Background: c-Met overexpression is common in non-small cell lung cancer (NSCLC), gastroesophageal adenocarcinoma (GEA), and colorectal cancer (CRC). There is a need for effective therapies that target c-Met–overexpressing tumors, as there are currently no approved options available. The antibody-drug conjugate (ADC) ABBV-400 consists of the c-Met–targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor (Top1i) payload. ABBV-400 exhibited sustained antitumor activity in patient-derived xenograft models of c-Met–expressing NSCLC, GEA, and CRC. Herein, we present data from the dose escalation of the first-in-human study of ABBV-400 monotherapy. Methods: A phase 1 dose escalation/expansion study of ABBV-400 has been initiated in patients with advanced solid tumors (NCT05029882). Primary objectives are to evaluate safety, tolerability, and pharmacokinetics (PK) of ABBV-400, to determine the recommended phase 2 dose, and to assess preliminary efficacy. PK will be characterized for the conjugate, total antibody, and free payload. Adults (≥18 years) with an advanced solid tumor that progressed on standard therapies were enrolled during dose escalation, without restrictions on the basis of c-Met overexpression status. Results: As of January 2023, 47 patients had enrolled in dose escalation with a median follow-up of 6.5 months. Median age was 58 years (range, 34–79), 25 (53%) patients were male, and the most common cancer types were CRC (n=21), NSCLC (n=5), and GEA (n=5). The median number of prior treatment lines was 4 (1–13). Most common hematologic adverse events (AEs) were anemia (66%; grade [G]≥3: 38%), neutropenia (62%; G≥3: 43%), thrombocytopenia (43%; G≥3: 26%), and leukopenia (32%; G≥3: 19%). Nausea (60%, all grade 1–2), fatigue (49%; G≥3: 4%), and vomiting (38%, all grade 1–2) were the most frequent non-hematologic AEs. One patient experienced grade 1 interstitial lung disease. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were dose and exposure dependent. Clinical activity was observed with ABBV-400, with an objective response rate of 24.4% (11/45; 95% CI: 12.9, 39.5). All responses were confirmed partial responses (PR). In addition, 23 patients (50.0%) had stable disease (SD) and 7 (15.2%) had progressive disease. Among patients with CRC, 4/21 (19.0%) had a PR and 13/21 (61.9%) had durable SD, with a disease control rate of 81.0% (95% CI: 58.1, 94.6). Outside of CRC, PRs were observed in patients with NSCLC (EGFR wildtype and mutant), uterine cancer, and acral melanoma. Conclusions: On the basis of DLTs, a maximum tolerated dose of ABBV-400 was identified. At this dose, safety results appear comparable with other Top1i ADCs. Promising antitumor activity was seen with ABBV-400 across tumor types, justifying further evaluation in the ongoing dose expansion in NSCLC, GEA, and CRC. Clinical trial information: NCT05029882.