Abstract CT176: Effect of JAK/STAT or PI3Kδ plus PD-1 inhibition on the tumor microenvironment: Biomarker results from a phase Ib study in patients with advanced solid tumors
Authors: John M. Kirkwood, Nicholas Iannotti, Daniel Cho, Steven O'Day, Geoffrey Gibney, F. Stephen Hodi, Pamela Munster, Paul Hoyle, Sherry Owens, Michael Smith, Niharika Mettu
Journal: Cancer Research (2018)

Abstract Inhibitory pathway blockade has emerged as an important therapeutic modality in cancer. However, tumors escape immune surveillance by multiple mechanisms, which suggests a need to target combinations of distinct immunosuppressive pathways within the tumor microenvironment for optimal therapeutic benefit. JAK/STAT signaling functions downstream of several inflammatory cytokines, promoting a proinflammatory tumor microenvironment, increasing the number of immunosuppressive cells, and inhibiting dendritic cell activity. The PI3Kδ pathway reduces antitumor immunity by modulating effector and memory CD8+ T-cell differentiation. Preclinical studies of JAK and PI3Kδ inhibitors combined with anti-PD-1 demonstrate enhanced immune-mediated antitumor activity compared with single-agent JAK and PI3Kδ inhibitor treatment. We initiated a phase 1b, multicenter, open-label study using multiple biomarker technologies to evaluate the immune effects of inhibitors of either (1) JAK1 (itacitinib) or (2) PI3Kδ (INCB050465) combined with pembrolizumab anti-PD-1 therapy (pembro), in patients (pts) with advanced solid tumors. In part 1a of the study, pts received escalating doses of itacitinib (200-400 mg QD) or INCB050465 (0.3-30 mg QD) in combination with pembro 200 mg Q3W in a 3+3 design over a 21-d cycle. In part 1b (safety expansion) pts with select solid tumors previously treated with or naive to PD-1 therapy received combined therapy at the maximum tolerated and pharmacologically active doses identified in part 1a. Tumor biopsies at baseline and during weeks 3-5 were evaluated for CD3+, CD8+, and FoxP3+ T-cell infiltration by immunohistochemistry. Flow cytometry for peripheral T-cell activation and multiplexed plasma cytokine analysis were performed on samples collected on day 1 of cycles 1, 2, 4, 6, and 8. Part 1a enrolled 42 pts (itacitinib, n=8; INCB050465, n=34) and part 1b enrolled 89 pts (n=41 and n=48, respectively); 27 pts remain on study. Treatment with itacitinib 300 mg plus pembro did not significantly change intratumoral CD8+ T cell and Treg cell counts and reduced peripheral T-cell activation (p&amp;lt;0.05). By contrast, INCB050465 at various doses plus pembro significantly reduced the number of intratumoral Treg cells and increased the CD8+:FoxP3+ ratio (each p&amp;lt;0.05). The differential regulation of plasma proteins by itacitinib and INCB050465 was also evaluated. In conclusion, itacitinib combined with pembro was associated with unfavorable changes in the tumor microenvironment and peripheral immune profile, and will not be investigated further. The combination of INCB050465 plus pembro was associated with more favorable changes in the tumor microenvironment and peripheral T-cell activation and is under further exploration in pts with small cell lung cancer, non-small cell lung cancer, and urothelial carcinoma. Citation Format: John M. Kirkwood, Nicholas Iannotti, Daniel Cho, Steven O'Day, Geoffrey Gibney, F. Stephen Hodi, Pamela Munster, Paul Hoyle, Sherry Owens, Michael Smith, Niharika Mettu. Effect of JAK/STAT or PI3Kδ plus PD-1 inhibition on the tumor microenvironment: Biomarker results from a phase Ib study in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT176.