A Prospective, Phase 1 Trial of Nivolumab, Ipilimumab, and Radiotherapy in Patients with Advanced Melanoma

Abstract

Purpose: Preclinical data suggest that radiotherapy (RT) is beneficial in combination with immune checkpoint blockade. Clinical trials have explored RT with single-agent immune checkpoint blockade, but no trials have reported RT with the combination of nivolumab and ipilimumab.

Patients and methods: We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of RT. Patients had at least one melanoma metastasis that would benefit from palliative RT and one metastasis that would not be irradiated. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg and extracranial RT with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety.

Results: Twenty patients were treated (10 in each cohort). The rates of treatment-related grade 3-4 adverse events in Cohort A and B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to RT. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T-cell receptor diversity in some responding patients.

Conclusions: RT with nivolumab and ipilimumab was safe compared with historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab.

Figure 1.

Spider plots of maximum target lesion change. In Cohort A, 10 patients were assessed for overall response rate. Only eight were included in the outside irradiated volume spider plot, as two patients experienced clinical progression and did not receive additional scans for RECIST assessment. Only seven patients were included within the irradiated volume as one additional patient did not have measurable lesions within the irradiated volume at baseline. In Cohort B, nine patients were evaluable for overall response rate outside the irradiated volume and included in the plot. Among these nine, seven patients were included in the plot of tumor changes inside the irradiated volume because one did not have a measurable lesion within the irradiated volume at baseline and another did not have a measurable lesion at a post-treatment initiation timepoint. Patients are matched by color.

Figure 2.

CyTOF and Flow Cytometry immune correlates. A, CyTOF showing the proportion (of 1.0, y axis) and flow cytometry. B, Flow Cytometry showing the percentage (of 100, y axis) of cells positive for respective markers at pretreatment baseline (V1), after the completion of RT/before the third dose of immunotherapy (week 6–9, V2), and at the timepoint of first radiographic assessment (Week 10–14, V3). Panel headers refer to numerator and denominator of respective cellular populations (i.e., “ICOS⁺/CD4” is the percentage of ICOS⁺CD4⁺ among all CD4⁺ cells). Patients with response (green), stable disease (yellow), and progressive disease (red) outside of the irradiated volume are shown. Symbols reflect unique patients.

Figure 2.

CyTOF and Flow Cytometry immune correlates. A, CyTOF showing the proportion (of 1.0, y axis) and flow cytometry. B, Flow Cytometry showing the percentage (of 100, y axis) of cells positive for respective markers at pretreatment baseline (V1), after the completion of RT/before the third dose of immunotherapy (week 6–9, V2), and at the timepoint of first radiographic assessment (Week 10–14, V3). Panel headers refer to numerator and denominator of respective cellular populations (i.e., “ICOS⁺/CD4” is the percentage of ICOS⁺CD4⁺ among all CD4⁺ cells). Patients with response (green), stable disease (yellow), and progressive disease (red) outside of the irradiated volume are shown. Symbols reflect unique patients.

Figure 3.

T-cell receptor (TCR) clonal diversity. Change in TCR clonal diversity during treatment. TCR-beta sequencing was assessed using the Adaptive Biotechnologies immunoSEQ (version 4) assay using DNA from peripheral blood mono-nuclear cells gathered before and at the first post-baseline timepoint (6–9 weeks after treatment initiation). The Simpson index (a measure of TCR clonal diversity) remained mostly stable indicating no change in the TCR diversity. All patients had lower diversity than healthy individuals (range for healthy indicated by blue area in the log scale plot; ref. 21). Patients who had extremely low diversity (Simpson above 0.005) and did not increase diversity upon treatment, were consistently nonresponders.