INCB86550 / Incyte - LARVOL DELTA

Evaluation of small molecule PD-1/PD-L1 inhibitors in a T cell reporter system. (PubMed, Biochem Pharmacol) - "We found that ARB-272572, INCB086550, Evixapodlin, and PD-1/PD-L1 Inhibitor 3 completely reversed the inhibitory effects of PD-1...AUNP-12, BMS1, BMS202, CA170, and PD-1/PD-L1-IN-9 were ineffective at reducing PD-1-mediated reporter inhibition. Moreover, our data indicate that adverse effects on T cell reporter activation compromise the activity of several of the tested compounds. In summary, our results revealed that the majority of small molecule PD-1/PD-L1 blockers possess a limited capacity to reverse PD-1 inhibition in a T cell reporter platform and highlight the importance of cellular assays to assess the therapeutic potential of drugs targeting the PD-1/PD-L1 axis."

Journal • Oncology

Preclinical Characterization of ALG-094295, a highly potent and orally bioavailable small molecule PD-1/PD-L1 inhibitor targeting dimerization, internalization and degradation of PD-L1 (AACR 2026) - "In a humanized PD-L1 MC38 mouse model, a single oral dose of ALG-094295 (5 mg/kg) achieved PD-L1 target engagement comparable to INCB086550 (150 mg/kg PO). Daily oral dosing of ALG-094295 (50 or 150 mg/kg) in humanized PD-L1 MC38 mice over 21 days resulted in tumor growth inhibition equivalent to twice-weekly administration of durvalumab (10 mg/kg IV), with tumor size correlating with increased CD8⁺ T-cell infiltration... ALG-094295 is a highly potent and orally bioavailable small molecule PD-1/PD-L1 inhibitor that promotes PD-L1 dimerization, internalization and degradation. ALG-094295 has the potential to overcome some limitations of antibody-based therapies due to potent PD-L1 blockade, oral delivery and novel mechanism of action."

Preclinical • Oncology • CD8

Preclinical characterization of ALG-093940, a potent and orally bioavailable small molecule PD-1/PD-L1 inhibitor targeting PD-L1 dimerization, internalization and degradation (AACR 2026) - "ALG-093940 showed comparable T-cell activation potency to INCB086550 an orally dosed small molecule PD-L1 inhibitor which demonstrated clinical responses in a phase I study. ALG-093940, an orally available small molecule, is a potent PD-1/PD-L1 inhibitor targeting PD-L1 dimerization, internalization and degradation. ALG-093940 demonstrated excellent efficacy and safety, warranting further evaluation as a potential clinical candidate for the treatment of cancer."

Preclinical • Oncology • CD8

Research Progress and Clinical Translation Challenges of Small-Molecule Inhibitors Targeting PD-L1. (PubMed, ChemMedChem) - "Notable compounds like CA-170 and INCB086550 have shown promising properties and potential in these studies...Researchers are actively exploring innovative strategies for drug design and synthesis, while carefully assessing critical factors such as safety and efficacy. Given the essential role of the PD-1/PD-L1 pathway in immune evasion by tumors, this review provides a concise overview of the signaling and structure of PD-1/PD-L1, summarizes current progress on clinical candidate drugs targeting this pathway, discusses the challenges in translating small-molecule inhibitors to clinical practice, and outlines future directions in drug development."

Journal • Review • Oncology

Small-Molecule Inhibitors Targeting PD-1/PD-L1 in Colorectal Cancer: Mechanisms, Challenges, and Clinical Prospects. (PubMed, ChemMedChem) - "Early clinical trials of CA-170, INCB086550, and ASC61 indicate encouraging activity in solid tumors, including CRC. This review summarizes the role of the PD-1/PD-L1 axis in CRC and discusses the therapeutic potential and future prospects of small-molecule inhibitors as next-generation immunotherapies for CRC."

IO biomarker • Journal • Review • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • B2M • MSI

Characterization of Clinically Evaluated Small-Molecule Inhibitors of PD-L1 for Immunotherapy. (PubMed, ACS Med Chem Lett) - "In this study, we characterized three small-molecule PD-L1 inhibitors, Evixapodlin, MAX-10181, and INCB086550, currently undergoing clinical trials for cancers such as non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, hepatocellular carcinoma, and melanoma...Cellular assays revealed dose-dependent T-cell activation, demonstrating the immunomodulatory potential of each compound and its cytotoxicity profiles. These findings underscore the promise of small-molecule PD-L1 inhibitors as viable alternatives to antibody-based therapies in cancer immunotherapy."

Journal • Genito-urinary Cancer • Hepatocellular Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

Dual inhibition of JAK3 and PD-L1 boosts immune response in triple negative breast cancer. (PubMed, Anticancer Drugs) - "We verified the efficacy of the combination of the selective TYK2 inhibitor Deucravacitinib and the small molecule inhibitor of PD-L1, INCB086550, in two TNBC animal models: a syngeneic mouse model (4T1 with humanized PD-L1) and a peripheral blood mononuclear cell (PBMC)-humanized model (MDA-MB-231). This enhanced antitumor effect is associated with the modulation of antitumor immune-related gene expression by the combined therapy. The combination of TYK2 inhibitors and immune checkpoint inhibitors is a potentially effective strategy for treating TNBC."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • TYK2

To assess the safety, tolerability and pharmacokinetics of INCB86550 in healthy adult population. (ANZCTR) - P1 | N=75 | Completed | Sponsor: Incyte Corporation | Not yet recruiting ➔ Completed

Trial completion • Oncology

Discovery and preclinical characterization of ALG-093940, a potent and orally bioavailable small molecule PD-L1 inhibitor for the treatment of cancer (SITC 2024) - "Recently, PD-L1 small molecule inhibitors have been developed, e.g., INCB086550 that demonstrated clinical responses in a phase I study.1 Here, we report the discovery and preclinical characterization of ALG-093940, a potent and orally bioavailable small molecule PD-L1 inhibitor, that may overcome the limitations of PD-1/PD-L1 antibodies...ALG-093940 demonstrated excellent, dose-dependent tumor growth inhibition, target engagement and tumor T-cell infiltration in a humanized PD-L1 MC38 subcutaneous mouse model. The properties of ALG-093940 warrant further development as a potential clinical candidate for the treatment of cancer."

Preclinical • Oncology • CD4 • CD8

Study of INCB086550 in Select Solid Tumors (clinicaltrials.gov) - P2 | N=16 | Terminated | Sponsor: Incyte Corporation | Trial completion date: Aug 2024 ➔ Mar 2024 | Active, not recruiting ➔ Terminated; Strategic business decision to terminate the study effective immediately. This is due to a company decision to prioritize another oral PD-L1 inhibitor with a more favorable profile.

Checkpoint inhibition • Trial completion date • Trial termination • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Hepatology • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

A Study Exploring the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INCB086550 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=138 | Completed | Sponsor: Incyte Corporation | Active, not recruiting ➔ Completed

Metastases • Trial completion • Oncology • Solid Tumor • MSI

Discovery of ALG-094103, a liver-targeted and orally bioavailable small molecule PD-L1 inhibitor for the treatment of liver cancer (SITC 2023) - "In the in vivo PD-L1 target occupancy model, oral dosing of ALG-094103 at 50 mg/kg demonstrated higher PD-L1 target occupancy than oral dosing of INCB086550 at 150 mg/kg and IV dosing of durvalumab at 5 mg/kg. Conclusions We have discovered a novel liver-targeted and orally bioavailable PD-L1 small molecule inhibitor, ALG-094103, with comparable in vitro potency to INCB086550. The properties of ALG-094103 will be further evaluated as a potential candidate for drug development."

Gastrointestinal Cancer • Liver Cancer • Oncology • Solid Tumor

Discovery of ALG-093989, a highly potent and orally bioavailable small molecule PD-L1 inhibitor for the treatment of cancers (SITC 2023) - "ALG-093989 has similar T-cell activation potency as durvalumab, and approximately 10-fold improved T-cell activation potency vs. INCB086550, a PD-L1 small molecule inhibitor that demonstrated clinical response in a phase I study. ALG-093989 has the same target occupancy in mice following oral dosing at a 30-fold lower dose than INCB03989. The properties of ALG-093989 warrant further evaluation as a potential candidate for drug development."

Oncology

DISCOVERY OF A LIVER TARGETED ORAL PD-L1 SMALL MOLECULE INHIBITOR FOR THE TREATMENT OF CHRONIC HEPATITIS B AND LIVER CANCER (AASLD 2023) - "In the in vivo PD-L1 target occupancy model, oral dosing of ALG-094103 at 50 mg/kg demonstrated higher PD-L1 target occupancy than oral dosing of INCB086550 at 150 mg/kg and IV dosing of durvalumab at 5 mg/kg. We have discovered a novel liver targeted oral PD-L1 small molecule inhibitor, ALG-094103, with similar in vitro potency to ALG-093702 and INCB08655, and with significantly improved oral bioavailability. ALG-094103 will be further evaluated as a potential candidate for drug development."

Gastrointestinal Cancer • Hepatitis B • Hepatology • Infectious Disease • Liver Cancer • Oncology • Solid Tumor

Study of INCB086550 in Select Solid Tumors (clinicaltrials.gov) - P2 | N=16 | Active, not recruiting | Sponsor: Incyte Corporation | N=150 ➔ 16 | Trial completion date: May 2023 ➔ Aug 2024 | Trial primary completion date: May 2023 ➔ Mar 2024

Checkpoint inhibition • Enrollment change • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Hepatology • Immune Modulation • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

A Study Exploring the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INCB086550 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=138 | Active, not recruiting | Sponsor: Incyte Corporation | Trial completion date: Sep 2023 ➔ Feb 2024

Metastases • Trial completion date • Oncology • Solid Tumor • MSI

A Study Exploring the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INCB086550 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=138 | Active, not recruiting | Sponsor: Incyte Corporation | Trial completion date: Feb 2023 ➔ Sep 2023 | Trial primary completion date: Feb 2023 ➔ Sep 2023

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • MSI

Phase 1 study of INCB086550, an oral PD-L1 inhibitor, in immune-checkpoint naive patients with advanced solid tumors (SITC 2021) - P1 | "Trial Registration Clinicaltrials. gov identifier NCT03762447"

Clinical • IO biomarker • P1 data • Microsatellite Instability • Oncology • Solid Tumor • MSI

To Assess the Safety, Tolerability and Pharmacokinetics of INCB086550 (clinicaltrials.gov) - P1 | N=3 | Terminated | Sponsor: Incyte Biosciences Japan GK | Trial completion date: Nov 2021 ➔ May 2022 | Trial primary completion date: Nov 2021 ➔ May 2022

Trial completion date • Trial primary completion date • Oncology • Solid Tumor

A phase 1 study exploring the safety and tolerability of the small molecule PD-L1 inhibitor, INCB086550, in patients with select advanced tumors (SITC 2022) - P2 | "Approval numbers are: EC/FAHMP (Belgium), P/2020-149; ARS/RHA (Regional Health Authority) (France), 2018-2610; AIFA (Italy), 133700; IRAS (UK), 282291; REC (UK), 20/LO/1001; (USA), RM 598, 1254008, 2018-0765, MOD00971017, 20182238, 1291221. All patients provided written informed consent."

Clinical • P1 data • Anal Carcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI • PD-L1

A phase 1 study exploring the safety and tolerability of the small-molecule PD-L1 inhibitor, INCB099280, in patients with select advanced solid tumors (SITC 2022) - P1 | "Unlike with the first-generation oral PD-L1 inhibitor INCB086550, no dose-limiting immune-mediated peripheral neuropathy has occurred to date with INCB099280. Approval numbers are: WIRB (USA), 20202491; University of Texas, MD Anderson Cancer Center (USA), 2020-0082; Alfred HREC (Australia), HREC/60995/Alfred-2020; Bellberry (Australia), HREC2020-05-463; EudraCT EC (Belgium), 2019-004967-35 (Ref#, 5407); EudraCT EC (France), 2019-004967-35 (FR EC, 20.10.09.40853). All patients provided written informed consent."

Clinical • P1 data • Gastrointestinal Cancer • Oncology • Solid Tumor

A phase 1 study exploring the safety and tolerability of the small-molecule PD-L1 inhibitor, INCB099318, in patients with select advanced solid tumors (SITC 2022) - P1 | "Unlike with the first-generation oral PD-L1 inhibitor, INCB086550, no dose-limiting immune-mediated peripheral neuropathy has occurred with INCB099318 to date. Approval numbers are: Comité d’éthique Institut Jules Bordet (Belgium), CE3326; Ethics Committee Research UZ/KU Leuven (Belgium), S65537; Ethisch Comite UZA/Antwerpen (Belgium), 2021-0592-Edge 001759; Medical Ethics Committee UZ Brussel – VUB (Belgium) EC-2021-285; UZ Gent Etische Commissie (Belgium), BC-10108 CE3326; National Videnskabsetisk komite (Denmark), 2110272; HUS Hospital District of Helsinki and Uusimaa (Finland), HUS/2452/2021; REK South-East Kulmu A (Norway), 253989; Linkoping Department Medicine EC (Sweden), 2021-02574; NHS Fast Track REC (United Kingdom), 21/FT/0058; WIRB (USA), 20201315; Vanderbilt IRB (USA), 211153; WCG IRB (USA), 20201315, 1300136, 1308493. All patients provided written informed consent."

Clinical • P1 data • Oncology • Solid Tumor

Characterization of HZ-G206: A potent and oral small molecule PD-L1 inhibitor (SITC 2022) - "HZ-G206 shows stronger PD-L1 internalization and degradation potency than clinical stage compounds INCB86550 and INCB99318 in hPD-L1-MC38 cell line and IFN-g stimulated human PBMC with IC90 values of 18.1nM and 105.6nM respectively...In in-vivo anti-tumor evaluation, oral administration of HZ-G206 BID can significantly suppress the growth of tumor in a dose dependent manner, the TGI of middle dose group is comparable to Atezolizumab...The compound is identified with potent in-vitro activity which translates to anti-tumor efficacy in pre-clinical animal study. In conclusion, HZ-G206 is an excellent drug candidate for further clinical development."

Oncology • IFNG

Data From Incyte’s Oncology Portfolio to Be Presented at the Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting (Businesswire) - "Incyte...will be presented at the upcoming Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting, held November 8-12, 2022, in Boston and virtually....'We look forward to presenting data at the SITC Annual Meeting from our immuno-oncology pipeline, including our oral PD-L1 program, as we make progress toward our goal of identifying new solutions for patients with cancer who need additional options'."

P1 data • P2 data • Cervical Cancer • Cutaneous Melanoma • Endometrial Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Head and Neck Cancer • Hepatocellular Cancer • Kidney Cancer • Liver Cancer • Lung Cancer • Melanoma • Merkel Cell Carcinoma • Mesothelioma • Nasopharyngeal Carcinoma • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Skin Cancer • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Squamous Cell Skin Cancer • Urothelial Cancer

Phase 1 study of INCB086550, an oral PD-L1 inhibitor, in immune-checkpoint naive patients with advanced solid tumors (SITC 2021) - P1 | "Conclusions Immune-related AEs observed in this ongoing phase 1 study are consistent with those seen with antibody immune checkpoint inhibitors, with the exception of peripheral neuropathy. Preliminary efficacy of INCB086550 in tumor types known to be responsive to anti-PD-(L)1 therapy is encouraging and warrants further investigation."

Clinical • IO biomarker • P1 data • Microsatellite Instability • Oncology • Solid Tumor • MSI