Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL

Abstract

and 9 Gilead Sciences Inc., Foster City, CA Key Points• Concomitant PI3Kd and SYK inhibition resulted in treatment-emergent pneumonitis, necessitating early study termination.• Initial trials of novel combinations should use conservative designs that are focused on safety.Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase d and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatmentemergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-g and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity.

Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies

“…18,[44][45][46] However, even with the successful deployment of BTK and PI3Kd inhibitors, limitations persist as complete remission is rarely achieved, 19,47 acquired resistance can develop, 48 and toxicity has emerged as a serious limitation to the targeting of PI3Kd with idelalisib, especially when in combination. 11,12,49,50 Preclinical and clinical data confirmed that PDE4 inhibitors suppress the activity of components of the BCR-signaling machinery in mature B-cell malignancies.…”

“…11,49,50 The anti-inflammatory/immunomodulatory activity of roflumilast and apremilast (a PDE4 inhibitor FDA-approved for psoriatic arthritis) associates with suppression of numerous proinflammatory cytokines, including IL-6, IL-10, IL-17A, tumor necrosis factor a (TNFa), IFNg, granulocyte-macrophage colony-stimulating factor , as well as an increase in Treg numbers. [51][52][53][54] For these reasons, we suggest that inclusion of a PDE4 inhibitor in association with, or replacing, idelalisib in doublets and triplets of targeted agents will significantly limit toxicity while effectively inhibiting BCR-related signals.…”

The PI3K Pathway in Human Disease

“…Subsequent trials of idelalisib, which included trials of other combinations and trials in younger and treatment-naïve patients, encountered more severe adverse events, such as colitis, pneumonitis and high-grade liver enzyme elevations (Barr et al, 2016; Cheah et al, 2015; Lampson et al, 2016). Unfortunately, several drug-related deaths occurred as a result of Pneumocystis jirovecii or cytomegalovirus infection, leading to trial discontinuation.…”

Idelalisib in the management of lymphoma

“…In 5 patients (8%), mechanical ventilation was required, and 2 patients died of respiratory failure. 31 The authors noted increases in Th1 cytokines among patients who experienced pneumonitis, and bronchoalveolar lavages showed a CD8…”