Efficacy and safety of immunotherapy combinations in advanced esophageal and gastric cancers: A systematic review and bayesian network meta-Analysis

doi:10.21203/rs.3.rs-3244113/v1

Download PDF

Research Article

Efficacy and safety of immunotherapy combinations in advanced esophageal and gastric cancers: A systematic review and bayesian network meta-Analysis

https://doi.org/10.21203/rs.3.rs-3244113/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background Immune checkpoint inhibitors (ICIs) have yielded a revolution in the treatment of esophageal, gastroesophageal junction, and gastric cancers cancers. We made a Bayesian network meta-analysis to systematically compare the efficacy and safety of various immunotherapies, chemotherapy, and supportive treatment, and to further identify the best benefitting subgroup.

Methods We systematically searched Pubmed/MEDLINE, Embase, Cochrane Library and the conference abstracts of oncology conferences up to July 25, 2022. The Bayesian network meta-analysis was performed with a random-effect model using R, package gemtc and package JAGS. The primary outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and grade 3-5 adverse events (AEs).

Results Totally 11719 patients from 20 RCTs (19/20 were phase 3) were included, which were divided into 12 treatment regimens. Immune monotherapies yield superior OS benefit (HR = 0.89, 95% CI: 0.83–0.95), but inferior PFS (HR = 0.75, 95% CI: 0.7–0.8) compared with chemotherapy. Except for Nivo_5FCisp (HR = 0.8, 95% CI: 0.49–1.32), Nivo_S1Oxal (HR = 0.9, 95% CI: 0.75–1.08), Tori_PacCisp (HR = 0.91, 95% CI: 0.77–1.07), the other ICIs combined chemotherapy (IO) had a significant OS benefit compared with chemotherapy. Except for Nivo_5FCisp, the other IO regimens had significant PFS benefits than chemotherapy. There were no significantly statistical differences of ORR and grade 3-5 AEs. Sin_PacCisp and Cam_PacCisp achieved an effective balance between efficacy and safety. The former regimen ranked second for OS (48.3%), PFS (29.5%), ORR (18.4%), and sixth for grade 3-5 AEs (7.2%), the later one ranked third for OS and PFS, fifth for ORR and ninth for grade 3-5 AEs. Esophagogastric cancers with higher PD-L1 expression levels might benefit more from immunotherapies.

Conclusion We found immunotherapis were more likely to provide OS and PFS superiority compared with chemotherapy, with no significantly statistical differences of ORR and grade 3-5 AEs. Sin_PacCisp and Cam_PacCisp achieved an effective balance between efficacy and safety. Esophagogastric cancers with higher PD-L1 expression levels might benefit more from immunotherapies.

Immunotherapy combinations

Esophageal gastric cancer

Systematic review

Efficacy and safety

Bayesian network meta-analysis

Esophageal, gastroesophageal junction, and gastric cancers belong to upper gastrointestinal cancers. These cancers exhibit similarities in molecular expression and are often classified together due to their common clinical features and prognosis(1). Upper gastrointestinal cancers are still among the leading causes of cancer-related deaths worldwide(2). Due to their atypical symptoms, early esophagogastric cancers are difficult to detect, with around 40% of patients presenting with clinical symptoms already in the advanced stages, with some patients experiencing distant metastases, losing the opportunity for surgery(3).

For advanced esophagogastric cancers, a combination of 5-fluorouracil and platinum-based chemotherapy is the standard first-line treatment(4, 5). However, most patients experience disease progression after first-line treatment, the median overall survival was reported only about 7 months(6). Second-line or third-line treatments, including docetaxel, paclitaxel, irinotecan alone or in combination, have also been widely used in clinical practice for many years(4, 5). Yet, the effectiveness of later-line chemotherapy is limited and adverse effect are significant. Moreover, patients who suffered later-line chemotherapy have poor physical condition and are unable to tolerate subsequent treatment. In recent years, targeted therapies have certain value in the treatment of esophagogastric cancers, such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2), and vascular endothelial growth factor (VEGF) related antibodies(7, 8). However, the benefits are limited, and new treatments are urgently needed to improve the prognosis of this disease and reduce local recurrence and distant metastasis.

Recent data from multiple clinical trials have shown that immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors play a role in the treatment of advanced esophagogastric cancers, opening a new potential option in the treatment of these cancers. Malignant tumors acquired immune escape due to the lack of tumor cell antigen expression or the establishment of immune tolerance environment. ICIs are a new type of treatment drug, which are designed by activating compensatory T cell-related checkpoints, such as CTLA-4 checkpoint, PD-1 checkpoint and its ligand PD-L1 checkpoint(9-11). ICIs have achieved significant therapeutic effects in melanoma, renal cancer, and non-small cell lung cancer(12, 13). Recently, they have become a focus in the treatment of gastrointestinal malignant tumors. Previous studies have shown that compared with traditional chemotherapy, PD-1/PD-L1 inhibitors bring considerable sustained treatment responses and less adverse effects. Some ICIs have gradually been first recommended to second-line or more-line treatment of advanced esophagogastric cancer.

In addition, previous preclinical studies have found that adding chemotherapy to immunotherapy may provide greater benefits, as chemotherapy drugs not only have direct cytotoxic effects, but also induce synergistic effects by enhancing immune cell death(14, 15). However, it is currently unclear which treatment regimen has more effects for the treatment of esophagogastric cancer. Previous research data have found a correlation between the level of PD-L1 expression and the effectiveness of ICIs. Therefore, we collected randomized controlled trials (RCTs) of advanced esophageal, gastric, or gastroesophageal junction cancer in recent years and conducted a network meta-analysis to systematically compare the efficacy and safety of various immunotherapies, chemotherapy, and supportive treatment, and to further identify the best benefitting subgroup.

Literature sources and searches

The network meta-analysis was followed the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), covering Pubmed/MEDLINE, Embase, and the Cochrane Library up to July 25, 2022, and abstracts from AACR 2020, ASCO 2020, ESMO GI 2020, ESMO 2020, ESMO Asia 2020, ASCO GI 2021, ASCO 2021, and ESMO 2021. We also checked reference lists of relevant review articles and related studies to prevent omissions. In addition, the abstracts presented in Chinese Society of Clinical Oncology, European Society for Medical Oncology, American Association for Cancer Research, and American Society of Clinical Oncology conferences were manually searched for identifying any further potential RCT. The query terms for the search including: “Immunotherapy, nivolumab, pembrolizumab OR camrelizumab OR sintilimab OR toripalimab OR tislelizumab；chemotherapy，pharmacotherapy，docetaxel OR paclitaxel OR Taxoid OR taxotere OR cisplatin OR platin* OR carboplatin OR fluorouracil OR 5-fluorouracil OR fluoro-uracil OR 5FU，esophageal cancer OR gastroesophageal adenocarcinoma OR gastric cancer ”(Figure 1).

Inclusion and exclusion criteria

The inclusion criteria according to the "PICOS" guidelines：Patients (P): Adults with histologically confirmed advanced esophageal cancer, gastroesophageal junction cancer and gastric cancer; Interventions (I): Studies that compared survival benift and safety between immunotherapy plus chemotherapy and chemotherapy alone; Comparators (C): chemotherapy, placebo; outcomes (O): overall survival (OS, defined as the time from randomization until death from any cause), progression-free survival (PFS, defined as the time from randomization to disease progression or death from any cause), objective response rate (ORR, defined as the proportion of patients who achieved an objective response), disease control rate (DCR), adverse events (AEs, classified into grade 3-5 AEs and all grade AEs, which was based on National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0); Study design (S): randomized controlled trial.

Besides, the results of the trials should be written in English. If the same trial has several versions, we choose the most recent one or the one containing the appropriate information. Exclusion criteria were: (1) Insufficient data. (2) Case report, retrospective study, letter, review, and meta-analysis.

Data extraction

Two investigators (CZ and CL) independently checked titles, abstracts and full texts. Then they cross-check their works. Any discrepancies between the two investigators were resolved by the third investigator to evaluate availability. Then we extracted the relevant resources from eligible trails: the trial name, National Clinical trail number, publication year, phase of RCTs, population size, median age of each arm, sex distribution, treatment regimens of each arm and relevant clinical outcomes. The primary outcomes including OS, PFS, ORR and grade 3-5 AEs.

Data synthesis and statistical analysis

The Bayesian network meta-analysis was performed with a random-effect model using R, package gemtc and package JAGS. The pooled hazard ratio (HR) with 95% credible intervals (CIs) were used as the effect sizes for OS and PFS, while odd risks (ORs) with 95% CI were used to estimate the ORR and AEs. Subgroup analysis was performed according to PD-L1 combined positive score (CPS). A multiple treatments comparison was conducted by a Bayesian network framework with a Monte Carlo Markov Chain (MCMC) model, using a consistency model16. We conducted 4 MCMC chains simultaneously; the number of simulations was set up to 5000; the number of iterations was set up to 2,0000.

The deviation information criterion (DIG) value of the consistency model and the inconsistency model was compared to assess the degree of the model fit. If the difference of DIG <5, the fit of these two models is consistent; if the difference >5, when there is a closed loop, the consistency of direct and indirect comparison will be assessed by the inconsistent factor (IF). When the 95% confidence interval (CI) starting point of the IF value is 0, it indicates that direct and indirect comparison tend to be consistent.

We also used the node splitting to evaluate local inconsistencies. The convergence of the model was assessed by the tract and density plot and the Brooks-Gelman-Rubin diagnosis plot. If the overlap area of each MCMC chain in the track covers most of the chain fluctuation range, the density graph is normally distributing, and the Bandwidth approaches zero and keeps stability, the model was considered a high degree of convergence. Heterogeneity to be assessed using I² statistic.

Included studies and treatment groups

During the initial literature search, we identified a total of 3405 records from databases and 68 additional online records from conference proceedings. After removing 1030 duplicated records and 1217 non-pertinent articles based on title，1226 studied underwent abstract screening. 58 studies were considered eligible for full-text filtering and 20 studies finally were collected in the network meta-analysis. The majority of included RCTs (19/20) are in phase 3(Table 1). 8 trials were published in 2022 (16-23), 3 in 2021(24-26), 4 in 2020(27-30), 2 in 2018(31, 32), 1 in 2014(33), 1 in 2011(34). Besides, 8 trials recruited patients with esophageal squamous cell carcinoma, 6 trials recruited patients with gastroesophageal junction cancer and gastric cancer, 2 trials recruited patients with esophageal cell carcinoma and gastroesophageal junction cancer, 2 trials recruited patients with esophageal cell carcinoma, gastroesophageal junction cancer and gastric cancer. 1 trial recruited patients with esophageal squamouscell carcinoma or adenocarcinoma. The baseline characteristics of participants were well-balanced between intervention and control arms in all RCTs. The median age ranged from 59 to 67 years.

Participants included in these RCTs were distributed all over the world. Most of the patients were male. The detailed characteristics of included RCTs were summarized in Table 1.

According to the treatment intervention, xxxx participants were grouped into the following 12 treatment categories: chemotherapy (Chemo), nivolumab with tegafur–gimeracil–oteracil potassium plus oxaliplatin (Nivo_S1Oxal), pembrolizumab with paclitaxel (Pem_Pac), Sintilimab with paclitaxeland and cisplatin (Sin_PacCisp), Toripalimab with paclitaxel and cisplatin (Tori_PacCisp), Pembrolizumab with capecitabine and cisplatin (Pem_CapCisp), nivolumab with 5-fluorouracil and cisplatin (Nivo_5FCisp), immune checkpoint inhibitors monotherapy (Immu), Placebo (Control), Nivolumab with leucovorin and 5-fluorouracil and oxaliplatin (Nivo_FOLFOX), Camrelizumab with paclitaxel and cisplatin (Cam_PacCisp), Pembrolizumab with 5-fluorouracil and cisplatin (Pem_5FCisp).

Efficacy outcomes of OS

As the efficacy outcomes of OS, we gathered 12 treatment regimens with 10919 patients as 12 nodes in network meta-analysis (Figure 2A). Firstly, immunotherapis were more likely to get better OS benefit than chemotherapy. Immune monotherapies yield superior OS benefit than chemotherapy (HR = 0.89, 95% CI: 0.83–0.95). Regarding immunotherapy combined chemotherapy (IO), except for Nivo_5FCisp (HR = 0.8, 95% CI: 0.49–1.32), Nivo_S1Oxal (HR = 0.9, 95% CI: 0.75–1.08), Tori_PacCisp (HR = 0.91, 95% CI: 0.77–1.07), the other IO all had a significant OS benefit compared with Chemo. Secondy, Pem_5FCisp was considered to give significant benefits on comparision with Pem_Pac (HR = 0.58, 95% CI: 0.34–0.97), Tori_PacCisp (HR = 0.63, 95% CI: 0.45–0.86), Nivo_S1Oxal (HR = 0.63, 95% CI: 0.45–0.88), Immu (HR = 0.64, 95% CI: 0.48–0.85), Pem_CapCisp (HR = 0.68, 95% CI: 0.5–0.93). The same phenomenon was also found in Sin_PacCisp compared with these groups. Thirdly, with the same immune checkpoint inhibitor, perhaps Pem_5FCisp is better than Pem_CapCisp (HR = 0.68, 95% CI: 0.5–0.93). While with the same chemotherapy, there is a trend of Sin_PacCisp better than Cam_PacCisp than Tori_PacCisp. Forthly, all the treatment regimens have significant OS benefit than control arm. Futhermore, the ranking of OS benefits for each treatment was discerned as Pem_5FCisp＞Sin_PacCisp＞Cam_PacCisp＞Nivo_FOLFOX＞Nivo_5FCisp＞Pem_CapCisp＞Immu＞Nivo_S1Oxal ＞Tori_PacCisp ＞Pem_Pac＞Chem＞Control(Figure 3A).

Efficacy outcomes of PFS

As the efficacy outcomes of PFS, we gathered 12 treatment regimens with 10701 patients as 12 nodes in network meta-analysis (Figure 2B). Firstly, chemotherapy and all IO regimens had sigificant PFS benefit than immune monotherapy. All treatment regimens were better than control. Secondly, except for Nivo_5FCisp (HR = 0.84, 95% CI: 0.68–1.04), the other IO regimens had significant PFS benefits than Chemo. Thirdly, compared with Nivo_5FCisp, Pem_5FCisp (HR = 0.77, 95% CI: 0.61–0.97), Tori_PacCisp (HR = 0.69, 95% CI: 0.5–0.94), Cam_PacCisp (HR = 0.66, 95% CI: 0.5–0.89), Sin_PacCisp (HR = 0.66, 95% CI: 0.5–0.88), Pem_Pac (HR = 0.58, 95% CI: 0.35–0.97) were considered to give significant benefits on PFS. Forthly, with the same chemotherapy, there is a trend of Sin_PacCisp is better than Cam_PacCisp than Tori_PacCisp. Futhermore, the ranking of PFS benefits for each treatment was discerned as Pem_Pac＞Sin_PacCisp＞Cam_PacCisp＞Tori_PacCisp＞Pem_5FCisp＞Nivo_S1Oxal＞Nivo_FOLFOX＞Pem_CapCisp＞Nivo_5FCisp＞Chem＞Immu＞Control (Figure 3A).

Efficacy outcomes of ORR

As the efficacy outcomes of ORR, we gathered 11 treatment regimens with 9222 patients as 11 nodes in network meta-analysis (Figure 2C). Although there are no significantly statistical differences among these different treatment regimens, Nivo_5FCisp might be considered as the best treatment with regard to the ORR, following Sin_PacCisp＞Tori_PacCisp＞Pem_5FCisp＞Cam_PacCisp＞Nivo_S1Oxal＞Immu＞Chem＞Pem_Pac＞Nivo_FOLFOX＞Pem_CapCisp (Figure 3B).

Safety outcoms of AEs

Considering that clinicians were more concerned about serious AEs (which were defined as grade 3-5). We gathered 12 treatment regimens with 10368 patients as 12 nodes in network meta-analysis (Figure 2D). The treatment of ranking No.1 represented the highest incidence of AEs.The results showed that the incidence of grade 3-5 AEs in each treatment group was similar, with no significantly statistical difference (Figure 3B).

Nivo_S1Oxal: nivolumab with tegafur–gimeracil–oteracil potassium plus oxaliplatin; Pem_Pac: pembrolizumab with paclitaxel; Sin_PacCisp: Sintilimab with paclitaxeland and cisplatin; Tori_PacCisp: Toripalimab with paclitaxel and cisplatin. Pem_CapCisp: Pembrolizumab with capecitabine and cisplatin; Nivo_5FCisp: nivolumab with 5-fluorouracil and cisplatin; Immu: immune checkpoint inhibitors monotherapy; Nivo_FOLFOX: Nivolumab with leucovorin and 5-fluorouracil and oxaliplatin; Cam_PacCisp: Camrelizumab with paclitaxel and cisplatin; Pem_5FCisp: Pembrolizumab with 5-fluorouracil and cisplatin; Control: Placebo; Chemo: chemotherapy.

Rankings

The consistency of the ranking results with the direct and indirect pooled results obtained using HRs and ORs suggests that the framework is stable and reliable (Figure 4). Pem_5FCisp was most likely to rank first for OS (cumulative probability of 66.4%), Pem_Pac was most likely to rank first for PFS (57.8%), Nivo_5FCisp was most likely to rank first for ORR (19.7%), and Pem_CapCisp was most likely to lead highest incidence of grade 3-5 AEs (22.4%, Table s1-s4). In case of Sin_PacCisp, an effective balance between three efficacy outcomes and safety was achieved, the treatment ranked second for OS (48.3%), PFS (29.5%), ORR (18.4%), and sixth for grade 3-5 AEs (7.2%, Table s1-s4). The other one was Cam_PacCisp also appeared an effective and safety balance, with ranked third for OS, third for PFS, fifth for ORR and ninth for grade 3-5 AEs.

Two-dimensional analysis

Then we made a two-dimensional outcome analysis graph with OS on the x-axis and the SUCRA value for the incidence of grade 3-5 AEs on the y-axis. The graph showed that higher values on the x-axis and lower values on the y-axis indicated the best drug performance, with the most significant improvement in OS and the lowest incidence of grade 3-5 AEs. This two-dimensional graph provides additional evidence supporting the conclusion drawn from the ranking plot described earlier. As shown in the gragh, Pem_5FCisp, Sin_PacCisp and Cam_PacCisp demonstrated excellent balance between OS and grade 3-5 AEs (Figure 5)

Subgroup analysis of PD_L1 expression level

Then, we estimated the clinical outcomes of OS with different PD-L1 expression levels in the subgroup analysis. The participants were divided into the following six subgroups according to the levels of PD-L1 expression: less than 1%, greater than or equal to 1%, less than 5%, greater than or equal to 5%, less than 10%, greater than or equal to 10%. The optimal treatment regimen differed across the six subgroups.

For patients with PD-L1 less than 1%, 5 immune treatment regimens were included in the subgroup analysis. Nivo_FOLFOX (HR=0.78, 95% CI: 0.70-0.87) were significantly superior to chemotherapy. As patients with PD-L1 greater than or equal to 1%, 7 immune treatment regimens were included in the subgroup analysis. Cam_PacCisp (HR=0.59, 95% CI: 0.43-0.80), Tori_PacCisp (HR=0.61, 95% CI: 0.44-0.87), Nivo_5FCisp (HR=0.69, 95% CI: 0.56-0.84) were significantly superior to chemotherapy (Figure 6A).

For patients with PD-L1 less than 5%, 2 immune treatment regimens were included in the subgroup analysis. Nivo_FOLFOX (HR=0.74, 95% CI: 0.66-0.84) were significantly superior to chemotherapy. As patients with PD-L1 greater than or equal to 5%, also 2 immune treatment regimens were included in the subgroup analysis. Nivo_5FCisp (HR=0.69, 95% CI: 0.55-0.87) were significantly superior to chemotherapy (Figure 6B).

For patients with PD-L1 less than 10%, 4 immune treatment regimens were included in the subgroup analysis. Tori_PacCisp (HR=0.61, 95% CI: 0.40-0.93) were significantly superior to chemotherapy. As patients with PD-L1 greater than or equal to 10%, also 6 immune treatment regimens were included in the subgroup analysis. Pem_5FCisp (HR=0.62, 95% CI: 0.49-0.78), Sin_PacCisp (HR=0.63, 95% CI: 0.51-0.78), Nivo_FOLFOX (HR=0.66, 95% CI: 0.56-0.77), Nivo_5FCisp (HR=0.63, 95% CI: 0.47-0.84), Pem_CapCisp (HR=0.69, 95% CI: 0.49-0.97) were significantly superior to chemotherapy (Figure 6C).

Stability, eplicability, heterogeneity and inconsistency

The trajectory plot showed that the MCMC chains were stable with good overlap when the number of iterations exceeded 5000. The density plot revealed that the Bandwidth approached 0 and stabilized when the number of iterations reached 20000, indicating that the model had converged well (Figure S1-S4). The convergence plot indicated that the model had reached a satisfactory state (Figure S5-S8). These results represent the stability and replicability of the inferential iterations for each Markov Chain Monte Carlo chain. The methodological heterogeneity including different cancer histology, treatment line, various ICIs and chemotherapy regimens caused the high heterogeneities among each group (Figure S9-S12).

For esophageal, gastroesophageal junction, and gastric cancers with immunotherapy, this is the first systematic review and network meta-analysis comparing the efficacy and safety profiles of currently available 20 RCTs and 12 treatment groups. To our knowledge, the present study was the largest and most comprehensive analysis focused on esophagogastric with immunotherapy.

The results we founded were as follows: firstly, immunotherapis were more likely to provide OS and PFS superiority compared with chemotherapy, except for immune monotherapy had worse PFS benefit than chemotherapy. Secondly, there were no significantly statistical differences of ORR and grade 3-5 AEs between all therapeutic regimens. Thirdly, Sin_PacCisp and Cam_PacCisp achieved an effective balance between efficacy and safety. The former ranked second for OS, PFS and ORR, and sixth for grade 3-5 AEs while the later ranked third for OS and PFS, fifth for ORR and ninth for grade 3-5 AEs. Fourthly, esophagogastric cancers with higher PD-L1 expression levels might benefit more from immunotherapies.

Esophagogastric cancer are common causes of cancer-related deaths globally. In clinical practice, a comprehensive treatment model combining surgery with chemotherapy, radiation therapy, or targeted therapy is followed for esophagogastric cancer(35, 36). First-line standard treatment methods for advanced esophagogastric cancer include chemotherapy drugs such as 5-FU, platinum agents, and taxanes. Clinical evidence shows that due to the heterogeneity of histology, molecular biology and etiology, esophagogastric cancer inherently exhibit resistance to systemic treatment, limiting the response to subsequent treatments after first-line treatment(37). The application of targeted therapy has improved survival, but the use of targeted drugs in esophagogastric cancer is highly restricted. In recent years, immunotherapy, especially PD-1/PD-L1 inhibitors, has been introduced as a new treatment model for advanced esophagogastric cancer. PD-1 is a negative costimulatory molecule that is mainly expressed on activated T cells, particularly on tumor-infiltrating T lymphocytes, and is a cell surface protein member of the CD28 family(38). It mainly contains two ligands named PD-L1 and PD-L2. After PD-1 binds to PD-L1 or PD-L2, it can inhibit the activity of T lymphocytes, block their migration and proliferation, weaken their anti-tumor immune response and secretion of cytotoxic mediators, and further inhibit the function of tumor-infiltrating lymphocytes (TIL), leading to T cell apoptosis, which enables tumor cells to escape immune surveillance, thereby promoting tumor development(39). Thus, inhibiting the binding of PD-1 to its ligand can relieve the immune suppression state, promote the anti-tumor immune response of T lymphocytes, and inhibit the growth of tumor cells(40).

We observed that the benefit of single-agent immunotherapy in terms of PFS was significantly inferior to chemotherapy, but OS was significantly better than chemotherapy. We speculate that this difference may be due to the distinct anti-tumor response of immunotherapy compared to traditional treatments. The onset of immunotherapy is later than chemotherapy, but it has a longer duration of response(41). Such as the data from ATTRACTION-3(20) showed that the median time to onset of immunotherapy was later than chemotherapy (2.6 vs. 1.5 months). While the median duration of response to immunotherapy in KEYNOTE-061(31), ESCORT(29), and ORIENT-2(16), which was longer than chemotherapy (18.0 vs 5.5, 6.9 vs 3.9, 7.4 vs 3.4, 8.3 vs 6.2 months). These results indicates that patients who respond to immunotherapy may achieve more sustained relief and slower disease progression compared to those who respond to chemotherapy. Some patients may experience pseudo-progression after immunotherapy, which refers to the temporary immune cell infiltration rather than tumor growth. This is a unique mechanism of action of ICIs in the treatment of malignant tumors(20). Our study found that Sin_PacCisp and Cam_PacCicp achieved an effective balance between OS, PFS and ORR. This may guide us to boldly assume that the best combination of immunotherapy and chemotherapy could be developed, combining the benefits of both.

KEYNOTE-181 trial(28) found that in the subgroup of advanced esophageal squamous cell cancer with PD-L1≥10%, the Pembrolizumab group had a significantly longer median OS compared to the chemotherapy group (9.3 vs 6.7 months, HR=0.69, 95%CI:0.52-0.93), and an increase in PFS and ORR. In the KEYNOTE-062 trial(27), for the subgroup of advanced gastric/gastroesophageal junction cancer with PD-L1≥10%, pembrolizumab prolonged median OS compared to chemotherapy (17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97). However, some studies have shown that PD-L1 expression leval may not be a reliable biomarker for predicting the prognosis of immunotherapy in esophagogastric cancer. ATTRACTION-2(30) and ATTRACTION-3(20) trials showed that nivolumab showed better OS benefits regardless of PD-L1 expression for advanced esophageal squamous cell cancer and gastroesophageal junction cancer and gastric cancer. ESCORT trial(29) revealed the benefit in overall survival with camrelizumab versus chemotherapy regardless of PD-L1 expression. Our study founded that although immunotherapies offered more survival benefits compared to chemotherapy in all participants, there is a trend that subgroups with higher PD-L1 expression levels (PD-L1≥10%), had a higher probability of immune benefit. The results of the ASTRUM-007 trial(42) (NCT03958890) were published after we completed our article search. It evaluated the efficacy and safety of first-line serplulimab plus cisplatin and 5-FU chemotherapy versus placebo plus chemotherapy in patients with locally advanced or metastatic, PD-L1-positive (CPS ≥ 1) ESCC. Serplulimab plus chemotherapy significantly improved PFS compared with placebo plus chemotherapy (median PFS of 5.8 months and 5.3 months, respectively, P < 0.0001). Serplulimab plus chemotherapy also significantly prolonged OS compared with placebo plus chemotherapy (median OS of 15.3 months and 11.8 months, respectively, P = 0.002). The prespecified subgroup analyses showed that patients with PD-L1 CPS ≥ 10 had an HR of 0.59 (95% CI, 0.40–0.88), compared with 0.74 (95% CI, 0.54–1.03) for those with 1 ≤ CPS < 10. The predictive role of PD-L1 and other biomarkers in esophageal and gastric cancer required further study.

Our study specifically analyzed the incidence of serious AEs (grade 3-5), and found no statistically significant difference between immune monotherapy, immune combination therapy and chemotherapy. ESCORT(29) and ESCORT-1st(25) trials have separately reported a special immune-related adverse event (irAEs) from camrelizumab, which is reactive cutaneous capillary endothelial proliferation in the skin. Although the incidence rate is high, most cases are grade 1-2 (79-80%), and the incidence rate of grade 3 or above is about 1%. Some studies have indicated that the incidence of immune-related adverse events is positively correlated with survival benefits, which indicated clinicians should trade-off the efficacy and irAEs produced by ICIs(43, 44).

Several limitations should be noted. Firstly, the methodological heterogeneity including different identification of PD-L1 scoring, different cancer histology, inconsistent treatment line, various ICIs and chemotherapy regimens would inevitably cause heterogeneities among each group. Secondly, we could not compare the efficacy between PD-1 and PD-L1 inhibitors due to the insufficient data of PD-L1 inhibitors.

We found immunotherapis were more likely to provide OS and PFS superiority compared with chemotherapy, with no significantly statistical differences of ORR and grade 3-5 AEs. Sin_PacCisp and Cam_PacCisp achieved an effective balance between efficacy and safety. Esophagogastric cancers with higher PD-L1 expression levels might benefit more from immunotherapies. We hope our findings may be valuable for clinical decisions.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest

Lin EW, Karakasheva TA, Lee DJ, Lee JS, Long Q, Bass AJ, Wong KK, Rustgi AK (2017) Comparative transcriptomes of adenocarcinomas and squamous cell carcinomas reveal molecular similarities that span classical anatomic boundaries. PLoS genetics. 13: e1006938. doi: 10.1371/journal.pgen.1006938
Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics, 2022. CA Cancer J Clin. 72: 7-33. doi: 10.3322/caac.21708
Di Corpo M, Schlottmann F, Strassle PD, Nurczyk K, Patti MG (2019) Treatment Modalities for Esophageal Adenocarcinoma in the United States: Trends and Survival Outcomes. Journal of laparoendoscopic & advanced surgical techniques. Part A. 29: 989-94. doi: 10.1089/lap.2019.0350
Ajani JA, D'Amico TA, Bentrem DJ et al. (2022) Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 20: 167-92. doi: 10.6004/jnccn.2022.0008
Ajani JA, D'Amico TA, Bentrem DJ et al. (2019) Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 17: 855-83. doi: 10.6004/jnccn.2019.0033
Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, Ho J, Unverzagt S (2017) Chemotherapy for advanced gastric cancer. The Cochrane database of systematic reviews. 8: Cd004064. doi: 10.1002/14651858.CD004064.pub4
Xu RH, Zhang Y, Pan H et al. (2021) Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia): a randomised, multicentre, double-blind, phase 3 trial. The lancet. Gastroenterology & hepatology. 6: 1015-24. doi: 10.1016/s2468-1253(21)00313-7
Makiyama A, Sukawa Y, Kashiwada T et al. (2020) Randomized, Phase II Study of Trastuzumab Beyond Progression in Patients With HER2-Positive Advanced Gastric or Gastroesophageal Junction Cancer: WJOG7112G (T-ACT Study). J Clin Oncol. 38: 1919-27. doi: 10.1200/jco.19.03077
Wu M, Huang Q, Xie Y, Wu X, Ma H, Zhang Y, Xia Y (2022) Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation. Journal of hematology & oncology. 15: 24. doi: 10.1186/s13045-022-01242-2
Rowshanravan B, Halliday N, Sansom DM (2018) CTLA-4: a moving target in immunotherapy. Blood. 131: 58-67. doi: 10.1182/blood-2017-06-741033
Iwai Y, Hamanishi J, Chamoto K, Honjo T (2017) Cancer immunotherapies targeting the PD-1 signaling pathway. Journal of biomedical science. 24: 26. doi: 10.1186/s12929-017-0329-9
Wu Z, Chen Q, Qu L et al. (2022) Adverse Events of Immune Checkpoint Inhibitors Therapy for Urologic Cancer Patients in Clinical Trials: A Collaborative Systematic Review and Meta-analysis. European urology. 81: 414-25. doi: 10.1016/j.eururo.2022.01.028
Zhang Q, Tang L, Zhou Y, He W, Li W (2021) Immune Checkpoint Inhibitor-Associated Pneumonitis in Non-Small Cell Lung Cancer: Current Understanding in Characteristics, Diagnosis, and Management. Frontiers in immunology. 12: 663986. doi: 10.3389/fimmu.2021.663986
Park SJ, Ye W, Xiao R, Silvin C, Padget M, Hodge JW, Van Waes C, Schmitt NC (2019) Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer. Oral oncology. 95: 127-35. doi: 10.1016/j.oraloncology.2019.06.016
Wang W, Wu L, Zhang J, Wu H, Han E, Guo Q (2017) Chemoimmunotherapy by combining oxaliplatin with immune checkpoint blockades reduced tumor burden in colorectal cancer animal model. Biochemical and biophysical research communications. 487: 1-7. doi: 10.1016/j.bbrc.2016.12.180
Xu J, Li Y, Fan Q et al. (2022) Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2). Nature communications. 13: 857. doi: 10.1038/s41467-022-28408-3
Wang ZX, Cui C, Yao J et al. (2022) Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer cell. 40: 277-88.e3. doi: 10.1016/j.ccell.2022.02.007
Shitara K, Ajani JA, Moehler M et al. (2022) Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 603: 942-8. doi: 10.1038/s41586-022-04508-4
Shen L, Kato K, Kim SB et al. (2022) Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 40: 3065-76. doi: 10.1200/jco.21.01926
Okada M, Kato K, Cho BC et al. (2022) Three-Year Follow-Up and Response-Survival Relationship of Nivolumab in Previously Treated Patients with Advanced Esophageal Squamous Cell Carcinoma (ATTRACTION-3). Clinical cancer research : an official journal of the American Association for Cancer Research. 28: 3277-86. doi: 10.1158/1078-0432.Ccr-21-0985
Lu Z, Wang J, Shu Y et al. (2022) Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ (Clinical research ed.). 377: e068714. doi: 10.1136/bmj-2021-068714
Kang YK, Chen LT, Ryu MH et al. (2022) Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. The Lancet. Oncology. 23: 234-47. doi: 10.1016/s1470-2045(21)00692-6
Doki Y, Ajani JA, Kato K et al. (2022) Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. The New England journal of medicine. 386: 449-62. doi: 10.1056/NEJMoa2111380
Sun JM, Shen L, Shah MA et al. (2021) Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet (London, England). 398: 759-71. doi: 10.1016/s0140-6736(21)01234-4
Luo H, Lu J, Bai Y et al. (2021) Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. Jama. 326: 916-25. doi: 10.1001/jama.2021.12836
Chung HC, Kang YK, Chen Z et al. (2021) Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients. Cancer. 128: 995-1003. doi: 10.1002/cncr.34019
Shitara K, Van Cutsem E, Bang YJ et al. (2020) Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 6: 1571-80. doi: 10.1001/jamaoncol.2020.3370
Kojima T, Shah MA, Muro K et al. (2020) Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 38: 4138-48. doi: 10.1200/jco.20.01888
Huang J, Xu J, Chen Y et al. (2020) Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study. The Lancet. Oncology. 21: 832-42. doi: 10.1016/s1470-2045(20)30110-8
Chen LT, Satoh T, Ryu MH et al. (2020) A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data. Gastric Cancer. 23: 510-9. doi: 10.1007/s10120-019-01034-7
Shitara K, Özgüroğlu M, Bang YJ et al. (2018) Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet (London, England). 392: 123-33. doi: 10.1016/s0140-6736(18)31257-1
Bang YJ, Ruiz EY, Van Cutsem E et al. (2018) Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 29: 2052-60. doi: 10.1093/annonc/mdy264
Ford HE, Marshall A, Bridgewater JA et al. (2014) Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. The Lancet. Oncology. 15: 78-86. doi: 10.1016/s1470-2045(13)70549-7
Thuss-Patience PC, Kretzschmar A, Bichev D et al. (2011) Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). European journal of cancer (Oxford, England : 1990). 47: 2306-14. doi: 10.1016/j.ejca.2011.06.002
Patel MA, Kratz JD, Lubner SJ, Loconte NK, Uboha NV (2022) Esophagogastric Cancers: Integrating Immunotherapy Therapy Into Current Practice. J Clin Oncol. 40: 2751-62. doi: 10.1200/jco.21.02500
Joshi SS, Badgwell BD (2021) Current treatment and recent progress in gastric cancer. CA Cancer J Clin. 71: 264-79. doi: 10.3322/caac.21657

No competing interests reported.

DataSheet1.zip

Download PDF

Version 1

posted

You are reading this latest preprint version

Efficacy and safety of immunotherapy combinations in advanced esophageal and gastric cancers: A systematic review and bayesian network meta-Analysis

Status:

Version 1

Abstract

Figures

Introduction

Methods

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1