First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: Results in colorectal cancer.

person Manish Sharma START Midwest, Grand Rapids, MI info_outline Manish Sharma, John H Strickler, David Sommerhalder, Yasutoshi Kuboki, Ruth Perets, Jonathan Cohen, Judith Raimbourg, Takako Eguchi Nakajima, Noboru Yamamoto, Marcia Cruz-Correa, Bert O'Neil, François Ghiringhelli, Kanwal Pratap Singh Raghav, Rui Li, Gladys Morrison Thiele, Martha Raluca Neagu Aristide, Kevin Jay Freise, Carla Biesdorf de Almeida, Athanasios Vasilopoulos, John D. Powderly

Authors person Manish Sharma START Midwest, Grand Rapids, MI info_outline Manish Sharma, John H Strickler, David Sommerhalder, Yasutoshi Kuboki, Ruth Perets, Jonathan Cohen, Judith Raimbourg, Takako Eguchi Nakajima, Noboru Yamamoto, Marcia Cruz-Correa, Bert O'Neil, François Ghiringhelli, Kanwal Pratap Singh Raghav, Rui Li, Gladys Morrison Thiele, Martha Raluca Neagu Aristide, Kevin Jay Freise, Carla Biesdorf de Almeida, Athanasios Vasilopoulos, John D. Powderly Organizations START Midwest, Grand Rapids, MI, Duke University School of Medicine, Durham, NC, NEXT Oncology, San Antonio, TX, National Cancer Center Hospital East, Kashiwa, Japan, Rambam Medical Center and Technion-Israel Institute of Technology, Haifa, Israel, Sharett Institute of Oncology, The Wohl Institute for Translational Medicine, Hadassah Medical Center, Hadassah Hebrew-University Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel, Insitut de Cancérologie de l’Óuest – Centre René Gauducheau, Saint-Herblain, France, Kyoto University Graduate School of Medicine, Kyoto-Shi, Japan, National Cancer Center Hospital, Tokyo, Japan, The University of Puerto Rico, Medical Sciences Campus, and Pan-American Center for Oncology Trials, San Juan, Puerto Rico, Community Health Cancer Center North,, Indianapolis, IN, Centre Georges-François Leclerc, Dijon, France, The University of Texas MD Anderson Cancer Center, Houston, TX, AbbVie Inc., North Chicago, IL, Carolina BioOncology Institute, Huntersville, NC Abstract Disclosures Research Funding AbbVie Background: c-Met (MET protein) is frequently overexpressed in several advanced solid tumors including colorectal cancer (CRC). There are no approved therapies specific for c-Met–overexpressing tumors in CRC. The antibody-drug conjugate ABBV-400 comprises c-Met–targeting antibody telisotuzumab conjugated to a novel topoisomerase 1 inhibitor payload. A phase 1 study of ABBV-400 was initiated for adults with advanced solid tumors and progression on standard therapies (NCT05029882); results from dose escalation (ESC) at doses 1.6–6.0 mg/kg once every 3 weeks (Q3W) were previously presented and showed preliminary efficacy (Sharma et al. ASCO 2023. Abstract 3015). We present data from dose ESC and expansion (EXP) cohorts in CRC. Methods: During EXP, patients (pts) with CRC were randomized to receive ABBV-400 at 1.6, 2.4, or 3.0 mg/kg Q3W. Primary objectives were to evaluate the safety, tolerability, pharmacokinetics, preliminary efficacy, and the recommended phase 2 dose of ABBV-400. Results: As of Oct 2023, 122 pts (ESC: 29; EXP: 93) were included. Median age: 56 years; 65 (53%) males. Median prior treatments was 4. Follow-up was longer in ESC vs EXP (14.8 vs 3.8 months). Seventy-eight (64%) pts had a grade (G)≥3 treatment-emergent adverse event (TEAE); 41% had a serious TEAE. Most frequent hematologic TEAEs were anemia (52%; G≥3: 30%), neutropenia (37%; G≥3: 25%), leukopenia (25%; G≥3: 12%), and thrombocytopenia (23%; G≥3: 12%); nonhematologic TEAEs were nausea (57%, G≥3: 3%), fatigue (43%; G≥3: 2%), and vomiting (39%, G≥3: 4%). G≥3 diarrhea was < 1%. Unadjudicated interstitial lung disease/pneumonitis rate was 7% (G≥3: 2%). Treatment-related AEs leading to discontinuation occurred in 11 (9%) pts. Preliminary efficacy outcomes are shown in the Table. The majority of tissues expressed c-Met. In pts with higher c-Met expression, an increased ORR of > 30% was observed at efficacious doses (≥2.4 mg/kg). Activity was also seen at lower c-Met expression levels (10–15% ORR). Conclusions: ABBV-400 at 2.4 and 3.0 mg/kg Q3W has a tolerable and manageable safety profile, with promising antitumor activity. Long-term tolerability appears improved at 2.4 relative to 3.0 mg/kg, with higher relative dose intensity and generally lower TEAEs. The study is also evaluating ABBV-400 with bevacizumab in pts with CRC. Clinical trial information: NCT05029882. Preliminary efficacy outcomes. CRC Dosing Cohorts 1.6 mg/kg Q3W (n = 32) 2.4 mg/kg Q3W (n = 40) 3.0 mg/kg Q3W (n = 41) Confirmed ORR, n (%) 0 6 (15) 8 (20) CBR12, n (%) 11 (34) 23 (58) 15 (37) Median duration of response, months (95% CI) - 4.1 (2.7, NE) 5.5 (2.8, NE) Median progression-free survival, months (95% CI)* 4.0 (2.6, NE) 5.3 (3.8, 5.5) 4.5 (2.6, 6.8) Median overall survival, months (95% CI)* 9.7 (4.3, NE) 8.7 (6.3, NE) 12.2 (5.9, NE) *Immature data. CBR12, clinical benefit rate at 12 weeks; CI, confidence interval; NE, not estimable; ORR, objective response rate.

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