Adjuvant Camrelizumab plus Capecitabine Extends Recurrence-Free Survival in Resected Intrahepatic Cholangiocarcinoma: Results from the Phase 2 ACC Trial

Highlights

• The combination of camrelizumab and capecitabine as adjuvant therapy for intrahepatic cholangiocarcinoma (iCCA) demonstrated a median recurrence-free survival (RFS) of 24.29 months.
• The 33.73-month median follow-up revealed a recurrence rate of 55%, with the majority of relapses occurring intrahepatically (67% of recurrences).
• The safety profile was manageable; while 23% of patients experienced Grade 3 treatment-related adverse events, no Grade 4 events or deaths were reported.
• Reactive cutaneous capillary endothelial proliferation (RCCEP) was the most common adverse event, occurring in 69% of the study population.

Background and Disease Burden

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy arising from the epithelial lining of the intrahepatic bile ducts. It accounts for approximately 10–15% of all primary liver cancers, and its incidence has been steadily increasing worldwide over the last few decades. Despite advancements in surgical techniques, the prognosis for patients with iCCA remains sobering. Radical surgical resection (R0) offers the only potential for a cure, yet postoperative recurrence rates remain high, often exceeding 50–70% within five years of surgery.

The high frequency of recurrence—both intrahepatic and extrahepatic—suggests that micrometastatic disease is frequently present at the time of surgery. Consequently, there is an urgent clinical need for effective adjuvant therapies. For years, the standard of care was informed by the BILCAP trial, which established capecitabine as a reference adjuvant treatment, although its benefit in the intention-to-treat population only reached borderline statistical significance. More recently, the success of immune checkpoint inhibitors in the first-line advanced setting (e.g., TOPAZ-1 and KEYNOTE-966) has sparked significant interest in moving immunotherapy into the adjuvant space to eradicate residual disease and improve long-term outcomes.

Study Design: The ACC Trial

The ACC trial was a single-arm, single-centre, open-label, phase 2 trial conducted at Zhongshan Hospital, Fudan University, in Shanghai, China. The study targeted a specific high-risk cohort: adult patients (18–75 years) with R0-resected, pathologically confirmed iCCA. Eligible patients were staged as IA (with G3 classification) or IB–III according to the AJCC 8th edition staging system. Importantly, patients had to have no evidence of extrahepatic metastases and a preserved performance status (ECOG 0 or 1).

The therapeutic regimen commenced 4–8 weeks post-surgery and consisted of eight 21-day cycles. Each cycle included:

• Camrelizumab: 200 mg administered intravenously on day 1.
• Capecitabine: 1250 mg/m2 administered orally twice daily on days 1–14, followed by a 7-day rest period.

The primary endpoint was recurrence-free survival (RFS), assessed in the full analysis set (FAS), which included all patients who received at least one dose of the study medication. This design aimed to evaluate whether the synergistic effect of chemotherapy-induced immunogenic cell death and PD-1 blockade could translate into a meaningful clinical delay in recurrence.

Key Findings: Survival and Recurrence Patterns

Between September 2020 and November 2022, 65 patients were enrolled. The cohort was predominantly male (62%) with a median age of 64 years. At the data cutoff in November 2024, the median follow-up duration reached 33.73 months, providing a robust window for evaluating medium-term outcomes.

Recurrence-Free Survival (RFS)

The median RFS was 24.29 months (95% CI 13.54–not reached). This figure is particularly noteworthy when compared to historical data for high-risk iCCA, where median RFS often hovers between 12 and 18 months. The durability of the response is further emphasized by the fact that the upper bound of the confidence interval had not yet been reached at the time of analysis.

Patterns of Failure

Recurrence was documented in 36 of the 65 patients (55%). A detailed analysis of the recurrence patterns showed:

• Intrahepatic recurrence only: 24 patients (67% of recurrences).
• Combined intrahepatic and extrahepatic recurrence: 6 patients (17% of recurrences).
• Extrahepatic recurrence only: 6 patients (17% of recurrences).

The predominance of intrahepatic recurrence underscores the unique biology of iCCA and suggests that while systemic therapy is beneficial, the liver remains the primary site of failure, potentially necessitating further investigation into localized adjuvant strategies in combination with systemic agents.

Safety and Tolerability Profile

The safety set included all 65 patients. Overall, the combination was well-tolerated, with a safety profile consistent with the known effects of the individual agents. No new or unexpected safety signals were identified.

Common Adverse Events

The most frequent treatment-related adverse event (TRAE) was reactive cutaneous capillary endothelial proliferation (RCCEP), occurring in 45 patients (69%). This is a known, typically self-limiting side effect specific to camrelizumab. Other common TRAEs included nausea (32%), hand-foot syndrome (29%), pruritus (17%), and fatigue (17%).

Severe and Serious Adverse Events

Grade 3 TRAEs occurred in 15 patients (23%). The most frequent Grade 3 event was elevated bilirubin (3%). Serious TRAEs (SAEs) were reported in four patients (6%), comprising single cases of myocarditis, myalgia, type 1 diabetes, and hypothyroidism. Crucially, there were no Grade 4 TRAEs and no treatment-related deaths, indicating that the regimen is safe for use in the postoperative recovery setting.

Expert Commentary

The ACC trial provides important preliminary evidence that the addition of a PD-1 inhibitor to standard chemotherapy may shift the survival curve for resected iCCA. From a mechanistic standpoint, capecitabine may not only provide direct cytotoxic effects but also modulate the tumor microenvironment to become more ‘immunologically hot,’ thereby enhancing the efficacy of camrelizumab.

However, clinicians must interpret these results with caution. As a single-arm, phase 2 trial, the lack of a concurrent control group limits the ability to definitively attribute the observed RFS solely to the addition of camrelizumab. The population was also restricted to a single center in China, where the underlying etiology of iCCA (often associated with HBV infection) may differ from Western populations (often associated with NASH or primary sclerosing cholangitis). The high rate of intrahepatic recurrence also raises questions about whether future trials should incorporate hepatic arterial infusion chemotherapy (HAIC) or radiotherapy alongside systemic immunochemotherapy.

Conclusion

The combination of camrelizumab and capecitabine represents a promising adjuvant strategy for patients with resected intrahepatic cholangiocarcinoma. With a median RFS of over 24 months and a manageable safety profile, this regimen addresses a critical unmet need in biliary tract cancer. While these findings are encouraging, they serve as a foundation for larger, multicentre, randomized controlled trials to confirm the survival benefit and define the role of immunotherapy in the standard adjuvant algorithm.

Funding and clinicaltrials.gov

This study was funded by the Clinical Research Special Fund of Zhongshan Hospital, Fudan University. The trial is registered with ClinicalTrials.gov, identifier NCT04295317.

References

Wang Z, Li L, Huang P, Tu H, Zhang X, Yu L, Liang F, Huang C, Qiu S, Ye Q, Ding Z, Huang X, Shi Y, Song K, Sun H, Wang X, Xu Y, Yu Y, Gao Q, Zhang L, Fan J, Zhou J. Adjuvant camrelizumab combined with capecitabine in patients with intrahepatic cholangiocarcinoma after surgical resection in China (ACC): a single-arm, single-centre, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2026 Feb;11(2):124-136. doi: 10.1016/S2468-1253(25)00268-7. Epub 2025 Nov 27. PMID: 41319673.