Initial results from the phase 2A trial of visugromab (CTL-002) + nivolumab in advanced/metastatic anti-PD1/-L1 relapsed/refractory solid tumors (The GDFATHER-TRIAL).

2501 Background: Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical role in tumoral immunosuppression. Apart from blocking immune-cell entry into the tumor microenvironment, GDF-15 also has a major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block immunotherapy success. Here we report initial results of the phase 2a part of the GDF-15 neutralizing antibody visugromab (CTL-002) in combination with nivolumab. Methods: At cut-off date (06-Feb-2023), a total of 79 pts with advanced/metastatic solid tumors have been enrolled and were treated with visugromab 10 mg/kg Q2W in combination with nivolumab 240 mg Q2W in the phase 2a expansion part of the CTL-002-001 phase 1/2 trial (NCT04725474). The primary endpoint of the phase 2a expansion is the Objective Response Rate (ORR) according to RECIST v1.1. Tumor assessments were performed every 8 weeks and patients had to be relapsed/refractory to a minimum of 12 weeks continuous prior anti-PD1/-PD-L1-containing therapy, with relapse or progression after initial response to have occurred on continued anti-PD1/PDL1 therapy. Phase 2a contained several indication-specific expansion cohorts (e.g. NSCLC, Bladder Cancer, HCC, Melanoma), following a Simon 2-stage design, and two cohorts were already expanded to stage 2 in light of initial responses observed. An additional expansion cohort is a pan-tumor basket cohort with sequential tumor biopsies for biomarker analyses. A key component of this multi-arm trial is an extensive translational research program to identify response-predictive tumor and immunologic marker and pattern. Results: Across several expansion cohorts, durable tumor regressions were observed, including several partial responses (PR) and one complete response (CR) in heavily pretreated patients with a median of 3 prior lines of systemic therapy for advanced/metastatic cancer, including at least one prior line of anti-PD1/-PD-L1 therapy and being relapsed/refractory to it. In NSCLC, so far 13 pts underwent at least one tumor assessment. Of these, two experienced a PR (one confirmed), three additional tumor shrinkage > 5% (TS) and one longer-term SD (LT-SD) were seen. In bladder cancer, 7 patients underwent at least one tumor assessment with 1 confirmed CR, 1 TS and 1 LT-SD. The treatment was overall well tolerated. Conclusions: These initial phase 2a results demonstrate promising clinical activity for the combination of visugromab and nivolumab in heavily pretreated anti-PD1/-PD-L1 refractory/relapsed solid tumor patients across various indications, including induction of confirmed partial and complete responses. Extensive biomarker evaluations are ongoing to further evaluate potential response-predictive markers identified during phase 1 development. Clinical trial information: NCT04725474 .