Phase 1 dose‐escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma

Abstract

BACKGROUND: On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated. METHODS: Adult patients with mRCC who had received 1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. RESULTS: Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n ¼ 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. CONCLUSIONS: In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses >6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity. Cancer 2011;117:758-67.

Coinhibitory Pathways in Immunotherapy for Cancer

“…Conversely, patients who received vemurafenib after ipilimumab or PD-1 blockade experienced pronounced drug hypersensitivity reactions (186,187). High rates of renal toxicity were observed when sunitinib was combined with tremelimumab in metastatic renal cell carcinoma (188), whereas combination of nivolumab with sunitinib or pazopanib appeared to be well tolerated in early studies (189). Combination of tremelimumab with aromatase inhibition for breast cancer or with androgen deprivation for prostate cancer was also well tolerated, with evidence of biologic activity (190,191).…”

Immunotherapy of Renal Cell Carcinoma

“…Pro přehlednost ještě zmíníme jinou anti-CTLA-4 protilátku -tremelimumab, který se ve studii fáze I zkoušel v kombinaci se sunitinibem u pa cientů s mRCC. Studie však byla předčasně zastavena pro časné vý-skyty renálních selhání, RR však byl až 43 % [23]. Nově se zkouší tremelimumab v neoadjuvantním podání v kombinaci s anti-PD-L1 protilátkou -durvalumabem (studie fáze I, NCT02762006).…”

Immuno-oncology Combinations: A Review of Clinical Experience and Future Prospects

“…82). It is also noteworthy that dose-limiting toxicities have been observed in patients with RCC treated with the targeted agent sunitinib and either rhIL21 (hematologic toxicity) or the anti-CTLA-4 agent tremelimumab (renal failure), further emphasizing the need for caution when evaluating combinations (83,84).…”