Background: TTX-080 is an IgG1 monoclonal antibody targeting HLA-G. This Ph1a/1b study evaluated the safety and preliminary efficacy of TTX-080 alone or in combination with cetuximab (Cetx) or pembrolizumab (Pem) in multiple solid tumor cohorts (NCT04485013). Herein, we report the safety from the Ph1a and preliminary efficacy data from Ph1b cohorts evaluating TTX-080 + Cetx in pts with head and neck squamous cell carcinoma (HNSCC) and WT RAS/BRAF, HER2-Neg metastatic colorectal cancer (mCRC) tumors. Methods: In Ph1a, pts with advanced solid tumors received single agent TTX-080 at escalating doses in a 3+3 design from 0.2-20 mg/kg IV Q3W. In the mCRC and HNSCC arms of Ph1b, pts were treated with RP2D of TTX-080 + Cetx. Patients were followed for safety and anti-tumor activity. Biopsies and blood samples were collected for biomarker analyses. Results: As of 08-Dec-23, 202 pts have received TTX-080 alone or in combination (40 pts in Ph1a and 162 pts in Ph1b). In Ph1a TTX-080 monotherapy dose-escalation, MTD was not reached and no DLT was reported. TTX-080 treatment-related AE (TRAE) of arthralgia, fatigue, and decreased appetite were seen in at least 5% of pts. R2PD for TTX-080 was determined to be 20 mg/kg IV Q3W. In Ph1b of TTX-080 alone or in combination (Cetx or Pem), the most common TRAEs in at least 5% of subjects were fatigue, nausea, anemia, diarrhea, AST increase, headache, vomiting and pruritis. Preliminary efficacy data from the select Ph1b TTX-080 + Cetx subset of pts are shown in Table. Significant HLA-G related immune cell changes in the peripheral blood and in tumors will be presented. Conclusions: TTX-080 is well tolerated alone and in combination with Cetx. TTX-080 + Cetx demonstrates promising activity in pts with HPV-Neg HNSCC and WT RAS/BRAF/Her2-Neg mCRC as manifested by the responses and PFS. These early findings warrant further investigation of TTX-080 + Cetx in a randomized controlled study against standard of care in mCRC and HNSCC. Clinical trial information: NCT04485013.

*ORR is the best response reported from start of treatment until end of treatment. Tumor assessment based on RECIST 1.1 per Central Assessment.