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

Abstract

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 δ 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 treatment-emergent 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-γ 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. This trial was registered at www.clinicaltrials.gov as #NCT01796470.

Figure 1

Treatment-emergent AEs (N = 66). (A) Serious treatment-emergent AEs included pyrexia, diarrhea, pneumonitis, dyspnea, pneumonia, febrile neutropenia, lung infection, sepsis, and hypoxia. Grade ≥3 events included fatigue, rash, diarrhea, pneumonitis, dyspnea, pneumonia, febrile neutropenia, lung infection, sepsis, and hypoxia. Time to onset of pneumonitis in each patient. (B) The onset of pneumonitis occurred after study day 50 in each patient. In 9 of the 12 patients, pneumonitis onset occurred between days 50 and 100. In 3 of the 12 patients, onset occurred between days 100 and 150. There was no relationship between dose level and pneumonitis onset. Computed tomography images of severe pneumonitis. (C) Representative computed tomography images from 2 patients who developed severe pneumonitis. Diffuse ground-glass opacities and interstitial infiltrates are demonstrated.

Figure 2

Cytokine changes over time in patients who did and did not develop pneumonitis. IL-6, IL-7, IL-8, and interferon-γ serum levels were measured by Luminex immunoassays and are depicted separately for patients with (n = 12) and without pneumonitis (n = 27) onset while on idelalisib and entospletinib and for patients treated with entospletinib monotherapy (n = 15). Data are represented as fold change from baseline ×100. Greater elevations of cytokines/chemokines associated with immune cell activation support immunologic mechanisms for the observed pneumonitis pathogenesis. Cell recruitment and Th1 responses, as well as a greater median increase in cytokines/chemokines associated with pneumonitis, were observed in patients with pneumonitis onset compared with patients without pneumonitis onset. *Patients treated on the open-label phase 2 trial of entospletinib.