Cohort expansion of a phase I study of PLN-101095, a first-in-class dual α v β 8 /α v β 1 integrin inhibitor, in combination with pembrolizumab in patients with advanced solid tumors refractory to immune checkpoint inhibitors (ICI).

TPS2690 Background: Transforming growth factor-β (TGF-β) drives immunosuppression and T-cell exclusion in solid tumors and contributes to immune checkpoint inhibitor (ICI)-acquired resistance. The integrins α v β 8 and α v β 1 activate latent TGF-β in the tumor microenvironment, promoting immune escape. PLN-101095 is a first-in-class, oral dual α v β 8 /α v β 1 inhibitor designed to block TGF-β activation and restore antitumor immunity in patients with advanced solid tumors refractory to prior ICI. Part 1 of our study (NCT06270706) employed a Bayesian optimal interval design for dose escalation. The Part 2 expansion cohorts were driven by Part 1 efficacy signals, including 4 responders with secondary resistance to ICI, most of whom had high tumor mutational burden (TMB-H) prior to baseline. Methods: This is an ongoing Phase 1 open-label multicenter study conducted in the United States. Part 1 (dose escalation) enrolled patients with advanced or metastatic solid tumors who had either primary or secondary resistance to prior ICI. Part 2 (dose expansion) will enroll only patients meeting Society for Immunotherapy of Cancer (SITC) criteria for secondary resistance to prior ICI therapy based on a Simon 2-stage design. The Part 2 expansion cohorts will be as follows: 1) non-small cell lung cancer; 2) head and neck squamous cell carcinoma; 3) clear cell renal cancer; and 4) TMB-H tumors (historical ≥10 mutations/megabase, as determined by local testing with a Clinical Laboratory Improvement Amendments–certified next-generation sequencing NGS assay). The target sample size for cohorts 1-3 is 19 patients each, and the target for cohort 4 is 36 patients. The primary endpoints are objective response rate (ORR) and disease control rate (DCR) per immune RECIST. The secondary endpoints are pharmacokinetics (PK), safety and tolerability, and duration of response (DOR). Planned exploratory biomarkers analyses include characterization of integrin expression, TGF-β and immune-related gene expression, and tumor microenvironment (TME) in tumor biopsies. Plasma cytokine profiling and circulating tumor DNA (ctDNA) will also be examined. Clinical trial information: NCT06270706 .