1020P Rescue by radiotherapy and anti-CTLA4/PD-1 after failure of anti-PD-1 therapy in metastatic NSCLC patients: The RECLAIM study

Primary and acquired resistance to anti-programmed cell death 1 therapy (anti-PD-1) is an important unmet need in non-small cell lung cancer (NSCLC), especially in patients with a low or negative PD-L1 tumors. We hypothesized that the combination of ipilimumab, nivolumab and medium dose radiotherapy (IPI-NIVO and mRT) could overcome resistance to anti-PD-1. In this study, we studied the safety and efficacy of IPI-NIVO and mRT, in metastatic NSCLC patients who progressed on chemotherapy and anti-PD-1. This single-arm, prospective phase II trial aimed to enroll 30 evaluable metastatic NSCLC patients with disease progression after chemo and anti-PD-1. Patients with low (1-49%) and negative (<1%) PD-L1 expressing tumors were included. Co-primary end-points were safety, disease control rate (DCR) and objective response rate (ORR), measured on non-irradiated tumor lesions. The study tested a prespecified ORR threshold of 10%, comparable with the ORR of standard-of-care chemo in the 2nd line and beyond. On day 1, IPI 1 mg/kg Q6W and NIVO 240 mg Q2W was given for 6 weeks, followed by IPI 1 mg/kg Q6W and NIVO 360 mg Q3W until disease progression or unacceptable toxicity. Radiotherapy was given using 3 fractions of 8Gy on days 8, 10 and 12 to a max of 4 tumor sites, at least 1 measurable lesion was not irradiated. Treatment related frequencies for activated CD4+ and CD8+ effector and memory subsets in peripheral blood and tumor biopsies were analyzed. To date, an ORR was achieved in 9 out of 31 (29%) patients in the intention-to-treat population. Stable disease was seen in another 26% as best response. No ORR difference was seen between tumors with negative (N=15) vs low PD-L1 (N=16). The toxicity of the combination of IPI-NIVO and mRT was acceptable (Grade 3-4 treatment-related adverse events were 31%). No treatment-related deaths occurred. Our results indicate that the combination of IPI-NIVO and mRT is safe and well tolerated. In patients with both low and negative PD-L1 expressing tumors, resistant to anti-PD-1 therapy, IPI-NIVO and mRT achieved substantial tumor responses. These data support further research using this combination in metastatic NSCLC after disease progression on chemo-immunotherapy.