Long-term follow-up of a phase 1/2 trial of anti-GDF-15 antibody visugromab plus anti-PD-1 antibody nivolumab in anti-PD-1/-L1 relapsed/refractory solid tumors

Abstract Background Resistance to anti–PD-1/PD-L1 therapy is a major unmet need. Growth Differentiation Factor 15 (GDF-15) has been identified as a key resistance factor for anti–PD-1/PD-L1 immunotherapy. Visugromab, a neutralizing anti–GDF-15 antibody, plus the anti–PD-1 antibody nivolumab (V+N) was evaluated in the first-in-human phase 1/2a GDFATHER-01 trial in heavily pretreated participants with locally advanced/metastatic non-squamous non-small-cell lung cancer (nsq NSCLC), urothelial carcinoma (UC), or hepatocellular carcinoma (HCC), stringently defined as anti–PD-1/PD-L1-relapsed/refractory, and showed encouraging objective responses. This analysis reports long-term follow-up of these three phase 2 expansion cohorts of the GDFATHER-01 trial. Methods Seventy-seven participants with nsq NSCLC (N=22), UC (N=27), and HCC (N=28) received visugromab (10 mg/kg) plus nivolumab (240 mg) every two weeks until disease progression or unacceptable toxicity. Results Objective response rates (RECIST v1.1) were 18.2% for nsq NSCLC (4/22; 95%CI 5.2–40.3), 18.5% for UC (5/27; 95%CI 6.3–38.1), and 14.3% for HCC (4/28; 95%CI 4.0–32.7). Median duration of response (DoR) was 32.2 months (95%CI 5.5–38.0), 28.8 months (95%CI 7.4–39.4), and 19.4 months (95%CI 5.8–39.7; with protracted recruitment), respectively, with 7/13 responses (53.8%) ongoing. Confirmed complete response or complete metabolic response (CR or CMR) among responders was 61.5% (8/13), with 7/8 ongoing. In addition, 46.2% (6/13) of responders achieved a deeper response on V+N per RECIST v1.1 than with the prior anti–PD-(L)1 therapy; median DoR on V+N was 28.8 months (95%CI 7.4–38.0) versus 12.0 months (95%CI 8.0–24.0) on initial anti–PD-1/PD-L1 treatment. V+N was generally well tolerated. Conclusions In heavily pretreated, advanced/metastatic participants with nsq NSCLC, UC, or HCC who were anti–PD-1/PD-L1-relapsed/refractory, V+N achieved deep and durable objective responses. The observed DoR, depth of response, and CR+CMR rate among responders exceeded those reported for their initial anti–PD-1/PD-L1 therapy. These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti–PD-1/PD-L1 responses, and warrant further exploration in randomized trials. Registry ClinicalTrials.gov, TRN: NCT04725474, Registration date: 25 January 2021; EudraCT, TRN: 2020-002103-19, Registration date 16 Dec 2020