|Year : 2021 | Volume
| Issue : 5 | Page : 1234-1240
Efficacy and safety of sintilimab-based regimens against advanced gastric and gastroesophageal junction adenocarcinoma
Yusheng Wang1, Jian Zhao2, Hongmei Yu3, Jie Wang4, Ninggang Zhang2, Bangwei Cao5
1 Beijing Friendship Hospital Cancer Center, Capital Medical University, Beijing; Department of Gastrointestinal Oncology, Shanxi Provincial Cancer Hospital, Affiliated to Shanxi Medical University, Shanxi, China
2 Department of Gastrointestinal Oncology, Shanxi Provincial Cancer Hospital, Affiliated to Shanxi Medical University, Shanxi, China
3 Department of Health Statistics, School of Public Health, Shanxi Medial University, Shanxi, China
4 Graduate School, Shanxi Medical University, Shanxi, China
5 Beijing Friendship Hospital Cancer Center, Capital Medical University, Beijing, China
|Date of Submission||27-May-2021|
|Date of Acceptance||07-Oct-2021|
|Date of Web Publication||27-Nov-2021|
Cancer Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing 100050
Source of Support: None, Conflict of Interest: None
Aims: Our study assessed the efficacy and safety of sintilimab-based regimens for real-world treatment of advanced gastric and gastroesophageal junction adenocarcinoma (G/GEJAC).
Materials and Methods: Cases of advanced nonresectable G/GEJAC treated with sintilimab-based regimens in the Department of Gastroenterology of Shanxi Provincial Cancer Hospital between December 2018 and September 2020 were retrospectively examined. Endpoints included median progression-free survival (mPFS), median overall survival (mOS), disease control rate (DCR), objective response rate (ORR), and adverse events (AEs). Univariate and multivariate analyses were conducted to determine the effect of stratification factors on efficacy.
Results: Among the 37 included patients, mPFS and mOS were 4.27 and 7.3 months, respectively. Efficacy was evaluated at least once in 32 of 37 patients. The ORR and DCR were 12.5% and 65.63%, respectively. Among four patients with mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H) lesions, two achieved partial remission, and two displayed stable disease, resulting in a DCR of 100%. The most observed AEs included leukopenia, neutropenia, thrombocytopenia, nausea, and skin rash. mPFS was 4.90 months in patients who received sintilimab in the first- or second-line setting, versus 3.00 months in other patients. A significant survival difference was found between these groups in univariate and multivariate analyses.
Conclusions: The application of sintilimab-based regimens achieved good disease control and tolerability for the real-world treatment of advanced G/GEJAC. The treatment was more effective when administered in the first- or second-line setting. Patients with dMMR/MSI-H lesions may also benefit from sintilimab-based regimens.
Keywords: Gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, PD-1 inhibitor, sintilimab
|How to cite this article:|
Wang Y, Zhao J, Yu H, Wang J, Zhang N, Cao B. Efficacy and safety of sintilimab-based regimens against advanced gastric and gastroesophageal junction adenocarcinoma. J Can Res Ther 2021;17:1234-40
|How to cite this URL:|
Wang Y, Zhao J, Yu H, Wang J, Zhang N, Cao B. Efficacy and safety of sintilimab-based regimens against advanced gastric and gastroesophageal junction adenocarcinoma. J Can Res Ther [serial online] 2021 [cited 2022 Jan 17];17:1234-40. Available from: https://www.cancerjournal.net/text.asp?2021/17/5/1234/331313
| > Introduction|| |
Gastric cancer is the fifth most prevalent and third most fatal neoplastic disease globally. Of all new cases, 42% were diagnosed in China., Due to an effective early screening, gastric cancer is much less fatal in Japan and South Korea than in other countries, with a 5-year survival rate exceeding 70%. Conversely, patients in China often present with advanced disease because of low early screening rates, resulting in poor prognoses. Previously, the treatment of advanced gastric cancer was limited to systemic chemotherapy and palliative treatment until the successful ToGA study launched a new era of targeted therapy, in which trastuzumab combined with chemotherapy emerged as a new standard first-line treatment for HER2-positive advanced gastric cancer. Recently, ramucirumab was approved by the United States Food and Drug Administration as a second-line treatment for advanced gastric cancer and gastroesophageal junction (GEJ) adenocarcinoma (G/GEJAC) based on evidence from the REGARD and the RAINBOW studies.
In China, advanced gastric cancer is mainly treated using systemic chemotherapy, notably using fluoropyrimidines, platinum-based agents, taxanes, and irinotecan, alone or in combination. A phase III clinical trial led by Li et al. also demonstrated the benefits of apatinib as a third-line treatment for advanced gastric cancer. However, targeted therapies such as trastuzumab are only available for HER2-positive patients, and apatinib is only approved as a third-line treatment, thus limiting the options for patients with advanced gastric cancer. According to a real-world study conducted in China, current therapeutic regimens for advanced gastric cancer, including chemotherapy, trastuzumab, and apatinib, only provide a median survival time of 11.4 months.
Immune checkpoint inhibitors are currently considered the most promising therapies for solid tumors. Clinical trials demonstrated that PD-1 inhibitor-based regimens are effective as first-, second-, or third-line treatments for gastric adenocarcinoma. For PD-L1-positive patients, mismatch repair (MMR) deficiency and microsatellite instability-high (dMMR/MSI-H), Epstein–Barr virus, and those with a high tumor mutational burden, PD-1 inhibitors represent treatments of last resort. Follow-up data from the last 3 years of the ATTRACTION-2 study were presented at the 2020 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. At the same time, nivolumab monotherapy was approved in China as a third-line treatment for advanced G/GEJAC. In later lines of treatment for advanced gastric cancer, patients are usually in poor general health conditions, limiting the benefits of therapy. Furthermore, data from the CHECKMATE-649, ATTRACTION-4, and KEYNOTE-059 (Cohort 2) studies found that PD-1 inhibitors, combined with chemotherapy in the first- or second-line treatment of advanced gastric cancer, remarkably improved the objective response rate (ORR), median progression-free survival (mPFS), or median overall survival (mOS).
Sintilimab (TYVYT) is a recombinant humanized IgG4 monoclonal antibody directed against PD-1 that has been studied for the treatment of nonsmall cell lung cancer, non-Hodgkin lymphoma,, and advanced gastric cancer. Sintilimab is often used to treat advanced gastric cancer because of its lower cost in the real world. In the present study, we assessed the efficacy and safety of sintilimab-based regimens in 37 patients with advanced, nonresectable G/GEJAC who were treated in the Department of Gastroenterology, Shanxi Provincial Cancer Hospital.
| > Materials and Methods|| |
In total, 37 patients with advanced, nonresectable G/GEJAC who were treated with sintilimab-based regimens in the Department of Gastroenterology, Shanxi Provincial Cancer Hospital, between December 2018 and September 2020 were enrolled. The inclusion criteria were the histological diagnosis of G/GEJAC, a locally advanced or distant metastatic disease without indication for surgical resection or other local therapy, and receipt of at least one sintilimab-based regimen. There were no limits on the line of treatment or use of monotherapy or combination therapy. The dosage of sintilimab (100 mg/vial) was 3 mg/kg or 200 mg delivered via intravenous infusion every 3 weeks.
This retrospective study examined real-world evidence supporting the use of immunotherapy for the treatment of advanced G/GEJAC. Two experienced physicians collected and summarized data from medical records, including demographic and clinical features such as gender, age, time of diagnosis, time of treatment, pathological classification, expression of MMR proteins, treatment plan, treatment received before immunotherapy, number of immunotherapy cycles, imaging assessment, information from follow-up records, laboratory results, and information from medical imaging. Data were accessed from the Center of Medical Records, Shanxi Provincial Cancer Hospital, and information on follow-up visits was obtained from the Center of Follow-up Care at the hospital. Statisticians were responsible for the processing of data and supervision of the study. The immunotherapeutic agent of interest, sintilimab, was manufactured by Innovent (Suzhou, China). This study was conducted according to the Declaration of Helsinki, and the study proposal was approved by the Ethics Committee of the Shanxi Provincial Cancer Hospital. No informed consent was required for this retrospective, noninterventional study.
Efficacy and safety
Efficacy was assessed via computed tomography and tumor marker assessments every three cycles. The primary endpoint was the progression-free survival (PFS). Responses were assessed twice according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and the modified RECIST 1.1 for immune-based therapeutics. Responses were then categorized as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD). Secondary endpoints were the disease control rate (DCR), ORR, and overall survival (OS). PFS was defined as the period between the initiation of treatment and progression or death, whereas OS was defined as the period between the initiation of treatment and death or loss of follow-up. DCR was defined as the total percentage of patients with CR, PR, or SD, whereas ORR was defined as the total percentage of patients with CR or PR. Patients who received at least one dose of sintilimab were included in the safety analysis set to record adverse events (AEs) and assess safety profiles. AEs were graded according to the Common Terminology Criteria for Adverse Events version 4.0.
Quantitative data were presented as the mean ± standard deviation or median (interquartile range), whereas qualitative data were presented as frequencies and percentages. Survival was calculated using life tables. OS and PFS were calculated via Kaplan–Meier analysis, and survival curves were plotted. Univariate and multivariate analyses were conducted using the Cox proportional hazards regression model, and data were presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Statistical significance was considered for P < 0.05. All the statistical analyses were conducted using SPSS 21.0 (IBM Corp., Armonk, NY, USA), and the figures were prepared using GraphPad Prism 7 (GraphPad, San Diego, CA, USA).
| > Results|| |
The median patient age was 62 years (21–86). The population included 26 men (70.27%) and 11 women (29.73%). The primary tumor locations included the stomach in 20 patients (54.05%) and GEJ in 17 patients (45.95%). The histological type was adenocarcinoma, adenocarcinoma with signet ring cell carcinoma, mucinous adenocarcinoma, and unknown in 26 (70.27%), four (10.81%), two (5.41%), and five patients (13.51%), respectively. The degree of differentiation was poor, poor to moderate, moderate, and unknown in 19 (51.35%), 11 (29.73%), one (2.70%), and six patients (16.22%), respectively. The primary tumor was previously resected in 17 patients (45.95%). Liver metastasis was also detected in 19 patients (51.35%), whereas nine patients (24.32%) had peritoneal metastasis. The number of metastatic sites was under or equal to two in 11 cases (29.73%). Immunotherapy was administered in the first, second, third, fourth, and fifth lines in 12 (32.43%), 12 (32.43%), seven (18.92%), five (13.51%), and five patients (2.71%), respectively. In addition, the Eastern Cooperative Oncology Group (ECOG) performance status (PS) was one, two, and three in 15 (40.54%), 20 (54.05%), and two patients (5.41%), respectively. The MMR status was tested in 19 patients, and four had dMMR/MSI-H lesions. The HER2 status was assessed in 25 patients, and five were positive. The PD-L1 combined positive score (CPS) was calculated in nine patients, and three patients had scores of ≥1%. Three participants with dMMR/MSI-H tumors further received sintilimab monotherapy, and the remaining participants received sintilimab-based combination regimens [Table 1].
Progression-free survival and overall survival
After a median follow-up of 10.77 months (95% CI = 6.70–14.84), mPFS and mOS were 4.27 months [95% CI = 2.82–5.12; [Figure 1]a] and 7.3 months [95% CI = 2.33–12.27; [Figure 1]b], respectively. The clinical characteristics examined for associations with PFS following sintilimab treatment were the age, gender, previous history of surgical intervention, presence or absence of liver and peritoneal metastasis, number of metastatic organs (≤2 vs. >2), lines of treatment (≤2 vs. >2), ECOG PS (<2 vs. ≥2), and primary site of cancer (stomach vs. GEJ). The study revealed a statistically significant difference in PFS between patients receiving sintilimab in the first- or second-line setting and those treated in later lines, whereas no significant difference in PFS was found for other clinical characteristics [Table 2]. For patients receiving sintilimab in the first or second line of treatment, mPFS was 4.90 months (95% CI = 3.46–6.34), compared with 3.00 months (95% CI = 2.38–3.62) in patients treated in later lines. Survival significance differed between these groups in both univariate (HR = 2.607, 95% CI = 1.142–5.953, P = 0.023) and multivariate [HR = 4.483, 95% CI = 1.533–13.109, P = 0.006; [Table 2] analyses.
|Figure 1: (a) Survival curve of progression-free survival in patients treated with sintilimab (n = 37) and (b) Survival curve of overall survival in patients treated with sintilimab (n = 37)|
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|Table 2: Exploratory analysis of factors to predict progression-free survival of sintilimab|
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To further determine the effect of the treatment line (≤2 vs. >2) on PFS and exclude possible effects of other clinical features, four models were developed. The treatment line was included as the only factor in Model 1, resulting in an HR of 2.607 (95% CI = 1.142–5.953) and P = 0.023, consistent with the univariate analysis results. Model 2 was developed by adding age and gender to Model 1, resulting in an HR of 2.978 (95% CI = 1.207–7.351) and a P = 0.018. In Model 3 (ECOG PS), the primary tumor site and previous history of surgical intervention were included, leading to an HR of 4.681 (95% CI = 1.623–13.502) and P = 0.004. In Model 4, the number of metastatic organs and presence or absence of liver and peritoneal metastasis were considered, resulting in an HR of 4.483 (95% CI = 1.533–13.109) and a P = 0.006. Significant differences were consistently observed in all four models [Table 3].
|Table 3: Association between the line of treatment and progression-free survival|
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Regarding the duration of sintilimab treatment, the treatment duration was longer in patients receiving the drug in the first- or second-line setting compared with later settings. Three of the four patients with dMMR/MSI-H tumors remained under treatment, whereas the fourth patient discontinued therapy for financial reasons, although the treatment discontinuation did not increase its disease progression [Figure 2]. In this patient, the tumor was successfully converted despite treatment in later lines. Radical surgery was performed, and adjuvant therapy was planned.
Objective response rate and disease control rate
Efficacy was assessed at least once in 32 of 37 patients. No participant achieved CR, whereas four (12.50%), 17 (53.13%), and 11 patients (34.38%) exhibited PR, SD, and PD, respectively. The ORR was 12.5% (4/32), and the DCR was 65.63% (21/32). Of the four patients with dMMR/MSI-H lesions, two each had PR and PD, resulting in a DCR of 100% [Table 4].
The most common AEs observed in the 37 patients included leukopenia, neutropenia, thrombocytopenia, nausea, skin rash, liver function abnormalities, hyperglycemia, anemia, vomiting, proteinuria, diarrhea, hypothyroidism, and hyperthyroidism. AEs of grade three or higher included neutropenia, leukopenia, thrombocytopenia, liver function abnormalities, anemia, nausea, and vomiting. There were no treatment-related deaths [Table 5].
| > Discussion|| |
In recent years, increasing evidence has supported the use of PD-1 inhibitor monotherapy or combined therapy for the treatment of refractory G/GEJAC. In 2017, nivolumab (Opdivo) and pembrolizumab (Keytruda) were respectively approved in Japan and the United States as third-line treatments for G/GEJAC, thus launching the era of immunotherapy for gastric cancer treatment. In March 2020, after the publication of the 3-year follow-up data from the ATTRACTION-2 study, nivolumab was also approved in China for systemic therapy in patients with advanced G/GEJAC under second or later lines of treatment. Data from CHECKMATE-649 provided additional evidence for the use of immune checkpoint inhibitors as first-line treatments for gastric cancer. Compared with nivolumab and pembrolizumab, domestically manufactured agents such as sintilimab are more readily available, whereas strong evidence supporting their use for the treatment of advanced gastric cancer is accumulating.
In this real-world study, we retrospectively analyzed 37 patients with advanced G/GEJAC who received sintilimab. No patient achieved CR, whereas four (12.50%), 17 (53.13%), and 11 patients (53.13%) exhibited PR, SD, and PD, respectively. The ORR was 12.50% (4/32), and the DCR was 65.63% (21/32). In the ATTRACTION-2 study, the CR rate was also 0%, whereas the PR and SD rates were 11.2% and 29.1%, respectively. Nevertheless, the PD rate was as high as 46.3%. The ORR was 11.2%, and the DCR was 46.55%. More favorable outcomes were recorded in our study than in the ATTRACTION-2 study, a real-world study of nivolumab (ORR = 11.2%), and the LEAP-005 study of lenvatinib and pembrolizumab in combination for advanced gastric cancer treatment (ORR = 9.7%). One possible explanation for these apparently discordant findings was the inclusion in our study of patients who received sintilimab in the first- or second-line setting, whereas some participants received sintilimab in combination with chemotherapy. Moreover, the participants included in our study had a lower ECOG PS than those in the ATTRACTION-2 study.
Four patients had dMMR tumors in the present study. Three of these patients received sintilimab monotherapy, and the remaining patients received sintilimab in combination with S-1. The DCR was 100%, with two patients each achieving PR and SD, and all four patients remain alive. These findings indicate that patients with biomarkers favoring the use of immunotherapy may benefit from single-agent immunotherapy. Hence, testing for MMR during patient selection appears necessary to maximize benefits in clinical practice.
The 6-month survival rate in all participants was 65%, and the 12-month survival rate was 36%. The mPFS and mOS were 4.27 and 7.3 months, respectively. Compared with the 12-month survival rate of 27.3% and mOS of 5.26 months in the ATTRACTION-2 study, in which patients who failed chemotherapy received third-line nivolumab, sintilimab-based regimens may provide increased benefits. Among the 32 patients from Taiwan included in the ATTRACTION-2 study, mOS was only 5.06 months. In Cohort 1 of the KEYNOTE-059 study, the safety and efficacy of pembrolizumab monotherapy as a third-line treatment for G/GEJAC were also assessed by evaluating disease progression or intolerable toxicity. The mOS was 5.5 months, and the mPFS was 2 months. Based on these results, sintilimab-based regimens provide remarkable efficacy as late-line treatments for advanced G/GEJAC.
The first- and second-line treatments for advanced gastric cancer in China primarily include combination regimens and monotherapies. Patients with HER2-positive lesions are suitable for trastuzumab therapy. In the third-line setting, apatinib is another targeted therapy option, resulting in a median survival time of under 1 year in patients with advanced gastric cancer. After the introduction of nivolumab as a third-line treatment for advanced gastric cancer, survival time was slightly prolonged but remains far from satisfactory. The KEYNOTE-061 study compared pembrolizumab with the standard treatment paclitaxel monotherapy in a second-line setting for patients with advanced gastric cancer. The primary endpoints compared were OS and PFS in patients with CPS ≥1, without statistically significant difference. Possible OS benefits were only observed in the CPS ≥10 subgroup. Cohort 2 of the KEYNOTE-059 study further examined the outcomes of pembrolizumab and 5-fluorouracil/cisplatin for the first-line treatment of HER2-negative GC/GEJAC, resulting in an ORR of 60%. In patients with PD-L1-positive lesions (CPS ≥1%), the ORR was 69%, whereas the mOS was 13.8 months. Cohort 3 of the KEYNOTE-059 study additionally investigated pembrolizumab as a first-line treatment for patients with advanced PD-L1-positive G/GEJAC (CPS ≥1%), indicating an ORR of 26%.
Although no significant benefit was revealed by the KEYNOTE-062 study of immunotherapy in the first-line setting, the CHECKMATE-649 study by the conference of 2020 European Society for Medical Oncology found that the use of immune checkpoint inhibitors was more beneficial in the first- or second-line setting. The mOS in all patients receiving nivolumab combined with chemotherapy was 13.8 months, versus 11.6 months in those receiving chemotherapy alone. The difference was more statistically significant in the CPS ≥1% and CPS ≥5% subgroups. The immunotherapy-based regimens were significantly superior in terms of PFS in all the subgroups, whereas the ORR in patients receiving nivolumab combined with chemotherapy was also higher than in patients receiving chemotherapy alone in the CPS ≥5% subgroup. The ATTRACTION-4 study was conducted in two parts. The first part was a phase II trial of 40 participants, reporting for the first the safety and efficacy of nivolumab combined with S-1/oxaliplatin or capecitabine/oxaliplatin as a first-line treatment for HER2-negative advanced gastric cancer. The second part was a phase III trial comparing the efficacy of nivolumab and a placebo, both combined with chemotherapy. In summary, the currently available data suggest that PD-1 inhibitors combined with chemotherapy may represent a promising first-line treatment option for patients with advanced G/GEJAC.
It was interesting in the current retrospective study to find among patients receiving sintilimab in the first- or second-line setting an mPFS of 4.90 months, compared with 3.00 months for those treated in later lines. Both univariate (HR = 2.607, 95% CI = 1.142–5.953, P = 0.023) and multivariate (HR = 4.483, 95% CI = 1.533–13.109, P = 0.006) analyses indicated statistically significant differences between the groups.
However, some limitations should be considered when interpreting our results, including the retrospective study design, relatively short observation period, and a small number of patients. A well-designed prospective trial with a larger sample size should thus be conducted based on these preliminary findings.
| > Conclusion|| |
In summary, sintilimab is widely used in real-world practice because of its availability. We demonstrated the efficacy and safety of sintilimab for the treatment of advanced G/GEJAC by retrospectively examining data from patients treated in our department. The benefits of the drug were stronger in the first- or second-line setting than in later lines of treatment.
Financial support and sponsorship
This study was sponsored by Beijing Key Clinical Specialty (grant no. 2018-2020).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]