PLN-101095 (dual αvβ8/αvβ1 integrin; TGF-β activation blocker) + pembrolizumab delivers 40% iRECIST responses in ICI-secondary–refractory solid tumors

PLN-101095 is a first-in-class oral small-molecule dual αvβ8/αvβ1 integrin inhibitor intended to block latent TGF-β activation in the tumor microenvironment and potentially re-sensitize tumors to PD-1 blockade; it was evaluated in an ongoing first-in-human Phase 1a/1b dose-escalation study as monotherapy lead-in then combination with pembrolizumab 200 mg Q3W (NCT06270706) in advanced solid tumors refractory to prior ICI (n=16; 75% ICI secondary refractory; median 3 prior systemic lines; median prior ICI exposure 12 months). Safety was largely grade 1-2 (rash 50%; anemia and diarrhea 18.8% each); 5 SAEs occurred with 2 attributed to PLN-101095 (keratoacanthoma; immune-mediated hepatitis), and immune-mediated hepatitis was the only reported DLT. At doses ≥1000 mg BID, PK achieved 24-hour αvβ8 IC90 coverage and PD showed systemic immune activation signals (↑plasma IFN-γ, CXCL9, granzyme B); in ICI-secondary–resistant patients treated at ≥1000 mg BID (n=10), there were 1 CR (MSI-high cholangiocarcinoma) and 3 PRs (melanoma, NSCLC, HNSCC) by iRECIST with median time on treatment 15 months—an ORR of 40% in a population where PD-1 “re-challenge” activity is typically low (~4-20%) and MSI-H status itself predicts sensitivity to pembrolizumab (KEYNOTE-158 ORR 33.8% across MSI-H/dMMR non-CRC tumors, even without an integrin/TGF-β add-on).