A pilot study of tremelimumab (treme) with or without cryoablation (cryo) in patients (pts) in metastatic renal cell carcinoma (mRCC)

Abstract Background Cryo is an effective intervention for palliation and local control for small primary and metastatic tumours in mRCC. Pre-clinical murine tumour modeling found cryo recruits effector immune cells and synergizes with anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) to inhibit tumour rechallenge as compared to either therapy (tx) alone, leading to a prospective pilot study evaluating safety/tolerability. Methods NCT02626130 randomized pts to treme (CTLA-4) 10mg/kg every 4 weeks alone (arm A) or after cryo (arm B) for two doses followed by surgery (sx) or biopsy (bx) followed by maintenance treme. Best confirmed responses (ORR) were defined using RECIST v1.1, toxicity (tox) tabulated using CTCAE v4 with ≥ grade 3 adverse events (AE) possibly related reported, and time on study was defined as event free survival (EFS). Immune monitoring data (IMD): tissue based IHC, CyTOF, and RNA Nanostring. Results 30 pts accrued, 29 pts received tx on study. More patients in Arm B had intermediate and poor risk disease as per IMDC criteria and had received >1 line of treatment as compared to Arm A leading to an imbalance between arms. Toxicity on study was similar between arms with six patients on each arm requiring treatment discontinuation due to AEs. IMD found clear cell histology (CC) had an inflamed tumor microenvironment (TME) with increased immune infiltration (IC) post treme in both arms compared to non-clear cell (NCC). CyTOF analysis identified an activated CD4+ T cell cluster expressing ICOS in the TME of CC pts compared to NCC. Conclusions Cryo+treme was tolerated similar to treme alone. IMD found a differential TME response to treme in CC vs NCC pts and in EFS >3 mo vs EFS Table . 963P Arm A n = 14 Arm B n = 15 Histology Clear cell (CC) Non-clear cell (NCC) 9 5 9 6 IMDC Good (CC/NCC) Intermediate Poor 4 (4/0) 9 (5/4) 1 (0/1) 0 11 (6/5) 4 (3/1) Prior nephrectomy 7 (50%) 5 (33%) Prior treatment 0 1 >1 10 2 2 10 0 5 Tissue collected 6 sx, 4 bx, 4 no tissue 5 sx, 4 bx, 6 NT ORR All (CC/NCC) PR SD PD Not measurable 0 9 (7/2) 3 (2/1) 2 (0/2) 1 (1/0) 4 (3/1) 5 (1/4) 5 (4/1) EFS mo (Arm A v Arm B) 4.9 vs 3.2 (HR 0.73, 95%CI 0.35-1.58) EFS mo (CC v NCC) 3.3 vs 2.9 (HR 1.16, HR 95%CI 0.54-2.51) EFS > 6 mo, #pts, (range) Arm A: 4 (7.6-29.9), Arm B: 3 (6.3-30.3) EFS> 6 mo (range) CC v NCC CC: 4 (11.7-30.3), NCC 3 (6.3-7.8) Clinical trial identification NCT02626130. Legal entity responsible for the study The authors. Funding AztraZeneca. Disclosure M.T. Campbell: Honoraria (self): Pfizer; Honoraria (self): Genentech; Honoraria (self): Apricity Health LLC; Advisory / Consultancy: EMD Serono, Inc; Advisory / Consultancy: Genentech, Inc. E. Jonasch: Research grant / Funding (self), Research grant / Funding (institution): Exelixis; Research grant / Funding (self), Research grant / Funding (institution): Novartis; Research grant / Funding (self), Research grant / Funding (institution): Peloton; Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Eisai; Honoraria (self): Exelixis; Honoraria (self): Genentech; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche. A.Y. Shah: Honoraria (self): Eisai; Honoraria (self): Oncology Information Group; Honoraria (self): Roche Pharmaceuticals; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): BMS; Research grant / Funding (institution): EMD Serono. All other authors have declared no conflicts of interest.