TOPLINE:

In an interim analysis of a phase 2/3 study, neoadjuvant therapy with gemcitabine-oxaliplatin, lenvatinib, and toripalimab (GOLP regimen) more than doubled the median event-free survival time vs surgery followed by adjuvant capecitabine in patients with resectable high-risk intrahepatic cholangiocarcinoma. The regimen demonstrated a manageable safety profile with primarily low-grade adverse events and subsequent surgical intervention was safe and feasible in nearly all the patients.

METHODOLOGY:

• Resectable intrahepatic cholangiocarcinoma with high-risk features frequently recurs soon after surgery and is associated with poor long-term survival. Because randomized data are lacking, guidelines do not recommend neoadjuvant therapy. The GOLP regimen — gemcitabine-oxaliplatin plus lenvatinib and an anti-PD-1 antibody — has shown promising activity as both first-line and conversion therapy, providing a rationale to evaluate it in the neoadjuvant setting in this population.
• To assess efficacy and safety of the GOLP regimen, researchers conducted a multicenter, randomized, controlled, phase 2/3 trial at 11 hospitals in China, involving 178 patients with resectable high-risk intrahepatic cholangiocarcinoma between January 2021 and February 2025. High-risk factors included a tumor diameter of > 5 cm, vascular invasion, multiple intrahepatic tumors, hepatic portal lymph-node metastasis, or elevated cancer antigen 19-9 level.
• Patients were randomly assigned (1:1) either to receive neoadjuvant GOLP (n = 88 patients), consisting of toripalimab (240 mg intravenously every 3 weeks for three cycles), lenvatinib (8 mg orally once daily for 9 weeks), and gemcitabine (1 g/m² intravenously on days 1 and 8) plus oxaliplatin (85 mg/m² intravenously on day 1 every 3 weeks for three cycles), followed by curative resection and adjuvant capecitabine, or to receive curative resection followed by adjuvant capecitabine (control group; n = 90).
• The primary endpoint was event-free survival. Secondary endpoints included overall survival, objective response, R0 resection, major pathologic response, pathologic complete response, recurrence-free survival, and safety. The current study presented the prespecified interim analysis of the trial at a median follow-up duration of 16.9 months.
• Overall, 97% of patients in the neoadjuvant group and 99% in the control group underwent surgery, and 85% and 80%, respectively, received adjuvant capecitabine.

TAKEAWAY:

• At a median follow-up duration of 16.9 months, the median event-free survival was significantly longer in the neoadjuvant group than in the control group (18.0 months vs 8.7 months; P < .001). Because hazards were nonproportional, the restricted mean survival time at 46.2 months was reported: 23.1 months in the neoadjuvant group vs 16.6 months in the control group.
• At the interim overall survival analysis, 49 deaths occurred — 18 (20%) in the neoadjuvant group and 31 (34%) in the control group. At 24 months, the overall survival was 79% in the neoadjuvant group vs 61% in the control group; the hazard ratio for death was 0.43 (P = .005), which did not meet the prespecified significance boundary.
• In the neoadjuvant group, 55% of patients (n = 48) achieved an objective response with partial response, 19% (n = 17) had a major pathologic response, and 5% (n = 4) had a pathologic complete response. R0 resection rates were 95% in the neoadjuvant group and 93% in the control group, and the median recurrence-free survival was 15.4 months vs 9.7 months, respectively.
• Across all treatment phases, adverse events occurred in 97% of patients in the neoadjuvant group vs 70% in the control group; during the neoadjuvant phase, adverse events of grade 3 or higher occurred in 28% of patients in the neoadjuvant group, with treatment-related adverse events of grade 3 or higher in 26%. Immune-related events occurred in 36% of patients in the neoadjuvant group (most commonly rash and thyroid dysfunction). No treatment-related adverse event led to death.
• Surgical outcomes were similar between groups — operative time, intraoperative blood loss, and postoperative length of stay — and surgical complication rates were 24% with neoadjuvant therapy vs 34% with control treatment.

IN PRACTICE:

“The neo-GOLP regimen significantly prolonged event-free survival, as compared with control treatment, with mainly low-grade toxic effects,” the authors wrote, however, noting that longer follow-up is needed, as the “final overall survival analysis is planned at 60% data maturity.”

SOURCE:

This study, led by Guo-Ming Shi, MD, Zhongshan Hospital, Fudan University, Shanghai, China, was published online in The New England Journal of Medicine.

LIMITATIONS:

The generalizability of the findings may have been restricted as the trial enrolled a fit population at high-volume academic centers in China. The chemotherapy backbone was gemcitabine-oxaliplatin, which was chosen for its practicality and safety profile in China, so applicability with other regimens or in other settings requires international validation. The unusually high R0 resection rate may not reflect outcomes at centers with lower resection rates.

DISCLOSURES:

This study received support from grants provided by the Clinical Research Plan of Shanghai Hospital Development Center, the Program of Shanghai Academic Research Leader, and the Shanghai Health Commission Clinical Research Special Project, with partial funding from Shanghai Junshi Biosciences. One author declared being an employee of Shanghai Junshi Biosciences. Another author declared having ties with Eisai, F. Hoffmann-La Roche, and Merck Sharp & Dohme. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.