PD-1 inhibitor combined with chemotherapy or Lenvatinib in advanced gallbladder cancer: A retrospective comparative study

doi:10.21203/rs.3.rs-3332782/v1

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PD-1 inhibitor combined with chemotherapy or Lenvatinib in advanced gallbladder cancer: A retrospective comparative study

https://doi.org/10.21203/rs.3.rs-3332782/v1

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Background

Gallbladder cancer (GBC) is a refractory primary cancer. Some patients are prone to recurrence even after surgical resection. Chemotherapy is the most common non-surgical treatment used in these patients. The emergence of PD-1(programmed cell death protein 1) inhibitors and targeted therapy have provided an additional option for many advanced tumors.

Methods

This was a retrospective study of patients with advanced GBC treated at the Eastern Hepatobiliary Surgery Hospital between June 2019 and June 2022. The patients receiving a PD-1 inhibitor(Tislelizumab) with chemotherapy or with Lenvatinib were retrospectively analyzed. RECIST1.1 (response evaluation criteria in solid tumors) was used as the efficacy evaluation standard. The overall survival(OS), progression-free survival(PFS), objective response rate(ORR), disease control rate(DCR), tumor marker CA199 were evaluated.

Results

61 patients with advanced GBC were included in the study. Including 32 patients received Tislelizumab plus GS(Gemcitabine and TS-1) chemotherapy, 29 patients received Tislelizumab combined with lenvatinib. Tislelizumab plus GS group median overall survival(OS) and progression-free survival(PFS) were 19.64 ± 11.81 (95% CI: 16.47–25.20) and 15.44 ± 13.42 (95% CI: 12.08–22.25) months. Tislelizumab plus Lenvatinib group median overall survival and progression-free survival were 13.06 ± 9.41 (95% CI: 9.72–16.63) and 10.34 ± 10.03 (95% CI: 6.56–14.13) months. The objective response rate, disease control rate were 59.38%, 81.3% with a Tislelizumab plus GS group, signifcantly longer than plus Lenvatinib group. Treatmentrelated adverse events were similar between two group.

Conclusion

Tislelizumab plus GS chemotherapy provides a safe and more efficient treatment option for advanced GBC patients.

gallbladder cancer

PD-1 inhibitors

chemotherapy

Lenvatinib

retrospective study

GBC is a highly malignant tumor, which metastasizes at distant sites through hepatoduodenal ligament lymph nodes^[1–2]. Surgical resection is the only way to cure GBC, but about 60% of cases are not eligible for surgery and are insensitive to conventional chemotherapy^[3]. According to previous reports, the objective response rate of chemotherapy is currently only 26%, with a median survival time of only 11.7 months^[4]. PD-1 inhibitors and targeted drugs exert significant therapeutic effects on malignant tumors. However, in the treatment of GBC, there are few clinical reports on it is better whether PD-1 inhibitors combined with chemotherapy or targeted drugs^[5].

1. Patients

We retrospectively screened 83 gallbladder cancer patients treated in Shanghai Eastern Hepatobiliary Surgery Hospital between June 2019 and June 2022. 12 patients withdrew consent before treatment, 10 patients were lost to follow-up after one course of treatment(Fig. 1). Finally, 61 patients were enrolled in this study, include 32 of whom received Tislelizumab plus GS chemotherapy, and 29 of whom received Tislelizumab plus Lenvatinib. All patients had a PS score below 2 and could take care of themselves. The baseline characteristics of the patients are summarized in Table 1. The study was approved by the Institutional Review Board and Ethics Committee of Affiliated Hospital of Guangdong Medical University(No.2018B01092). This research was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.

Table 1

Baseline characteristics
Characteristic	Tislelizumab plus chemotherapy (n = 32)	Tislelizumab plus Lenvatinib (n = 29)	P value
Age (n, %)			0.120
≥ 60	17(53.1%)	19(65.5%)
< 60	15(46.9%)	10(34.5%)
Sex (n, %)			0.054
Male	20(62.5%)	10(34.5%)
Female	12(37.5%)	19(65.5%)
Hepatitis Virus infection(n, %)			0.841
Yes	6(18.7%)	7(24.1%)
No	26(81.3%)	22(75.9%)
Smoking history(n, %)			0.883
Yes	16(50%)	16(55.2%)
No	16(50%)	13(44.8%)
Gall stone disease (n, %)			0.972
Yes	20(62.5%)	18(62.9%)
No	12(37.5%)	11(37.1%)
Obstructive jaundice(n, %)			0.768
Yes	11(34.4%)	8(27.6%)
No	21(65.6%)	21(72.4%)
Performance status(n, %)			0.736
0–1	25(78.1%)	24(82.8%)
2	7(21.9%)	5(17.2%)
Previous surgery(n, %)			0.249
Yes	24(75%)	26(89.7%)
No	8(25%)	3(10.3%)

2. Inclusion and Exclusion Criteria

(1) Inclusion criteria were

1) gallbladder cancer confirmed by pathology; 2) according to TNM staging, tumor stage III or IV; 3) no radiotherapy or targeted therapy; 4) voluntarily choice to receive long-term follow-up; 5) PS score < 2; 6) ineligibility for radical surgical resection or recurrence after surgery; 7) at least one measurable lesion prior to treatment initiation.

(2) Exclusion criteria were

1) undiagnosed gallbladder cancer; 2) other concurrent tumors; 3) concurrent insufficiency of major organs; 4) severe mental disorders and no complete evaluation at the time of data collection.

3. Patient Evaluations and Adverse Events

Based on the Response Evaluation Criteria for Solid Tumors version 1.1^[6], tumor response was rated as complete remission, partial remission, stable disease or disease progression. The ORR includes CR and PR cases; the DCR includes CR, PR and SD cases. Both progression-free survival and overall survival were evaluated. PFS referred to the time from the patient receiving immunotherapy to the first occurrence of disease progression or death from any cause. Adverse events were judged according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE)^[7]. Safety was continuously evaluated every 3 weeks by laboratory tests, including blood routine, liver function, thyroid function, myocardial enzyme and chest X-ray.

4. Sample collection and Detection immunogenic markers

All tumor specimens were reviewed by two independent pathologists to confirm the pathologic diagnosis and select the appropriate areas for macrodissection, which was performed to evaluate tumor content and percentage of tumor cells. Next-generation sequencing(NGS) panel encompassed all coding exons of 450 cancer-related genes in solid tumors. Comprehensive genomic alteration analyses of the tumor and matched blood samples were performed using an assay panel that captured 450 cancerrelated genes and selected introns of 38 genes frequently rearranged in cancer (YuansuTM, OrigiMed, Shanghai, China). TMB was estimated for each sample by counting its somatic mutations. MSI was determined by Shanghai Zhiben Medical Laboratory (Shanghai, China). PD-L1 expression was detected by immunohistochemical staining of FFPE tumor sections using an anti-PD-L1 antibody (clone 22C3; OrigiMed, Shanghai, China). The threshold for PD-L1 positivity was set at > 10% according to 2021 National Comprehensive Cancer Network (NCCN) guidelines. PD-L1 was considered positive when ≥ 1% of the tumor cells showed any intensity of complete or incomplete cell membrane staining.

5. Treatment

32 patients who receive PD-1 inhibitor(tislelizumab) plus GS(gemcitabine and TS-1); Another 29 patients receive Tislelizumab plus Lenvatinib. All patients signed the relevant informed consent before treatment. Tislelizumab was administered at 200 mg on the first day, in a 3-week medication cycle. Gemcitabine was administered at 1000 mg per square meter of body surface area on the second day. TS-1 was administered at 40 mg orally twice a day for 2 consecutive weeks and discontinued for 1 week. Gemcitabine was administered again on day 8. After 8 courses of treatment, gemcitabine was discontinued and continue taking TS-1 orally. Tislelizumab were continued for every 3 weeks. All patients received at least 2 cycles of treatment. Lenvatinib was administered orally at a dose of 12 mg for patients with body weight ≥ 60 kg or 8 mg for patients with body weight < 60 kg once a day. All the above drugs should be used on time until intolerable side effects or disease progression occur.

All patients underwent routine blood test, serum tumor marker analyses, and imaging tests such as CT. Imaging studies were used to assess the treatment effect after at least 3 cycles of treatment, and adverse events were recorded.

6. Follow Up

Follow-up was carried out by means of case reviews, telephone calls and follow-up visits. The follow-up started the date of the first immunotherapy and ended at the time of the last follow-up. The follow-up deadline was the 30 June 2022.

7. Statistical Analysis

Continuous variables were presented as mean ± standard deviation or median (interquartile range) according to distribution. Categorical variables were analyzed by the chi-square test and Fisher's exact test, and continuous variables were analyzed by the independent samples T test. Survival analyses were performed using the Kaplan–Meier method. A significant threshold was set at a value of p < 0.05. All analyses used SPSS (V.23.0, Chicago, Illinois, USA).

General findings Between June 2019 and June 2022, 61 patients who met the eligibility criteria were categorized into two treatment cohorts: 32 were in the Tislelizumab plus chemotherapy combination group, 29 were in the Tislelizumab plus Lenvatinib group. Baseline patient characteristics were reported(Table 1). There are 36 patients over the age of 60, accounting for 51.3% and 65.5% respectively. There are a total of 30 males in both groups, accounting for approximately 50%. Only 13 people have been infected with hepatitis virus in the past. 38 patients had gallstones, accounting for 68.7% of all cases. All patients had ECOG scores below 2. Most patients had a normal BMI. The two groups don’t have signifcantly difference with previous surgery. Subgroup analyses of prespecified baseline factors are presented in Fig. 2. There was no difference in the treatment effect between the subgroups.

Efficacy and prognosis analysis

As of the end of June 2022, a total of 21 deaths occurred in the Tislelizumab combined GS chemotherapy group and 23 deaths in the combined Lenvatinib group. The median OS was 17.8 months(95% CI 13.73–22.07) in the combined GS chemotherapy group, longer than Lenvatinib group(12.5 months, 95% CI : 10.6–14.3). The median PFS was 12.1 months in the combined GS chemotherapy group, signifcantly longer than Lenvatinib group (5.1 months, 95% CI 3.59–6.61).(Fig. 2a). As of the end of the study, 7 patients in the chemotherapy group and 3 patients in the Lenvatinib group still survive(Fig. 3).

A total of 9 patients in both groups showed complete remission, including 6 in the combined chemotherapy group and 3 in the combined Lenvatinib group. 27 patients showed partial remission of tumors to varying degrees, including 19 in the combined chemotherapy group and 8 in the combined lenvatinib group(Table 2). The disease control rate and objective response rate were 71.9% and 59.38% in the combined chemotherapy group, respectively, while 55.2% and 31.03% in the combined lenvatinib group(Fig. 4). Some patients' tumors can be significantly reduced on CT. According to the evaluation standard of recist 1.1, the tumor shrinks by more than 30%, reaching a partial reaction degree. There was also one case of lung metastasis. After treatment, the tumor shrank significantly and partially disappeared(Fig. 5).In addition, there was a significant difference in CA199 levels between the two groups. After 3 months of treatment, the CA199 values of patients in the combined chemotherapy group generally decreased, significantly lower than those in the combined lenvatinib group(Table 3)

Table 2

Tumor response to treatment
	Tislelizumab plus chemotherapy(n = 32)	Tislelizumab plus Lenvatinib(n = 29)	P value
PFS(month)	14.09 ± 12.76	8.2 ± 9.31	0.046
OS(month)	19.14 ± 11.45	12.72 ± 9.5	0.021
Overall response(n, %)
DCR	23(71.9%)	16(55.2%)	0.276
ORR	19(59.38%)	9(31.03%)	0.027
CR	6(18.8%)	3(10/3%)	0.355
PR	19(59.4%)	8(27.6%)	0.013
SD	23(71.9)	16(55.2%)	0.276
PD	10(31.3%)	12(41.4%)	0.411

Table 3

CA199 changes in two groups
Blood test time	Tislelizumab plus chemotherapy(n = 32)	Tislelizumab plus Lenvatinib(n = 29)	P value
Before treatment	343.69 ± 291.41	293.63 ± 311.57	0.475
3 months later	137.56 ± 179.12	297.55 ± 310.22	0.042
6 months later	118.32 ± 153.45	283.52 ± 306.45	0.034
12 months later	78.11 ± 187.90	294.89 ± 358.41	0.020

Adverse events

Treatment-related adverse events (TRAEs) in the Tislelizumab plus GS chemotherapy group and Lenvatinib group was 84.37% (27/32) and 89.65%(26/29), respectively(Table 4). The incidence of grade TRAEs are similar in two groups. No drug-related deaths occurred in any group. The most common side effects of the combination chemotherapy group are nausea, vomiting, fatigue, and reduced granulocytes, while patients in the combination lenvatinib group have slightly more rash and oral ulcers, and there is no significant difference in other drug side effects between the two groups(Fig. 6).

Table 4

Treatment-related adverse events
Adverse events(n, %)	Tislelizumab plus chemotherapy(n = 32)	Tislelizumab plus Lenvatinib(n = 29)	P value
Fever	10(31.3%)	5(17.2%)	0.331
Celialgia and Diarrhea	9(28.1%)	6(20.7%)	0.501
Fatigue	15(46.9%)	6(20.7%)	0.032
Skin rash	6(18.8%)	9(31%)	0.266
Nausea and Omitting	26(81.3%)	16(55.2%)	0.028
Leukopenia	17(53.1%)	7(24.1%)	0.021
Hypothyreosis	3(9.4%)	4(13.8%)	0.589
Myocarditis	1(3.1%)	3(10.3%)	0.255
ALT or AST elevation	7(21.9%)	5(17.2%)	0.649
Hypertension	5(15.6%)	8(27.6%)	0.255
Hand foot syndrome	4(12.5)	5(17.2%)	0.602
Pneumonia	1(3.1%)	2(7.1%)	0.476
Oral ulcer	8(25%)	12(41.4%)	0.174

Table 5

Common mutated genes in gallbladder cancer
Mutated genes (n, %)	Tislelizumab plus chemotherapy(n = 32)	Tislelizumab plus Lenvatinib(n = 29)	P value
Expression of PD-L1	6(18.75%)	7(24.14)	0.608
TMB	12 ± 20.15	6.8 ± 7.64	0.272
TP 53	20(69%)	22(68.8%)	0.986
ERBB2	8(25%)	4(13.8%)	0.438
CDKN2A	9(28.1%)	8(27.6%)	0.963
ARID1A	7(21.9%)	9(31%)	0.417
SMAD4	8(25%)	6(20.7%)	0.689
CCND1	5(15.6%)	6(20.7%)	0.607
ATM	9(28.1%)	4(13.8%)	0.172
ARID2	5(17.2%)	5(15.6%)	0.865
BARCA	6(18.8%)	3(10.3%)	0.355
TERT	4(12.5%)	3(10.3%)	0.792

Gallbladder cancer has the characteristics of high malignancy and poor prognosis. Radical surgery is the only possible cure for this disease. However, because early diagnosis is hard to achieve, most cases are at an advanced or late disease stage at the first diagnosis, with no opportunity of radical surgery, requiring comprehensive treatment including chemotherapy, radiotherapy, targeted therapy, immunotherapy and supportive treatment. In recent years, non-surgical treatment of GBC has not made great progress^[8]. At present, there is no approved targeted drug for GBC in China^[9]. With the rapid development of immunotherapy, especially the emergence of ICIS, there is hope for the treatment of GBC. ICIS has been successfully used in the treatment of various solid tumors, including malignant melanoma and lung cancer, but its application in GBC is still in the exploratory stage^[10]. PD-L1 has been reported to be strongly related to the response to PD-1 inhibitors in several tumors^[11], the predictive value in GBC should be further validated. Chemotherapy is the mainstay of treatment for advanced GBC. Cancer chemotherapy is viewed as a method that mainly afects tumor cells, increasing evidence indicates that cytotoxic drugs also affect the immune system and T cells[12]. At present, the treatment of unresectable gallbladder cancer mostly adopts PD-1 or PD-L1 combined with targeted therapy or chemotherapy. The specific efficacy of which treatment plan is better still needs to be confirmed in clinical practice. This study evaluated the efficacy and safety of Tislelizumab in combination with GS chemotherapy and Tislelizumab plus Lenvatinib in advanced GBC patients. We selected 61 patients with unresectable gallbladder cancer and divided them into 2 groups for comparative study. In our study, the addition of Tislelizumab to chemotherapy signifcantly extended survival time and improved the proportion of patients who achieved an objective response. The overall survival period of patients in the combined chemotherapy group was significantly longer than that in the combined Lenvatinib group. Chemotherapy could also affect the tumor microenvironment and promote antigen expression and antitumor immune response^[13]. Therefore, theoretically, immunotherapy and chemotherapy in combination could exert synergistic effects and improve survival outcomes. A previous study reported a median survival time in patients with advanced GBC is only 6–9 months, and very lower 2-year survival rate^[14]. While in this study, nearly 31% of patients survived for more than 2 years. These findings suggest that Tislelizumab combined with GS chemotherapy could significantly prolong patient survival. There was no statistical difference in the complete remission rate between the two groups of patients, but the partial remission rate in the combined chemotherapy group was significantly higher than that in the combined lenvatinib group, and the objective remission rate was also higher than that in the combined lenvatinib group.

With the wide application of PD-1 inhibitor for treating tumors, Immune-Related Adverse Events (IRAEs) have gradually attracted attention. IRAEs could occur in any organ and tissue, mainly involving skin, gastrointestinal tract, endocrine organs, liver and lung. Many clinical studies have reported incidence rates for ir-AEs of 60–80%^[17–18]. The adverse events experienced by the patients examined in this study were mainly grade 1 or 2. The incidence of TRAEs in the Tislelizumab plus chemotherapy group was similar with plus lenvatinib group. There were a total of 13 drug-related side effects in both groups of patients, among which nausea, vomiting, fatigue, and granulocytopenia were more common in the chemotherapy group. However, after receiving symptomatic treatment for antiemesis, the patient's symptoms quickly improved. Before each chemotherapy, the patient needs to review their blood routine. If there is granulocytopenia, recombinant human granulocyte growth factor should be injected subcutaneously. The most common side effects of medication such as skin itching and maculopapules were observed in patients in the combined lenvatinib group, while digestive system symptoms were less common than those in the chemotherapy group. Due to the mild symptoms of patients, symptomatic treatment was given and medication continued. In the process of immunotherapy, attention should be paid to some serious ir-AEs, including immune-related pneumonia, nephritis and myocarditis. If such adverse events were not timely addressed, they might endanger the patient's life. In this study, there were 7 cases of grade 3 ir-AEs, including 3 immune-related pneumonia and 4 immune-related myocarditis cases. The symptoms were improved after drug withdrawal and active treatment with glucocorticoids.

In order to further analyze the differences in the effectiveness of medication between the two groups of patients, we also conducted genetic testing on all patients to determine if there were any differences in gene mutations between the two groups of patients. Studies have reported that high expression of PD-L1, MSI-H and elevated TMB could predict the effect of immunotherapy in patients with GBC^[15–16]. The results showed that 6 patients in the combination chemotherapy group were PD-L1 positive, and 5 patients in the lenvatinib group were positive(Table. 5). There was no significant difference between the two groups. However, we found that PD-L1 positive patients, after immunotherapy, had significantly reduced tumor size and generally had a longer survival period. There was no significant difference in TMB values and common mutated genes between the two groups of patients. The most common mutated genes were still TP53, CDKN2A, ARID1A, SMAD4, ERBB2, etc. (Fig. 7). This indicates that the difference in treatment efficacy between the two groups is the key role played by chemotherapy drugs. Due to the small number of cases in this study, more rigorous clinical studies were needed for confirmation.

This study suggested that Tislelizumab had a certain value in the treatment of advanced GBC, but its overall response rate remained low. The strategy combining chemotherapy could improve the response rate. It was also worth further assessing whether such patients should be treated by immunotherapy before surgery. This study was a single center trial based on clinical practice.

Conflict of Interest

The authors state that there is no conflict of interest.

Ethical Recognition

This clinical research was approved by the Ethics Committee of Affiliated Hospital of Guangdong Medical University(GuangDong, China).

Funding

This study was supported by Study on the distribution of bacterial communities and drug sensitivity analysis in patients with gallstones(2018B01092).

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No competing interests reported.

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Version 1

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PD-1 inhibitor combined with chemotherapy or Lenvatinib in advanced gallbladder cancer: A retrospective comparative study

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

BACKGROUND

METHODS

1. Patients

2. Inclusion and Exclusion Criteria

3. Patient Evaluations and Adverse Events

4. Sample collection and Detection immunogenic markers

5. Treatment

6. Follow Up

7. Statistical Analysis

RESULTS

Efficacy and prognosis analysis

Adverse events

DISCUSSION

Declarations

References

Additional Declarations

Status:

Version 1