Abstract CT002: First-in-human phase I study of PLN-101095, a first-in-class dual αvβ8/αvβ1integrin inhibitor, as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors refractory to immune checkpoint inhibitors (ICI

Abstract Background: TGF-β drives immunosuppression and T-cell exclusion in solid tumors and contributes to ICI-acquired resistance. The integrins αvβ8 and αvβ1 activate latent TGF-β in the tumor microenvironment, promoting immune escape. PLN-101095 is a first-in-class, oral dual αvβ8/αvβ1 inhibitor designed to block TGF-β activation and restore antitumor immunity in patients with advanced solid tumors refractory to prior ICI (NCT06270706). Methods: This ongoing Phase 1a/1b, dose-escalation study evaluated PLN-101095 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors refractory to prior ICI. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity. Patients received PLN-101095 monotherapy for 14 days, then pembrolizumab (200 mg Q3W) starting on D15. Accelerated titration (n=1) was permitted at 250 and 500 mg BID. Cohorts of ≥3 patients were enrolled at 1000 mg BID, 1000 mg TID, and 2000 mg BID. Results: Sixteen patients with nine advanced solid tumor types were enrolled. The population was predominantly white, with balanced sex distribution and median age of 60 years. Most patients (75%) were ICI secondary refractory, with median prior ICI exposure of 12 months and a median of 3 prior systemic therapies. The regimen was well tolerated; the most common treatment-emergent adverse event (TEAE) were grade 1-2 rash (50%), anemia, and diarrhea (18.8% each). Five SAEs occurred, two related to PLN-101095 (keratoacanthoma in cohort 1; immune-mediated hepatitis in cohort 3), the latter being the only dose-limiting toxicity. PLN-101095 showed dose-dependent PK with 24-hour αvβ8 IC90 coverage at doses ≥1000 mg BID. PD analyses reported increased plasma IFN-γ, CXCL9, and Granzyme B after monotherapy (D14) and combination therapy (D28). Among ICI-secondary-resistant patients at ≥1000 mg BID (n=10), antitumor activity included 1 complete response (MSI-high cholangiocarcinoma) and 3 partial responses (melanoma, NSCLC, HNSCC) by iRECIST, with a median time on treatment of 15 months. IFN-γ induction during monotherapy was significantly higher in responders vs. nonresponders (p<0.01 at D14, p<0.05 at D28) and correlated with increased soluble PD-L1; ctDNA was undetectable by week 10 in responders with baseline detectable ctDNA. Conclusion: PLN-101095 and pembrolizumab had durable antitumor activity in heavily pretreated ICI-secondary resistant tumors. Early systemic induction of IFN-γ emerged as a potential PD marker associated with clinical response and warrants further investigation. Based on these findings PLN-101095 is advancing to Part 1b, evaluating tumor-specific expansion cohorts in ICI-resistant populations. Citation Format: Timothy A. Yap, Andrae Vandross, Jenny Amaya-Amaya, Chris N. Barnes, Shuguang Ma, Martin Decaris, Keithryn Nicolas, Alexander Spira, Jacqueline Brown, Patricia LoRusso, Manish R. Sharma. First-in-human phase I study of PLN-101095, a first-in-class dual αvβ8/αvβ1integrin inhibitor, as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors refractory to immune checkpoint inhibitors (ICI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT002.