Randomized phase II study of stereotactic body radiotherapy and interleukin-2 versus interleukin-2 in patients with metastatic melanoma

Brendan Curti, Marka Crittenden, Steven K Seung, Christopher B Fountain, Roxanne Payne, ShuChing Chang, Jessica Fleser, Kimberly Phillips, Ian Malkasian, Lyn B Dobrunick, Walter J Urba, Brendan Curti, Marka Crittenden, Steven K Seung, Christopher B Fountain, Roxanne Payne, ShuChing Chang, Jessica Fleser, Kimberly Phillips, Ian Malkasian, Lyn B Dobrunick, Walter J Urba

Abstract

Background: A pilot study of stereotactic body radiation therapy (SBRT) followed by high-dose interleukin-2 (IL-2) showed a higher than anticipated objective response rate (ORR) among patients with metastatic melanoma (MM). We performed a prospective randomized study to determine if the ORR of SBRT + IL-2 was greater than IL-2 monotherapy in patients with advanced melanoma.

Methods: Patients with MM who had adequate physiological reserve for IL-2 and at least one site suitable for SBRT were eligible. There was a 1:1 randomization to SBRT + IL-2 or IL-2 monotherapy. Patients received one or two doses of SBRT (20 Gy per fraction) with the last dose administered 3 days before starting the first cycle of IL-2. IL-2 (600,000 IU per kg via intravenous bolus infusion) was given every 8 hours for a maximum of 14 doses with a second cycle after a 2-week rest. Responding patients received up to six IL-2 cycles. Patients assigned to IL-2 monotherapy who exhibited progression of melanoma after cycle 2 were allowed to crossover and receive SBRT and additional IL-2. Response Evaluation Criteria in Solid Tumors 1.1 criteria were applied to non-irradiated lesions for response assessment.

Results: 44 patients were included in the analysis. The ORR in the SBRT + IL-2 group was 54%: 21% complete response (CR), 33% partial response (PR), 21% stable disease (SD) and 25% progressive disease (PD). The ORR in patients receiving IL-2 monotherapy was 35%: 15% CR, 20% PR, 25% SD and 40% PD. Seven patients assigned to IL-2 subsequently received SBRT + IL-2. One CR and two PRs were observed in the crossover group. There was no difference in progression-free or overall survival (OS). At 5 years the OS was 26% in the SBRT + IL-2 group and 25% in the IL-2 monotherapy group. The disease control rate (DCR) was higher in the SBRT + IL-2 group (75% vs 60%, p=0.34).

Conclusions: SBRT + IL-2 induced more objective responses with a higher DCR compared to IL-2 monotherapy in MM. IL-2 monotherapy resulted in a significantly higher ORR than anticipated. Some patients in the crossover group also achieved objective responses.

Trial registration number: NCT01416831.

Keywords: clinical trials, phase II as topic; melanoma; radiotherapy.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
(A) Waterfall plot of best response to SBRT + IL-2. The radiated lesions were excluded from RECIST assessment of target lesions. The responses of patients who participated in the crossover portion of the study are excluded from this analysis. (B) Waterfall plot of best response, IL-2 monotherapy before crossover. The responses to additional IL-2 cycles after crossover are excluded. IL-2, interleukin-2; RECIST, Response Evaluation Criteria inSolid Tumors; SBRT, stereotactic body radiation therapy.
Figure 2
Figure 2
(A) Kaplan-Meier plot of progression-free survival by treatment group. Patients who participated in the crossover group are included with the IL-2 group. (B) Kaplan-Meier plot of overall survival by treatment group. Patients who participated in the crossover group are included in the IL-2 group. IL-2, interleukin-2; OS, overall survival; PFS, progression-freesurvival; SBRT, stereotactic body radiationtherapy.
Figure 3
Figure 3
(A) Swimmers plot for SBRT + IL-2 patients. Each bar represents an individual patient’s treatment history with the bar color indicating survival status and subsequent treatment. (B) Swimmers plot for IL-2 patients (including crossover). Each bar represents an individual patient’s treatment history with the bar color indicating participation in the crossover, survival status and subsequent treatment. IL-2, interleukin-2; SBRT, stereotactic body radiation therapy.
Figure 4
Figure 4
(A) Uric acid (mg/dL) by treatment group comparing baseline and peak values during cycle 1. In most patients, the peak uric acid value occurred on day 5 or 6 after IL-2 started. There was no statistically significant difference in the timing or the peak uric acid level comparing SBRT + IL-2 or IL-2 monotherapy although there was a trend toward high uric acid levels among SBRT + IL-2 responders compared with non-responders. (B) Baseline and peak procalcitonin (ng/ml) by treatment group during cycle 1. The peak procalcitonin was observed on day 5 or 6 after IL-2 started. There was no statistically significant difference in the timing or the peak procalcitonin level comparing SBRT + IL-2 or IL-2 monotherapy although there was a trend toward lower procalcitonin levels among SBRT + IL-2 responders compared with non-responders. IL-2, interleukin-2; SBRT, stereotacticbody radiation therapy.

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