Phase Ib study of pembrolizumab in combination with bevacizumab for the treatment of metastatic renal cell carcinoma: Big Ten Cancer Research Consortium BTCRC-GU14-003.

Abstract

559 Background: Renal cell carcinoma (RCC) tumor vasculature is abnormal and does not provide nutritive blood flow, which results in regions of hypoxia. This hypoxia contributes to the immune tolerance of tumor cells by impeding the homing of cytotoxic T cells into tumor parenchyma. In addition, tumor angiogenesis enhances activity of myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that suppress innate anti-cancer immunity. It has been demonstrated in preclinical models that antiangiogenic therapy decreased the number of MDSCs and changed polarization of TAMs from an immunosuppressive (M2-like) to an immunostimulatory (M1-like) phenotype. We hypothesized that therapy with bevacizumab will normalize the tumor vasculature, promote M1-like phenotype of TAMs, and thus potentiate the immunotherapeutic activity of pembrolizumab. As a prerequisite to testing this hypothesis, the objective of this study was to establish the safe dose of bevacizumab when used in combination with pembrolizumab. Methods: Our subject population included males and females (age > 18 y) with metastatic clear cell RCC after failure of at least one systemic therapy. In this Phase Ib dose escalation study, pembrolizumab (200 mg fixed dose every 3 weeks) was given in combination with bevacizumab (either at 10 mg/kg or 15 mg/kg every 3 weeks). The primary endpoint was to establish the maximum safe dose. Results: 12 subjects have been enrolled: 10 males (ages 33-68 y, mean: 52.7, median: 54.5) and 2 females (ages 61 and 62 y). To date 3 patients have received 1 cycle; 2 patients have received 2, 3, and 4 cycles each; and there are single patients who have received 5, 6, and 7 cycles each. No dose-limiting toxicity or serious adverse events related to the study drug have been reported. There were no grade 3 or 4 drug-related toxicities noted, and the most common grade 1 and 2 toxicities were diarrhea, fatigue, fever, hypertension, nausea, rash, and rigors. Conclusions: The 200 mg fixed dose of pembrolizumab and 15 mg/kg dose of bevacizumab, both given every 3 weeks, was determined to be safe and recommended for a multicenter Phase 2 study that is ongoing. Clinical trial information: NCT02348008.

The Future of Immunotherapy-Based Combination Therapy in Metastatic Renal Cell Carcinoma

“…In the Big Ten Cancer Research Consortium sponsored Phase Ib/II clinical trial, the safety and antitumor activity of pembrolizumab in combination with bevacizumab was evaluated in 61 patients with metastatic ccRCC, who at received at least one prior systemic therapy [25]. No dose-limiting toxicities had been reported.…”

Immunotherapy of Renal Cell Carcinoma

“…Ve studii fáze Ib se podávala kombinace bevacizumab + pembrolizumab předléčeným pa cientům s mRCC, zatím zde nebyla zaznamenána toxicita stupně 3 nebo 4, RR byl 71 % [26]. Nyní probíhá studie fáze II se stejnou kombinací léků (bevacizumab 15 mg/ kg + pembrolizumab 200 mg à 3 týdny, NCT02348008).…”

Renal cell carcinoma: molecular characterization and evolving treatment paradigms

“…The phase Ib portion of the trial recently reported that the combination was well tolerated with no dose-limiting toxicity or serious adverse events and no grade 3 or 4 drug-related toxicities. This established a 200 mg fixed dose of pembrolizumab and 15 mg/kg dose of bevacizumab, both given every 3 weeks, as the regimen to be evaluated in the on-going phase II portion of the study (NCT02348008) [52]. While preliminary, these data suggest that the combination of anti-VEGF antibodies with PD-1 blockade may be more tolerable than VEGF TKI/checkpoint blockade combination therapies.…”