Discussion
NSCLC, tumor, T-cell, pembrolizumab
TUMOR, INFILTRATION, GROUP B, ENDOMETRIAL ADENOCARCINOMA, MINOR, SOLID TUMORS, OF LUNG ADENOCARCINOMA, SECONDARY, ADENOCARCINOMA, NSCLC, CHOLANGIOCARCINOMA
This phase Ib platform study evaluated the safety, efficacy, and pharmacodynamics of itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) in combination with pembrolizumab (anti-PD-1) in patients with advanced or metastatic solid tumors. The study primary objective was to define a preliminary safety profile of itacitinib or parsaclisib in combination with pembrolizumab, and results were consistent with previously reported data (The study secondary objective was to investigate clinical efficacy and correlative pharmacodynamics. In Part 1a/Group B (parsaclisib 0.3–30 mg once daily or 2.5 mg every other day plus pembrolizumab 200 mg every 3 weeks), one patient achieved a CR (NSCLC) and 6 patients had a PR (adenocarcinoma, endometrial adenocarcinoma, NSCLC, cholangiocarcinoma, Analysis of tumor biopsies demonstrated that itacitinib in combination with pembrolizumab had no consistent effect on immune-cell infiltration into the tumor or stroma. The combination of itacitinib plus pembrolizumab resulted in only minor changes in a small number (nine) of plasma proteins. Notably, IFN-inducible proteins, such as CXCL9 and CXCL10, which are hallmark markers of anti-PD-(L)1 treatment, were not induced in patients treated with itacitinib, suggesting that coadministration of a JAK1 inhibitor with pembrolizumab blocks activation of the IFN pathway, which is required for T-cell activation. Moreover, in Part 1b/Groups A-1/A-2, 4 patients achieved a PR with no remarkable efficacy observed in any one tumor type treated with itacitinib plus pembrolizumab. In a database analysis study of lung adenocarcinoma transcriptome profiles, JAK1 expression was positively correlated with immune-cell infiltration, suggesting a potential role of JAK1 in the immune response (Pharmacodynamic evaluation of samples collected in Part 1 (Group B, B-1/B-2) demonstrated an increase in CD8Although a T-cell inflamed preclinical model demonstrated PI3Kδ inhibition together with PD-L1 blockade resulted in enhanced antitumor efficacy (In conclusion, PD-1 blockade in combination with either JAK1 or PI3Kδ inhibition in our study did not demonstrate significant clinical efficacy beyond that anticipated with pembrolizumab alone, despite encouraging preclinical activity in mouse models (