Systemic Therapies and Surgery for CCA

At the 2025 Annual Cholangiocarcinoma Foundation Conference, a working group led by Gonzalo Sapisochin, Hop Tran Cao, and Keri Koerkamp presented on surgery for cholangiocarcinoma (CCA) and a working group led by Rachna Shroff and Lorenza Rimassa presented systemic therapies for CCA.

Gonzalo Sapisochin first presented on surgery classification. Resectability for CCA is not well defined due to its heterogeneous anatomy and subjective assessments. Outcomes after resection are dismal in most cases. As with other hepato-pancreato-biliary malignancies such as hepatocellular carcinoma or pancreatic cancer, it is essential to define resectability. This definition may aid with future trial design, especially given increasing neoadjuvant approaches. A systematic review was done to identify known risk factors, to define resectability of CCA, and to define what is considered resectable, borderline resectable, and unresectable in patients with intrahepatic cholangiocarcinoma (iCCA), hilar CCA (hCCA), gallbladder cancer, and distal CCA. For example, according to this systematic review, iCCA is considered resectable if it is a single tumor <5 cm, has no periportal nodes, no vascular invasion, and no need for vascular resection and reconstruction. iCCA is considered borderline resectable if it is multifactor unilobar disease, a single tumor >5 cm, has satellite nodules, has pathologic periportal nodes (stations 5, 8, 9, and 12), has vascular invasion, there is a need for vascular resection and reconstruction, and risk of R1 margin. It is important to define the ideal and optimal imaging characteristics and modality and serologic factors for accurate staging using defined common language terminology.

Hop Tran Cao next presented on perioperative therapy with a focus on iCCA. The incidence of iCCA is rising, and there has been little progress on its management. Surgery is the mainstay of treatment, and, as of now, adjuvant capecitabine is the standard of care based on the phase 3 BILCAP study. The rationale for a neoadjuvant approach to resectable biliary tract cancer (BTC) includes tumor downsizing, improved chance of R0 resection, and that early systemic therapy can be used to address occult distant metastatic spread. The NEO-GAP trial was a single-arm, phase 2 feasibility study of neoadjuvant gemcitabine, cisplatin, and nab-paclitaxel for resectable, high-risk iCCA. All patients tolerated all 4 of the neoadjuvant cycles and 73% completed surgery. The median follow-up for all patients was 17 months. Ten (33%) patients experienced grade ≥3 treatment-related adverse events, the most common being neutropenia and diarrhea and 50% required ≥1 dose reductions. The disease control rate was 90% (progressive disease, 10%; partial response, 23%; stable disease, 67%). There was zero treatment-related mortality. The NEO-GAP trial showed that neoadjuvant therapy is feasible and safe. This therapy does not negatively impact the opportunity for resection, and neoadjuvant therapy may be associated with favorable R0 rates.

Lastly, Keri Koerkamp presented on transplantation for iCCA and hCCA. Liver transplantation offers an alternative to resection in select patients. It achieves tumor-free margins, treats parenchymal invasion, and removes the underlying tumor. A retrospective French multicenter analysis of patients with iCCA compared liver transplant versus resection for tumors 2 to 5 cm. The overall survival (OS) and recurrence-free survival for liver transplant improved compared with liver resection. All patients received bridge therapy. For perihilar CCA, the patients who received liver transplant primarily have been done under the Mayo Clinic Protocol. According to this protocol, if patients have a mass present, it must be <3 cm with a malignant appearing stricture that is unresectable. Patients also cannot have any iCCA or have had a transperitoneal biopsy or prior surgical resection. Outcomes for the Mayo Clinic Protocol showed transplant had improved survival over resection and 42% of patients had no residual disease on explant. Almost all patients underwent arterial reconstruction with iliac artery conduit. In conclusion, liver transplantation has emerged as a viable and effective treatment option for select patients with iCCA and hCCA, offering improved survival rates and promising outcomes when performed under stringent protocols such as the Mayo Clinic Protocol.

Building on the discussion of surgical and transplant-based approaches for localized CCA, the focus shifts to systemic therapies for metastatic and unresectable BTC, highlighting advancements in first-line treatment strategies. The second working group started their discussion with the standard first-line treatment for metastatic and unresectable BTC. The triplet gemcitabine/cisplatin/durvalumab (gem/cis + durva) was investigated in the phase 3 TOPAZ-1 trial (NCT03875235). At data cutoff (August 11, 2021), the median duration of follow-up was 16.8 months (95% confidence interval [CI], 14.8-17.7) in the gem/cis + durva group and 15.9 months (95% CI, 14.9-16.9) in the placebo group. TOPAZ-1 showed a survival advantage with an OS of 12.8 months in the gem/cis + durva group compared with 11.5 months in the gem/cis + placebo group. It also showed a progression-free survival (PFS) advantage of 7.2 months in the gem/cis + durva group compared with 5.7 months in the gem/cis + placebo group.

The phase 3 KEYNOTE-966 study (NCT04003636) also showed an OS benefit in patients with advanced, unresectable, or metastatic BTC who were treated with gem/cis + pembrolizumab (12.7 months) compared with gem/cis + placebo (10.9 months) at a median study follow-up of 25.6 months (interquartile range [IQR], 21.7-30.4). Gem/cis + pembrolizumab is the current standard alternate first-line treatment in patients with advanced, unresectable, or metastatic BTC. In the second-line setting, one study investigated FOLFOX in patients with advanced BTC previously treated with gem/cis. Patients were randomized into cohorts with FOLFOX with active symptom control and active symptom control alone. Those who received FOLFOX had a median OS of 6.2 months versus 5.3 months in those who did not receive FOLFOX after a median follow-up of 21.7 months (IQR, 17.2-30.8). The ClarIDHy phase 3 study included patients with IDH1-mutant, chemotherapy-refractory CCA. Patients were treated with either ivosidenib or placebo. Compared with placebo, those treated with ivosidenib had longer PFS (2.7 months vs 1.4 months).

Approximately 50% of patients with advanced BTC receive therapies beyond the first line. If no targeted therapies are available, the median OS is approximately 6 months with standard-of-care chemotherapies. Primary and emerging resistance limits the clinical utility of targeted agents. Acquired mutations in gatekeeper and molecular brake residues in FGFR2 or adaptive feedback activation of EGFR signaling limit currently approved FGFR inhibitors’ activity. Ongoing studies of novel agents such as tinengotinib, lirafugratinib (RLY-4008), TYRA200, and others are addressing resistance with the aim of improving outcomes. There is an urgent need for new therapies, and participation in clinical trials is essential to advance outcomes in the second-line setting and beyond.

To summarize the treatment landscape, first-line treatment for CCA includes gem/cis + durva and gem/cis + pembrolizumab. Second-line treatment for CCA depends on whether there are targetable alterations. For those without targetable alterations, FOLFOX, FOLFIRI, and 5-fluorouracil and liposomal irinotecan are potential options, and those with targetable alterations including FGFR fusion, IDH1 mutations, BRAF^V600E, microsatellite instability-high, HER2, and KRAS^G12C may utilize targeted therapies such as ivosidenib, tinengotinib, and others.

Sources

Shroff R, Rimassa L. WG10-Systemic Therapies. Presented at: 2025 Annual Cholangiocarcinoma Foundation Conference. April 9-11, 2025; Salt Lake City, UT.

Sapisochin G, Cao HT, Koerkamp K. WG2-Surgery. Presented at: 2025 Annual Cholangiocarcinoma Foundation Conference. April 9-11, 2025; Salt Lake City, UT.