1886P - Pembrolizumab and denosumab in clear cell renal cell carcinoma (ccRCC): A phase II trial (KeyPAD, ANZUP1601)

Background

Anti-PD1 immune checkpoint inhibitors (ICI) are effective in some people with ccRCC. Preliminary data suggest inhibition of Receptor Activator of Nuclear Factor κB Ligand (RANKL) signaling may potentiate ICI. We evaluated the activity and safety of the RANKL-inhibitor denosumab (D) with pembrolizumab (P) in people with pretreated advanced ccRCC.

Methods

This single arm, multi-centre, phase 2 trial recruited participants (pts) with metastatic or unresectable ccRCC, progressing on or after vascular endothelial growth factor receptor inhibitors (VEGFi), and no prior treatment with an ICI or D. Study treatment was P 200mg IV q3w plus D 120mg SC on days 1, 8 and 22, then q3w until disease progression, unacceptable toxicity, or a maximum of 24 months. The primary endpoint was objective tumour response (OTR) per RECIST 1.1. Secondary objectives included median progression free survival (PFS), PFS at 6 months (PFS6), duration of response (DOR), and adverse events (AE). Biospecimens were collected for future correlative studies of immune and RANKL signaling.

Results

We recruited 59 of a planned 70 pts from Dec 2017 – Jul 2022; accrual was impacted by COVID-19. Pts were typical of this population; mostly male (81%), 48% International Metastatic Database Consortium favorable risk, one prior VEGFI in all pts, two or more prior agents in 16%. With median follow-up of 40 months in 58 evaluable pts, an OTR was documented in 31% (all partial; 95%CI 20-45%). Median DOR was 17 months. 53% of pts experienced PFS6 (95%CI, 39-65%), with mPFS 7.5 months. Immune related grade 3+ AE were reported in 20% of pts; study treatment discontinued for toxicity in 22%. One pt suffered G3 osteonecrosis of the jaw, one G3 hypocalcaemia. One pt died of myositis attributed to study treatment.

Conclusions

Compared to studies of anti-PD1 ICI in ccRCC progressing after VEGFi (Table), KeyPAD shows encouraging activity without overlapping toxicity, warranting further studies combining RANKL inhibitors like D with ICI like P.

Table: 1886P

Clinical trial identification

NCT03280667.

Editorial acknowledgement

Legal entity responsible for the study

ANZUP Cancer Trials Group.

Funding

Merck Sharpe Dohme and Amgen.

Disclosure

C. Gedye: Financial Interests, Personal, Advisory Board: Cadex Genomics, BCAL Diagnostics; Financial Interests, Institutional, Coordinating PI: BMS, Amgen, Merck Sharpe Dohme; Financial Interests, Institutional, Steering Committee Member: Ipsen. C.A. Harris: Financial Interests, Personal, Advisory Board: Pfizer, BMS, Astellas; Financial Interests, Personal, Other, Travel: Pfizer. M.R. Stockler: Financial Interests, Institutional, Research Grant, DASL: Bayer; Financial Interests, Institutional, Research Grant, Enzamet & Enzarad: Astellas; Financial Interests, Institutional, Research Grant, KEYPAD: Amgen, MSD; Financial Interests, Institutional, Research Grant, NIVORAD: BMS; Financial Interests, Institutional, Research Grant: Pfizer, Roche; Financial Interests, Institutional, Research Grant, ADELE: BeiGene; Financial Interests, Institutional, Research Grant, PARAGON2: Novartis; Financial Interests, Institutional, Other, Study Drug for Cannabis CINV Trial: Tilray. T. Ferguson: Financial Interests, Institutional, Local PI: MSD, AstraZeneca, Janssen, Pfizer, Eli Lilly; Non-Financial Interests, Advisory Role: MSD, Merck; Other, Other, Sponsorship for travel, accommodation and registration to attend 2023 ASCO Genitourinary Symposium: Bayer; Other, Other, Sponsorship for registration to (virtual meeting) 2021 ASCO ASM: MSD; Other, Other, Sponsorship for registration to (virtual meeting) 2022 ESMO meeting Sponsorship for registration to (virtual meeting) 2021 ASCO GUS: BMS. J.C.H. Goh: Financial Interests, Personal, Advisory Board, Prior member of the BMS RCC Advisory Board: BMS; Financial Interests, Personal, Advisory Board, Uterine Cancer Advisory Board: GSK; Financial Interests, Personal, Other, Chairing RCC meeting: Ipsen; Financial Interests, Personal, Invited Speaker, Speaking @ MSD sponsored event on Gynaecological cancer Speaking at MSD sponsored event on RCC: MSD; Financial Interests, Personal, Advisory Board, Met RCC Advisory Board: MSD/ Eisai; Financial Interests, Personal, Other, 1. Asia-Pacific Advisory Board member for prostate cancer2. Invited Speaker at AZ sponsored molecular/genomic testing meeting: AstraZeneca; Financial Interests, Personal, Stocks/Shares, Private Cancer Centres in Australia: ICON Cancer Centres; Financial Interests, Institutional, Funding, Funding for phase 2 metastatic cervical cancer trial: BeiGene; Non-Financial Interests, Principal Investigator, local PI for CHECKMATE-914, CHECKMATE-9KD trial, CHECKMATE-7DX & CHECKMATE-9ER trials: BMS. D. Pook: Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Advisory Board: BMS, MSD, Ipsen, Pfizer, Eisai, Astellas; Financial Interests, Institutional, Local PI: BMS, Astellas, Roche, MSD, Amgen; Financial Interests, Institutional, Coordinating PI: Pfizer, Ipsen. L.E.M. Krieger: Financial Interests, Personal, Advisory Board, Nubeqa / prostate cancer advisory board (local and international): Bayer; Financial Interests, Personal, Invited Speaker: Bayer, Ipsen; Financial Interests, Personal, Advisory Board, Bladder cancer advisory board: Astellas; Financial Interests, Personal, Advisory Board, Bladder cancer advisory boards: AstraZeneca; Financial Interests, Personal, Advisory Board, Bladder cancer advisory board (national and international): Merck; Financial Interests, Personal, Invited Speaker, Conference speaker: Merck; Financial Interests, Personal, Other, Steering committee member for prostate cancer national conferences: Janssen; Financial Interests, Personal, Advisory Board, Prostate cancer national board: Janssen; Financial Interests, Personal, Advisory Board, Renal carcinoma advisory boards (national and international): Ipsen; Financial Interests, Personal, Advisory Board, International advisory board: Telix; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board, National advisory board: Ferring, BMS; Financial Interests, Institutional, Local PI, Institutional support of Phase 2 / 3 clinical studies: Bayer; Financial Interests, Institutional, Local PI, Institutional support of phase 2 / 3 clinical studies: Roche, Astellas; Financial Interests, Institutional, Local PI, Institutional support of phase 2/ 3 clinical studies: Janssen; Financial Interests, Institutional, Local PI, Institutional support of phase 2/3 studies: Ipsen; Financial Interests, Institutional, Local PI, Institutional support of phase 2/3 clinical studies: Merck, BMS; Non-Financial Interests, Other, Review article publication: Janssen. A.J. Joshi: Financial Interests, Personal, Advisory Board: BMS, Ipsen, Novartis. D.S. Zebic: Financial Interests, Institutional, Invited Speaker, case presentation: use of tepotinib: Merck. A. Zhang: Financial Interests, Personal, Advisory Board: Merck Sharpe Serono, Astellas, Pfizer, Merck, Bayer, Janssen; Financial Interests, Personal, Invited Speaker: Merck Sharpe Serono, Astellas, Janssen, Ipsen, Mundipharma, Bayer; Non-Financial Interests, Principal Investigator: Astellas, Merck Sharpe Serono, TYRA therapeutics, BMS; Non-Financial Interests, Member: American Society of Clinical Oncology, Medical Oncology Group of Australia, Australia and New Zealand Urogenital and Prostate (ANZUP) grop. A.M. Joshua: Financial Interests, Personal, Stocks/Shares: Pricillium Therapeutics; Financial Interests, Institutional, Local PI, No financial interest: AstraZeneca, BMS, Eisai, Ipsen, Janssen, Merck Serono, Neolukin, Novartis, Noxopharm, Pfizer, Sanofi; Financial Interests, Institutional, Steering Committee Member, No financial interest: Iqvia; Non-Financial Interests, Advisory Role: AstraZeneca, Bayer, BMS, Corvus, Eli Lilly, Janssen, Macrogenics, Mayne, Merck, Pfizer, Roche. I.D. Davis: Financial Interests, Personal, Full or part-time Employment, Professor of Medicine and Head of Eastern Health Clinical School: Monash University; Financial Interests, Personal, Full or part-time Employment, Professor of Medicine; Head, Eastern Health Clinical School; medical oncologist: Eastern Health; Financial Interests, Personal, Royalties, Authorship royalties for: Health Press; Financial Interests, Personal, Other, Remuneration for associate editor role in Therapeutic Advances in Medical Oncology: SAGE; Financial Interests, Institutional, Local PI, Institutional support for clinical research: Movember Foundation, Merck/MSD, BMS, Exelixis, Astellas, Pfizer, AstraZeneca, Roche/Genentech, Eisai, Bayer, Janssen, Ipsen, Seagen; Non-Financial Interests, Member of Board of Directors, Director and Chair: ANZUP Cancer Trials Group; Non-Financial Interests, Advisory Role, All honoraria and payments are made directly to ANZUP Cancer Trials Group with no pass-through payment: Roche, Eisai, Pio Therapeutics, Xennials Therapeutics, Telix Therapeutics; Non-Financial Interests, Other, Member of Council: Clinical Oncology Society of Australia; Non-Financial Interests, Member: ASCO, Clinical Oncology Society of Australia, Medical Oncology Group of Australia, American Association for Cancer Research, Australian Academy of Health and Medical Sciences. All other authors have declared no conflicts of interest.