Dose escalation phase 1 study of radiotherapy in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody ipilimumab in patients with metastatic melanoma

Abstract

BackgroundA synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma.Patients and methodsA 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics.Results19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5–2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2–1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS.ConclusionWhen combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation.Trial registration numberNCT01557114.

Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade

“…There was no association seen between CD8 T cell infiltration or PD-L1 expression and response, however RT-induced IFNb secretion and sustained TCR clonal expansion was associated with an abscopal response (29). Conversely, a recent phase I study evaluating RT in combination with anti-CTLA-4 in metastatic melanoma showed CD8 infiltration to be significantly correlated with PFS (NCT01557114) (110). McBride et al also evaluated the mechanics of the abscopal effect in a phase II study of Nivolumab with or without SBRT in metastatic HNSCC.…”

Radiotherapy–Immunotherapy Combination: How Will We Bridge the Gap Between Pre-Clinical Promise and Effective Clinical Delivery?

“…Co-stimulatory [77] 9 Gy [77] IO given before (week 1), concurrently (week 4) and after (weeks 7 and 10) RT [77] NSCLC [38] NCT02221739; Interventional Phase 1-2; n: 39 Increased level of serum IFN-β; changes in T cell clones; systemic anti-tumor response T cell-mediated [38] 5 × 6 Gy, 3 × 9.5 Gy [38] IO given concurrently and after RT (on day 22, 43, 64 of the treatment regimen) [38] PD-1/PD-L1 (Programmed Death/Ligand-1)…”

Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression

“…This pivotal trial led to Ipilimumab being the first immune checkpoint blockade therapy approved by the Food and Drug Administration (FDA) in 2011 for patients with advanced melanoma, a disease stage for which there was no previous standard of care therapy that prolonged survival. Since then, αCTLA-4 blockade has been examined extensively in pre-clinical studies and clinical trials as a single agent and in combination with chemotherapy [ 288 , 289 , 290 ], radiotherapy [ 291 , 292 , 293 ], cancer vaccination [ 294 ], and other immunotherapies [ 295 , 296 , 297 ]. However, it is the combination of αPD-1/αCTLA-4 blockade that has demonstrated the greatest therapeutic efficacy in the clinic, with ipilimumab (αCTLA-4) and nivolumab (αPD-1) approved for treatment of patients with advanced solid tumours ( Table 2 ).…”