Prior ICI Exposure Linked to Higher Dermatitis Risk With Lirafugratinib in FGFR2-Altered Tumors

Prior exposure to immune checkpoint inhibitors (ICIs) was associated with a higher risk of mucocutaneous adverse effects (mcAEs), particularly dermatitis, in patients with advanced or metastatic FGFR2-altered solid tumors treated with the FGFR2 inhibitor lirafugratinib (Lyrfigtu), according to a post hoc analysis of the ReFocus trial (NCT04526106). Efficacy in patients with cholangiocarcinoma (CCA) did not appear to differ by prior ICI exposure.

Jia Jenny Liu, MD, PhD, FRACP, medical oncologist and translational lead of early phase drug development at The Kinghorn Cancer Centre, St Vincent's Hospital Sydney, presented the findings in an e-poster at the 2026 European Society for Medical Oncology (ESMO) Congress.

What did the analysis find?

Of 385 patients treated with lirafugratinib 70 mg daily, 123 (32%) had prior ICI exposure and 262 did not. Earlier mcAE development and higher cumulative incidence by day 90 were observed in patients with prior ICI exposure (subdistribution HR [sHR], 1.68; 95% CI, 1.32-2.15; adjusted P <.001). At 90 days, 90% of patients overall had any-grade mcAEs and 36% had grade 3 or higher events. Among those who developed mcAEs, 54% and 44% required dose interruptions and reductions, respectively. Palmar-plantar erythrodysesthesia syndrome (PPES) had the highest rates of interruption (33%) and reduction (25%).

Patients with prior ICI exposure had a 94% risk (95% CI, 88%-97%) of any-grade mcAEs vs 89% (95% CI, 84%-92%) in those who did not receive prior ICI (sHR, 1.8; 95% CI, 1.4-2.3; adjusted P < .01). Dermatitis showed the largest difference at 48% (95% CI, 39%-57%) vs 14% (95% CI, 10%-19%), respectively (sHR, 4.2; 95% CI, 2.9-6.1; adjusted P < .01). Mucositis was also more common with prior ICI exposure (72% [95% CI, 63%-79%] vs 59% [95% CI, 53%-65%]; sHR, 1.5; 95% CI, 1.2-2.0; adjusted P < .01).

Grade 3 or higher dermatitis occurred in 11% (95% CI, 6%-18%) of patients with prior ICI exposure vs 1.0% (95% CI, 0.1%-3%) without (sHR, 10.4; 95% CI, 3-36; adjusted P < .01). Overall rates of grade 3 or higher mcAEs were similar at 33% (95% CI, 25%-42%) in those with prior ICI vs 37% (95% CI, 31%-43%) in those without (sHR, 0.9; 95% CI, 0.6-1.4; adjusted P = .9). PPES, nail changes, and hair loss did not differ significantly between groups.

Prior ICI exposure was also associated with a higher likelihood of dose interruptions or reductions due to mcAEs (sHR, 1.4; adjusted P = .02). The poster noted that mcAEs tended to develop earlier in patients with prior ICI exposure, particularly dermatitis.

How was the post hoc analysis conducted?

The analysis included patients with advanced or metastatic solid tumors with FGFR2 alterations and at least 1 prior systemic therapy who received lirafugratinib at 70 mg daily. Of those included in the analysis, 60% had CCA. The investigators used Gray’s test and Fine-Gray sHRs to account for competing risks (death, progression, and withdrawal for reasons other than mcAEs) and reported landmark incidences at 3 months. Benjamini-Hochberg adjustment was used for multiple comparisons, with adjusted P < .05 considered significant.

The primary end point of the analysis was 90-day mcAE incidence by subtype, grade, and impact on lirafugratinib dose intensity.

The investigators noted that ICIs plus chemotherapy are now the standard first-line treatment in advanced or metastatic CCA, which may influence the host immune environment and the risk of toxicity with subsequent targeted therapy. On-target toxicities of FGFR2 inhibitors can affect tolerability and dose intensity.

Did prior ICI exposure affect lirafugratinib efficacy?

Among 114 patients with FGFR inhibitor-naive CCA, efficacy was similar by prior ICI exposure. Objective response rate was 48.6% (95% CI, 36.7%-60.7%) without prior ICI exposure vs 42.9% (95% CI, 27.7%-58.0%) with prior ICI exposure (OR, 0.79; 95% CI, 0.34-1.82; P = .57). The median progression-free survival was 13 months vs 11 months, respectively (adjusted HR, 1.43; 95% CI, 0.83-2.46; P = .2).

What did the investigators conclude?

“This exploratory analysis suggests ICI exposure may alter rate, severity, and clinical burden of mcAEs in [patients] treated with FGFR2 inhibition,” Liu and coauthors wrote in the abstract. They added that prospective validation may inform sequencing strategies for ICIs and targeted therapies, including mcAE prophylaxis, multidisciplinary onco-dermatology input, and mechanistic studies to guide toxicity management. In the poster, they wrote that differences in dose intensity due to mcAEs “do not appear to reduce efficacy of [lirafugratinib] in [CCA] in [patients] treated with prior ICIs.”

References

Pham J, Hollebecque A, Borad M, et al. Immune checkpoint inhibitors (ICI) and risk of mucocutaneous adverse events (mcAEs) on FGFR2 inhibition: post-hoc analysis of the lirafugratinib (Lira) ReFocus trial. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 1096eP.