2369P - Phase II study of nivolumab (nivo) and ipilimumab (ipi) for advanced bladder cancer with variant histologies (BCVH)

Background

Patients (pts) with BCVH have poor outcomes. We previously reported an ORR of 37% in 19 patients with BCVH for the combination of nivo+ipi. Herein, we report the analysis of the fully accrued BCVH cohorts. (NCT 03333616).

Methods

Eligible pts had locally advanced unresectable or metastatic BCVH (>90% [JB1] variant histology) and ECOG performance status ≤2. Prior immunotherapy was prohibited; no limit on prior chemotherapy. Pts received nivo 3 mg/kg + ipi 1 mg/kg IV q3 weeks for 4 cycles followed by nivo 480 mg IV q4 weeks until unacceptable toxicity or progression. Primary endpoint was objective response rate (ORR) by RECIST 1.1.

Results

49 patients were enrolled from 4/2018 to 12/2022; including 19 pts previously reported; 30 pts were newly enrolled (including 7 from neuroendocrine cohort). 35 (71%) pts were treatment experienced. 28 (57%) pts received 4 doses of nivo+ipi and 24 pts received nivo maintenance: median number of cycles was 10.5 (range, 1-57). Median follow-up for surviving pts was 14.7 (range 1.4-56.7) months. ORR was 35% (80% CI, 26%-45%, N=17) (Table). Median duration of response was not reached; 9 pts maintained response > 12 months. 17 (35%) pts developed treatment-related grade ≥ 3 toxicities with one grade 5 toxicity; 3 pts had treatment unrelated grade 5 toxicities. 16 (33%) required high dose steroids (≥40 mg prednisone or equivalent). Table: 2369P

Response summary by tumor histologies

*Plasmacytoid N=2, Spindle Cell/Sarcomatoid N=4, Clear Cell N=2 CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, NE = Not Evaluable

Conclusions

The combination of nivo+ipi resulted in objective and durable responses in a subset of pts with BCVH notably with no responses in adenocarcinoma and 50% ORR in small cell carcinoma; toxicities were manageable. This is targeting an unmet need for these pts.

Clinical trial identification

NCT 03333616.

Editorial acknowledgement

Legal entity responsible for the study

Dana Farber Cancer Institute.

Funding

BMS.

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. 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. M.A. Bilen: Financial Interests, Personal, Advisory Board: Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera, Genomic Health, Nektar, EMD Serono, SeaGen, Sanofi; Financial Interests, Institutional, Local PI: Merck; Financial Interests, Institutional, Research Funding: Xencor, Bayer, BMS, SeaGen, Incyte, Nektar, AstraZeneca, Trilkon, Genome and Company, AAA. A. Mortazavi: Financial Interests, Personal, Other, Consultant: Targeted Oncology - Intellisphere, Llc; Financial Interests, Personal, Advisory Board: Pfizer, Seattle Genetics; Financial Interests, Institutional, Local PI, My institution (not me) has received research funding for conducting clinical trials: Seattle Genetics, Acerta Pharma, Genentech, Roche, Merck, Novartis, Astellas Pharma, Mirati Therapeutics, Bristol Myers Squibb, Debiopharm Group, GSK plc. A. Shah: Financial Interests, Personal, Advisory Board: Pfizer, Exelixis, BMS; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Local PI: BMS, Eisai, 4D Pharma; Financial Interests, Institutional, Coordinating PI: EMD Serono. D. Einstein: Financial Interests, Institutional, Trial Chair: Bristol Myers Squibb, Cardiff Oncology, Puma Biotechnology, MiNK Therapeutics; Financial Interests, Institutional, Research Grant: Novartis, Sanofi. 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. R.R. McKay: Financial Interests, Personal, Advisory Board: Aveo, AstraZeneca, Bayer, Calithera, Dendreon, Exelixis, JNJ, Merck, Pfizer, Sanofi, Tempus, BMS, Lilly, Sanofi, SeaGen, Telix, Sorrento Therapeutics; Financial Interests, Personal, Other, Molecular tumor board: Caris; Financial Interests, Personal, Other, Consultant: Dendreon, Myovant; Financial Interests, Personal, Invited Speaker: Exelixis, Merck, Novartis, Pfizer; Financial Interests, Steering Committee Member: Aveo, Merck, Eli Lilly; Financial Interests, Local PI: JNJ, SeaGen, Calibr, Poseida, Oncternal, Scholar Rock, Merck, Xencor, Genentech, Eli Lilly, BMS; Financial Interests, Trial Chair: Bayer, AstraZeneca; Financial Interests, Institutional, Local PI: Exelixis. A.O. Siefker-Radtke: Financial Interests, Personal, Other, Consulting/advisory fees: AstraZeneca; Financial Interests, Personal, Other, Consulting/advisory honorarium: Bavarian Nordic, Bristol Myers Squibb, Genentech, Gilead, Ideeya Biosciences, Immunomedics, Janssen, Loxo, Merck, Mirati, Nektar Therapeutics, Seattle Genetics, Taiho; Financial Interests, Institutional, Local PI, Clinical research trial: Basilea Pharmaceutica, Bristol Myers Squibb; Financial Interests, Institutional, Local PI, Clinical research trial: Janssen, Merck, Millennium, Nektar. 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. 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: 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, 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, 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. All other authors have declared no conflicts of interest.