Sintilimab Plus Nanoparticle Polymeric Micellar Paclitaxel and S-1 as First-Line Treatment in HER2-Negative Advanced Gastric Cancer: A Real-World Study

Abstract

Background

This study evaluated the efficacy and safety of a regimen consisting of sintilimab, nanoparticle polymeric micellar paclitaxel (NPMP) and S-1 in HER2-negative advanced gastric cancer (AGC).

Method

In this real-world study, patients with HER2-negative AGC received first-line sintilimab plus NPMP and S-1. The primary endpoint was overall survival (OS) and progression free survival (PFS), while objective response rate (ORR), disease control rate (DCR), and safety were evaluated as secondary endpoints.

Results

Among 33 enrolled patients, 14 patients (42.4%) achieved partial response (PR), 17 (51.5%) maintained stable disease (SD), 2 (6.1%) showed progressive disease (PD). ORR and DCR were 42.4% and 93.9%. Median OS reached 15.4 months (95%CI: 13.0-17.6), median PFS was 7.8 months (95%CI: 5.8–9.3). Subgroup analysis revealed significant differences in OS and PFS according to PD-L1 expression and cycles of treatment. Observed adverse events (AEs) were fatigue (60.6%), leukopenia (54.5%),anemia (51.5%),thrombocytopenia (36.4%),nausea (30.3%) and vomiting (15.1%). Most toxicities were manageable and predominantly grade 1–2.

Conclusions

The combination of sintilimab, NPMP and S-1 demonstrates promising antitumor effects and controllable toxicity as first-line treatment in patients with HER2-negative with AGC.

Introduction

Gastric cancer (GC) stands as the fifth detected cancer and the fourth cause of death globally, seriously posing threats to public health [1]. Approximately 1.1 million new GC are reported each year, with nearly 44% occurring in China [1]. However, only 20% of patients are diagnosed before progression [2]. Most patients present with advanced stages, resulting in a 5-year overall survival (OS) less than 30% [3].

For patients with HER2-negative advanced gastric cancer(AGC), systemic chemotherapy continues to be fundamental treatment. Standard first-line treatment typically consists of doublet or triplet regimens [4]. Fluoropyrimidine plus platinum is widely used as first-line treatment for HER2-negative AGC [5]. In many Asian countries, including China, S-1, an oral fluoropyrimidine, is frequently adopted due to its convenience of administration [6, 7]. Regimens e.g. DCF (docetaxel, cisplatin, fluorouracil) and CF (cisplatin, fluorouracil) are also considered first-line options; however, their clinical utility is limited by severe toxicities [8]. Platinum-based therapies are associated with high incidences of gastrointestinal and neurotoxicities, as well as hematological adverse events(AEs) [8]. In the first-line setting, paclitaxel has also been incorporated into non-platinum doublets, which are widely accepted in some Asian regions because of their similar efficacy and reduced toxicity relative to platinum-based regimens [9]. A meta-analysis revealed no significant benefits in response rate or OS when platinum-based regimens compared to newer non-platinum regimens e.g. S-1 or paclitaxel [10]. However, conventional paclitaxel depends on Cremophor EL(CrEL) to improve solubility [11], which is associated with hypersensitivity reactions and neurotoxicity, etc [11]. To overcome these limitations, a new nanoparticle polymeric micellar paclitaxel (NPMP), free of CrEL, was introduced in 2018 [12]. A clinical trial evaluating NPMP plus 5-fluorouracil/leucovorin as first-line therapy for AGC showed a superior objective response rate(ORR) compared to conventional paclitaxel, maintaining a favorable safety, suggesting its potential clinical value [13].

Targeting immune checkpoint inhibitor(ICI) represent a promising therapeutic strategy for solid tumors, significantly improving the treatment effect of AGC [14, 15]. In the CheckMate-649 study, adding nivolumab to chemotherapy in patients with PD-L1 combined positive score (CPS) ≥ 5, improved median progression free survival (PFS) and OS of 8.3 and 14.4 months versus 6.1 and 11.1 months with chemotherapy alone [14]. Accoding to these findings, the U.S. Food and Drug Administration approved nivolumab combined with chemotherapy as first-line therapy in AGC in April 2021. Similarly, results from the ATTRACTION-4 [15], and KEYNOTE-059 trials confirmed that ICI plus chemotherapy in first- or second- line treatment, significantly improved ORR, OS, and PFS [16].

Sintilimab, an IgG4 monoclonal antibody against PD-1, exhibits promising antitumor effects in various malignancies [17]. The ORIENT-16 Trial demonstrated that first-line sintilimab with chemotherapy significantly prolong median OS (15.2 vs. 12.3 months) and PFS (7.1 vs. 5.7 months) than chemotherapy alone in AGC [18], attributable to the therapeutic efficacy of ICI from both its cytotoxic properties and its ability to trigger immunological mechanisms [19]. Accordingly, Chinese Society of Clinical Oncology recommends sintilimab combined with chemotherapy as first-line regimen for AGC [18]. However, real-world study regarding the effectiveness and tolerability of sintilimab plus NPMP and S-1 for HER2-negative AGC is limited in China.

We hypothesised this regimen could be a new option to first-line treatment for HER2-negative AGC patients.

Materials and Methods

Patient

Patients with HER2-negative AGC received first-line sintilimab-based regimens in JiangSu Cancer Hospital, between January 2021 and January 2024 were enrolled.

Eligibility criteria: (I) histologically confirmed AGC either unresectable, metastatic, or recurrent after surgery and HER-2 statu was negative. (II) age ≥ 18 with predicted survival of > 10 weeks. (III) at least one measurable lesion evaluable by computed tomography (CT) or magnetic resonance imaging (MRI), without previous chemotherapy or local interventions for target lesions at either primary or metastatic sites. (IV) normal hematologic, hepatic and renal function.

Exclusion Criteria: (I) patients lacked of obvious pathological data; (II) patients were staged I, II and III; (III) patients with severe disorders of consciousness; severe impairment of cardiac, renal, or other essential organ function; hematologic disorders; or autoimmune diseases (IV) patients with double or multiple primary malignancies.

Treatment Method

Patients received NPMP (Shanghai Yizhong Biotechnical Co., Ltd.) 130mg/m² by intravenous infusion (iv) on day1 and day8, along with S-1(Jiangsu Hengrui Pharmaceuticals Co., Ltd) by oral in doses of 40 mg(BSA<1.25m²), 50 mg(1.25 ≤ BSA<1.50m²), and 60 mg(BSA>1.50m²) bid on days 1–14, Additionally, sintilimab (Innovent Biologics (Suzhou) Co.,Ltd) 200 mg, on day1 was administered by iv every 3 weeks. The regimen was given for a minimum of two cycles. Maintenance therapy was sintilimab plus S-1 until disease progression, unacceptable toxicity, or death.

Response Evaluation

Laboratory tests were obtained at least once both prior to initiation and following completion of each treatment cycle. The efficacy was evaluted by CT or MRI after two cycles of treatment. In accordance with the World Health Organization (WHO) guidelines for evaluating acute and subacute toxicities of anticancer drugs, adverse events were categorized into five grades, ranging from 0 to IV. Clinical response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) and divided into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) [20]. ORR was the proportion of patients exhibiting CR or PR. Disease control rate (DCR) included patients with CR, PR, or SD. OS was the duration from the first use of treatment to death. PFS was the time from the first administration of treatment until disease progression.

Statistical Analysis

Descriptive statistics was employed to describe the treatment outcomes and the incidence of toxicity. Graphpad Prism was used for statistical analysis. Kaplan-Meier method was uesd to evaluate OS and PFS, and group differences were assessed by the log-rank test. P < 0.05 was considered statistically significant.

Results

Patients Characteristics

Thirty three patients were recruited, with baseline characteristics presented in Table 1. Median age was 61 years (range 35–78 years), with 25 (75.8%) males and 8 (24.2%) females. Pathological types included adenocarcinoma (97%) and squamous cell carcinoma (3%), Adenocarcinoma included the following subtypes: signet-ring cell carcinoma (2 cases, 6.1%), mucinous adenocarcinoma (2 cases, 6.1%), and hepatoid adenocarcinoma (1 case, 3.0%), respectively. PD-L1 positivity was observed in 22 patients (66.7%), and 11 patients (33.3%) showed negative expression, CPS was <5 in 14 patients (42.4%) and ≥ 5 in 19 patients (57.6%). All enrolled patients exhibited metastases, with distribution in lymph nodes(78.8%), peritoneum (21.2%), liver (21.2%), and bone (12.1%). Prior gastrectomy was performed in 36.4% of patients, while 63.6% did not received gastrectomy. Twenty patients(60.6%) underwent more than 4 treatment cycle, while 13 patients (39.4%) received 4 or fewer chemotherapy cycle.

Table 1.

Baseline demographic and patient characteristics (n = 33)

Characteristics	number of patients
Gender
Male	25(75.8%)
Female	8(24.2%)
Age (years)
Median (range)	61(35–78)
Pathological Type
Adenocarcinoma	32(97.0%)
Signet-ring cell carcinoma	2(6.1%)
Mucinous adenocarcinoma	2(6.1%)
Hepatoid adenocarcinoma	1(3.0%)
Squamous carcinoma	1(3.0%)
PD-L1 statu
Positive	22(66.7%)
Negative	11(33.3%)
PD-L1 expression
CPS<5	14(42.4%)
CPS ≥ 5	19(57.6%)
Previous gastrectomy
Yes	12(36.4%)
No	21(63.6%)
Metastatic sites
Lymph node	26(78.8%)
Peritoneum	7(21.2%)
Liver	7(21.2%)
Bone	4(12.1%)
Others	5(15.2%)
Cycles of regimen
≤ 4	13(39.4%)
>4	20(60.6%)

Response Evaluation

In this study, no CR was observed, PR was achieved in 14 cases, SD in 17, and PD in 2. The ORR and DCR were 42.4% (14/33) and 93.9% (29/33), respectively (Table 2). Median OS and PFS was 15.4 months (95%CI: 13.0–17.6) and 7.8 months (95%CI: 5.8–9.3) (Fig. 1).

Table 2.

Tumor response (n = 33)

Response										number of patients
CR										0(0.0%)
PR										14(42.4%)
SD										17(51.5%)
PD										2(6.1%)
ORR										14(42.4%)
DCR										29(93.9%)

CR complete response

PR partial response

SD stable disease

PD progressive disease

ORR objective response rate

DCR disease control rate

Fig. 1.

Kaplan-Meier curve of OS and PFS for the overall study patients

To identify the target population for combined treatment, we analyzed clinicopathological characteristics and their association with survival outcomes. No significant differences in OS or PFS were observed when stratified by gender, age or previous gastrectomy. Patients received more than four cycles showed a median OS of 17.8 months (95%CI:13.7–20.9) and PFS of 9.4 months (95%CI:7.1–12.0) versus 13.8 months OS (95%CI:10.7–14.7) and 7.5 months PFS (95%CI:4.9–8.2) in patients received four or fewer cycles (OS, p = 0.019; PFS, p = 0.036).

Finally, we assessed the PD-L1 expression of our regimen on survival outcomes. Median OS and PFS were 17.2 months (95%CI:14.1–19.7) and 8.9 months (95%CI:6.4–11.4) in PD-L1–positive patients, compared with 11.9 months (95%CI:8.4–16.2) and 6.0 months (95%CI:3.4–7.2) in PD-L1–negative patients (OS, p = 0.049; PFS, p = 0.028). Patients were divided into two groups according to CPS status, patients with CPS ≥ 5 had significantly longer OS (18.4 (95%CI:14.6–21.1) vs. 13.8 (95%CI:9.9–15.8) months, p = 0.020) and PFS (9.2 (95%CI:7.0–13.5) vs. 7.3 (95%CI:4.0–10.2) months, p = 0.022) than those with CPS < 5 (Fig. 2).

Fig. 2 .

Kaplan-Meier curves of OS and PFS in different subgroups of patients. (A)OS of different gender, age, previous gastrectomy, cycles of treatment, PD-L1 expression, CPS (B)PFS of different gender, age, previous gastrectomy, cycles of treatment, PD-L1 expression, CPS

Safety

The most common AEs were fatigue (60.6%), leukopenia (54.5%), anemia (51.5%), thrombocytopenia (36.4%), nausea (30.3%) and vomiting (15.1%). Grade 3 AEs included anemia (9.1%), leukopenia (6.1%), thrombocytopenia (6.1%), nausea (3.0%), vomiting (3.0%) and fatigue (3.0%). One patient was diagnosed with immune-related AE (immune-related pneumonitis), which was graded as grade 1–2. Overall, AEs were generally manageable, and no treatment-related deaths occurred (Table 3).

Table 3.

Treatment-related adverse events

	Any grade	Grades	Grades
Adverse events	n (%)	1–2, n (%)	≥ 3, n (%)
Anemia	17(51.5%)	14(42.4%)	3(9.1%)
Leukopenia	18(54.5%)	16(48.5%)	2(6.1%)
Thrombocytopenia	12(36.4%)	10(30.3%)	2(6.1%)
Nausea	10(30.3%)	9(27.3%)	1(3.0%)
Vomiting	5(15.1%)	4(12.1%)	1(3.0%)
Fatigue	20(60.6%)	19(57.6%)	1(3.0%)
Renal function injury	5(15.1%)	5(15.1%)	0(0.0%)
Liver function injury	8(24.2%)	8(24.2%)	0(0.0%)
Hand-foot syndrome	3(9.1%)	3(9.1%)	0(0.0%)
Allergic reaction	2(6.1%)	2(6.1%)	0(0.0%)
Immune-related AE	1(3.0%)	1(3.0%)	0(0.0%)

Discussion

In this real-world study of first-line sintilimab plus NPMP and S-1 for patients with HER2-negative AGC, we observed an ORR of 42.4%, DCR of 93.9%, OS of 15.4 months, and PFS of 7.8 months. These results suggest favorable antitumor activity and acceptable tolerability. Notably, our efficacy compares similar with historical data for paclitaxel-plus-fluorouracil regimens. Prior trials of first-line paclitaxel + fluorouracil combinations reported ORRs ranging roughly from 31.7% to 56.3%, with median OS around 12.6–15.0 months and PFS around 5.2–7.7 months [21–24]. Lan YQ et al. reported ORR 56.4% and median OS 12.6 months with paclitaxel plus fluorouracil [23]. whereas another study reported ORR 31.7% (median OS 15.0 months) with a paclitaxel/leucovorin/fluorouracil regimen [22].

Moreover, the ORR in our cohort (42.4%) is comparable to that achieved with sintilimab plus oxaliplatin-capecitabine in the randomized phase III ORIENT-16 trial (ORR 58.2%), and our median OS (15.4 vs. 15.2 months) and PFS (7.8 vs. 7.1 months) were similar or slightly better [18]. One possible reason is that 20 nm micelle structure of NPMP may penetrate tumors more efficiently than conventional paclitaxel, potentially enhancing efficacy [25]. It should be noted that although NPMP is approved in China as a micellar paclitaxel formulation, its clinical use for AGC has been clarified by previous study [13], thus its use in our cohort reflects real-world clinical practice.

We found that patients with PD-L1-positive tumors had significantly longer OS and PFS than PD-L1–negative patients, aligning with previous reports that PD-L1 expression predicts benefit from PD-1 inhibitor in GC [26]. A meta-analyses have shown that only patients with PD-L1 CPS ≥ 1 derive a survival advantage from PD-1/PD-L1 inhibitors [26]. Patients with CPS ≥ 5 achieved superior OS and PFS relative to those with CPS < 5, indicating that a higher CPS may serve as a favorable prognostic factor. This finding is consistent with previous studies reporting that CPS could stratify patients expected to derive benefit from immunotherapy [27, 28]. We also noted that treatment duration mattered: patients receiving more than four cycles tended to had better OS/PFS than those with fewer cycles. This observation showed the importance of sufficient exposure and dose intensity in chemoimmunotherapy, as was seen in prior trials where longer therapy correlated with improved outcomes [29].

In our study, sintilimab plus NPMP and S-1 was generally well tolerated. We observed no grade 3/4 hand-foot syndrome or severe allergic reactions. Hematologic toxicities were the most common grade ≥ 3 AEs, consistenting with other regimens [30, 31]. The most frequent hematologic toxicities (all grades) were anemia (51.5%), leukopenia (54.5%), and thrombocytopenia (36.4%). For comparison, a phase II study of paclitaxel + fluorouracil reported grade ≥ 3 neutropenia in 61.7% of patients [22]. Non-hematologic AEs were mostly mild: nausea occurred in 30.3%, vomiting in 15.1%, and fatigue in 60.6% of patients, with few high-grade events. Historical data on S-1 and paclitaxel confirm that diarrhea, stomatitis, and hand-foot syndrome are common with fluoropyrimidines [32] and that alopecia, neuropathy, and mild neutropenia are common with paclitaxel [23]. It is worth noting that although common irAEs associated with PD-1 inhibitors are well documented, our cohort did not show the incidence of grade 3–4 irAEs. This might be related to the relatively small sample size of our cohort, which may reduces the incidence of detecting rare grade 3–4 irAEs, and patients with baseline autoimmune diseases or poor physical conditions, who may be at higher risk of irAEs, were not included. These factors should be taken into account when interpreting the observed irAEs.

Limitations include the single-center, small-sample nature of this analysis, and potential under-documentation of irAEs. Larger randomized trials are warranted to confirm these results and better define biomarkers of benefit.

In summary, sintilimab with NPMP plus S-1 shows favorable efficacy and an acceptable toxicity as first-line treatment in HER2-negative AGC. PD-L1 expression(positivity and CPS ≥ 5) emerged as a potential predictor of benefit, while treatment intensity (number of cycles) also influenced outcomes. These findings support further study of this regimen and patient selection strategies.

Author Contributions

(I) Conception and design: XE Huang, AG Cao, YQ Cao; (II) Collection and assembly of data: YQ Cao, FY Wang, XM Huang; (III) Data analysis and interpretation: YQ Cao, M Song, J Cao; (IV) Manuscript writing and revision: All authors; (V) Final approval of manuscript: All authors. (VI)Accountable for all aspects of the work: XE Huang, AG Cao.

Funding

The study was fund by the Grant from the key projects of Jiangsu Committee of Health ZD2022019; General Program of National Natural Science Foundation of China(82272671).

Data Availability

The data generated in the present study may be requested from the corresponding author: huangxinen06@163.com.

Declarations

Ethics Approval and Consent to Participate

Not applicable.

Ethics Statement

The study was approved by the Institutional Ethics Committee of Jiangsu Cancer Hospital, and was carried out in accordance with the principles of the Declaration of Helsinki(2024-07-01/KY-2024-055).

Patient Consent for Publication

Not applicable.

Competing interests

The authors declare no competing interests.