550P Initial results of a phase Ia/Ib study of NGM120, a first-in-class anti-GDNF family receptor alpha like (GFRAL) antibody in patients (pts) with advanced solid tumors

Growth Differentiation Factor 15 (GDF15) has been shown to have both protumorigenic and procachectic effects. NGM120 is a novel, 1st-in class, humanized monoclonal antibody that inhibits GFRAL (the receptor for GDF15) resulting both in antitumor and anticachexia effects in experimental models. In a healthy volunteer study, NGM120 (10-400 mg) was well tolerated with a favorable safety profile. We present the data from Ph1a/1b dose finding study (NCT04068896) of NGM120 and NGM120 + gemcitabine (Gem)/nab-paclitaxel (nab-P) in advanced cancer pts. NGM120 (30 or 100 mg) was given to pts with advanced solid tumors Q3W SC as monotherapy (Ph1a), or to pts with metastatic pancreatic cancer in a 1st line setting Q4W SC in combination with Gem/nab-P (Ph1b). Primary endpoints were safety and tolerability. Secondary endpoints were PK, ORR per RECIST v1.1, progression free survival, lean body mass (LBM) by CT scans at the level of L3, and body weight (BW) changes. Pts received NGM120 monotherapy (n=18) and NGM120 in combination with Gem/nab-P (n=8). Median age was 64 and 67 years for Ph1a and Ph1b, respectively; 94% previously received ≥3 lines of therapies (Ph1a). No dose-limiting toxicities were observed and MTD was not reached. Treatment-related AEs were reported in 33% (Ph1a) and 38% (Ph1b); most were Grade 1/2. NGM120 exhibits dose-proportional exposure with the half-life of ∼35 days. Although no objective response was observed in Ph1a, 4/11 evaluable (36%) pts showed >3.5% gain in LBM at Week (wk) 9. Preliminary results for Ph1b at wk 16 include 2 pts PR (extending >24 wks), 4 pts SD; 2 pts discontinued early due to toxicity attributed to Gem/nab-P. Among the 6 evaluable pts, the disease control rate is 100% at wk 16 and 4 pts showed >5% BW gain and mean 2.9% LBM gain based on maximum change from baseline. NGM120 given as monotherapy or with Gem/nab-P was well tolerated and showed potential pathway engagement evidenced by increased LBM and BW. Disease control at wk 16 in evaluable Ph1b patients was encouraging. A Ph2a study is ongoing to further evaluate NGM120 in the 1st line setting of pancreatic cancer, with pts randomized to either NGM120 or placebo in combination with Gem/nab-P.