2360O - The double antibody drug conjugate (DAD) phase I trial: Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) as ≥ second-line therapy for metastatic urothelial carcinoma (mUC)

Background

Antibody-drug conjugates are a mainstay in treatment of mUC. Given different targets, payloads with non-overlapping toxicities and preclinical synergy of SG with anti-microtubule agents, we evaluated the safety and efficacy of SG+EV in a phase I trial (NCT04724018).

Methods

Patients (pts) with mUC and ECOG ≤1 who progressed on platinum and immunotherapy or were cisplatin ineligible and received one line of therapy were enrolled. SG+EV were dosed D1,8 of a 21-day cycle until progression of unacceptable toxicity. To assess the feasibility and safety of combining SG+EV, doses were adjusted based on the incidence of dose-limiting toxicities (DLTs) during cycle(C) 1 and the total number of pts treated at four pre-specified dose levels (DL) using a Bayesian Optimal Interval design (Table). Adverse events (AE) were assessed using CTCAE 5.0.

Results

24 pts were enrolled (9 DL1, 9 DL2, 6 DL3) from 5/2021 to 4/2023. At data cutoff on May 1, 2023, 23 pts were evaluable for DLT assessment; one pt in DL3 never started therapy. Median age was 69 years (range 41-88); 22 received ≥ 2 lines of therapy. After 2 pts in DL1 experienced febrile neutropenia (FN) prophylactic granulocyte stimulating factor (GCSF) was permitted; 18 pts received GCSF. 70% pts experienced ≥ grade 3 AE at any DLs with one grade 5 AE (pneumonitis possibly related to EV) during C2 (pt in DL3.) The table summarizes DLTs at corresponding DLs; DL2 has been selected for future studies. Among 21 pts evaluble for response, objective response rate was 71% (15/21, 90% Confidence interval: 51-87) with 2 complete and 13 partial responses; 2 pts had progressive disease. With median follow-up 11.9 months, 11/15 responses are ongoing from 1.1+ to 21.6+ months. Table: 2360O

Conclusions

SG+EV was safe with an ORR of 71% in pts with treatment refractory UC. Further DAD expansion cohorts in treatment refractory and naïve setting are in development; triplet therapy with immunotherapy is being explored.

Clinical trial identification

NCT04724018.

Editorial acknowledgement

Legal entity responsible for the study

Dana Farber Cancer Institute.

Funding

Gilead.

Disclosure

B.A. McGregor: Financial Interests, Personal, Advisory Board: Exelixis, BMS, Dendreon, SeaGen, Astellas, Eisai, Pfizer; Financial Interests, Personal, Invited Speaker: EMD Serono, SeaGen; Financial Interests, Institutional, Trial Chair: Pfizer, Exelixis, Exelixis, BMS, Gilead; Financial Interests, Institutional, Local PI: Calithera, SeaGen, Aveo; Non-Financial Interests, Member: ASCO. G.P. Sonpavde: Financial Interests, Personal, Advisory Board: EMD Serono/Pfizer, Bristol Myers Squibb, Genentech, Merck, Sanofi, Seattle Genetics, Exelixis, Janssen, Bicycle Therapeutics, Immunomedics/Gilead, Scholar Rock, G1 Therapeutics, Loxo Oncology, Lucence, Tempus, Syapse; Financial Interests, Personal, Advisory Board, Editor of Bladder cancer virtual center of excellence for Practice Update: Elsevier; Financial Interests, Personal, Other, Member of Data Safety Monitoring Board: Mereo; Financial Interests, Personal, Other, Author of chapter: Uptodate; Financial Interests, Personal, Invited Speaker: Research to practice, Seattle Genetics, Gilead, Exelixis, Janssen; Financial Interests, Personal, Advisory Board, to develop a trial in bladder cancer: Servier Pharmaceuticals; Financial Interests, Institutional, Research Grant: Sanofi, Gilead, QED, Predicine, EMD Serono, Jazz Pharma; Non-Financial Interests, Principal Investigator, Steering committee of trial: Bristol Myers Squibb; Non-Financial Interests, Principal Investigator: G1 Therapeutics; Non-Financial Interests, Leadership Role, steering committee of trial: QED; Non-Financial Interests, Other, steering committee of trial: Merck; Other, Spouse employment: Myriad Genetics. X. Gao: Financial Interests, Personal, Advisory Board: Bayer, Flare Therapeutics, Silverback Therapeutics, PureTech, Myovant Sciences, PathAI; Financial Interests, Institutional, Local PI: Arvinas, Exelixis, Harpoon Therapeutics, Aprea Therapeutics, Takeda, Aravive, Merck, Poseida Therapeutics, TopAlliance BioSciences, Novartis, Regeneron, ALX Oncology; Financial Interests, Institutional, Coordinating PI: Bayer. C. Mantia: Financial Interests, Personal, Advisory Board, I participated in a one-time advisory board: Aadi Bioscience; Financial Interests, Institutional, Coordinating PI, Institutional funding for research: Bristol Myers Squibb. X.X. Wei: Financial Interests, Personal, Advisory Board: novartis; Financial Interests, Institutional, Coordinating PI: Bristol Myers Squibb. J.E. Berchuck: Financial Interests, Personal, Invited Speaker, Speaker honoraria: Guardant; Financial Interests, Personal, Advisory Board, Consulting fees: Genome Medical, Oncotect, Precede, TracerDx; Financial Interests, Personal, Writing Engagement: Digital Science Press; Financial Interests, Personal, Stocks/Shares: Cityblock Health, Genome Medical, Oncotect, Precede, TracerDx. M.D. Michaelson: Financial Interests, Personal, Advisory Board: Merck, Eisai, Exelixis, Janssen. T.K. Choueiri: Financial Interests, Personal, Advisory Board, Advice on GU/RCC drugs: BMS, Pfizer, Merck, Exelixis, AstraZeneca; Financial Interests, Personal, Advisory Board, Advice on Onc drugs: Lilly, EMD Serono, Infinity; Financial Interests, Personal, Advisory Board, Advice on RCC drug: Calithera; Financial Interests, Personal, Invited Speaker, RCC drug: Ipsen; Financial Interests, Personal, Advisory Board, Advice on GU Onc drugs: Surface Oncology; Financial Interests, Personal, Other, Consultant on onc drugs: Analysis Group; Financial Interests, Personal, Invited Speaker, CME, ww2.peerview.com: Peerview; Financial Interests, Personal, Invited Speaker, CME, gotoper.com: PER; Financial Interests, Personal, Invited Speaker, CME, researchtopractice.com: ResearchToPractice; Financial Interests, Personal, Invited Speaker, National Association of Managed Care: NAMC; Financial Interests, Personal, Invited Speaker, ASCO-related event: ASCO-SITC; Financial Interests, Personal, Other, Grant review to Orien Network: Orien; Financial Interests, Personal, Advisory Board, Advising oncology strategy: Aptitude Health; Financial Interests, Personal, Invited Speaker, Best of ASCO19 talk: Advent health; Financial Interests, Personal, Invited Speaker, Best of ESMO20 talk: UAE Society of Onc; Financial Interests, Personal, Invited Speaker, CME, mjhlifesciences.com (OncLive): MJH life sciences; Financial Interests, Personal, Invited Speaker, Grand Rounds: MDACC; Financial Interests, Personal, Invited Speaker, RCC webinar: Cancernet; Financial Interests, Personal, Invited Speaker, CME, Kidney Cancer Association: France Foundation; Financial Interests, Personal, Invited Speaker, CME, RCC: Springer, WebMed; Financial Interests, Personal, Invited Speaker, CME, ImmunoOncology in RCC: ASiM, CE; Financial Interests, Personal, Invited Speaker, CME, PodCast in RCC: Caribou Publishing; Financial Interests, Personal, Invited Speaker, Reimbursement: Kidney Cancer Association; Financial Interests, Personal, Other, member of the DSMB for clinical trial: Aravive; Financial Interests, Personal, Other, on the DMC of clinical trial: Aravive; Financial Interests, Personal, Advisory Board, GU cancer drug development: alkermes, Gilead; Financial Interests, Personal, Member of Board of Directors, unpaid: ACCRU; Financial Interests, Personal, Member of Board of Directors, Unpaid: KidneyCan; Financial Interests, Personal, Other, External Advisory Board Member: Gustave Roussy; Financial Interests, Personal, Stocks/Shares: Pionyr (not publicly traded), Tempest (publicly traded), Osel (not publicly traded), Nuscan (not publicly traded), Curesponse; Financial Interests, Personal, Royalties, For writing and updating chapters in GU Oncology: Up-To-Date online textbook; Financial Interests, Institutional, Funding, National Chair: BMS, Merck, Takeda, Exelixis, AstraZeneca, Tracon, Peloton; Financial Interests, Institutional, Local PI: Roche, Surface Oncology, GSK; Financial Interests, Institutional, Funding, National Co-Chair: Pfizer, EMD-Serono; Financial Interests, Institutional, Funding, Chair of trial: Lilly; Financial Interests, Institutional, Funding, SC member: Eisai; Financial Interests, Institutional, Funding, National co-chair on 3 ongoing trials: ALLIANCE Cooperative Group; Financial Interests, Institutional, Research Grant, for GU oncology translational research through IION program: BMS; Financial Interests, Institutional, Research Grant, for GU oncology translational research: Exelixis; Financial Interests, Institutional, Research Grant, For Health outcomes research: Roche; Financial Interests, Institutional, Local PI, leads trials as PI: Nikang; Non-Financial Interests, Leadership Role, Co-Chair of the meeting, 2019: Kidney Cancer Research Summit of KidneyCAN; Non-Financial Interests, Principal Investigator, Trial Global and National PI with GU Cancers, mostly Kidney Cancer: Multiple Academic and Industry entities; Non-Financial Interests, Personal, Other, Track Leader/Session chair/Speaker/Discussant: ASCO; Non-Financial Interests, Personal, Other, Speaker/Discussant/Track Leader: ESMO; Non-Financial Interests, Institutional, Other, Access to genomic database: Foundation Med, Guardant, Invitae; Non-Financial Interests, Member: ASCO, AACR; Non-Financial Interests, Personal, Other, Grants reviewers: AACR; Non-Financial Interests, Personal, Other, Reviewer of papers: Various journals (e.g. NEJM, Lancet, JCO); Non-Financial Interests, Personal, Other, Medical writing and editorial assistance support (e.g. ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, pharmagenesis, and others). However, first draft frequently initiated by myself when I am 1st author: Medical Communication; Non-Financial Interests, Other, Political vote usually as “independent”, not a member of any political party. I am an issue voter: General US Politics; Other, Employee at DFCI. I am also the past President of Medical Staff at DFCI 2015-2018: Dana-Farber Cancer Institute (DFCI); Other, Professor (non-profit school): Harvard Medical School (HMS); Other, No financial interest. Institutional. Filed patents related to biomarkers of immune checkpoint blockers, and circulating free methylated DNA. No money made and some patents were abandoned: Filed patents. 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. All other authors have declared no conflicts of interest.