First-in-human phase 1 dose escalation trial of OMTX705, a novel anti-fibroblast activation protein (FAP) antibody drug conjugate (ADC), in monotherapy and in combination with pembrolizumab in patients with solid tumors.

3028 Background: Cancer Associated Fibroblasts (CAFs) are key components of tumor microenvironment and have immunosuppressive functions. FAP is expressed in a restricted fashion on CAFs. OMTX705 is a first-in-class ADC targeting FAP with a novel tubulysin payload. OMTX705 demonstrated a good safety profile in relevant toxicology models and high linker stability in plasma. We report the dose escalation phase 1 trial of OMTX705 in monotherapy and in combination with pembrolizumab (PEM). Methods: Patients (pts) with advanced carcinomas or sarcomas received 1-18 mg/kg of OMTX705 monotherapy and 2-10 mg/kg with standard PEM. Escalation used a classical 3+3 design with backfilling. OMTX705 schedule is Day 1, 8 every 21 days. The primary endpoint is safety and key secondary are efficacy, pharmacokinetics and biomarkers. Biopsy and blood samples were collected for biomarker analysis. Results: A total of 78 pts have been dosed: 31 pts in monotherapy in 9 dose cohorts and 47 in combination in 7 cohorts of 3 pts each plus 2 backfilling cohorts at 4 and 7.5 mg/kg in pancreatic adenocarcinoma (PDAC) and microsatellite stable (MSS) colorectal cancer (CRC). Median age was 60, 43% male and ECOG PS 0 in 44%. Main histologies were PDAC 33% and MSS CRC 21% with median of 2 (1 to 5) and 3 (1 to 5) prior lines of therapy, respectively. Median treatment exposure was 44 days (range 8 to 113) in monotherapy and 92 days (1 to 422) in combination. OMTX705 relative dose intensity was ~100% in all dose levels. No DLT has been observed. The most frequent related TEAEs were asthenia 35%, AST increased 14%, diarrhea 8%, anemia 8%, and nausea 8%. Grade 3 related TEAEs (pts): anemia (2), immune-mediated hepatitis (2), GGT increased (1), neutropenia (1) and asthenia (1). In monotherapy, best response was SD in 26%. In combination, PR was achieved in 4% (1 MSS CRC and 1 PDAC; DOR 11+ and 8 months, respectively), SD in 33%, PD in 51%, and NE in 13%. In 13 pts there was target lesion reduction: median -17% (-46 to -1%). Median PFS was 1.4 months (0 to 14+). In combination, 20% PDAC (4/20) and 21% CRC (3/14) pts showed PFS > 4 months. 2/3 NSCLC with previous checkpoint inhibitor treatment, 2 PDAC, and 2 MSS CRC showed PFS > 7 months. High FAP expression (H-score > 30) was observed in 86% PDAC, 64% CRC and 50% other carcinomas. CD8+ and CD56+ immune-cell infiltration in tumor biopsies and downregulation of immunosuppressive cytokines in plasma samples were observed in PDAC and CRC best responders. OMTX705 tubulysin payload was detected in both CAFs and tumor epithelial apoptotic regions. Conclusions: OMTX705 is a novel anti-FAP ADC with excellent safety profile. The combination with PEM showed disease control in some heavily pretreated PDAC, MSS CRC and NSCLC. Changes in immune infiltrates and cytokines suggest that OMTX705 may revert CAF-mediated immunosuppression. Clinical trial information: NCT05547321 .