FIGHT-302 Phase 3 Trial: First-Line Pemigatinib Significantly Improves PFS Over Chemotherapy in FGFR2-Rearranged Cholangiocarcinoma

　　Cholangiocarcinoma(CCA)is a highly aggressive malignancy arising from the biliary epithelium,with approximately 70%of patients presenting with unresectable advanced disease at diagnosis.For over a decade,the combination of gemcitabine and cisplatin(GemCis)has served as the standard first-line chemotherapy,yet overall survival benefits remain modest,with median overall survival typically below one year.The identification of fibroblast growth factor receptor 2(FGFR2)fusions or rearrangements—present in approximately 10%to 16%of intrahepatic cholangiocarcinoma cases—as a key actionable driver alteration has transformed the therapeutic landscape and positioned FGFR-targeted therapy at the forefront of precision oncology in biliary tract cancers.

　　Pemigatinib:The First Approved FGFR-Targeted Agent for Cholangiocarcinoma.Pemigatinib(brand name Pemazyre)is an oral,highly selective small-molecule inhibitor of FGFR1/2/3.In April 2020,based on positive results from the phase 2 FIGHT-202 trial(NCT02924376),pemigatinib received accelerated approval from the U.S.Food and Drug Administration(FDA)for adult patients with previously treated,unresectable locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements as detected by an FDA-approved test.This landmark approval made pemigatinib the first molecularly targeted therapy ever approved for cholangiocarcinoma.The phase 3 FIGHT-302 trial(NCT03656536),whose results were presented at the 2026 ASCO Annual Meeting,now extends pemigatinib's therapeutic positioning from the second-line setting into the first line.

　　Trial Design:The Largest Randomized Study in FGFR2-Rearranged CCA.FIGHT-302 is an international,open-label,randomized,active-controlled phase 3 trial comparing pemigatinib monotherapy against gemcitabine plus cisplatin as first-line treatment for patients with confirmed FGFR2-rearranged,unresectable,locally advanced,or metastatic cholangiocarcinoma.A total of 4,563 patients underwent pre-screening for FGFR2 rearrangement globally,of whom 196 proceeded to formal screening.Ultimately,167 patients with confirmed FGFR2 rearrangement were randomized 1:1 to receive either pemigatinib(n=83)or gemcitabine plus cisplatin(n=84).

　　Patients in the pemigatinib arm received 13.5 mg orally once daily on days 1 through 14 of each 21-day cycle.Those in the chemotherapy arm received gemcitabine 1,000 mg/m²plus cisplatin 25 mg/m²intravenously on days 1 and 8 of each 21-day cycle,for up to 8 cycles.Notably,patients with urgent treatment needs were permitted to receive one cycle of GemCis prior to randomization as bridging therapy.The primary endpoint was progression-free survival(PFS)assessed by independent central review.Key secondary endpoints included objective response rate(ORR),disease control rate(DCR),duration of response(DOR),overall survival(OS),and safety.

　　Baseline Characteristics Were Well Balanced.The median age was 61 years(range 25–82)in the pemigatinib arm and 59.5 years(range 28–79)in the chemotherapy arm.Both arms had a majority of female patients(55.4%vs.60.7%),predominantly White populations(72.3%vs.67.9%),and similar proportions of ECOG performance status 0(65.1%vs.63.1%).Most patients were enrolled from Western regions(86.7%vs.84.5%),had distant metastases(78.3%vs.78.6%),and had intrahepatic disease(98.8%vs.96.4%).Prior to randomization,13.3%of pemigatinib-arm patients and 15.5%of chemotherapy-arm patients had received one bridging cycle of GemCis.The mean time from diagnosis to enrollment was approximately 0.6 years in both arms.

　　Primary Endpoint:Significant PFS Improvement.At median follow-up of 42.1 months(pemigatinib)and 42.9 months(chemotherapy),the median PFS was 8.34 months(95%CI:6.51–12.22)with pemigatinib versus 6.80 months(95%CI:6.05–8.25)with gemcitabine plus cisplatin(HR 0.584;95%CI:0.393–0.868;P=0.0078),representing an approximately 42%reduction in the risk of disease progression or death.

　　Secondary Endpoints:Superior Response Rates and Disease Control.The ORR was 47.0%with pemigatinib(6.0%complete responses,41.0%partial responses)compared with 15.5%for chemotherapy(3.6%complete,11.9%partial;OR 5.57;P<0.0001).The DCR was 89.2%versus 67.9%(OR 4.10;P=0.0007).Median DOR reached 14.2 months(95%CI:8.7–24.7)with pemigatinib versus 6.3 months(95%CI:4.3–not estimable)with chemotherapy(HR 0.40;95%CI:0.16–1.01;P=0.0526),indicating both deeper and more durable responses.Remarkably,five patients in the pemigatinib arm underwent subsequent surgical resection,and all remained alive at data cutoff,suggesting potential conversion to resectability.

　　Overall Survival:No Significant Difference Amid High Crossover.Median OS was 24.4 months(95%CI:18.6–35.9)with pemigatinib versus 25.0 months(95%CI:18.7–34.2)with chemotherapy(HR 1.095;95%CI:0.733–1.637;P=0.6581).However,approximately 80%of chemotherapy-arm patients crossed over to receive FGFR inhibitors(including pemigatinib)upon progression,substantially diluting the OS difference.Among the 14 chemotherapy-arm patients who did not receive post-progression FGFR inhibitor therapy,median OS was only 11.1 months—far below that of patients who crossed over.This subgroup finding underscores the indispensable role of FGFR inhibition in this molecularly defined population.

　　Safety Profile:Favorable Tolerability With Lower Discontinuation Rate.All patients in the pemigatinib arm(n=83)and all evaluable patients in the chemotherapy arm(n=73)experienced at least one treatment-emergent adverse event(TEAE).Grade≥3 TEAEs occurred in 78.3%and 67.1%of patients,respectively.However,the TEAE-related permanent discontinuation rate was lower with pemigatinib(6.0%)than with chemotherapy(11.0%).Three fatal TEAEs were reported in the pemigatinib arm(sepsis,asthenia,and renal failure),but none were assessed as related to the study drug.The most common TEAEs(≥40%)in the pemigatinib arm included hyperphosphatemia,alopecia,palmar-plantar erythrodysesthesia,stomatitis,constipation,and diarrhea.Hyperphosphatemia,a class effect of FGFR inhibition related to FGFR1-mediated phosphate homeostasis,was manageable with dietary modification,phosphate binders,or dose adjustments.No new safety signals were identified.

　　Resistance Mechanisms:Secondary FGFR2 Mutations Drive Progression.An exploratory circulating tumor DNA(ctDNA)analysis revealed that approximately one-third of patients who progressed on pemigatinib developed acquired secondary FGFR2 kinase domain mutations.Among 63 evaluable patients treated with pemigatinib at any line,21 harbored new FGFR2 mutations;among 45 first-line patients,15 were positive;and among 18 patients who crossed over from chemotherapy,6 were positive.The most frequently detected variants were FGFR2 p.Asn549(40%)and p.Val564(23%).These findings identify secondary FGFR2 mutations as a predominant mechanism of acquired resistance and provide a rationale for developing next-generation FGFR inhibitors and optimized sequential treatment strategies.

　　Clinical Implications.FIGHT-302 represents the largest randomized controlled trial conducted to date in first-line FGFR2-rearranged cholangiocarcinoma.The results provide robust phase 3 evidence supporting pemigatinib as a first-line option for this molecularly defined population,particularly for patients who are ineligible for or decline chemotherapy.The trial simultaneously confirms pemigatinib's established role in the post-chemotherapy setting.Looking ahead,the ctDNA resistance landscape will inform the development of next-generation FGFR inhibitors designed to overcome secondary mutations,further refining the precision management paradigm for FGFR2-driven biliary malignancies.