Interleukin-2 chronotherapy for metastatic renal cell carcinoma: Results of a phase I-II study

Highlights

• Feasibility, safety, activity and tolerability of IL-2 chronoinfusion in metastatic RCC.

• Prognostic value of prolactin and MSKCC score on survival.

• Prognostic value of IL-2 dose and ECOG performance score on survival.

• Long-term survival with IL-2 chronoinfusion in metastatic RCC.

Abstract

Background

Interleukin-2 (IL-2) was the cornerstone treatment for metastatic renal cell carcinoma (RCC) until the advent of tyrosine kinase inhibitors, but it still has therapeutic value. As a single bolus of IL-2 causes toxicity, there is interest in administration regimens with better tolerability and efficacy. Chronotherapy is the administration of therapy according to the circadian rhythm’s influence on the immune and hormonal systems. This phase I-II trial evaluated the safety of IL-2 chronotherapy in metastatic RCC patients and determined the maximum tolerated dose. The secondary objective was to identify prognostic factors for survival.

Methods

Three chronomodulation schedules (5:00–13:00, 13:00–21:00, and 21:00–5:00) were tested. Each schedule was an 8-h IL-2 infusion, with a Gaussian distribution of drug concentration peaking at 4 h. To identify the maximum tolerated dose, the dose for different patients was escalated from 2 MIU/m² (level I) to 18.6 MIU/m² (level VI).

Results

Thirty patients were enrolled and completed treatment. Two patients were treated at 5:00–13:00, 15 at 13:00–21:00, and 13 at 21:00–5:00. Nine cases of grade 3 toxicity occurred in 7 patients at the highest dose (18.6 MIU/m²); no grade 4 toxicity occurred. The maximum tolerated dose was 14.0 MUI/m². Patients were followed for a median of 16 months (range, 2–107). One patient was lost to follow-up, 3 patients were alive at last contact, and 26 patients died. Six patients achieved long-term survival (≥48 months). There was one complete response, four partial responses, 11 cases of stable disease and 14 of progressive disease. The response rate was 16% (5/30) and disease-control rate was 53% (16/30). Median progression-free survival was 4.5 months, and median overall survival was 14.5 months. Kaplan-Meier analyses revealed significant associations between overall survival and ECOG performance score (0 vs. 1–2), MSKCC score (0–2 vs. ≥ 3), IMDC risk score (0–2 vs. ≥ 3), IL-2 dose level (IV-VI vs. I-III), and prolactin (increase vs. no increase), and but not for chronotherapy schedule.

Conclusion

IL-2 chronotherapy appears to be safe, moderately toxic and active in metastatic RCC. It may represent a new modality of IL-2 administration for these patients.

Introduction

In 2018, there were over 400 thousand new cases of kidney cancer and over 175 thousand deaths attributed to kidney cancer [1]. Ninety per cent of these cases are renal cell carcinoma (RCC) [2]. The treatment of choice for localized RCC is radical nephrectomy, but prognosis and risk of recurrence depend on pathological stage [3] and other factors. Postoperative therapy may improve prognosis and survival, but early experiences with radiotherapy, hormone therapy or immunotherapy were ineffective (reviewed in [4]). The S-TRAC randomized placebo-controlled trial found that sunitinib, an inhibitor of the vascular endothelial growth factor (VEGF) pathway, significantly prolonged disease-free survival (median 6.8 vs. 5.6 years) in RCC patients at high risk of recurrence after nephrectomy [5].

About 30% of RCC patients have metastatic disease at the time of diagnosis [6]. Treatment for metastatic RCC includes inhibitors of VEGF and VEGF receptors and, more recently, the anti-PD-1 monoclonal antibody nivolumab alone or combined with the anti-CTLA4 monoclonal antibody ipilimumab. These drugs have improved survival in metastatic RCC but require continuous administration and cause side effects such as colitis, pneumonitis and hypophysitis [7], [8], [9], [10]. Another molecule used to treat metastatic RCC is the cytokine interleukin-2 (IL-2). This immunotherapy results in a durable, complete remission in about 10% of cases, but presents substantial toxicity [11], [12]. To optimize the treatment benefits, different administration regimens have been used, including bolus, continuous infusion and subcutaneous injection, without substantial differences in survival.

An alternative modality of drug administration that takes into consideration daily fluxes in metabolism and excretion is chronotherapy [13]. Chronotherapy, which delivers drugs according to the natural circadian rhythm, aims to maximize the dose intensity and subsequent outcomes while minimizing the toxicity by considering the interactions between drugs and the human body that are modified by the circadian rhythm. The circadian rhythm is controlled by the suprachiasmatic nucleus, which sends signals throughout the body to regulate metabolic processes such as the sleep-wake cycle, the immune system and potentially tumor-modulating processes [14]. Studies in rodents have shown that circadian timing affects the tolerability and efficacy of anticancer agents, and clinical studies have shown that chronomodulation of cancer therapy is beneficial (reviewed in [14]). For these reasons, we applied chronomodulation to the treatment of metastatic RCC with IL-2 in a prospective, single-arm trial. Preliminary results from 22 patients have already been published [15], while here we report the full analysis on 30 patients.