and progressive disease(PD). If the combined treatment group(CG) has a negative progression after evaluation, it will be reassessed according to the modified RECIST1.1(iRECIST1.1). We classified TRAEs according to Toxicity Criteria version 5.0. Disease control rate(DCR) is defined as the proportion of PD cases post-medication, and ORR is defined as the percentage of patients with CRs and PRs.

2.3.3 Statistical methodology

SPSS V22.0 software (IBM Corp) and R (Version 4.3.2) was used for statistical analysis. Report continuous measurement data that follows a normal distribution is the mean (standard deviation), and those do not obey the normal distribution are presented as the median (first quartile, third quartile). Categorical variables were expressed as the number of cases (percentage), and the X²test or Fisher test was used for comparison between two groups. Survival curves were constructed using the Kaplan-Meier method and log-rank test used for comparison. COX proportional hazard analysis was used to conduct univariate and multivariate analysis to explore the impart of variables on survival rate. P<0.05 indicated statistical significance.

3.1 Analysis of clinical data in both arms

The current study enrolled 126 patients with advanced BTC receiving second-line treatment (Figure 1 and Table 1). Patients were divided into two groups, the simple chemotherapy group(SC group) and the combined treatment group (CT group), according to whether additional ICIs with or without target therapy were treated. The SC group had 69 patients, and the CT group included 57 patients. The ECOG score range of all patients was 0-2. No significant differences were observed between the two groups in terms of differences in age(p=0.214), ECOG score(p=0.372), diagnosis(p=0.125), T stage(p=0.432), N stage(p=0.06), hepatic metastases status(p=0.245), multisite metastasis status(p=1), whether surgery(p=0.201), CEA(p=0.662) and CA199(p=0.615) before treatment.

3.2 Patient outcomes and survival analysis

All 126 patients received at least two treatments on a regular basis and had at least one efficacy assessment. In the CT group, 5.26% (3/57) of patients achieved PR, 49.1% (28/57) of patients achieved SD and 45.6% (26/57) of patients achieved PD. In the SC group, 1.45% (1/69) of patients achieved PR, 31.9% (22/69) of patients achieved SD and 52.2% (36/69) of patients achieved PD. All two arms showed that without patients were achieved CR. The ORR rate of the combined treatment group (5.26%) show better than that of the simple chemotherapy group (1.45%), but did not show significant difference between these two groups(p=0.157). The DCR of the combined group was 54.39%, which was better than the 33.33% of the simple chemotherapy group, no significant difference between these two groups was found (p=0.157)(Table 1). In the CT group, the most common immune drug was sintilimab (43.9%) and the most common target drug was lenvatinib (24.6%). The survival curve demonstrate that OS and PFS in the CT group (30.26±26.54; 4.68±4.93) was significantly higher than that in the SC group(17.14±7.19; 3.50±3.19)(p<0.001;p=0.0012)(Figure 2). In the subgroup analysis of the combined treatment group, although the OS of the ICIs with target therapy with chemotherapy group was prolonged versus the ICIs combined with chemotherapy group, it did not show statistical significance(64.12 months ±17.41 vs 43.28 months±7.43; p=0.85; Fig.3). Among the 32 patients in the ICIs combined with chemotherapy group, 1 (3.12%) patient had PR, 15 (46.9%) patients had SD, 16 (50%) patients had PD, the ORR was 3.13% and the DCR was 50%. Among the 25 patients in the ICIs combined with taergeted therapy with chemothetapy group, 2 (8%) patients had PR, 13 (52%) had SD, 10 (40%) patients had PD, the ORR was 8% and the DCR was 60%. Both groups of patients showed better ORR and DCR, but no statistically significant differences between the two subgroups were observed (p=0.157; p=0.157)(Table 4).

3.3 Univariate and multifactorial results of dinicopathological feature associated with OS

Univariate analysis of all 126 patients showed that TNM stage, T stage, histological grade, whether CA199 decreased, and therapeutic evaluation grade were related to OS (p<0.05, Table 2). Otherwise, multivariate COX regression analysis was conducted on variables with p<0.05. The results demonstrated that well histologic differentiation (p=0.009) and CA199 decreased (p=0.003) are independent prognostic factors for OS (Table 2).

3.4 Adverse events (AEs)

All 126 patients completed at least two cycles of the second-line treatment. Table 3 summarizes the AEs for enrolled patients. Overall, in all 126 patients, the most common non-hematological AEs were stomachache (22.22%), and the most common hematological AEs were hemoglobin count decreased (74.6%). Respectively, the most common non-hematological AEs in the simple chemotherapy group and the combined treatment group were stomachache (23.19% vs 21.05%), while the most common hematological AEs were serum albumin decreased (84.06% vs 61.41%). In the CT group, the highest incidence of grade 3-4 was hemoglobin count decreased (31.58%). On the contrast, the highest incidence of grade 3-4 was hemameba count decreased (31.88%). After infusion of human hemoglobin, patients with hemoglobin count decreased up to grade 3-4 returned to normal. And all patients with decreased in hemameba count returned normal after receiving infusion of human blood albumin. All grade 3-4 TRAEs that occurred were controlled after the patient received symptomatic medications, and did not affect subsequent treatment. Most of grade 1-2 TRAEs that happened returned normal after the patient was suspended from treatment or received symptomatic medications, and also did not affect subsequent treatment.

In our study, the OS of the CT group and the SC group were 30.26 months and 17.14 months respectively, with a 13.12 months (p<0.001) and the difference between the two groups was statistically significant. Otherwise, the PFS of the CT group and the SC group were 4.68 months and 3.50 months, with a 1.18 months (p=0.0012) and the difference between the two arms was statistically significant. In detail, compared with the SC group, ORR in the CT group increased by 3.81% (5.26% vs 1.45%) and DCR increased by 21.06% (54.39% vs 33.33%), which increased by 20.39% compared to the KEYNOTE-028 trial (34%)^[15], patients with advanced BTC may benefit from the use of ICIs combined with chemotherapy with or without target therapy as the second-line treatment regimen. The result also is in agreement with the finding of the NCT03111732 trial^[18]. However, the ORR and DCR did not show statistically significant (p=0.157; p=0.157), which due to the small amount of data. In another phase II clinical trial (NCT03875235)^[19], the result indicated that the ORR in patients treated with durvalumab plus tremelimumab plus chemotherapy was 50% (15/30) during the second-line treatment, through which showed that it did not achieve more significant improvement in ORR compared to those who use ICIs in combination with first-line treatment (70%, 33/47). Furthermore, compared with the ICIs combined with chemotherapy, the ORR of patients in the ICIs combined with targeted therapy with chemotherapy increased by 4.87% (8% vs 3.13%, p=0.157), and the DCR increased by 10% (60% vs 50%, p=0.157). But no statistical differences were observed. We also found that OS was not statistically difference between the ICIs combined with chemotherapy group and the ICIs with target therapy with chemotherapy group (p=0.85). These may be due to the small sample of patients and insufficient patient follow-up time.

In this retrospective study, we found that patients with TNM-III (p=0.003), TNM-IV (p=0.006), T3 (p=0.024), T4 (p=0.025), well and morderately histologic differentiation (p=0.001, p=0.007), CA199 decreased (p=0.006), SD (p=0.025), PD (p=0.014) are independent prognostic factors affecting OS (Table 2). These results also indicate the efficacy of immunotherapy in combination with chemotherapy with or without targeted therapy in the second-line treatment of advanced BTC.

Immunotherapy has achieved valuable therapeutic effects in various carcinomas, and has approved in the use of first-line treatment of advanced BTC. Our study showed that TRAEs occurred in both two groups. Basecally, consistent with previous phase II and phase III clinical studies of immunotherapy, common TRAEs mainly include leukopenia, neutropenia, thrombocytopenia, hyperbilirubinemia, hypoalbuminemia and stomachache. Most patients can be reversed through dose adjustment or symptomatic treatment, and no discontinuation due to TRAEs.

Our results show that immunotherapy in combination with chemotherapy with or without targeted therapy is safety and efficacy for second-line therapy of advanced BTC patients. However, our work also has certain limitations. First, due to the limited number of individuals included in this work, no meaningful results can be obtained on the efficacy of immunotherapy combined with chemotherapy alone or immunotherapy plus targeted therapy combined with chemotherapy in the treatment of advanced BTC patients. Secondly, because this is a single-center retrospective study with a small sample, there is certain selection and reporting bias. Third, we did not evaluate the PD-1/PD-L1 expression levels in individuals treated with ICI and were unable to further explore the correlation between immunotherapy and patient genomes. Fourth, this research also did not record gene detection information so that it was impossible to explore the correlation between related genes and efficacy. The specific survival advantage of immunotherapy in combination with chemotherapy with or without targeted therapy for second-line therapy of patients with advanced BTC is still unclear. Prospective, multi-center, large-sample, and long-term follow-up cohort studies are still needed.

In summary, compared with chemotherapy alone, immunotherapy in combination with chemotherapy with or without targeted therapy can substantially optimize the ORR and prolong OS and PFS in second-line advanced BTC patients with acceptable tolerability. However, multicenter research is needed to explore the improvement of this treatment in the long-term prognosis of patients.

Funding

This work was supported by grants from Wu Jieping Medical Foundation of China (No. 320.6750.2021-16-20).

Confict of Interest

The authors declare that there were no commercial or financial relationships that could be interpreted as potential conflicts of interest in this research.

Author Contributions

Conception/design: C.J. Provision of study material or patients: C.J., L.Y., L.K. Collection and/or assembly of data: C.J., L.Y., L.K., T.F., L.C., L.H., Q.M, Y.C., W.W. Data analysis and interpretation: C.J., L.Y., L.K., T.F., Z.M., Q.L. Conceptualization,methodology, and validation: Z.M. Supervision, conceptualization, resources, and writing: Q.L., J.T. Manuscript writing and final approval of manuscript: All authors.

Data Availability

Data, code, and other materials available on request from the authors.

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The efficacy and safety analysis of immunotherapy combined with chemotherapy with or without targeted therapy versus chemotherapy alone as second-line treatment for advanced biliary tract malignant tumors

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Abstract

Objective

Methods

Results

Conclusion

Figures

Introduction

Data and Methods

2.1 The inclusion and exclusion criterion

2.2 Therapeutic regimen

2.3 Research Methods

2.3.1 Clinical information

Results

Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1