230P - Fibroblast growth factor receptor (FGFR) co-alteration (co-alt) landscape and its impact on erdafitinib (erda) response in the phase II open-label, single-arm RAGNAR trial

Background

FGFRalts are present in 1%-20% of all cancers. Erda is an oral selective pan-FGFR inhibitor approved to treat locally advanced or metastatic (adv/met) urothelial carcinoma in adults with susceptible FGFR3/2alt who have progressed during or after ≥1 line of platinum-based chemotherapy. Interim results of RAGNAR showed tumor agnostic efficacy in patients (pts) with adv/met solid tumors with predefined FGFRalt after failure of standard therapies (Loriot et al, ASCO 2022 ). Here, we evaluated the FGFR co-alt landscape and its impact on response to erda treatment (tx) in RAGNAR.

Methods

Archival tumors from pts with adv/met solid tumors were prospectively screened for FGFR1-4alts using FoundationOne (FM) or, for those pts enrolled based on local results, retrospectively tested using FM. 217 pts received erda until progression or intolerable toxicity. The impact of co-alts on erda tx was evaluated with respect to objective response rate (ORR) (primary end point) using Fisher exact test, Kaplan-Meier analysis for duration of response (DOR), and Wilcoxon rank-sum test for maximum tumor shrinkage (MTS).

Results

Of 217 pts, 175 (81%) had tumors with pathogenic co-alts, most prevalent in TP53 (27%), PIK3CA (18%), and CDK2NA (15%). Co-alts were histology dependent. TP53 was altered in 75% of esophageal, 75% of ovarian, and 71% of colorectal; TERT mutations were seen in 55% of high-grade gliomas. ORR did not show an association between the presence or burden of co-alts (p=0.51). Of the 12 most prevalent co-alts and pathways, none were significantly associated with response vs non-response. Within each histology, individual co-alts were not associated with response. Among responders, TP53 alt was associated with shorter DOR (HR=0.29 [95% CI, 0.15-0.58]; p=0.002). Further, RTK-RAS pathway co-alts were associated with less MTS (p=0.034).

Conclusions

High prevalence of FGFR co-alts reflects the complex genomic landscape of tx-refractory adv/met solid tumors. Despite most pts having histology-specific co-alts, erda showed clinical activity in these pts, supporting FGFRalts as oncogenic drivers in these tumors.

Clinical trial identification

NCT04083976.

Editorial acknowledgement

Legal entity responsible for the study

Janssen Research & Development.

Funding

Janssen Research & Development.

Disclosure

Y. Loriot: Financial Interests, Institutional, Speaker, Consultant, Advisor, Consultancy Fees: Loxo/Lilly, Pfizer/EMD Serono, Roche, and Taiho Pharmaceutical, MSD Oncology, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Immunomedics, Janssen; Financial Interests, Personal, Other, Travel Reimbursement: Astellas, AstraZeneca, Janssen Oncology, MSD Oncology, and Roche; Financial Interests, Institutional, Research Funding: Astellas Pharma, AstraZeneca, Basilea, Bristol Myers Squibb, Exelixis, Gilead Sciences, Incyte, Janssen Oncology, Merck KGaA, MSD Oncology, Nektar, Pfizer, Roche, Sanofi, and Taiho Pharmaceutical. S. Pant: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Zyemworks, Ipsen, Novartis, Janssen; Financial Interests, Institutional, Research Funding: Mirati Terapeutics, Lilly, Xencor, Novarits, Rgenix, Bristol Myers Squibb, Astellas Pharma, Purple Biotech, 4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Bissceinces, Elicio Therapeutics. O. Witt: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Bayer US, LCC, Bristol Myers Squibb, Day One Therapeutics, Novartis, and Roche; Financial Interests, Institutional, Research Funding: AstraZeneca, Bayer US, LLC, Blueprint Medicines, Day One Therapeutics, GSK, Janssen, Lilly, Loxo, Novartis, and Roche. D.A. Reardon: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Advantagene, Agenus, Agios, AnHeart Therapeutics, Bayer, Bristol Myers Squibb, Delmar Pharmaceuticals, Ellipses Pharma, EMD Serono, Genenta Science, Imvax, Kintara Therapeutics, Kiyatec, Medicenna, Merck, Merck KGaA, Novocure, Oncorus, Regeneron, Taiho Ph; Financial Interests, Personal, Other, Honoraria: Advantagene, Agenus, AnHeart Therapeutics, Bayer, Bristol Myers Squibb, Deciphera, DelMar Pharmaceuticals, Ellipses Pharma, EMD Serono, Genenta Science, Imvax, Inovio Pharmaceuticals, Kintara Therapeutics, Kiyatec, Medicenna, Merck, Merck KGaA, Neuvogen, ; Financial Interests, Institutional, Research Funding: Acerta Pharma, Agenus, Celldex, EMD Serono, Enterome, Incyte, and Omniox. T. Doi: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: AbbVie, Amgen, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Janssen, Kaken Pharmaceutical, Kyowa Kirin, MSD, Otsuka, PRA Health Science, Rakuten Medical, Shionogi, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, and Takeda; Financial Interests, Personal, Other, honoraria: AstraZeneca, Bristol Myers Squibb Japan, Chugai Pharma, Daiichi Sankyo, Ono Pharmaceutical, Rakuten Medical Japan, and Taiho Pharmaceutical; Financial Interests, Institutional, Research Funding: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo, Eisai, IQVIA, Janssen, MSD, Ono Pharmaceutical, Novartis, Pfizer, PRA Health Sciences, Sumitomo Dainippon Pharma, and Taiho Pharmaceutical. J. Tabernero: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai Pharma, Daiichi Sankyo, F. Hoffman LaRoche, Genentech, HalioDx, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, Mirati Therapeutics, MSD, NeoPhore, ; Financial Interests, Personal, Other: Imedex/HMP, Medscape, MJH Life Sciences, Peerview, Physicians’ Education Resource; and stock and other ownership interests from Oniria Therapeutics. G. Iyer: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Basilea, Bayer, Flare Therapeutics, Janssen, Loxo/Lilly, and Mirati Therapeutics; Financial Interests, Personal, Speaker’s Bureau: Gilead Sciences and Lynx Group; Financial Interests, Institutional, Research Funding: Bayer, Debiopharm Group, Janssen, Mirati Therapeutics, Novartis, and Seagen. C. Massard: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, Bristol Myers Squibb, Celgene, Debiopharm Group, Faron Pharmaceuticals, Genentech/Roche, Innate Pharma, Ipsen, Janssen, Lilly, MSD, Novartis, Orion, Pfizer, PharmaMar, Sanofi, and T. D. Arnold: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: CE Oncology, Amgen, Art Tempi Media, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Personal Aptitude Health, Clinical Care Options (CCO), CRA International, Eli Lilly, Hexal, Imedex, Ipsen, IQVIA, Ketchum, MedAhead, Merck Serono, Merck, Sh; Financial Interests, Personal, Leadership Role: OncoLytics . I. Lugowska: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Boehringer Ingelheim; honoraria from Agenus, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celon, Cullinan Oncology, Jacobio, Janssen, Loxo, Macrogenics, Menarini, MSD, Pfizer, Rhizen, Roche, Sanofi, and Takeda; institutional research funding from Ag; Financial Interests, Personal, Other, Travel Expenses: Bristol Myers Squibb. M. Gutierrez: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Celularity and Guardant. H. Sweiti, S. Thomas, M. Gormley, J. Zhang, S. Triantos: Financial Interests, Personal, Other, Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Janssen. M.H.H. Schuler: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Janssen Oncology, Merck Serono, Novartis, Roche, Sanofi, and Takeda; Financial Interests, Personal, Other, honoraria: Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen-Cilag, and Novartis; Financial Interests, Institutional, Research Funding: AstraZeneca and Bristol Myers Squibb; Financial Interests, Personal, Other, institutional patents, royalties, or other intellectual property for a highly sensitive method for mutation detection: PCR. All other authors have declared no conflicts of interest.