{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T12:39:08Z","timestamp":1786451948537,"version":"build-2736575974"},"reference-count":33,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"unspecified","delay-in-days":10,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017655","name":"Incyte","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100017655","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,7,27]]},"published-print":{"date-parts":[[2026,8]]},"abstract":"\n Background<\/jats:title>\n Orally administered small-molecule programmed death ligand 1 (PD-L1) inhibitors may have the potential to improve patient outcomes in the treatment of a range of cancers compared with their antibody-based counterparts. A small molecule might achieve better tumor tissue penetration, and oral administration could significantly improve convenience and access for patients.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Three phase 1 open-label, non-randomized, dose escalation, and expansion studies evaluated the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of three agents in patients with advanced solid tumors: INCB086550 (\n NCT03762447<\/jats:ext-link>\n ), INCB099280 (\n NCT04242199<\/jats:ext-link>\n ), and INCB099318 (\n NCT04272034<\/jats:ext-link>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Overall, 138, 182, and 104\u2009patients received INCB086550, INCB099280, and INCB099318, respectively. Most had previously received \u22652 lines of cancer therapy for advanced or metastatic disease; 9.6%\u201316.5%\u2009had received prior immunotherapy. All three agents were rapidly absorbed and showed stable dose-dependent PK. With INCB086550, 88\u2009patients (63.8%) had \u22651 treatment-related treatment-emergent adverse event (TEAE), and 19 (13.8%) had \u22651 treatment-related grade \u22653\u2009TEAE. In total, 14 patients (10.1%) had a nervous system-associated TEAE for which an immune-mediated etiology could not be ruled out; events were predominantly peripheral sensory and motor neuropathies. With INCB099280 and INCB099318, 144 (79.1%) and 69 (66.3%) of patients had \u22651 treatment-related TEAE, and 25 (13.7%) and 12 (11.5%) had \u22651 treatment-related grade \u22653\u2009TEAE, respectively. The most frequent immune-related adverse events were skin reactions (INCB099280 and INCB099318) and hepatitis (INCB099280). No dose-limiting toxicities (DLTs) occurred during dose escalation with INCB086550 or INCB099318; two DLTs occurred in two patients with INCB099280 (grade 2 vomiting with 600\u2009mg once daily and grade 2 maculopapular rash with 800\u2009mg two times per day). Overall objective response rates for INCB086550, INCB099280, and INCB099318 were 10.9% (95% CI 6.2% to 17.3%; n=15), 8.8% (95% CI 5.1% to 13.9%; n=16), and 8.7% (95% CI 4.0% to 15.8%; n=9), respectively. Target engagement and PD activity were demonstrated, including PD-L1 binding, and increases in cytokine and chemokine production, as well as T-cell activation and proliferation.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Both INCB099280 and INCB099318 had an acceptable safety profile, with preliminary evidence of antitumor activity. The risk of immune-mediated neuropathy led to discontinuation of the clinical program for INCB086550.<\/jats:p>\n <\/jats:sec>","DOI":"10.1136\/jitc-2026-015334","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T12:10:22Z","timestamp":1786450222000},"page":"e015334","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Phase I safety, efficacy, and biomarker response evaluations of three oral PD-L1 inhibitors: INCB086550, INCB099280, and 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