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BackgroundTargeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment.MethodsThe open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors.ResultsThe most common treatment-related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)-naïve patients (16.1%) compared with patients who had received previous CPI (4.1%). Epacadostat pharmacodynamics were evaluated by comparing baseline kynurenine levels with those on therapy at various time points. Only the 300-mg epacadostat dose showed evidence of kynurenine modulation, albeit unsustained.ConclusionsEpacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. ORR was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested >300 mg epacadostat twice daily is needed to ensure sufficient drug effect.Clinical trial informationA study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO-203) (NCT02318277).

PurposeBromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137).Patients and methodsPatients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability.ResultsSixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses.ConclusionsINCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.

On ensemble‐based coupled data assimilation, cross‐component parameter estimation (CPE), has not been as extensively developed and applied as weakly coupled state and parameter estimation along with cross‐component state estimation. This discrepancy is partially attributed to the lack of emphasis on the instantaneous response of coupled model states with respect to parameters across different components. We define so‐called response as the instantaneous parameter sensitivity (IPS). Under the framework of sequential assimilation, the prior information heavily relies on the IPS of coupled states with different time scales. Based on the IPS analysis for an intermediate coupled model, a series of twin experiments of state and parameter estimation are conducted, in which an IPS‐inspired adaptive inflation scheme for parameter ensemble is introduced. Results show that the success of a parameter estimation strategy is closely tied to the significant IPS of the observed state to the parameter targeted for optimization, as it maintains a high signal‐to‐noise ratio in the error covariance between parameter and prior state, thereby enhancing parameter estimation. An interesting finding in the context of IPS‐based CPE is: an atmospheric parameter can be successfully estimated by assimilating observations from slow‐varying oceanic component, but not vice versa. In comparison with cross‐component state estimation, successful CPE significantly enhances the estimation accuracy of coupled states by mitigating model bias. Plain Language Summary: The sequential data assimilation, exemplified by the ensemble‐based methods, focuses on adjusting model state and/or parameter instantaneously. Its underlying theoretical basis lies in the fact that random fluctuations characterize the Earth system in nature. Previous studies on ensemble‐based parameter estimation concentrated on the climatological response of state to parameter. However, this study emphasizes the instantaneous impact of parameter on state, denoted as the instantaneous parameter sensitivity (IPS), which is crucial for interpretating the feasibility of cross‐component parameter estimation (CPE) in the scope of strongly coupled data assimilation (CDA). Assimilating fast‐varying atmospheric observation has been employed to estimate slow‐varying oceanic state, but it cannot be taken for granted to optimize oceanic parameter. Conversely, assimilating oceanic observation can optimize atmospheric parameter and coupling coefficient since the ocean significantly responds to their direct modulation. The IPS serves as a tool for researchers to preliminarily assess the feasibility of CPE, representing a valuable advance particularly in the realm of strongly CDA. Key Points: The instantaneous parameter sensitivity plays a crucial role in interpreting the feasibility of ensemble‐based parameter estimationThe significant instantaneous response of model state to parameter maintains a high signal‐to‐noise ratio in their error covarianceAtmospheric parameter and coupling coefficient related to ocean‐atmosphere interaction can be optimized by assimilating oceanic observation [ABSTRACT FROM AUTHOR]