Background: Tisotumab vedotin (TV; TIVDAK) is a tissue factor (TF)-directed antibody-drug conjugate that has been granted accelerated approval in the US for treatment of adults with recurrent/metastatic (r/m) cervical cancer with disease progression on or after chemotherapy. TV remains investigational in other tumor types including squamous cell carcinoma of the head and neck (HNSCC) and squamous non-small cell lung cancer (sqNSCLC). This abstract presents the addition of Part D to innovaTV 207 (NCT03485209), a global, open label, multicenter phase 2 trial investigating the safety, tolerability, and activity of TV in solid tumors. Untreated patients (pts) with r/m HNSCC or sqNSCLC enrolled in Part D will receive either TV in combination with pembrolizumab (pembro) or TV + pembro and a platinum agent. Based on encouraging preliminary safety and efficacy results with 2.0 mg/kg TV once every 3 weeks (Q3W) in combination with pembro or carboplatin (carbo) in innovaTV 205 cervical cancer study cohorts, TV is being evaluated at 2.0 mg/kg Q3W in combination with pembro or pembro + carbo (or cisplatin). Methods: Up to 140 treatment-naive pts with r/m HNSCC or sqNSCLC will be enrolled in Part D of innovaTV 207. First, the All-Comers cohorts for HNSCC and sqNSCLC will each enroll up to 30 pts, regardless of PD-L1 expression, for Q3W dosing with 2.0 mg/kg TV in combination with 200 mg pembro and AUC 5 carbo. After enrollment in the HNSCC All-Comers Cohort is complete, up to 20 pts with HNSCC will be enrolled into a Cisplatin Safety Cohort for dosing with 2.0 mg/kg TV in combination with 200 mg pembro and 100 mg/m² cisplatin. Completion of enrollment in the All-Comers Cohort for each tumor type will also be followed by enrollment of up to 30 pts with HNSCC (CPS ≥1) and 30 pts with sqNSCLC (TPS ≥1%) into PD-L1 Selected cohorts for dosing with TV in combination with 200 mg pembro. Response will be assessed every 6 weeks for the first 6 months, every 12 weeks for the next 6 months, and then every 6 months after that. Pts with HNSCC must have had no previous systemic therapy for metastatic disease (exception is systemic therapy given as part of multimodal treatment for locally advanced disease completed > 6 months prior). Pts with NSCLC must have histologically or cytologically documented squamous cell NSCLC and must not have had any previous systemic therapy for metastatic disease or radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of study drug. The primary endpoint is investigator-determined confirmed ORR per RECIST v1.1. Secondary endpoints include confirmed and unconfirmed ORR per RECIST v1.1, disease control rate, duration of response, time to response, PFS, OS, safety and tolerability, pharmacokinetics, and immunogenicity. The trial opened in June 2018 and was amended to add Part D in November 2021. Part D enrollment will begin in early 2022; updates will be provided at the meeting. Clinical trial information: NCT03485209.