Denosumab and Pembrolizumab in Clear Cell Renal Carcinoma

Inclusion Criteria: * Adults, aged 18 years and older, with histologically confirmed unresectable or metastatic renal cell carcinoma with a clear cell component * Disease progression during or after VEGFR TKI treatment * At least 1 target lesion according to RECIST v1.1 * ECOG performance status of 0-2 * Adequate bone marrow function (done within 14 days prior to registration * Haemoglobin ≥ 90g/L * Platelet ≥ 75x109/L * Neutrophil count ≥ 1.5x109/L * Adequate liver function (done within 14 days prior to registration and with values within the ranges specified below): * Bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome * AST or ALT ≤ 3.0 x ULN (or ≤ 5.0x ULN in the presence of liver metastases) * Adequate renal function (done within 14 days prior to registration and with values within the ranges specified below): * Creatinine ≤ 1.5x ULN OR * Creatinine clearance (CrCl) ≥ 30mL/min * Serum calcium or albumin-adjusted serum calcium ≥2.0 mmol/L * Tumour tissue available for tertiary correlative studies * Willing and able to start treatment within 14 days of registration, and to comply with all study requirements, including the timing and/or nature of the required treatment and assessments * Signed, written informed consent Exclusion Criteria: * Prior treatment with pembrolizumab, or with any other anti-PD-1, anti-PD-L1, Anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways * Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. * Any condition requiring systemic treatment with either corticosteroids (\>10mg daily prednisone or equivalent dose of alternative corticosteroid) or other immunosuppressive medications within 14 days of pembrolizumab administration. Intranasal, inhaled or topical steroids are permitted in the absence of active autoimmune disease. * Prior treatment with denosumab. * Untreated brain or leptomeningeal metastases or current clinical or radiological progression of known brain metastases, or requirement for steroid therapy for brain metastases. Patients with treated brain metastases are eligible if they have been stable and off steroids for ≥ 3 weeks. * Prior allogeneic organ transplant, inflammatory bowel disease, pneumonitis, tuberculosis, or primary immunodeficiency * Active infection requiring systemic therapy within 14 days before the first dose of pembrolizumab * Receipt of live attenuated vaccination within 30 days of the planned first dose of pembrolizumab * Active dental or jaw condition that precludes administration of denosumab: i) Significant dental/oral disease, including prior history or current evidence of osteonecrosis/osteomyelitis of the jaw, or; ii) Active dental or jaw condition which requires oral surgery, or; iii) Non-healed dental/oral surgery, or; iv) Planned invasive dental procedures during the course of the study * Clinically significant hypersensitivity to denosumab or any components of denosumab * Targeted small molecule therapy, surgery or radiation therapy within 2 weeks before registration, or persisting adverse event(s) of Grade 2 or more due to a previously administered agent. Note that participants who have had recent major surgery must have recovered adequately before registration. * Life expectancy of less than 3 months. * History of an active malignancy within the previous 5 years, except for locally curable cancers that have been apparently cured, such as low-grade thyroid carcinoma, prostate cancer not requiring treatment (Gleason grade ≤ 6), basal or squamous cell skin cancer, superficial bladder cancer, melanoma in situ, or carcinoma in situ of the prostate, cervix, or breast. Patients who have been free of other malignancies for ≥ 5 years prior to registration are eligible for this study. * Significant infection, including chronic active hepatitis B, hepatitis C, or HIV. - Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol * Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception. Subject is excluded if pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment. Female subject of child bearing potential is excluded if they are not willing to use, in combination with her partner, highly effective contraception during treatment and for 5 months after the end of treatment.