729MO Final results of the first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in combination with nivolumab in subjects with solid tumors relapsed/refractory to prior anti-PD1/PD-L1 treatment

Abstract

Growth and differentiation factor 15 (GDF-15) is a major tumor-derived immunosuppressant. Tumoral expression correlates with poor clinical outcome [Front Imm 2020 May 19;11:951]. Here we present the results of the first-in-human, phase 1 trial of the GDF-15 neutralizing antibody CTL-002. This was the first-in-human, phase 1 dose escalation clinical trial of CTL-002 given IV as monotherapy and in combination with nivolumab in subjects with advanced-stage solid tumors relapsed/refractory to at least one prior anti-PD-1/PD-L1 therapy and having exhausted all available therapeutic options. 25 subjects received escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in an integrated monotherapy-followed-by-combination-design with one cycle CTL-002 followed by combo with nivolumab. The combination of CTL-002 and nivolumab showed excellent tolerability, no DLT and Grade ≥ 4 AE occurred. A substantial tumor-selective influx of CD8+ and CD4+ T cells was detected in most patients under treatment, and significant increases in proliferating and cytotoxic (CD3+GrzB+) T cells in tumor tissue. Five patients relapsed/refractory to prior anti-PD1/PD-L1 treatment and with all other available treatment options exhausted experienced tumor regression, three of them as confirmed, lasting partial responses (> 8 months and ongoing; HCC, CUP tumor and Mesothelioma), others experienced prolonged stable disease.The tumor regression rate observed at dose level 4+5 was 25%. Biomarker-analyses identified a marker that was present in ∼25% of patients and if employed for patient selection would have resulted in a 50% partial response rate and a clinical benefit rate of > 65% in this heavily pre-treated, last-line mixed solid tumor population. CTL-002 neutralization of GDF-15 in combination with PD-1 blockade was safe, increased CD8+ and CD4+ T cell tumor infiltration and antitumoral activity and induced confirmed objective clinical responses and lasting tumor regression in heavily pre-treated and previously anti-PD-1/-PD-L1 relapsed/refractory patients at a rate of 25% for dose level 4 and 5. Phase 2 development is ongoing.