BM occur in 30% of patients (pts) with mRCC and are associated with symptomatic skeletal events (SSE) and worse outcomes with vascular-endothelial growth factor (VEGF)-targeted agents. Rad is a bone-seeking α-emitter that targets BM. We investigated the safety, efficacy and bone turnover markers (BTM) of Rad combined with P or S in pts with mRCC and BM.
30 pts received therapy (15 treatment-naïve pts: P 800 mg/d +Rad; 15 treatment-refractory: S 400 mg BID +Rad). Rad was administered monthly for up to 6 infusions. The primary endpoint was BTM. Secondary endpoints included safety, SSE rate, time to SSE, objective response rate (ORR), narcotic use and survival.
Of the 30 pts, 70% had clear cell histology, 17% were IMDC poor risk and 33% had liver metastases. Prior SSEs were reported in 100% and 65% of pts in the P and S cohorts, respectively. 1 pt had received denosumab. Median changes in BTM at cycle 2 and 4 compared to baseline are summarized in table and show declines in all BTMs. Best ORR by RECIST was partial response (PR) in 13% and stable disease (SD) 47%. Achieving > =50% decline in PINP at cycle 2 was associated with PR and SD (Fisher’s exact p-value 0.01). Median treatment duration was 3.6 mo (IQR 1.5, 5.5). Progression-free survival was 8.2 mo [95%CI 5.6, NR] and 4.6 mo [95%CI 2.1, NR] in pts treated with P and S. Overall survival was 11.9 mo [95%CI 7.8, NR] and 8.7 mo [95%CI 6, NR], respectively. Overall rate of SSE on study was 47%; 67% in the P cohort (median time to SSE 6.3 mo [95%CI 3.6, NR]) and 27% in the S cohort (median time to SSE NR [95%CI 6.6 mo, NR]). There was no dose-limiting toxicity. The rate of treatment-related grade ≥3 toxicity was 39.3% including 3.6% grade 3 anemia.
Rad combined with P or S is safe and well tolerated. All BTMs significantly declined with Rad combined with P or S suggesting biologic activity in mRCC with BM. Randomized trials are needed to evaluate the role of Rad on SSE prevention in these pts.Table:
|BTM||Baseline (IQR) N = 30||% change at cycle 2 median (IQR) N = 21||% change at cycle 4 median (IQR) N = 18|
|Bone-specific alkaline phosphatase (BALP)||11 (9, 16) ug/mL||−17 (-36, -7)||−23 (-32, -7)|
|Osteocalcin (OC)||16 (12, 19) ng/mL||−33 (-45, -21||−49 (-52, -31)|
|N-terminal propeptide of procollagen type I (PINP)||46 (30, 66) ug/mL||−57 (-63, -29)||−63 (-69, -44)|
|C-terminal cross-linked telopeptide of type I collagen (CTX)||432 (210, 595) pg/mL||−37 (-51, -1)||−34 (-49, -22)|
|N-terminal cross-linked telopeptide of type I collagen (NTX)||15 (11,21) nM BCE||−28 (-43, -7)||−28 (-43, -15)|
Clinical trial identification
Clinical trial information NCT02406521
Legal entity responsible for the study
Dana-Farber Cancer Institute
R.R. McKay: Research funding from Bayer and Pfizer. M.D. Michaelson: Advisory honoraria received from Novartis, Exelixis and Pfizer. H. Jacene: Research funding GTx, Inc, Seimens Healthcare. J. Bellmunt: Reports research support from Novartis and Sanofi; consulting support from OncoGenex, AstraZeneca, Merck, Bristol Myers-Squibb, Genentech, Inovio, Champions Oncology, Seattle Genetics and Pierre Fabre. L.C. Harshman: Advisory board of Genentech, Pfizer, Dendreon, NCCN, Medivation, Kew and has received research funding/support from Bayer, Medivation/Astellas, Pfizer, Dendreon, Sotio, Genentech, Merck, Bristol-Myers Squib, Jannsen. T.K. Choueiri: Received institutional research funding from Pfizer, exelixis, Bristol-Myers Squib, Novartis, and has an advisory role at Pfizer, Novartis, Genentech, Merck, Bristol-Myers Squib and Bayer. The remaining authors have no disclosures. All other authors have declared no conflicts of interest.