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At initial diagnosis 47% of NSCLC patients already have stage IV metastatic disease with limited treatment options and 1-5% 5-year overall survival (OS) rates. Current therapies emphasize the necessity for combinatorial treatment approaches. Interleukin-2 (IL2) plays an essential role in the activation phase of both specific and innate immune responses. To avoid IL2 induced systemic toxicity we have evaluated a more targeted approach using an immunocytokine consisting of the anti-EDB scFv L19 antibody coupled to IL2. Combination with radiotherapy (RT) in tumour models expressing high EDB resulted in long-term primary tumour responses, abscopal effects distant from the irradiated site, and an immunological memory. Aim of the current study was to evaluate preclinically and in a phase 2 clinical trial the combination of precise SABR with the well-tolerated tumour selective immunocytokine L19-IL2 and the immune checkpoint inhibitor (ICI) aPDL1 in an intermediate EDB expressing, immune cold LLC model.

Upon an average LLC tumour volume of 200mm³, C57BL/6 mice were randomised into following treatment groups: RT (10Gy) + vehicle/L19-IL2 + IgG or RT + vehicle/L19-IL2 + aPDL1/aCTLA4. Vehicle/L19-IL2 (1mg/kg), aCTLA4 (10mg/kg) and IgG (10mg/kg) were given i.v. on day 1, 3 and 5 after RT; aPDL1 (10mg/kg) and IgG were given i.p. 1, 3, 5, 7 and 9 days after RT, Figure 1. Tumour response was quantified as time to reach 4x initial tumour volume (T4xIV). This triple therapy is implemented as 1^st, 2^nd, or 3^rd line in the phase 2 trial, to treat WHO PS 0-1, advanced stage IV NSCLC patients. The main objective is improved PFS at 1.5 years. The secondary objectives will be OS, QoLQ, and abscopal response. The exploratory objectives will be biomarker studies, immune cell subsets, mutational burden, and stool collection will be performed.

L19-IL2 and aCTLA4 (p<0.05), but not aPDL1, enhanced the therapeutic effect of RT.  Furthermore, RT + L19-IL2 efficacy was better compared to RT + ICIs, especially for RT + aPDL1 (p<0.05). Adding aCTLA4 to RT + L19-IL2 did not improve outcome compared to RT + L19-IL2. However, RT + L19-IL2+aPDL1 enhanced therapeutic efficacy compared to RT + L19-IL2 (p<0.05) and RT + aPDL1 (p<0.001), resulting in 38% long-term tumour remission, Figure 2.

Based on preliminary results of the ImmunoSABR phase 1 trial (NCT02086721), 15 Mio IU L19-IL2 are safe after SABR. Treatment response was seen in 50% of patients with PFS and OS of >2 years. A phase 2 trial (NCT03705403) has been approved by the medical ethical board and is currently recruiting patients.

Our results suggest that radiotherapy would better synergize with immunocytokines than checkpoint inhibitors, and that triple combination with aPDL1 is able to make a tumour immune-permissive. Combining the knowledge gained from the successful phase 1 trial and pre-clinical evidence we expect prolonged PFS and OS in the multicentric ImmunoSABR phase 2 trial.