Combination treatment with the oral, highly selective FGFR4 inhibitor irpagratinib plus atezolizumab has shown promising efficacy in patients with untreated or immune checkpoint inhibitor (ICI)-exposed hepatocellular carcinoma (HCC) with fibroblast growth factor 19 overexpression (FGF19+), while being safe and well tolerated, according to the updated results of the phase II ABSK-011-201 study.

Over a median follow-up of 7.1 months, the primary endpoint of overall response rate (ORR) was 51.7 percent in the entire population, 50 percent in the treatment-naïve subgroup, and 52.9 percent in the pretreated subgroup. The confirmed ORRs in the respective subgroups were 33 percent and 41.2 percent. [ESMO GI 2025, abstract 149MO]

“Tumour response was deep and durable in most cases,” reported lead researcher Dr Qi Cheng of Tongji Hospital in Wuhan, China.

The median duration of response was not reached in both treatment-naïve and pretreated subgroups, and the disease control rate was 91.7 percent and 70.6 percent, respectively.

Median progression-free survival (PFS) was 7 months (95 percent confidence interval [CI], 2.8 to not evaluable [NE]) among treatment-naïve patients and 8.3 months (95 percent CI, 1.6 to NE) among those exposed to ICI-based treatment in the first-line setting.

Overall survival data were not evaluable, with only six deaths recorded at the time of analysis.

Cheng described the efficacy findings as remarkable, noting that FGF19+ HCCs are associated with poor prognosis and potentially do not respond well to standard, first-line treatments that use ICIs.

Tolerable safety profile

In the overall population, all patients experienced a treatment-emergent adverse event (TEAE), including grade ≥3 events in 45.5 percent.

The incidence of grade ≥3 treatment-related adverse events (TRAEs) was low. This included elevated alanine aminotransferase in 12.1 percent of patients, increased blood alkaline phosphatase in 6.1 percent, reduced white blood cell count in 6.1 percent, and elevated blood creatinine in 6.1 percent.

There were no reports of grade 4/5 TRAEs and, none of the patients discontinued treatment due to TRAEs.

Cheng noted incidences of diarrhoea and hyperphosphatemia, but these events were mostly mild and manageable.

The combination therapy was not associated with eye toxicity and did not cause any additional immune-related AEs compared with those reported in historic data of atezolizumab monotherapy, he added.

Taken together, the findings highlight the therapeutic potential of irpagratinib plus atezolizumab in the present population, according to Chen.

The efficacy data suggest that the combination may be an effective treatment option in HCC patients whose disease has progressed or recurred after initial treatment with an ICI. For untreated patients, the manageable safety profile of the combination underscores the feasibility of exploring triplet regimens that include irpagratinib and atezolizumab plus a third drug such as bevacizumab. Cheng said these treatment opportunities are being explored in clinical trials.

The analysis included 33 patients (median age 56 years, 84.8 percent male, 84.8 percent had hepatitis B infection) with FGF19+ advanced or unresectable HCC, ECOG performance status of 0 or 1, and Child-Pugh class A and B. Of these, 15 were naïve to treatment and 18 received ICI-based therapies in the first-line setting. Prior ICI treatments included sintilimab, tislelizumab, atezolizumab, finotonlimab, toripalimab, and camrelizumab.

The patients received oral irpagratinib at 220 mg twice daily plus intravenous atezolizumab at 1,200 mg every 3 weeks.

At baseline, the median sum of tumour lesions was 95 mm and was higher in the treatment-naïve subgroup than in the pretreated subgroup (120 vs 88 mm).