Precision Frontiers in Hepatobiliary Oncology: FGFR2 Selectivity and Immunotherapy in HCC and iCCA

Key Takeaways

• FGFR2 Selectivity: Lirafugratinib demonstrates a high ORR (46.5–63.6%) in iCCA, with activity against resistance mutations.
• Adjuvant HCC Limitations: KEYNOTE-937 and IMbrave050 failed to maintain long-term RFS benefits in early-stage HCC.
• Superior Response: CheckMate 9DW’s 36% ORR sets a new standard for first-line advanced HCC treatment.
• Timing Matters: Perioperative immunotherapy (CARES-009) appears more effective than adjuvant therapy due to better immune priming.

Introduction: Precision Oncology Is Transforming Hepatobiliary Cancer Treatment

The treatment landscape for biliary tract cancer (BTC) and hepatocellular carcinoma (HCC) is undergoing a paradigm shift, transitioning from a one-size-fits-all approach to a nuanced, molecularly-driven strategy. Biliary tract cancers, once considered a single entity with a dismal prognosis, are now recognized as a heterogeneous group of malignancies harboring a high frequency of actionable alterations. Among these, fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements have emerged as a primary therapeutic target, occurring in approximately 5% to 10% of patients with intrahepatic cholangiocarcinoma (iCCA).

Simultaneously, the management of HCC has been transformed by the success of immune checkpoint inhibitors (ICIs). While ICIs have established a firm foothold in the advanced stage (BCLC C), their application in earlier disease settings—specifically as adjuvant therapy following curative-intent resection or ablation—has yielded complex and sometimes conflicting results. This commentary analyzes the pivotal data from the ReFocus, KEYNOTE-937, IMbrave050, and CheckMate 9DW trials to determine how these findings should shape clinical practice in 2026 and beyond.

FGFR2 Selectivity and the ReFocus Trial in Intrahepatic Cholangiocarcinoma

Lirafugratinib (RLY-4008): A Next-Generation FGFR2 Inhibitor for iCCA

The development of lirafugratinib represents a significant technological leap in precision medicine. Unlike first-generation pan-FGFR inhibitors such as pemigatinib and erdafitinib, which target FGFR1, 2, and 3, lirafugratinib was specifically engineered for high selectivity toward FGFR2.

The rationale for this selectivity is twofold:

1. Toxicity Mitigation: Pan-FGFR inhibition is notoriously difficult to manage due to on-target as well as off-target effects. FGFR1 inhibition leads to hyperphosphatemia (often requiring phosphate binders), while FGFR3 inhibition is linked to skin and nail toxicities. By minimizing FGFR1/3 interaction, lirafugratinib aims to improve the therapeutic index.
2. Overcoming Resistance: Lirafugratinib was designed to maintain activity against "gatekeeper" mutations (such as N549H/K) that frequently emerge as resistance mechanisms during treatment with earlier-generation inhibitors.

What the ReFocus Trial(NCT04526106) Shows About FGFR2-Targeted Therapy

Results from the pivotal ReFocus study cohorts, presented at the 2026 ASCO GI Symposium, provide evidence for this selective approach. In Group 2A—consisting of FGFR inhibitor-naive patients who had progressed on prior chemotherapy—the confirmed objective response rate (ORR) was 46.5%, with a median duration of response (DOR) of 11.8 months.

Even more striking was the performance in treatment-naive patients (Group 6), where the ORR reached 63.6%. This suggests a "front-loading" benefit: the earlier a patient receives targeted therapy, the more likely they are to achieve a deep and durable response. The median overall survival (OS) in the pre-treated cohort reached 22.8 months, a significant milestone for a population that historically had few options after first-line gemcitabine/cisplatin.

However, the safety profile remains a point of expert debate. Despite the selective design, Grade 3+ treatment-related adverse events (TRAEs) occurred in 57.8% of the pivotal safety population. The most common were palmar-plantar erythrodysesthesia (32.8%) and stomatitis (12.1%). While hyperphosphatemia rates were potentially lower than with pan-inhibitors, the high rate of dose reductions (75.9%) indicates that "selectivity" does not mean "toxicity-free".

The Adjuvant Paradox in HCC: KEYNOTE-937 and IMbrave050

The failure of adjuvant ICIs to show definitive benefit in BCLC A HCC represents a major setback in the field.

KEYNOTE-937: Pembrolizumab Misses the Mark in Adjuvant HCC

The phase 3 KEYNOTE-937 trial evaluated pembrolizumab versus placebo in patients with a complete radiological response after surgery or ablation. The results were decisively negative: the median recurrence-free survival (RFS) was 46.7 months for pembrolizumab vs 45.5 months for placebo (HR 1.06; P=0.719).

From an expert perspective, this failure highlights a biological mismatch. In BCLC A patients who have undergone successful local therapy, the "tumor burden" is, by definition, undetectable. Immunotherapy typically requires the presence of tumor-associated antigens to prime and expand T-cell populations. Without these antigens, the one year of pembrolizumab may have offered no target for the immune system to engage, while still exposing patients to risks like immune-mediated hepatitis.

IMbrave050: Atezolizumab + Bevacizumab, Early Promise Without Durable Benefit

IMbrave050 initially showed promise with a significant RFS benefit at the 17.4-month interim analysis (HR 0.72). However, long-term follow-up presented in 2026 showed the benefit was not sustained, with the RFS curves eventually converging (updated HR 0.90). The fact that curves converged shortly after the 12-month treatment period ended suggests the regimen was merely delaying rather than preventing recurrence.

The Shift Toward Perioperative and Neoadjuvant Strategies: Why Perioperative Immunotherapy Is Gaining Momentum in HCC

The disappointing adjuvant results have shifted focus toward perioperative strategies, where therapy is initiated before the tumor is removed.

The CARES-009 study evaluated perioperative camrelizumab plus rivoceranib. This approach utilizes the intact tumor as an "in-situ vaccine." By exposing the immune system to the tumor before surgery, the therapy can generate a systemic memory T-cell response that targets micrometastases post-surgery.

The data support this rationale: median event-free survival (EFS) was 42.1 months with perioperative therapy compared to 19.4 months with surgery alone (HR 0.59; P=0.004). This suggests that the timing of immunotherapy, relative to the presence of the primary tumor, is a critical determinant of potential benefit.

First-Line Advanced HCC: CheckMate 9DW and the Challenge of "Crossing Curves"

In the advanced (BCLC C) setting, the 4-year follow-up of CheckMate 9DW (Nivolumab + Ipilimumab) has established a new benchmark. The combination achieved an ORR of 36%, the highest reported for a first-line HCC regimen.

The median OS was 23.7 months for Nivo/Ipi versus 20.6 months for TKI (HR 0.78). However, clinicians must address the "crossing curves" phenomenon: in the first 9–12 months, the Nivo/Ipi arm showed higher mortality than the TKI arm. This is likely due to early, severe immune-related adverse events. For patients with high tumor burden or fragile liver function, the immediate stability offered by a TKI might be preferable, whereas patients seeking long-term "durability" (as evidenced by the 31% 48-month OS rate) may opt for dual ICI.

How These Data Are Influencing Clinical Practice

The data summarized above have not changed my practice, and have instead further solidified my current practice. With regards to HCC, there is still no convincing evidence that adjuvant systemic therapy results in a significant clinical benefit that is worth the potential clinical and financial toxicity of doing post-operative ICI treatment. Moreover, although there is exciting and emerging EFS data from peri-operative ICI treatment for HCC, OS benefit remains the gold standard for us to convincingly adopt this approach in practice. Lastly, although a new FGFR2 inhibitor for iCCA may be clinically available in the near future, we have two other clinically available inhibitors with a similar side-effect profile. A better-tolerated and more durable FGFR2 inhibitor has yet to be discovered.

What Patients Should Know About Molecular Testing and Immunotherapy

For patients with liver or bile duct cancer, the most important takeaway is that your cancer's "genetic signature" matters. If you have a bile duct cancer, ask your doctor for "molecular profiling" or "NGS testing." If your cancer has an FGFR2 change, there are now highly specific drugs like lirafugratinib that can shrink tumors more effectively than standard chemotherapy.

For liver cancer patients, while the "after-surgery" preventive treatments are still being perfected, new combinations of immune therapies are helping people live significantly longer in the advanced stages. Always discuss the balance of side effects versus long-term benefits with your oncology team.

About Author

Dr. King is an associate professor of medical oncology at the Fred Hutchinson Cancer Center, University of Washington. He subspecializes in the treatment of hepatobiliary and pancreatic cancers. His research focus is on clinical trials of novel drugs and treatment strategies for these cancers, as well as the identification of potential biomarkers that predict benefit to treatment.

References

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