2394P - Biomarkers of treatment (Tx)-related toxicity in advanced urothelial carcinoma (aUC) pts treated with enfortumab vedotin (EV): Analysis of UNITE study

Background

EV is approved in aUC pts, but Tx duration is often limited by toxicity. We investigated pt characteristics and biomarkers associated with EV-related adverse events (EV AEs).

Methods

UNITE is a multi-site retrospective study of EV-treated aUC pts; pts treated with EV alone with available AE and next-generation sequencing (NGS) data were analyzed. EV AEs were assessed per CTCAE v5.0. For univariate analyses (UVA), Wilcoxon rank sum and Chi-squared tests assessed associations between clinical features or somatic gene alterations (GA; tissue or ctDNA) occurring in ≥5% of pts and most common AEs and EV Tx modifications (reduction, hold, or discontinuation). Using Cox regression models, GA were evaluated individually in separate multivariate analysis (MVA) models accounting for relevant clinical factors.

Results

Among 607 pts (16 US sites), 275 had EV AEs and NGS data. At EV start: median age 71; 183 (67%) men; 244 (88%) White; 216 (79%) ECOG PS 0-1; 186 (68%) with ≥2 prior Tx lines. Median time from initial diagnosis to EV start was 86 weeks [IQR 48, 165]; median time from EV start to AE onset 4 weeks [IQR 2, 11]. Most common all-grade AEs: neuropathy (46%), skin tox (41%), fatigue (25%), GI tox (22%), cytopenias (14%), anorexia (11%). In UVA, diabetes (DM), prior neuropathy, higher Hgb and albumin at EV start were associated with neuropathy (all p<0.05); lower white blood cell count and neutrophil:lymphocyte ratio (NLR), GFR ≥30 with skin tox (all p<0.01); TERT GA (p=0.04) and lower absolute lymphocyte count with cytopenias (p<0.01); male sex (p=0.03), liver mets (p=0.05) and KDM6A GA (p=0.04) with anorexia. Hyperglycemia was associated with higher BMI, DM, lower NLR, male sex (all p<0.01). Higher BMI and lower NLR were associated with more Tx modifications in 203 pts (p<0.05). In MVA, MLL2 GA was associated with cytopenias (p=0.05) and KDM6A with anorexia (p=0.02).

Conclusions

In EV-treated aUC pts, clinical variables and certain somatic GA were associated with common EV AEs. These hypothesis-generating findings suggest a limited role of somatic GA in predicting EV AEs, warranting further investigation of host and tumor-related factors underlying EV toxicity.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Nizam: Financial Interests, Personal, Advisory Board: AVEO Pharmaceuticals, Inc.; Financial Interests, Personal, Invited Speaker: Cleveland Clinic Foundation; Financial Interests, Personal, Other: Aptitude Health, Inc.; Non-Financial Interests, Member: American Society of Clinical Oncology / Association for Clinical Oncology PAC. O. Alhalabi: Financial Interests, Personal, Advisory Board: Seagen, Silverback therapeutics, Cardinal health; Financial Interests, Personal, Invited Speaker: Curio Science; Financial Interests, Local PI: Ikena Oncology, Arcus Biosciences; Financial Interests, Institutional, Local PI: AstraZeneca; Non-Financial Interests, Principal Investigator: Genentech. A. Basu: Financial Interests, Personal, Speaker, Consultant, Advisor: Sanofi Aventis, EMD Serono, Bristol Myers Squibb, Dendreon, Astellas, Eisai, Inc., Seattle Genetics; Financial Interests, Personal, Other: Eisai, Inc., Natera, Inc., Aveo Pharmaceuticals, Inc.; Financial Interests, Institutional, Research Funding: Natera, Inc., Merck, Pfizer, Rubius Therapeutics, Genentech, Bristol Myers Squibb, Aveo Pharmaceuticals, Inc., Daiichii Sankyo. C.J. Hoimes: Financial Interests, Personal, Advisory Board: Astellas, BMS, Foundation Medicine, Merck &Co, Seagen, Tempus; Financial Interests, Personal, Invited Speaker: BMS, Eisai; Financial Interests, Institutional, Advisory Board: Dynavax; Financial Interests, Institutional, Local PI: AbbVie, Alkermes, Astellas, BMS, Bayer, Bellicum, BioNTech, Dynavax, Genentech, Janssen, Mirati, NeoImmune Tech, Pfizer, Phosplatin, Prometheus; Financial Interests, Personal and Institutional, Steering Committee Member: Merck &Co, Seagen. Y. Zakharia: Financial Interests, Personal, Advisory Board: Pfizer, Eisai, Exelixis, Myovant, BMS. M.I. Milowsky: Financial Interests, Personal, Stocks or ownership: Pfizer, Merck, Gilead Sciences; Financial Interests, Personal, Advisory Role: Loxo/Lilly; Financial Interests, Institutional, Research Funding: Merck, Roche/Genentech, Bristol Myers Squibb, Mirati Therapeutics, Incyte, Seagen, G1 Therapeutics, Alliance Foundation Trials, Alliance for Clinical Trials in Oncology, Clovis Oncology, Arvinas, ALX Oncology, Loxo, Hoosie Cancer Research Network; Other, Personal, Other: Elsevier, Medscape, Research to Practice. D. Kilari: Financial Interests, Personal, Invited Speaker: Astellas, Janssen, Pfizer, Aveo oncology; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Institutional, Coordinating PI: Exelixis, Genentech; Financial Interests, Institutional, Local PI: Jounce. N.B. Davis: Financial Interests, Personal, Other, Chair, IDMC: Janssen Biotech; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, AstraZeneca, Merck, Gilead Sciences, Roche, Seagen, Exelixis, Immunomedics, Calithera Biosciences, Mirati Therapeutics, Pfizer, Incyte. H. Emamekhoo: Financial Interests, Personal, Advisory Board: Seattle Genetics, Janssen, Aveo, Cardinal Health. S. Gupta: Financial Interests, Personal, Advisory Board: Seattle Genetics, BMS, Pfizer, Bayer, Merck, Gilead, Loxo Oncology, Guardant, Foundation one; Financial Interests, Personal, Other, Speaker's Bureau: Janssen; Financial Interests, Personal, Other, Consultant: EMD Sorono; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Stocks/Shares: BioNTech, Moderna; Financial Interests, Personal, Steering Committee Member: BMS, Merck, Seattle Genetics, Acrivon; Financial Interests, Institutional, Local PI: EMD Sorono, Gilead, Roche, QED, Exelixis, Moderna. J. Bellmunt: Financial Interests, Personal, Advisory Board, Joined the Global adboard this year: Pfizer; Financial Interests, Personal, Advisory Board, Regular GU adboard for bladder cancer: AstraZeneca; Financial Interests, Personal, Invited Speaker, Lectures in the setting of National meetings: Merck; Financial Interests, Personal, Advisory Board, Bladder adboard: Merck; Financial Interests, Personal, Advisory Board, For the adjuvant study CM 247: BMS; Financial Interests, Personal, Invited Speaker, For ESMO Asia Symp 2020: MSD; Financial Interests, Personal, Stocks/Shares, Holdings: Bicycle; Financial Interests, Personal, Royalties, Role as Section Editor for Bladder: UpToDate; Financial Interests, Institutional, Coordinating PI, Pi of INDUCOMAIN Study (Avelumab first line in unfit patients) Though APRO Association: MSD; Financial Interests, Institutional, Coordinating PI, Pi of Prostate Study (Avelumab + Carboplatin) Though APRO Association: Pfizer; Non-Financial Interests, Other, Steering committee member of IMvigor 011: Genentech; Non-Financial Interests, Member: ASCO. P. Grivas: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Bristol Myers Squibb, Asieris Pharmaceuticals, Merck KGaA, Seattle Genetics, Aadi Bioscience, Pfizer, Janssen, Boston Gene, Mirati Therapeutics, Exelixis, Genentech/Roche, Gilead Sciences, CG Oncology, Dyania Health, Infinity Pharmaceuticals, QED Therapeutics, 4D Pharma PLC, ImmunityBio, Lucence Health, G1 Therapeutics, Fresenius Kabi, Guardant Health, PureTech, Regeneron Pharmaceuticals, Strata Oncology, Urogen, Silverback Therapeutics, Astellas Pharma; Financial Interests, Institutional, Local PI: Pfizer, Clovis Oncology, Bavarian Nordic, Gilead Sciences, Bristol Myers Squibb, Debiopharm Group, MSD, QED Therapeutics, GSK, Mirati Therapeutics, G1 Therapeutics, Merck KGaA. M.T. Campbell: Financial Interests, Personal, Advisory Board: Exelixis, Pfizer, Seagen, AstraZeneca, Curio Science, Eisai; Financial Interests, Institutional, Local PI: Pfizer, Aravive, Seagen; Financial Interests, Institutional, Coordinating PI: Exelixis, Janssen. A. Alva: Financial Interests, Personal, Advisory Role: AstraZeneca, Merck, Pfizer, Bristol Myers Squibb; Financial Interests, Personal, Other: Merck, Bristol Myers Squibb; Financial Interests, Institutional, Research Funding: Genentech, Bristol Myers Squibb, Merck Sharpe & Dohme, Prometheus Laboratories, Mirati Therapeutics, AstraZeneca, Roche, Bayer, Astellas Pharma, Arcus Biosciences, Progenics, Celgene, Janssen. V.S. Koshkin: Financial Interests, Personal, Advisory Board: Janssen, Clovis, Astellas, AstraZeneca, Pfizer, EMD Serono; Financial Interests, Personal, Other, Consulting: GLG, ExpertConnect, Guidepoint; Financial Interests, Institutional, Local PI: Merck, Taiho, Eli Lilly, Clovis, Novartis; Financial Interests, Institutional, Steering Committee Member: Seagen; Financial Interests, Personal and Institutional, Research Grant: Prostate Cancer Foundation. All other authors have declared no conflicts of interest.