Fibroblast growth factor receptor 3 (FGFR3) alterations in PROOF 302: A phase III trial of infigratinib (BGJ398) as adjuvant therapy in patients (pts) with invasive urothelial carcinoma (UC).

person Petros Grivas Division of Oncology, Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA info_outline Petros Grivas, Siamak Daneshmand, Vladimir Makarov, Joaquim Bellmunt, Srikala S. Sridhar, Guru P. Sonpavde, Suzanne Cole, Abhishek Tripathi, Bishoy Morris Faltas, Seth P. Lerner, Mark T. Fleming, Yohann Loriot, Joshua J Meeks, Viraj A. Master, Kimberlee Davis, David Friedrich Van Veenhuyzen, Shugufa Afifi, Sumanta Kumar Pal, Shilpa Gupta

Authors person Petros Grivas Division of Oncology, Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA info_outline Petros Grivas, Siamak Daneshmand, Vladimir Makarov, Joaquim Bellmunt, Srikala S. Sridhar, Guru P. Sonpavde, Suzanne Cole, Abhishek Tripathi, Bishoy Morris Faltas, Seth P. Lerner, Mark T. Fleming, Yohann Loriot, Joshua J Meeks, Viraj A. Master, Kimberlee Davis, David Friedrich Van Veenhuyzen, Shugufa Afifi, Sumanta Kumar Pal, Shilpa Gupta Organizations Division of Oncology, Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA, USC Institute of Urology, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, Cleveland Clinic Lerner Research Institute, Cleveland, OH, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada, AdventHealth Cancer Institute, Orlando, FL, University of Texas Southwestern Medical Center, Dallas, TX, City of Hope Comprehensive Cancer Center, Duarte, CA, Weill Cornell Medicine, New York, NY, Baylor College of Medicine, Houston, TX, Virginia Oncology Associates, U.S. Oncology Research, Norfolk, VA, Department of Cancer Medicine, Gustave Roussy Institute, INSERM 981, University Paris-Saclay, Villejuif, France, Northwestern University, Department of Urology, Feinberg School of Medicine, Chicago, IL, Winship Cancer Institute of Emory University, Atlanta, GA, BridgeBio Inc. (San Francisco, CA), San Francisco, CA, BridgeBio, Palo Alto, CA, Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH Abstract Disclosures Research Funding Pharmaceutical/Biotech Company QED therapeutics Background: Radical surgery with or without (neo)adjuvant cisplatin-based chemotherapy [(N)AC] is standard in fit pts with muscle invasive UC of bladder (UBC) or upper tract (UTUC). However, recurrence rates are high, underscoring the need for novel therapies. Since up to 70% of UTUC and 20% of UBC tumors were reported to harbor FGFR3 alterations, targeting this pathway is a rational approach. Infigratinib is a selective FGFR1–3 inhibitor with efficacy in advanced UC with FGFR3 alterations [Pal et al. 2018]. PROOF 302 investigated the efficacy and safety of adjuvant infigratinib vs placebo in pts with high-risk invasive UC. Methods: PROOF 302 was a global, randomized, double-blind, placebo-controlled, phase III trial for pts with high-risk invasive UTUC or UBC (≤15%) with FGFR3 alteration (i.e. mutation, gene fusion / translocation) with residual (≥ypT2 and/or ypN+) tumor after NAC, or pts ineligible for, or refusing, cisplatin-based AC, ≤120 days post-surgery. Pts were randomized 1:1 to infigratinib 125 mg or placebo daily on days 1–21 every 28 days for up to 52 weeks or until recurrence, unacceptable toxicity, or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: investigator-assessed DFS, metastasis-free survival, overall survival, safety/tolerability. Exploratory endpoints: QOL, pharmacokinetics, genomic analysis of tumor and cfDNA. Assessment of genomic alterations was pursued using descriptive statistics. Results: We present the results of the genomic analysis of radical surgery tissues from pts screened for the trial using the FoundationOne platform. Out of 617 pts screened, 188 (30.5%) had alterations in FGFR 1-4 genes: 102/237 (43%) in UTUC, 85/369 (23%) in MIBC and 1/11 (9%) with unknown tumor origin. Of these 188 pts, median age 74 (32-90 years), 76% were male, 55% had UTUC, 44% had UBC. Genomic alterations are shown. In UTUC, FGFR3 had 56% single-nucleotide variations (SNV) and insertions/deletions (INDELS), 40% amplifications and 70% structural variants (SV). In UBC, FGFR3 had 44% SNV and INDELS, 60% amplifications and 30% SV. Conclusions: FGFR3 alterations were seen in only 19% of all pts screened for PROOF-302, a trial that was enriched for UTUC: 71/237 (30%) of UTUC and 48/369 (13%) of UBC. The trial was stopped early by the sponsor, but the genomic analysis provides insights into the prevalence of FGFR3 alterations; assessment of correlations with the primary/secondary endpoints is ongoing. The nature and frequency of co-occurring alterations in tissue samples is being investigated to help inform combination therapy strategies and putative resistance mechanisms. Clinical trial information: NCT04197986. Known tumor origin FGFR 1-4 (%) FGFR1(%) FGFR2(%) FGFR3(%) FGFR4(%) UTUC 102/237 (43) 15% 20% 67% 10% UBC 85/369 (23) 30% 11% 55% 4%

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