NIPS Boosts Overall Survival Over PS in Gastric Cancer With Peritoneal Metastasis

Intraperitoneal and intravenous paclitaxel plus S-1 (NIPS) significantly improved overall survival (OS) over intravenous paclitaxel and S-1 alone (PS) with acceptable safety in patients with gastric cancer and peritoneal metastasis, according to data from the phase 3 DRAGON-01 trial (ChiCTR-IIR-16009802) presented during the 2025 Gastrointestinal Cancers Symposium.1

With a median follow-up of 60.2 months, the median OS in the NIPS group (n = 148) was 19.4 months (17.1-22.9) vs 13.9 months (95% CI, 10.3-16.1) in the PS group (n = 74), translating to a 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.49-0.88; P = .0056) with NIPS vs PS. In the NIPS group, the OS rates at 1, 3, and 5 years were 69.6%, 24.3%, and 11.4%, respectively; in the PS group, these respective rates were 54.1%, 12.2%, and 7.9%.

Moreover, the conversion surgery rate was significantly higher in the NIPS group vs the PS group, at 50.7% vs 35.1%, respectively (P = .028). In the NIPS group, the median survival was 33.1 months (95% CI, 26.6-39.3) for patients with conversion success and 11.1 months (95% CI, 9.1-14.9) for those with conversion failure (HR for death, 0.24; 95% CI, 0.17-0.35; P < .0001). In the PS group, the median survival was 18.8 months (95% CI, 16.0-41.4) for those with conversion success and 10.0 months (95% CI, 9.0-13.9) for those with conversion failure (HR for death, 0.31; 95% CI, 0.18-0.55; P < .0001).

“This is the first positive phase 3, multicenter, randomized clinical trial to definitively show the survival advantage of intraperitoneal chemotherapy, providing robust evidence to support changes in current clinical practices,” lead study author Chao Yan, MD, of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine in China, said in a presentation of the data.

DRAGON-01 Background and Design

Peritoneal metastasis represents the most common site of treatment failure. NIPS has generated promising results in this disease, but because there has been insufficient high-level evidence to further validate this approach, it has yet to be incorporated into major treatment guidelines, Yan said. In the phase 3 PHOENIX-GC trial (UMIN000005930), the median survival time was 17.7 months (95% CI, 14.7-21.5) with intraperitoneal paclitaxel (IP) vs 15.2 months (95% CI, 12.8-21.8) with cisplatin plus S-1 (SP; HR, 0.72; 95% CI, 0.49-1.04; P = .080).2 This trial showed a “survival trend [with NIPS] but did not achieve statistical significance,” Yan said.

Additional data from PHOENIX-GC showed that the 3-year OS rate in the IP arm was 21.9% (95% CI, 14.9%-29.9%) vs 6.0% (95% CI, 1.6%-14.9%) with SP. Yan noted that the “follow-up analysis further emphasizes the potential benefits of IP chemotherapy in improving long-term survival outcomes.”1

Yan shared his center’s standard operating procedure for NIPS treatment: “We usually perform 5 to 6 courses before conversion surgery. For patients with a peritoneal cancer index exceeding 20, we recommend 9 or more courses of treatment. Indications for conversion surgery include a resectable primary tumor, disappearance of peritoneal metastasis, [negative] cytology, and no other distant metastasis. These criteria are confirmed through CT scan and staging laparoscopy. After conversion surgery, we recommend using the same regimen as long as possible, especially IP chemotherapy.”

He added that since 2015, his center has conducted 4 phase 2 studies further evaluating NIPS and 1 phase 3 study: DRAGON-01. DRAGON-01 included patients with histologically confirmed gastric cancer with peritoneal metastasis confirmed by laparoscopy between the ages of 18 years and 75 years who had an ECOG performance status of 0 or 1 and an expected survival of at least 3 months. Patients were all required to have acceptable organ function.

Study participants were randomly assigned 2:1 to receive NIPS or PS. In the NIPS arm, patients were given S-1 at 80 mg/m2 for 14 days every 3 weeks plus intravenous (IV) paclitaxel at 50 mg/m2 on days 1 and 8 and intraperitoneal paclitaxel at 20 mg/m2 on days 1 and 8. In the PS arm, S-1 was given at 80 mg/m2 for 14 days every 3 weeks plus IV paclitaxel at 70 mg/m2 on days 1 and 8.

The primary end point of the study was OS in the modified intention-to-treat (mITT) population, and key secondary end points comprised conversion surgery rate, pathological response, and safety.

Baseline Characteristics

The trial enrolled patients across 9 clinical sites between May 2017 and March 2022. A total of 246 patients underwent screening for eligibility, and 238 of them underwent randomization. Of those patients, 158 were assigned to the NIPS group, and 80 were assigned to the PS group; 148 and 74 patients, respectively were included in the mITT population. All the patients in the mITT population were analyzed for efficacy and safety.

“When examining the baseline characteristics, both the NIPS and PS groups were generally well matched across various clinical pathological effects,” Yan noted. The median age was 58 years (range, 23-74), slightly more than half of patients were male (NIPS, 54.1%; PS, 51.4%), and most patients had an ECOG performance status of 0 (73.0%; 71.6%).

Additional Efficacy Findings

Subgroup analysis demonstrated consistent benefits with NIPS over PS across almost all subgroups, except for patients with an ECOG performance status of 1 (HR, 1.03; 95% CI, 0.59-1.80; P = .914). “The lack of significant interaction P value suggests that the survival advantage of NIPS is broadly applicable to the entire study population, rather than being confined to specific subgroups,” Yan said. “This reinforces the overall effectiveness of NIPS treatment in improving outcomes for [patients with] gastric cancer and peritoneal metastasis.”

Additional efficacy data underscored the importance of achieving an R0 resection with no residual tumor. In both groups, patients who achieved R0 resection experienced significantly better survival outcomes, according to Yan. In the NIPS group, those who achieved R0 resection experienced a median survival of 35.5 months (95% CI, 30.5-45.6); in the PS group, the median survival in those with R0 resection was 20.9 months (95% CI, 17.1-not applicable [NA]).

“Meanwhile, we need to notice that the effect of R2 resection with residual tumor was poor in both the NIPS and PS groups—especially in the PS group,” Yan said. Patients with R2 resection in the NIPS group had a median survival of 15.5 months (95% CI, 11.8-NA); in the PS group, those with R2 resection had a median survival of just 10.1 months (95% CI, 2.9-NA). “Therefore, R2 resection should be avoided as much as possible,” he added.

Safety Data and Limitations

Regarding safety, the incidence of grade 3 or 4 adverse effects (AEs) was noted to be comparable between the groups. The most common AEs included leukopenia (NIPS: grade 1/2, 49.4%; grade 3, 17.9%; grade 4, 3.8%), neutropenia (40.4%; 16.0%; 3.9%), and fatigue (51.9%; 7.7%; 0.0%).

“Overall, both treatments were tolerated with manageable AEs, highlighting the feasibility of the NIPS regimen in clinical practice,” he said.

Investigators also examined port-related complications in the NIPS group and deemed them to be generally manageable, with only a few cases requiring surgical involvement in the form of a removal or replacement. Grade 1/2 port site infections occurred in 3 patients, and grade 3 infections occurred in 4 patients. Grade 1/2 subcutaneous fluid accumulation occurred in 12 patients, and grade 3 accumulation occurred in 6 patients. “[These AEs] were predominantly low grade and effectively managed with treatment, allowing for the continuation of IP chemotherapy,” Yan said.

The study was not without limitations. For one, it was conducted exclusively in an Asian population, which could limit the generalizability of the data to other ethnic groups or geographic regions. Second, the control regimens used were based on guidelines that were prevalent at the time the study was designed, and they could differ from current standard practice, he concluded.

Disclosures: Dr Yan has no relationships to disclose.

References

1. Yan C, Yang Z, Shi Z, et al. Intraperitoneal and intravenous paclitaxel plus S-1 versus intravenous paclitaxel plus S-1 in gastric cancer patients with peritoneal metastasis: Results from the multicenter, randomized, phase 3 DRAGON-01 trial. J Clin Oncol. 2025;43(suppl 4):327. doi:10.1200/JCO.2025.43.4_suppl.327
2. Ishigami H, Fujiwara Y, Fukushima R, et al. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018;36(19):1922-1929. doi:10.1200/JCO.2018.77.8613