Background

Bladder cancer with HER2 high expression is related to pathological malignancy and poor prognosis. The standard care for muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy. For HER2 positive MIBC, the efficacy of cisplatin- based NAC are unsatisfied. This study aims to evaluate the safety and efficacy of RC48-ADC, an anti-HER2 antibody conjugation, and tislelizumab as a novel neoadjuvant treatment in this population.

Methods

The enrollment of this Ib/II, multi-center,study are 51 patients with cT2-4bN0-3M0-1a pathological and imaging diagnosed HER2 positive (Immunohistochemistry status 3+ or 2+ or 1+) MIBC. Of them, 6 patients are enrolled in the dose-escalation phase, and 45 patients enter into phase II study (the expected phase II dose for RC48-ADC is 2.0mg/kg). RC48-ADC is given every 2 weeks with a maximum dose of 120mg, and tislelizumab is given every three weeks at the dose of 200mg. Treatment efficacy will be performed by computed imaging and transurethral resection of tumors 4 months later. Patients will receive radical cystectomy or bladder-sparing therapies as their will after neoadjuvant treatment. The primary endpoints are clinical complete remission rate (cCR, T0/Ta/Tis), pathological complete remission rate (PCR) and safety.

Results

Until now, 6 patients are included, and the enrollment is currently ongoing. The median age is 62 years old. Of them, 5 patients are HER2(2+), and 1 patient is HER2(1+). The clinical stages are T3-4aN0-3M0. Four patients have the primary efficacy evaluation by now. Three patients are T0, and 1 patient is Tis. Hence the cCR rate is 100%. One patient suffered from immune-related adverse event, namely, Grade 2 myositis and Grade 1 elevated transaminase, which led to treatment interruption. And 3 patients experienced RC48-ADC related toxicities, including Grade 1 elevated transaminase, Grade 1 erythra and Grade 1 paresthesia. No treatment related dose reduction happened.

Conclusions

Neoadjuvant RC48-ADC combined with tislelizumab in patients with HER2 positive locally advanced MIBC initially shows satisfied efficacy and manageable toxicities, which will be verified by the final analysis.

Clinical trial identification

West China Hospital, Sichuan University (2022(546)) and Release Date (May 9th, 2022).

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

At the primary analysis of PROpel (NCT03732820; data cut-off [DCO]: 30/07/21), abi + ola significantly prolonged radiographic progression-free survival (rPFS) vs pbo + abi in 1L mCRPC (HR 0.66, 95% CI 0.54–0.81; P<0.0001). Overall survival (OS) trended towards a benefit with abi + ola vs abi + pbo (28.6% maturity; HR 0.86, 95% CI 0.66–1.12). We report biomarker analysis from the primary analysis and updated overall survival and safety data from a planned OS interim analysis (DCO2).

Methods

PROpel is a double-blind, pbo-controlled trial. 796 pts were randomized 1:1 to ola (300 mg twice daily [bid]) or pbo, and abi (1000 mg once daily) + prednisone or prednisolone (5 mg bid), irrespective of homologous recombination repair gene mutation (HRRm) status. The primary endpoint was rPFS by investigator assessment. OS was a key secondary endpoint. Aggregated results from tumour tissue (FoundationOne®CDx) and circulating tumour DNA (FoundationOne®Liquid CDx) tests were used to classify pts HRRm status.

Results

Pts with HRRm, including BRCAm, were balanced between treatment arms and rPFS favoured abi + ola for all biomarker subgroups, including pts with non-HRRm, HRRm and BRCAm status (HR 0.76, 0.50 and 0.23 respectively; Table). Sensitivity analysis of rPFS by blinded independent central review was consistent. At DCO2 (14/03/22) rPFS was consistent with the primary analysis (25.0 vs 16.4 months; HR 0.67, 95% CI 0.56–0.81). A trend towards improved OS with abi + ola vs abi + pbo continued (maturity 40%; HR 0.83; 95% CI 0.66–1.03). Safety and tolerability results remained stable.

Genes assessed were ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D and RAD54L
^†BRCA1 and/or BRCA2
ITT, intention-to-treat, NR, not reached
HRRm unknown pts (n=18) were excluded from the analysis.

Conclusions

Meaningful rPFS improvement of ≥5 months was observed with abi + ola vs abi + pbo in all assessed biomarker subgroups. Updated results show a continuing trend towards improved OS and support a superior clinical benefit with abi + ola vs abi + pbo as 1L therapy for pts with mCRPC.

Clinical trial identification

NCT03732820.

Editorial acknowledgement

Medical writing support was provided by Kirstin Spence, PhD, at Mudskipper Business Ltd., funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

AstraZeneca.

Funding

This study was supported by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA who are codeveloping olaparib.

Disclosure

M. Oya: Financial Interests, Personal, Advisory Role, Honoraria: Bayer; Financial Interests, Personal, Funding, Honoraria: Bristol Myers Squibb, Ono Pharmaceutical, AstraZeneca, Astellas, Takeda; Financial Interests, Personal and Institutional, Research Grant, Honoraria: Novartis, Pfizer. A.J. Armstrong: Financial Interests, Personal and Institutional, Advisory Role, Research funding: Janssen, Novartis, Myovant Sciences, Bayer, Dendreon, Merck, AstraZeneca, FORMA Therapeutics, Dendreon; Financial Interests, Personal, Advisory Role: Exelixis, GoodRx; Financial Interests, Personal and Institutional, Advisory Board, Research funding; Travel fees: Astellas Scientific and Medical Affairs Inc; Financial Interests, Personal, Advisory Role, Research funding: Pfizer, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Gilead Sciences, Roche/Genentech, Constellation Pharmaceuticals, Amgen; Financial Interests, Personal, Research Grant: BeiGene; Financial Interests, Institutional, Royalties: Circulating tumor cell novel capture technology. A. Thiery-Vuillemin: Financial Interests, Personal, Advisory Board, & public speaking: pfizer, astrazeneca, Janssen, Ipsen, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Sanofi, Novartis, Roche/Genentech, MSD, Astellas Pharma; Financial Interests, Institutional, Funding: pfizer, ipsen, bayer; Financial Interests, Institutional, Invited Speaker: Pfizer, AstraZeneca, Sanofi JNJ, Novartis, ipsen, roche, BMS, MSD, Astellas Pharma, excelixis, UNICANCER / GETUG, incyte; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, BMS; Non-Financial Interests, Personal, Member: ASCO, GETUG; Other, Personal, Other, Travel, Accommodations: Roche, MSD, JNJ, BMS, astrazeneca, pfizer, Astellas Pharma, Ipsen. N. Shore: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Foundation Medicine, Genesis Care Us, Invitae, Janssen, MDxhealth, Merck, Myovant, Myriad, Nymox, Pacific Edge, Pfizer, Phosphorous, Propella, PreView, Sanofi Genzyme, Speciality Networks, Sesen Bio, Tolmar, Urogen, Clarity, Lantheus, Lilly, Photocure, Telix, Sema4, Tempus, Photocure, Vaxiion, Asieris. G. Procopio: Financial Interests, Personal, Advisory Board, consultant fees: Astellas, AstraZeneca, Bayer, BMS, Janssen, Ipsen, Merck. MSD, Novartis, Pfizer; Financial Interests, Institutional, Research Grant, research funding for no profit clinical trial: Ipsen. Ç. Arslan: Financial Interests, Personal and Institutional, Advisory Role, Speaker's bureau; research funding; travel expenses: Amgen, AstraZeneca, Bristol Myers Squib, Janssen, Novartis; Financial Interests, Personal and Institutional, Advisory Role, Speaker's bureau; travel expenses: Pfizer, Teva; Financial Interests, Institutional, Research Grant: Incyte, Henlius, Yuhan, Lilly; Financial Interests, Personal and Institutional, Research Grant, Travel expenses: Merck. N. Mehra: Financial Interests, Personal, Advisory Board: Pfizer, Roche, MSD, AstraZeneca, Astellas, JNJ; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Funding: Astellas, Pfizer; Financial Interests, Personal and Institutional, Funding: Janssen; Financial Interests, Institutional, Invited Speaker: BMS, Janssen, BMS; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS; Non-Financial Interests, Personal, Leadership Role, Head of the Prostate Cancer Working group: Dutch Uro-Oncology Study Group; Non-Financial Interests, Personal, Principal Investigator, co-PI: Prospective Bladder Cancer Infrastructure (Netherlands); Non-Financial Interests, Personal, Leadership Role: Castration-resistant Prostate Cancer Registry. F. Parnis: Financial Interests, Personal, Advisory Role: Ipsen, Janssen Oncology, Merck Serono. F. Constans Schlurmann: Financial Interests, Personal, Advisory Role, Honoraria; travel expenses: AAA, AstraZeneca, Astellas, Bayer, BMS, Janssen, MSD, Pfizer. M. Sugimoto: Financial Interests, Personal, Research Grant, Honoraria; travel expenses: Janssen Pharmaceutical, AstraZeneca, Astellas Pharma; Financial Interests, Personal, Funding, Honoraria: Takeda Pharmaceutical; Financial Interests, Personal, Research Grant, travel expenses: BMS, MSD; Financial Interests, Personal, Research Grant: Pfizer; Other, Personal, Other, Travel expenses: Bayer. O. Sartor: Financial Interests, Personal and Institutional, Advisory Role, Research grant: Advanced Accelerator Applications, AstraZeneca, Bayer, Constellation, Janssen, Progenics, Tenebio; Financial Interests, Personal, Advisory Role: Astellas, Blue Earth Diagnostics, Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Dendreon, EMD Serono, Fusion, Isotopen Technologien Meunchen, Myovant, Myriad, Noria Therapeutics, Inc., Novartis, Noxopharm, POINT Biopharma, Pfizer, Sanofi, Telix, Theragnostics; Financial Interests, Institutional, Research Grant: Amgen, Endocyte, Invitae, Lantheus, Merck. Y. Liu: Financial Interests, Personal, Full or part-time Employment, Stocks: AstraZeneca. C.H. Poehlein: Financial Interests, Personal, Full or part-time Employment: Merck&Co. C. Desai: Financial Interests, Personal, Full or part-time Employment, Stocks: AstraZeneca. P.M.D. Del Rosario: Financial Interests, Personal, Full or part-time Employment, Stocks: AstraZeneca. N. Clarke: Financial Interests, Personal, Funding, Honoraria: Janssen, Bayer; Financial Interests, Personal, Advisory Board, Consulting fees; Advisory Board; Honoraria: AstraZeneca. F. Saad: Financial Interests, Personal, Advisory Board: Astellas, Bayer, BMS, Janssen, Sanofi, Pfizer, Myovant, Novartis; Financial Interests, Institutional, Invited Speaker: Novartis, Astellas, Bayer, Janssen, Sanofi, BMS, Amgen, Pfizer. All other authors have declared no conflicts of interest.