First-Line ICI Combinations Show Encouraging Response but No Definitive Survival Benefit in Advanced Pancreatic Cancer
核心洞察
A meta-analysis of eight trials (379 patients) found first-line immune checkpoint inhibitor (ICI) combinations improved objective response rate (OR 2.19, 95% CI 1.32–3.64) in advanced pancreatic ductal adenocarcinoma (搜索).
Overall survival (HR 0.83, 95% CI 0.65–1.06) and progression-free survival (HR 0.75, 95% CI 0.53–1.05) showed favorable but statistically non-definitive trends in RCT-only analyses.
The anti-angiogenic-containing NASCA regimen (fruquintinib plus camrelizumab plus chemotherapy) yielded the longest median OS (13.0 months) and an ORR of 51.1%, though requiring larger-trial confirmation.
A systematic review and meta-analysis published in Frontiers in Immunology evaluated the efficacy and safety of first-line immune checkpoint inhibitor (ICI)-based combination regimens in advanced pancreatic ductal adenocarcinoma (搜索) (PDAC), a malignancy with a five-year survival rate of only 12% according to the latest SEER database report. Synthesizing evidence from eight clinical studies—three randomized controlled trials (RCTs) and five non-randomized trials—comprising 379 patients, the analysis found that ICI-based combinations improved radiological response but did not establish a definitive survival benefit.
The study adhered strictly to PRISMA 2020 guidelines, searching PubMed, Embase, The Cochrane Library, Scopus, Web of Science, CNKI, Wanfang Data, VIP, and the China Biomedical Literature Database up to April 4, 2026. Eligible studies enrolled patients aged 18 years or older with pathologically confirmed advanced or metastatic pancreatic cancer who had received no prior systemic therapy.
Survival Outcomes Remain Statistically Non-Definitive
In RCT-only analyses, ICI-based combinations showed favorable but statistically non-definitive trends for overall survival (OS) and progression-free survival (PFS). The pooled hazard ratio (HR) for OS was 0.83 (95% CI: 0.65–1.06), while the pooled HR for PFS was 0.75 (95% CI: 0.53–1.05). Because the confidence intervals crossed the null value of 1.0, the authors concluded that "the current randomized evidence suggests a favorable numerical survival trend rather than a definitive OS benefit."
Among the individual RCTs, the Jia 2025 trial—evaluating the NASCA regimen combining fruquintinib (an anti-angiogenic agent), camrelizumab (an ICI), and chemotherapy—reported the longest median OS at 13.0 months (95% CI: 10.5–16.1) versus 11.0 months in the control arm (HR: 0.77; 95% CI: 0.47–1.28). Its median PFS was 7.9 months versus 5.3 months (HR: 0.63; 95% CI: 0.40–0.99). The Renouf 2022 trial (N = 180) reported an mOS of 9.8 months versus 8.8 months (HR: 0.94; 90% CI: 0.71–1.25), while Fu 2023 (N = 110) reported an mOS of 10.9 months versus 10.8 months (HR: 1.07; 95% CI: 0.69–1.68).
Objective Response Rate Significantly Improved
In contrast to the survival endpoints, the pooled odds ratio (OR) for objective response rate (ORR) across RCTs was 2.19 (95% CI: 1.32–3.64), indicating a statistically significant improvement with ICI-based combinations. The NASCA regimen demonstrated an ORR of 51.1% and a disease control rate (DCR) of 91.1%, compared with 24.4% and 88.9% in the control arm. Single-arm pooled analysis showed a median PFS of 6.2 months and an ORR of 38.0%.
The authors attributed the improved tumor response in part to immunogenic cell death induced by chemotherapy, which facilitates the release of tumor-associated antigens and activates antigen-presenting cells. They further noted that anti-angiogenic agents such as fruquintinib may contribute to vascular normalization, alleviating hypoxia and interstitial fluid pressure to increase effector T-cell infiltration.
Safety Profile Largely Mirrors Chemotherapy Backbones
Hematologic toxicity was the most prevalent adverse event, with Grade ≥3 neutropenia occurring in 33.3%–43.6% of patients across the three RCTs—consistent with historical benchmarks for FOLFIRINOX and gemcitabine/nab-paclitaxel regimens. Immune-related adverse events (irAEs) were observed in 22.2%–23.6% of experimental-arm patients, with severe (Grade ≥3) events accounting for only 4.4%–5.7%. Treatment-related mortality was rare, reported only in the Renouf 2022 trial (1.7% in the experimental arm versus 3.4% in the control arm).
The pooled relative risk for treatment discontinuation due to adverse events was 1.62 (95% CI: 0.83–3.17), which did not reach statistical significance. However, the Jia 2025 triple-therapy arm reported the highest discontinuation rate due to non-hematologic toxicities at 33.3%, suggesting that intensified regimens may impose greater physiological stress.
Limitations and Clinical Implications
The authors emphasized several limitations, including a modest overall sample size, substantial clinical heterogeneity across ICI agents, chemotherapy backbones, and the use of anti-angiogenic therapy, and reliance on aggregated study-level rather than individual patient data. Subgroup findings related to age, liver metastasis burden, chemotherapy backbone, and anti-angiogenic therapy were described as exploratory and underpowered.
"First-line ICI-chemotherapy combinations should still be regarded as investigational strategies with encouraging antitumor activity rather than established standard regimens," the authors concluded. They called for larger, adequately powered randomized trials with standardized patient stratification and biomarker assessment to determine whether the observed numerical trends translate into durable survival benefits.