Combined high dose radiation and pazopanib in metastatic renal cell carcinoma: a phase I dose escalation trial

Renal cell carcinoma (RCC) presents with metastatic disease in about 30% of patients, while another 30% of patients will ultimately develop metastases [1, 2]. Tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) are currently considered the mainstay treatment for metastatic patients in first line [3]. Nevertheless, durable responses are rare and most patients eventually develop progressive disease [4, 5]. More recently, PD-1/PD-L1 (programmed cell death ligand) targeting agents, especially nivolumab, have shown durable responses, but only in a minority of patients [6]. Therefore, new therapeutic approaches are needed to improve the number of patients benefiting from durable disease control. The combination of TKIs with high-dose radiation is a promising approach to increase response rate. Preclinical combination studies suggest synergistic radio-sensitizing effects. In addition, both treatments elicit antitumor immune responses making the tumor more susceptible to efficient elimination by immune cells [7]. We hypothesized that the combination of pazopanib (Votrient, Novartis), a first-line TKI, and high-dose radiotherapy could demonstrate superior efficacy compared to either treatment in monotherapy. Although high-dose radiotherapy can be delivered safely by making use of stereotactic body radiotherapy (SBRT) and the safety profiles of TKIs are well studied [8, 9], their concurrent administration may potentially exacerbate adverse events (AEs).

Our primary objective was to determine the maximum tolerated dose (MTD) of SBRT in combination with a fixed dose of pazopanib in patients with metastatic clear cell RCC (ccRCC). Secondary end points included objective response of the non-irradiated lesions, local control, and progression-free survival (PFS). An exploratory endpoint was to assess immunologic responses using peripheral blood samples.

Until recently, radiotherapy in metastatic RCC was primarily used to palliate symptomatic metastases [3] as RCC has been traditionally considered a radiation-resistant tumor. Although RCC might be resistant to conventional fractionated radiation, recent evidence suggested the opposite for high-dose radiotherapy [15]. By making use of SBRT, it is possible to safely deliver high radiation doses and SBRT for metastatic RCC has been associated with impressive 1-year local control rates ranging from 71% - 100% [15‐22]. This may be due to either the destruction of tumor microvasculature and/or the induction of antitumor immune responses associated with SBRT (6, 13). TKIs used as first-line therapy in metastatic RCC also have the potential to interact with the immune system. For example, sunitinib, the most-studied TKI in the treatment of RCC, has important immunostimulatory capacities [23, 24]. The immunomodulatory capacities of pazopanib are less well studied, but the effects may be similar. Combined treatment of SBRT and TKIs might therefore increase the antitumor activity of both treatments [7]. We hypothesized that the combination of pazopanib and SBRT could increase response rates. The safety of the combination of pazopanib with conventional radiotherapy has already been investigated [25, 26]. However, there are only limited retrospective cases reported on SBRT and pazopanib [27]. Since their concurrent administration could potentially exacerbate AEs, a prospective phase I dose-escalation trial was conducted. In our trial the MTD was not reached. In dose level 3 (36 Gy), 1 DLT of grade 4 hypoglycemia was reported in a patient with a history of diabetes mellitus type 2, who was irradiated on a mediastinal lesion. Importantly, no increase in radiation-induced toxicity was observed. The grade 4 hypoglycemia resolved completely after adjusting insulin treatment. Because it was assumed that SBRT could also potentially exacerbate pazopanib-related AEs [26, 27], all grade 4–5 metabolic or hematologic toxicities were defined as DLT, regardless of the radiotherapy field. In retrospect, this definition was possibly too strict. In the dose level 3 group, a slightly higher rate of thrombocytopenia was observed, though not dose limiting. We investigated whether a higher incidence of bony lesions or a higher radiation dose on the bone marrow in this group could be the cause, yet only 2 patients in dose level 3 and 1 patient in dose level 1 had bony lesions. In both groups only 1 patient was irradiated on a bony lesion. Therefore, the seemingly increase in thrombocytopenia in dose level 3 was probably due to chance since the number of patients in dose levels 1 and 2 were small.

This trial also provides evidence on antitumor activity of the combination treatment. All patients in our trial initially achieved local control and 1-year local control rates were comparable to those of SBRT in monotherapy [16‐22]. However, these data are mostly derived from patients with limited metastatic disease or inoperable localized disease, instead of patients with more extensive metastatic disease enrolled in our study. Regarding responses outside the radiation field, the ORR was 38% with 5 of 13 patients developing a PR. These data are comparable to the ORR of pazopanib in monotherapy [8]. To study the underlying immunomodulatory effects of the combination treatment, we analyzed PBMCs derived at fixed intervals during treatment. Since the number of patients in the trial was limited, the presented data should be interpreted as exploratory. Frequencies of memory Th17 cells were significantly higher in good responders as compared to bad responders. The role of Th17 cells in cancer is controversial with both tumor promoting and tumor suppressing functions being reported [28‐30]. This may rely on the existence of regulatory vs. pathogenic Th17 subpopulations, the latter subset being involved in auto-immune tissue damage and tumor rejection [31, 32]. Further contributing to the tumor suppressing function of Th17 cells is the production of the chemokines CXCL9 and CXCL10, which facilitates the recruitment of CD8+ T cells into the tumor [33]. The present study also revealed that lower frequencies of CD8+ T cells were associated with good prognosis, which may be due to the majority of CD8+ T cells being recruited into the tumors.

In our phase I study, the MTD was not reached, resulting in a recommended dose of 36Gy/3 for combination with pazopanib. To the author’s knowledge, this is the first report demonstrating that SBRT in combination with pazopanib is well tolerated. Local control and response rates outside the radiation field were good but seemed not to be superior when compared to SBRT or pazopanib in monotherapy. The combination of SBRT with pazopanib and investigation of CD8+ T cells and Th17 cells as a predictor of response warrant further study.