Lirafugratinib Associated With More Mucocutaneous AEs After Prior ICIs in FGFR2-Altered CCA and Other Solid Tumors

Prior exposure to immune checkpoint inhibitors (ICIs) increased the risk of mucocutaneous adverse effects (mcAEs), particularly dermatitis, in patients with FGFR2-altered solid tumors treated with lirafugratinib (Lyrfigtu), according to a post hoc analysis of the phase 1/2 ReFocus trial (NCT04526106) presented in a poster session at the 2026 ESMO Congress.¹

Among 385 patients with advanced or metastatic solid tumors who received lirafugratinib at 70 mg once daily (prior ICI, n = 123; no prior ICI, n = 262), 90% developed an mcAE of any grade within 90 days. Prior ICI exposure was associated with a higher cumulative incidence of any-grade mcAEs by day 90 (subdistribution HR [sHR], 1.68; 95% CI, 1.32-2.15; adjusted P < .001).

By mcAE subtype, prior ICI exposure increased the risk of dermatitis (adjusted sHR, 4.93) and mucositis (adjusted sHR, 1.53), whereas the adjusted sHRs for palmoplantar rash (0.90) and nail changes (1.10) were close to 1. Prior ICI exposure also increased the risk of dose reductions or interruptions due to any mcAE (adjusted sHR, 1.73) and dermatitis (adjusted sHR, 25.65). In unadjusted analyses at day 90, the sHR was 4.90 for dermatitis (95% CI, 3.20-7.48; Gray P < .001) and 1.55 for mucositis (95% CI, 1.19-2.04; Gray P = .001).

“Prior [ICI] treatment appears to increase risk of [mcAEs] on [lirafugratinib], particularly dermatitis, with impact on dose intensity and implications for treatment sequencing,” the study authors wrote in a poster of the data.

What was the design of the post hoc analysis of lirafugratinib in patients with solid tumors harboring FGFR2 alterations?

ReFocus is an open-label, first-in-human study evaluating lirafugratinib (RLY-4008) in patients with unresectable or metastatic cholangiocarcinoma (CCA) and other advanced solid tumors with FGFR2 alterations.²

In the present analysis, the investigators analyzed patients with advanced or metastatic solid tumors and FGFR2 alterations who had received 1 or more prior systemic therapies and started lirafugratinib at the recommended phase 2 dose of 70 mg once daily.¹ The primary end point was the incidence of mcAEs by day 90, assessed by subtype, grade, and effect on lirafugratinib dose intensity. Death, progression, and withdrawal for reasons other than mcAEs were handled as competing risks using Gray’s test and Fine-Gray subdistribution HRs. The investigators applied Benjamini-Hochberg adjustment for multiple comparisons and considered an adjusted P < .05 statistically significant. According to the poster, mcAEs are on-target effects of FGFR2 inhibition that occur outside the tumor and can limit tolerability and dose intensity; whether prior ICIs, now standard of care in advanced or metastatic CCA, alter that risk was unclear.

In the total population of patients, 32% had prior ICI exposure, the median age was 60 years (interquartile range, 49-67), 40.3% were male, and 47.0% had an ECOG performance status of 0. CCA was the most common tumor type (60.3%), followed by gastric cancer (7.8%) and breast cancer (5.5%), with other tumor types in 26.5% of patients. CCA made up 55.3% of patients in the prior ICI group and 62.6% of those in the group without prior ICI exposure, and gastric cancer made up 12.2% and 5.7% of patients, respectively.

What earlier ReFocus data supported the FDA approval of lirafugratinib for CCA?

On September 23, 2026, the FDA approved lirafugratinib for adult patients with CCA harboring an FGFR2 fusion or other rearrangement whose disease is unresectable, locally advanced, or metastatic and who have received prior therapy.³ The approval rested on data from 116 patients from ReFocus with unresectable or metastatic CCA previously treated with chemotherapy or chemoimmunotherapy. Per independent review committee assessment using RECIST 1.1 criteria, the objective response rate (ORR) was 46% (95% CI, 36%-55%), and the median duration of response was 11.8 months (95% CI, 7.5-13.0). Lirafugratinib is dosed at 70 mg orally once daily until disease progression or unacceptable AEs, and the labeled warnings include ocular toxicity, hyperphosphatemia with soft tissue mineralization, and embryo-fetal toxicity.

How did prior ICI exposure affect the incidence of grade 3 or higher mcAEs and mcAE onset with lirafugratinib?

In the current analysis, grade 3 or higher mcAEs overall were not associated with prior ICI exposure (unadjusted sHR, 1.26; 95% CI, 0.76-2.08; Gray P = .371).¹ By subtype, the unadjusted sHR for grade 3 or higher dermatitis was 26.26 (95% CI, 3.40-202.69; Gray P < .001), whereas the sHR for grade 3 or higher mucositis was 1.34 (95% CI, 0.61-2.95; Gray P = .465), and for grade 3 or higher palmoplantar rash, the sHR was 0.31 (95% CI, 0.09-1.03; Gray P = .043). Any-grade and grade 3 or higher mcAEs tended to develop earlier in patients with prior ICI exposure, particularly dermatitis.

Did prior ICI exposure change the efficacy of lirafugratinib in FGFR inhibitor–naive CCA?

Among efficacy-evaluable FGFR inhibitor–naive patients with advanced or metastatic CCA (n = 114; prior ICI, n = 42; no prior ICI, n = 72), the ORR was 42.9% (95% CI, 27.7%-59.0%) with prior ICI exposure vs 48.6% (95% CI, 36.7%-60.7%) without (odds ratio, 0.79; 95% CI, 0.34-1.82; P = .57). The median progression-free survival values were 11 months vs 13 months, respectively (adjusted HR, 1.43; 95% CI, 0.83-2.46; adjusted Cox P = .20).

What are the next steps for managing mcAEs with lirafugratinib after ICI therapy?

The investigators concluded that prior ICI treatment appears to raise the risk of mcAEs with lirafugratinib, particularly dermatitis, which affects dose intensity and bears on treatment sequencing. Differences in dose intensity attributed to mcAEs did not appear to reduce efficacy in patients with CCA and prior ICI exposure. The investigators called for prospective research on mcAE prophylaxis, preemptive onco-dermatology input, and mechanistic studies to guide the management of these effects.

References

1. 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 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 1096eP.
2. REFOCUS: a first-in-human study of highly selective FGFR2 inhibitor, RLY-4008, in patients with ICC and other advanced solid tumors. ClinicalTrials.gov. Updated February 27, 2026. Accessed October 29, 2026. https://clinicaltrials.gov/study/NCT04526106
3. FDA approves lirafugratinib for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma. FDA. September 23, 2026. Accessed October 29, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lirafugratinib-previously-treated-unresectable-locally-advanced-or-metastatic