Selective PI3Kδ Inhibitor Research Articles

Abstract CT162: Addition of parsaclisib (INCB050465), a PI3Kδ inhibitor, in patients with suboptimal response to ruxolitinib: A phase 2 study in patients with myelofibrosis

Abstract Background: Ruxolitinib improves outcomes in patients (pts) with myelofibrosis (MF); however, suboptimal response may occur due to persistent PI3K/AKT pathway activation despite continued JAK inhibition. This phase 2 study (NCT02718300) evaluated optimal dosing and efficacy of add-on parsaclisib, a potent, highly selective next-generation PI3Kδ inhibitor, in pts with MF and suboptimal ruxolitinib response. Methods: Patients had primary/secondary MF, ECOG ≤2, and suboptimal response (palpable spleen >10 cm below left subcostal margin [LSM]; or palpable spleen 5-10 cm below LSM and active symptoms) after ≥6 months of ruxolitinib (5-25 mg BID; stable dose, ≥8 weeks [wks]). Patients remained on their stable ruxolitinib dose and were randomized to add-on parsaclisib QD/QW (10 or 20 mg QD for 8 wks/same dose QW thereafter) or parsaclisib QD (5 or 20 mg QD for 8 wks/5 mg QD thereafter). Endpoints: baseline-to-wk-12 spleen volume (SV) change by MRI/CT (primary endpoint); spleen length and symptom changes (Myelofibrosis-Symptoms Assessment Form Total Symptom Score [MFSAF-TSS]). Results: At data cutoff (1/20/2020), 33 pts received parsaclisib QD/QW; 20 received QD (median treatment duration, 197 days; median average daily doses: parsaclisib, 4.9 mg/day; ruxolitinib, 30.0 mg/day). Baseline median (range) SV (cm3) was 2333 (327-5324) in QD/QW (n=30) and 1890 (434-3741) in QD (n=17); median MFSAF-TSS was 10.8 (n=28) and 18.7 (n=17). In QD/QW and QD, median percent SV change was −2.3 (n=30) and −15.4 (n=17) at wk 12; and −2.5 (n=24) and −25.4 (n=9) at wk 24. In QD/QW and QD, number of pts with wk 12 SV reduction ≥10% were 10/30 (33%) and 10/17 (59%); ≥25% were 1/30 (3%) and 4/17 (24%); and ≥35% were 0 and 1/17 (6%). Median percent change in MFSAF-TSS at wk 12 was −14.0 (n=21) in QD/QW; −39.6 (n=12) in QD. Nonhematologic AEs were primarily grade 1/2. Grade 3/4 treatment-related, nonhematologic AEs included disseminated tuberculosis, enteritis, fatigue, hypertension, increased alanine aminotransferase, and increased aspartate aminotransferase in QD/QW and stomatitis in QD. In QD/QW and QD, 6/33 and 6/20 pts had new-onset grade 3 thrombocytopenia; 7/33 and 0/20 pts had grade 4 thrombocytopenia; hemoglobin levels remained steady during the study in both groups. Serious treatment-related AEs were stomatitis, herpes zoster infection, varicella zoster infection, and disseminated tuberculosis (each n=1). No colitis/dose-limiting diarrhea/rash occurred. In QD/QW and QD, 18/33 and 10/20 pts interrupted parsaclisib, and 4/33 and 4/20 interrupted ruxolitinib for AEs. Conclusions: Add-on parsaclisib showed efficacy in pts with MF experiencing suboptimal ruxolitinib response; QD dosing appeared more efficacious than QD/QW dosing. Combination therapy demonstrated acceptable safety with limited grade 3/4 AEs and no dose-limiting AEs. Citation Format: Abdulraheem Yacoub, Eunice S. Wang, Raajit K. Rampal, Uma Borate, Marina Kremyanskaya, Haris Ali, Gabriela S. Hobbs, Casey O'Connell, Albert Assad, Sue Erickson-Viitanen, Feng Zhou, Timothy C. Burn, Naval G. Daver. Addition of parsaclisib (INCB050465), a PI3Kδ inhibitor, in patients with suboptimal response to ruxolitinib: A phase 2 study in patients with myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT162.

Abstract CT253: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Parsaclisib Plus Ruxolitinib in Patients with Myelofibrosis Who Have Suboptimal Response to Ruxolitinib

Abstract Background: Ruxolitinib (JAK1/JAK2 inhibitor) is indicated for the treatment of adults with intermediate (INT) or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF, but a subset of patients may exhibit a suboptimal response due to possible persistent PI3K/AKT activation. Targeting PI3K/AKT signaling may therefore have clinically relevant effects on MF disease burden. This phase 3, randomized, double-blind, placebo-controlled study will determine the effect of add-on parsaclisib, a highly selective PI3Kδ inhibitor, on signs and symptoms of MF in patients with suboptimal or declining response to stable ruxolitinib treatment (INCB 50465-304; NCT04551053). Methods: Eligible patients are aged ≥18 years with a diagnosis of at least INT-1-risk category according to the Dynamic International Prognostic Scoring System (DIPSS; Passamonti. Blood. 2010;115:1703-1708) primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF, have received ruxolitinib for ≥3 months with a stable dose (5-25 mg twice daily) for ≥8 weeks prior to receiving the first dose of study drug (Day 1), have evidence of suboptimal response to ruxolitinib (palpable spleen ≥5 cm below left subcostal margin, and total symptom score ≥10), and ECOG PS ≤2. Patients are excluded if they received prior therapy with any PI3K inhibitor, experimental or standard drug therapy for MF (except ruxolitinib) within 3 months of starting study drug, or have platelet count <50×109/L, recent history of inadequate bone marrow reserve, or inadequate liver or renal function at screening. Approximately 212 patients on a stable dose of ruxolitinib will be randomized (1:1) to receive add-on parsaclisib 5 mg daily or matching placebo beginning on Day 1, with stratification by platelet count (≥100×109/L or 50 to <100×109/L) and DIPSS risk category (high, INT-2, or INT-1) at randomization. Treatment will continue as long as tolerated and discontinuation criteria are not met. Upon patient completion of 24 weeks of treatment, he/she will be unblinded and if randomized to ruxolitinib plus placebo and with adequate hematology parameters, the patient will be able to crossover to receive ruxolitinib plus add-on parsaclisib. The primary objective is to evaluate and compare the efficacy of add-on parsaclisib versus placebo on spleen volume at Week 24. Secondary objectives are to evaluate and compare the effect of add-on parsaclisib versus placebo on: patient-reported MF symptoms, overall survival, time to onset and duration of spleen volume response, and safety and tolerability. Sites are opening throughout the US, EU, China and Japan. Citation Format: Abdulraheem Yacoub, Michael Stouffs, Feng Zhou, Albert Assad. A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Parsaclisib Plus Ruxolitinib in Patients with Myelofibrosis Who Have Suboptimal Response to Ruxolitinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT253.

The PI3Kδ inhibitor parsaclisib ameliorates pathology and reduces autoantibody formation in preclinical models of systemic lupus erythematosus and Sjӧgren’s syndrome

Dysregulation of phosphoinositide 3-kinase δ (PI3Kδ) signaling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases. Parsaclisib (INCB050465) represents a potent and selective PI3Kδ inhibitor, which is being clinically investigated for treatment of autoimmune hemolytic anemia and hematological malignancies. We characterized the potential of parsaclisib to ameliorate autoimmune mechanisms implicated in the pathophysiology of systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). Spontaneous mouse models of SLE and SS were utilized to elucidate the efficacy of orally administered parsaclisib on autoreactive B-cell-mediated antibody-driven disease. Parsaclisib significantly reduced disease symptoms and pathology in three distinct mouse models of SLE. Parsaclisib effectively preserved renal function as measured by glomerular filtration rate, abrogated histopathological evidence of nephritis, modulated discrete immune cell subsets, and decreased anti-dsDNA antibody level. Furthermore, parsaclisib demonstrated efficacy in two spontaneous mouse models of SS. Oral parsaclisib treatment ameliorated the severity of salivary gland inflammation and reduced circulating levels of autoantibodies. Parsaclisib mediated improvement of salivary gland inflammation coincided with reduced B-cell activating cytokine (BAFF) in saliva. Transcriptomic analysis of kidney and salivary gland tissues revealed a downregulation in inflammatory gene expression consistent with PI3Kδ pathway inhibition. Parsaclisib reduced autoreactive B-cells and autoantibody levels, and significantly improved nephritis and salivary gland inflammation. These data provide the scientific rationale for PI3Kδ inhibition as a therapeutic strategy for treatment of B-cell-mediated antibody-driven autoimmune diseases.

Idelalisib Interferes with the Crosstalk of Follicular Lymphoma and Its Immune Microenvironment and Potentiates the Activity of ABT-199

Background:The PI3K pathway is crucial in B-cell non-Hodgkin lymphoma (NHL) cell survival by regulation of cell cycle, apoptosis, proliferation, differentiation, homing, and retention. Idelalisib (IDELA/GS-1101/CAL-101) is a first-in-class PI3Kδ selective inhibitor that is approved for the treatment of relapsed chronic lymphocytic leukemia and follicular lymphoma (FL). The mechanisms of IDELA sensitivity and resistance remain to be fully elucidated.We aimed to characterize the cellular and molecular effects of IDELA in an in vitro model utilizing a primary FL cell co-culture system with follicular dendritic cells (FDC) or M2-polarized macrophages (M2), both subpopulations related to poor prognosis, in order to explore possible combinatorial regimens.Methods: FL primary cells from lymph node biopsies were co-cultured (or not) (24-72h) with FDC cells or M2 macrophages. Viability of FL cells was assessed by flow cytometry (AnnexinV/7-AAD). B cells were isolated using CD20 magnetic beads, RNA extracted and subjected to gene expression profiling (GEP), and data analyzed by Gene Set Enrichment Analysis (GSEA).Results: In the absence of accompanying cells, IDELA (100-500nM) induced a moderate cytotoxic effect on FL cells (n=10) that was maintained in FL-FDC and FL-M2 co-cultures. GEP analysis indicated that IDELA (500nM, 48h) induced a downregulation of genes related to germinal center (GC) program, CD40L, and NF-kB pathways, together with other pathways related to B cell-T cell crosstalk. In this sense, IDELA treatment reduced the expression on B-cells of key molecules such as ICOSL (TFH activation) and CCL22 (Treg activation).In the context of FL-FDC co-culture, FDC induced the transcription of genes related to B-cell receptor-, CD40- and NF-kB-signaling pathways, GC program, mechanistic target of rapamycin (mTOR), angiogenesis, extracellular matrix remodeling, and migration, among others. IDELA blocks the activation of the mTOR pathway in all FL samples analyzed (n=4), but displayed differential activity on the rest of the pathways. We are currently investigating the molecular basis of these selective molecular responses to IDELA in vitro and its possible correlation with the presence of somatic mutations in FL (CREBBP, EP300, EPHA7, EZH2, KMT2D, MEF2B, RRAGC, TNFAIP3 and TNFRSF14).We have also explored the combination of IDELA with the B-cell lymphoma 2 (BCL2) inhibitor ABT-199/Venetoclax and have uncovered a synergistic interaction between the two drugs that is maintained in FL-FDC/M2 co-cultures (n=9). This synergy may be linked to the downregulation of the anti-apoptotic proteins Mcl-1, Bcl-XL, and BFL-1 induced by IDELA, together with the induction of the pro-apoptotic BH3-only HRK and BIM. We are currently performing BH3 profiling of FL primary cellswith FDC-M2 co-cultures to identify which patients may be more susceptible to this drug combination.Conclusions: Our results suggest a differential role of IDELA in the context of FL-FDC/FL-T cell crosstalk that may be linked to the mutational patient profile. IDELA ABT-199 combination treatment is highly efficacious in FL-FDC/M2 co-cultures. DisclosuresYahiaoui:Gilead Sciences, Inc.: Employment, Equity Ownership. Lopez-Guillermo:Janssen: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Roche: Consultancy, Other: Research grant; Novartis: Consultancy. Roue:Gilead Sciences, Inc.: Research Funding. Tannheimer:Gilead Sciences, Inc.: Employment. Pérez-Galán:Gilead Sciences, Inc.: Research Funding.

Idelalisib-Rituximab Results in Considerable Toxicity but Induces Durable Clinical Remissions in Patients with TP53 Disrupted B Cell Prolymphocytic Leukemia

BackgroundB-cell prolymphocytic leukaemia (B-PLL) is a rare disorder representing 1% of lymphocytic leukemias. With a median age of 69 years, pts characteristically present with B symptoms, marked lymphocytosis, cytopenias, massive splenomegaly and minimal lymphadenopathy. The largest trial of B-PLL included only 14 patients (pts) (Döhner et al, 1993). There are no randomized trials published in B-PLL. The median overall survival is 3 years. 13q14, 11q23 and 17p deletions are common by fluorescence- in-situ hybridisation (FISH) (Lens et al, 1999). TP53 mutations are noted in >50%, conferring resistance to immunochemotherapy (Dearden 2012). In the absence of international guidelines or trial data, clinicians typically employ fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine-R (BR) in TP53- intact pts with allogeneic stem cell transplant (allo-SCT) consolidation in eligible, chemotherapy-sensitive pts (Castagna et al, 2005). For TP53 -disrupted B-PLL, alemtuzumab has efficacy but is associated with serious infectious toxicity.The B-cell-receptor signaling pathway plays a critical role in CLL pathogenesis, although little is known regarding its importance in B-PLL (Bernal et al, 2001). This pathway is partly mediated by the activation of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ) which is highly expressed in lymphoid cells (Herishanu et al, 2011). Idelalisib is a first-in-class, potent, oral, selective PI3Kδ inhibitor. Initial results of the first 5 pts in the compassionate use programme describe clear efficacy of idelalisib-rituximab (I-R) in TP53- disrupted B-PLL (Eyre et al, 2016). We update this series with considerably longer follow up and additional pts.Methods8 pts received I-R in a UK-wide compassionate use programme supported by Gilead. Data was retrospectively collected for adverse events (AEs), clinical and radiological responses. Rituximab (375 mg/m2) was given 2-weekly (cycle (C) 1-2) and then 4-weekly (C3-6). Idelalisib 150 mg b.d. was given continuously with dose interruption and reduction as required for toxicity and was continued in pts with response after C6 as monotherapy. Response was ascertained radiologically and clinically according to institutional practice. AEs were reported prospectively to Gilead. FISH for p53 deletion was performed in all pts. Sanger sequencing was performed in 3 pts. Standard infectious prophylaxis was routinely added at the time that the safety signal was announced.ResultsThe median age was 64.5 years (range: 57-76 years). 7 were male and 1 was female. The median time from diagnosis to first treatment was 9.5 months (range: 2-60 months). 1 pt had a prior splenectomy, but all others had small volume lymphadenopathy and splenomegaly prior to I-R. TP53 deletions by FISH were found in 7 pts. No known additional mutations were noted. Standard cytogenetics were not performed. 4 pts were treatment naïve, 1 pt received prior methylprednisolone, 1 pt BR, gemcitabine-cisplatin and alemtuzumab, 1 pt alemtuzumab and 1 pt R-CVP and then BR. 5 pts completed 6C x 28-day I-R. 3 pts stopped early: 1 pt died of an unrelated lung cancer in C2, and 2 pts stopped due to idelalisib-related grade (G) 4 colitis at C4.All 8 pts responded to I-R. The single pt who died early of lung cancer obtained a partial response. All other 7 pts obtained complete remission (CR) when assessed by examination, FBC, radiological and FISH. Of those 7 pts, only 1 progression has occurred. This pt subsequently responded to ibrutinib. 1 pt (treatment naïve) died in CR of G5 pneumonitis at 10 months on therapy. There are 5 ongoing CRs at a median of 18 months (range 17-29 months). 2 of these 5 have stopped idelalisib due to toxicity (both G3-4 colitis), 2 remain on monotherapy, and 1 has undergoing consolidation with an allo-SCT having stopped idelalisib (G3 diarrhoea). The median follow up for all pts is 18 months (range 1-29 months).ConclusionsI-R displays rapid, deep and durable remissions in TP53 -disrupted B-PLL. The toxicity profile of idelalisib is well described and is clearly demonstrated in this cohort. Pneumonitis, colitis and CMV reactivation were particularly noteworthy. Of interest, remissions were durable in the 2 pts that stopped therapy following colitis for 13 and 14 months respectively. Our data supports importance of compassionate use programme to study novel agents in rare disorders. Updated response and toxicity data will be presented. [Display omitted] DisclosuresFox:Gilead: Consultancy, Honoraria, Other: travel expenses, Speakers Bureau. Bloor:Roche: Honoraria; Gilead: Consultancy, Other: travel expenses; AbbVie: Honoraria, Other: travel expenses; Janssen: Other: travel expenses, Speakers Bureau. Dungawalla:Gilead: Honoraria. Shankara:Gilead: Honoraria, Other: Travel expenses, Speakers Bureau. Schuh:Abbvie: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria, Research Funding; Roche: Honoraria; Novartis: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Gilead: Consultancy; Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria.

Efficacy Results of a Phase 2 Trial Evaluating Idelalisib Plus Ofatumumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia

Efficacy Results of a Phase 2 Trial Evaluating Idelalisib Plus Ofatumumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia

Risk Factors for Grade 3/4 Transaminase Elevation in Patients with Chronic Lymphocytic Leukemia Treated with Idelalisib

Introduction: Idelalisib (IDELA) is a selective PI3Kδ inhibitor approved for use with rituximab in patients with previously treated chronic lymphocytic leukemia (CLL). Reversible transaminase elevation (TAE) has been observed in all CLL clinical trials involving IDELA, with frequencies of Gr ≥3 elevation in company sponsored Ph 2 and 3 studies utilizing the approved dose of 150 mg orally twice a day, ranging broadly from approximately 10% (Sharman ASH 2014) to 41% (Hillmen EHA 2017). TAE leads to permanent discontinuation of IDELA in approximately 3% of patients (Coutre EHA 2015). Risk factors for Gr ≥3 TAE are not well understood. Lampson et al. (Blood 2016) reported a trend toward increased risk in younger patients and those with mutated IGHV in a series of 24 previously untreated CLL patients who received IDELA monotherapy. In the present study, we analyze the rates of Gr ≥3 TAE across all fully enrolled, Gilead sponsored Ph 2 and 3 studies with the goal of identifying risk factors related to patient and treatment characteristics and selected CLL genetic alterations. Methods: Data were reviewed from patients who received at least 1 dose of IDELA in any of 6 Ph 2 or 3 studies, 3 for treatment naive (TN) and 3 for relapsed/refractory (R/R) CLL. The following variables were used for analysis: age, prior therapy (Y vs N), combination with bendamustine plus rituximab (BR; Y vs N), del(17p) (Y vs N), and IGHV mutated vs unmutated. Results: A total of 853 patients were enrolled and treated with IDELA (Table 1) and comprise the safety analysis set (SAS). The median age was 67 y (range: 37-90), and the median IDELA exposure time was 11 mo (range: Conclusions: In this ad hoc analysis of 853 patients treated in Gilead sponsored trials of IDELA, younger age and TN status were risk factors for developing Gr ≥3 elevation of hepatic transaminases, as was treatment with BR for patients with R/R CLL. The highest incidence of Gr ≥3 TAE was observed in a single-arm trial of previously untreated patients with del(17p). IGHV mutation status was not a significant risk factor in this dataset. A statistical model of risk factors for Gr ≥3 TAE will be presented, considering interactions between the factors. Disclosures Brown: Infinity Pharmaceuticals: Consultancy; Pharmacyclics: Consultancy; Sun BioPharma: Consultancy, Research Funding; Astellas Pharma: Consultancy; Redx: Consultancy; Janssen: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Honoraria; Roche/Genentech: Consultancy; Janssen Oncology: Honoraria; Gilead: Consultancy, Research Funding; Pfizer: Consultancy; AstraZeneca: Consultancy. Zelenetz: Genentech Roche: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Mei Pharma: Research Funding; Hospira: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria. Furman: TG Therapeutics: Consultancy; Verstem: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy, Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; Genentech: Consultancy. Lamanna: Gilead: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Mato: DTRM: Research Funding; Pharmacyclics: Research Funding; Portola: Research Funding; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity9s Board of Directors or advisory committees; Kite: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; TG Therapeutics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Regeneron: Research Funding; AbbVie: Consultancy, Research Funding. Montillo: Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Roche: Research Funding; Novartis: Honoraria; Genetech: Research Funding. O9Brien: CLL Global Research Foundation: Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy; Alexion: Consultancy; Acerta: Other: Research Support: Honorarium, Research Funding; GSK: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Vaniam Group LLC: Consultancy; AbbVie: Consultancy; ProNAI: Other: Research Support: Honorarium, Research Funding; Celgene: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Sunesis: Consultancy; Astellas: Consultancy; Aptose Biosciences, Inc.: Consultancy. Dreiling: Gilead Sciences, Inc.: Employment. Dubowy: Gilead Sciences, Inc.: Employment, Equity Ownership. Kim: Gilead Sciences, Inc.: Employment. Munugalavada: Gilead Sciences, Inc.: Employment, Equity Ownership. Robak: Janssen: Consultancy, Honoraria, Research Funding; Akari Therapeutics Plc: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Hillmen: Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Roche: Consultancy, Honoraria, Research Funding.

Idelalisib Impairs TREM-1 Mediated Neutrophil Inflammatory Responses

Introduction: Idelalisib is a selective PI3Kδ inhibitor approved for B-cell non-Hodgkin lymphoma (B-NHL). As adverse events recurrent and severe infectious complications have been observed and experimental data suggest an influence on innate immune defense. Since PI3K is involved in signal transduction of triggering receptor expressed on myeloid cells (TREM)-1, an activating receptor on polymorphonuclear neutrophils (PMN) and macrophages that is implicated in innate immune activation of these cells, we asked, whether PMN function might be impaired by this small-molecule inhibitor.Methods: PMN from healthy humans were isolated by dextran sedimentation and density gradient centrifugation and pretreated with idelalisib, selective PI3Kα/-β/-γ inhibitors (all 1 µg/ml) or vehicle control (DMSO). Cells were activated with anti-TREM-1 agonistic antibody, an isotype matched control antibody (both own production) or Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS, 1 µg/ml). Effector functions were evaluated by analyzing phagocytosis, CD62L shedding, degranulation and oxidative burst by flow cytometry or oxidative burst kinetics in a fluorescence reader, respectively. Interleukin-8 (IL-8) release was detected by ELISA. Western blot analyses of phosphorylated and non-phosphorylated proteins were used for the detection of the involved signaling events, and calcium flux was detected by flow cytometry. Similarly, blood samples of patients receiving idelalisib treatment were followed up for PMN functions as described above to investigate immunomudulatory effects in vivo .Results: We observed a significantly impaired oxidative burst, degranulation (CD66b and CD11b surface expression), CD62L shedding and cytokine (IL-8) release upon PMN activation via TREM-1 ligation and partly by LPS. Furthermore, TREM-1 mediated calcium flux was diminished and TREM-1 signaling was impaired regarding phosphorylation of p38MAPK, ERK1/2 and AKT indicating that the activation of Ca2+ flux as well as MAP kinases and AKT occur down stream of PI3K. Selective PI3Kα and PI3Kβ inhibitors (but not a PI3Kγ inhibitor) showed similar activation patterns, furthermore suggesting that impaired PMN functionalities are due to an unspecific PI3K class IA inhibitory effect. To assess whether our results obtained in vitro may be of relevance in vivo, we analyzed blood samples of B-NHL patients receiving idelalisib therapy ex vivo. Here we again detected an impairment of TREM-1 mediated and partly of TLR4 mediated PMN activation. PMN functions from one patient were analyzed during and after idelalisib therapy. Interestingly, PMN functions were restored after discontinuation of treatment, indicating that the functional PMN deficiencies are reversible.Conclusion: Small-molecule inhibitors might cause a neutropenia-like susceptibility to infections in patients by leading to impaired PMN functions. These side effects are largely unrecognized in daily clinical routine so far by monitoring just for counts of white blood cells, but not their functions. DisclosuresTeschner:Astellas Pharma GmbH: Other: Travel support; Gilead Sciences GmbH: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Jazz Pharmaceuticals Germany: Other: Travel Support; MSD Sharp & Dohme GmbH: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Pfizer Deutschland GmbH: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hess:Celgene: Other: Grants and personal fees; Pfizer: Other: Grants and personal fees; CTI: Other: Grants; Roche: Other: Grants and personal fees; Janssen: Other: Personal Fees. Radsak:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Gilead: Other: Travel support; Acceleron: Research Funding.

Exposure-Response of Idelalisib Administered in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Chronic Lymphocytic Leukemi

Background: Idelalisib (IDELA) is a potent and selective PI3Kδ inhibitor approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) (in combination with rituximab) and relapsed indolent non-Hodgkin lymphoma (iNHL) subtypes, follicular lymphoma, and small-cell lymphocytic lymphoma. The relationship between plasma exposures of IDELA and clinical efficacy and safety were evaluated in relapsed/refractory CLL subjects following administration of IDELA 150 mg twice daily (BID) in combination with bendamustine (B) and rituximab (R; Study GS-US-312-0115).Methods: IDELA peak and trough plasma samples were collected every 4 weeks (up to 24 weeks) starting at baseline. Data for safety and efficacy endpoints were collected every 2 and 12 weeks, respectively. IDELA plasma exposures (Cmax, AUCtau, and Ctau) were generated using a previously developed population pharmacokinetic (PK) model (Jin F, et al. CCP . 77: 89-98, 2016). Efficacy and safety data from the phase 3, randomized, double-blind, placebo-controlled study (GS-US-312-0115) were included in the PK/pharmacodynamics (PD) analyses. Efficacy endpoints, including best overall response rate (BOR), duration of response (DOR), progression-free survival (PFS), sum of products of the greatest perpendicular diameters (SPD) of index lesions, and lymph node response rate (LNR), were evaluated against IDELA exposures (AUCtau and Ctau). Safety endpoints, including Grade 3 or 4 adverse events of neutropenia, skin rash, infection, pneumonia, pneumonitis, diarrhea, colitis, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, were evaluated versus IDELA exposures (AUCtau and Cmax). The relationship between average daily dose of IDELA versus exposures (AUCtau and Cmax) was also evaluated. Statistical analysis (such as Kaplan-Meier survival analysis, Cox proportional hazard model, or logistic regression) was conducted for selected efficacy and safety endpoints.Results: Median IDELA exposures were similar in subjects who achieved an objective response (complete response or partial response) and subjects who did not respond (stable disease or progressive disease) and across the 4 response categories (p=0.68; Table 1). As IDELA exposure increased over quartiles, there was no clear trend of prolonged DOR (p=0.50), PFS (p=0.69), or change in SPD. No relationship between LNR (responder versus non-responder) and IDELA exposure was observed. No association was observed between IDELA exposure vs incidence of neutropenia (p=0.35), diarrhea (p=0.78), pneumonia (p³0.12), colitis (p=0.62), AST or ALT elevation (p=0.45), skin rash, and pneumonitis. An increase in the incidence of Grade 3 or 4 infections with higher IDELA exposures was observed (p=0.021). Overall, IDELA in combination with BR was well tolerated, as indicated by the comparable average daily doses (~300 mg) administered across quartiles of IDELA exposure.Conclusions: No exposure-response relationships were observed for efficacy or safety (except infections) endpoints at IDELA 150 mg BID. These results are consistent with the previously observed IDELA exposure-response relationship in subjects with CLL (in combination with rituximab or ofatumumab) and iNHL. Overall, this analysis supports IDELA 150 mg BID in combination with BR for the treatment of relapsed CLL in patients who are fit for immunochemotherapy. [Display omitted] DisclosuresDaryani:Gilead Sciences, Inc.: Employment, Equity Ownership. Sharma:Gilead Sciences, Inc.: Employment, Equity Ownership. Xing:Gilead: Employment, Equity Ownership. Silverman:Gilead Sciences, Inc.: Employment, Equity Ownership. Adewoye:Gilead Sciences, Inc.: Employment, Equity Ownership. Mathias:Gilead Sciences, Inc.: Employment, Equity Ownership.

Discovery, Optimization, and Evaluation of Quinazolinone Derivatives with Novel Linkers as Orally Efficacious Phosphoinositide-3-Kinase Delta Inhibitors for Treatment of Inflammatory Diseases.

Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade" of the propeller led to identification of a series of potent and selective PI3Kδ inhibitors. Among them, compound 50 afforded an optimum balance of PK profiles and potency. Oral administration of 50 attenuated the arthritis severity in a dose-dependent manner in a collagen-induced arthritis model without obvious toxicity. Furthermore, 50 demonstrated excellent pharmacokinetic properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.

A phase Ib study of a PI3Kδ inhibitor Linperlisib in patients with relapsed or refractory peripheral T-cell lymphoma.

7531 Background: PI3Kδ inhibitors have been shown to have important roles in blocking mitogenic and survival signaling within the tumor cell and the tumor microenvironment and activate antilymphoma immune responses. Linperlisib is an oral highly selective small molecule inhibitor of PI3Kδ and has been demonstrated to be well-tolerated with a favorable PK profile in patients with lymphomas at the RP2D. This phase Ib study is evaluating the efficacy and safety of Linperlisib in relapsed or refractory peripheral T-cell lymphoma (PTCL), a highly aggressive malignancy with few treatment options for patients. Methods: Eligible PTCL patients who must have received at least 1 prior systemic conventional therapy were administrated Linperlisib 80mg orally once daily (RP2D) in 28 days cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Tumor response was assessed by IWG 2007 criteria with CT performed every 2 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoint was toxicity assessed by NCI-CTCAE5.0. Results: As of February 2, 2021, 36 PTCL patients were enrolled in this exploratory trial. Most patients were stage III (38.2%) or IV (50%). Of the 27 evaluable patients to date, the PTCL histologies were PTCL-NOS (n=12), AITL (n=10), ALCL (n=3), NKTCL (n=1) and MEITL (n=1). 19 of the 27 evaluable patients had Investigator confirmed responses for a 70.4% ORR including 25.9% CR (7pt) and 44.4% PR (12pt). In the major subtypes, ORR was 50% (6/12) PTCL-NOS and 80% (8/10) AITL, respectively. A disease control rate of 100% was observed, and most responses occurred by first assessment at C2D28. One subject who had a CR at C2D28 is currently in cycle 9 and continuing on Linperlisib. 36 patients experienced at least 1 AE in the trial, with 95% of AEs ≤ grade 2. Consistent with previously treated lymphoma patients, no unexpected toxicities were observed. The most common TRAEs (≥10%) were neutrophil count decreased (55.6%), leukocyte count decreased (33.3%), hypertriglyceridemia (22.2%), aspartate aminotransferase increased (16.7%), hypercholesterolemia (16.7%), alanine aminotransferase increased (11.1%), creatinine increased (11.1%), rash (11.1%), thrombocyte count decreased (11.1%) and electrocardiogram T wave abnormal (11.1%). No AE grade 4 was observed. 6 patients (16.7%) experienced at least one SAE, in which 4 (11.1%) SAEs were considered to be drug-related, including neutrophil count and leukocyte count decreased (2.8%), gastritis (2.8%), and pneumonia (5.6%). Conclusions: The oral PI3Kd inhibitor Linperlisib had significant activity in patients with relapsed or refractory PTCL. Toxicities with Linperlisib therapy were generally tolerable and manageable. Further efficacy and safety is being evaluated. Clinical trial information: NCT04108325.

A phase Ib study of the PI3Kδ inhibitor linperlisib in patients with advanced solid tumors.

3099 Background: Phosphatidylinositol-3 kinase (PI3K) pathways are important elements of tumor survival and progression, and PIK3C genes are often mutated or overexpressed in many cancers. Additionally, PIK3D (PI3Kδ) modulates immune cell functions in tumors, elaborating another PI3Kδ inhibition feature with a potential clinical benefit. Linperlisib, an oral and highly selective PI3Kδ inhibitor, demonstrated potent anti-tumor activity in syngeneic animals from previous research. In this Phase 1b study, the safety, tolerability, and efficacy of linperlisib is under investigation for patients with advanced solid tumors. Methods: Linperlisib was given orally once daily (QD) in 28-day cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was assessed according to RECIST1.1 criteria. Results: As of December 28, 2020, 70 patients were enrolled in the Phase1b study, with advanced cancers, including colorectal (n = 22), breast (n = 8), lung (n = 8), kidney (n = 5), liver (n = 4), ovarian (n = 1), head and neck (n = 5), and esophageal (n = 1) cancers; sarcomas, (n = 4), small intestinal stromal tumor (n = 3), thymic (n = 2), gallbladder (n = 2), gastric (n = 4), and pancreatic (n = 1) carcinomas. The patients were heavily pretreated with an average of 4 previous lines of therapy. Among the 70 patients, the most common nonhematologic TEAEs (all grades/grade≥3) were proteinuria (37.14%/0%), elevated aspartate aminotransferase (20%/0%), nausea (20%/0%), oral mucositis (2.8%/2.8%), diarrhea (2.8%/2.8%). The most common hematological TEAEs were leukopenia (24.28%/0%) and neutropenia (17.14%/4.28%). There were no unexpected toxicities in this study. Of 42 patients evaluable for response, the overall response rate was 2.38%. Notably, the disease control rate (DCR) was 45.24% from monotherapy treatment. One patient with thymic carcinoma obtained a partial response (80.8% reduction of the target lesion), with a duration of response of more than 6 cycles. The treatment of this subject is continuing. A lung adenocarcinoma subject reached radiological stable disease associated with 13.7% reduction in the target lesion and disease control for approximately 6 months. Conclusions: In this study, the PI3K inhibitor, linperlisib exhibited a favorable safety profile as was previously seen in lymphoma patients. Monotherapy treatment with linperlisib was observed to impart a high DCR in advanced solid cancers of many types. Available data from linperlisib and other PI3K inhibitors suggests that linperlisib may limit tumor growth directly, but also by affecting the tumor immune microenvironment. With these promising indications of clinical tolerability and activity, further investigation of linperlisib alone or in key therapeutic combinations is warranted. Clinical trial information: NCT04049929.

Discovery of a new series of PI3K-δ inhibitors from Virtual Screening

PI3K-δ mediates key immune cell signaling pathways and is a target of interest for treatment of oncological and immunological disorders. Here we describe the discovery and optimization of a novel series of PI3K-δ selective inhibitors. We first identified hits containing an isoindolinone scaffold using a combined ligand- and receptor-based virtual screening workflow, and then improved potency and selectivity guided by structural data and modeling. Careful optimization of molecular properties led to compounds with improved permeability and pharmacokinetic profile, and high potency in a whole blood assay.

SAF-248, a novel PI3Kδ-selective inhibitor, potently suppresses the growth of diffuse large B-cell lymphoma.

PI3Kδ is expressed predominately in leukocytes and overexpressed in B-cell-related malignances. PI3Kδ has been validated as a promising target for cancer therapy, and specific PI3Kδ inhibitors were approved for clinical practice. However, the substantial toxicity and relatively low efficacy as a monotherapy in diffuse large B-cell lymphoma (DLBCL) limit their clinical use. In this study, we described a novel PI3Kδ inhibitor SAF-248, which exhibited high selectivity for PI3Kδ (IC50 = 30.6 nM) over other PI3K isoforms at both molecular and cellular levels, while sparing most of the other human protein kinases in the kinome profiling. SAF-248 exhibited superior antiproliferative activity against 27 human lymphoma and leukemia cell lines compared with the approved PI3Kδ inhibitor idelalisib. In particular, SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines (with GI50 values < 1 μM in 5 DLBCL cell lines). We demonstrated that SAF-248 concentration-dependently blocked PI3K signaling followed by inducing G1 phase arrest and apoptosis in DLBCL KARPAS-422, Pfeiffer and TMD8 cells. Its activity against the DLBCL cells was negatively correlated to the protein level of PI3Kα. Oral administration of SAF-248 dose-dependently inhibited the growth of xenografts derived from Pfeiffer and TMD8 cells. Activation of mTORC1, MYC and JAK/STAT signaling was observed upon prolonged treatment and co-targeting these pathways would potentiate the activity of SAF-248. Taken together, SAF-248 is a promising selective PI3Kδ inhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.

Phosphatidylinositol 3-Kinase δ Inhibitor-Induced Immunomodulation and Secondary Opportunistic Infection in the Cynomolgus Monkey (Macaca fascicularis).

Phosphatidylinositol 3-kinases (PI3Ks) regulate intracellular signaling events for multiple cell surface receptors. Phosphatidylinositol 3-kinase δ, 1 of 4 class I PI3K isoforms, is primarily found in leukocytes and regulates immune cell functions. Here, we report changes in the immune and digestive systems that were associated with AMG2519493, a highly selective small-molecule PI3Kδ inhibitor. Following 1- or 3-month oral repeat dosing in the cynomolgus monkey, changes were observed in circulating B cells, lymphoid tissues (spleen, lymph nodes, gut-associated lymphoid tissue, tonsil), and the digestive tract. Decreased circulating B cells and lymphoid cellularity in B cell-rich zones in lymphoid tissues were attributed to the intended pharmacologic activity of AMG2519493. Dose- and duration-dependent digestive system toxicity was characterized by inflammation in the large intestine and secondary opportunistic infections restricted to the digestive tract. Digestive tract changes were associated with moribundity and mortality at high-dose levels, and the effect level decreased with increased duration of exposure. These observations demonstrate the role of PI3Kδ in regulation of the immune system and of host resistance to opportunistic infections of the digestive tract.

Optimization of Versatile Oxindoles as Selective PI3Kδ Inhibitors.

The 3,3-disubstituted oxindole moiety is a versatile and rigid three-dimensionally shaped scaffold. When engineered with a purine hinge-binding core, exceptionally selective PI3Kδ kinase inhibitors were discovered by exploiting small differences in isoform selectivity pockets. Crystal structures of early lead 2f bound to PI3Kδ and PI3Kα helped rationalize the high selectivity observed with 2f. By attenuating the lypophilicity and metabolic liabilities of an oxindole moiety, we improved the preclinical species PK and solubility and reduced adenosine uptake activity. The excellent potency and kinome selectivity of 7-azaoxindole 4d and spirooxindole 5d, together with a low plasma clearance and good half-life in rat and dog, supported a low once-daily predicted human dose.

Discovery of (S)-2-(1-(4-Amino-3-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-3-cyclopropyl-5-fluoroquinazolin-4(3H)-one (IHMT-PI3Kδ-372) as a Potent and Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.

Accumulated pieces of evidence have shown that PI3Kδ plays a critical role in chronic obstructive pulmonary disease (COPD). Using a fragment-hybrid approach, we discovered a potent and selective PI3Kδ inhibitor (S)-18. In the biochemical assay, (S)-18 inhibits PI3Kδ (IC50 = 14 nM) with high selectivity over other class I PI3Ks (56∼83 fold). (S)-18 also achieves good selectivity over other protein kinases in the kinome (S-score (35) = 0.015). In the cell, (S)-18 selectively and potently inhibits the PI3Kδ-mediated phosphorylation of AKT T308 but not other class I PI3K-mediated signaling. Additionally, (S)-18 exhibits no apparent inhibitory effect on CYP isoforms except for a moderate effect on CYP2C9. Furthermore, it shows no apparent inhibitory activity against hERG (IC50 > 10 μM). In vivo, (S)-18 displays favorable PK properties for inhaled delivery and improves lung function in a rodent model of pulmonary inflammation. These results suggest that (S)-18 might be a new potential therapeutic candidate for COPD.

Safety Profile of Idelalisib in Patients with Refractory Follicular Lymphoma: Interim Analysis of a Noninterventional Study

Introduction: Idelalisib, a selective oral inhibitor of PI3Kδ, was approved by the FDA and EMA as monotherapy for patients with advanced follicular lymphoma (FL) based on positive efficacy and safety results from the registration phase 2 trial in patients with indolent non-Hodgkin lymphoma (iNHL) refractory to 2 prior regimens (NCT01282424; 101-09). Phase 3 studies of idelalisib in earlier lines of treatment for iNHL were terminated prematurely due to an increased risk of death and higher incidence of serious adverse events (AEs) associated with idelalisib. Herein, we present the preplanned interim results as of June 8, 2020, of the safety of idelalisib monotherapy in patients with refractory FL treated in the EU from one of the largest noninterventional trials of idelalisib. Methods: This was a noninterventional, partially retrospective cohort study conducted in 10 European countries (EUPAS19618; NCT03568929). Eligible patients were adults aged ≥18 years treated with idelalisib for refractory FL, per the Summary of Product Characteristics and treatment guidelines, in routine clinical practice. Data was collected from patients' medical records and anonymized. Safety events were evaluated and included treatment-emergent AEs (TEAEs), health outcomes of interest (HOIs) requested by the EMA (bowel perforations, Grade ≥3 diarrhea/colitis, progressive multifocal leukoencephalopathy, pneumonitis, Grade ≥3 rash, infections, Stevens-Johnson syndrome, transaminase elevations, and hepatocellular injury), and deaths. TEAEs were defined as AEs that occurred between first dose and 30 days after last dose. Data were summarized using descriptive statistics. Rates per person-year were calculated as the number of patients experiencing an AE divided by the person-time at risk. Results: For the 158 patients included in this analysis, median age was 67 years and 84 (53%) were male. A summary of patient and disease characteristics at baseline are presented in Table 1. At treatment initiation, 47 (30%) patients had grade 2 FL and 105 (66%) had Ann Arbor stage III/IV disease, though these characteristics were not captured for 42% and 20% of patients, respectively; 149 (94%) had ≥2 prior therapies. The median duration of idelalisib exposure was 165 (range 11-1321) days, and patients were observed for a median of 323 (range 12-1676) days. In total, 144 (91%) patients experienced a TEAE, with a rate of 3.36 per person-year. The proportion of patients experiencing Grade 3/4, severe, common, and HOI TEAEs are presented in Table 2. Diarrhea of any grade was the most common TEAE, and infections were the most common treatment-emergent HOI. During the TEAE period, 19 (12%) patients died (Table 2). The proportion of common TEAEs reported in this analysis were lower compared with a subgroup analysis of patients with FL from the registration trial (Salles Haematologica 2017; DOI: 10.3324/haematol.2016.151738), including diarrhea 27% vs 51%, cough 9% vs 32%, fever/pyrexia 10% vs 29%, pneumonia 5% vs 11%; treatment-emergent Grade 3/4 diarrhea/colitis and transaminase elevations were also lower in this analysis: 8% vs 17% and 4% vs 14%. This comparison is limited due to differences in study populations, namely that patients in the registration trial had more advanced disease (stage III/IV, 66% vs 83%) and had a higher median number of prior therapies (3 vs 4). Conclusions: This interim analysis of the safety of idelalisib in patients with refractory FL in this large noninterventional safety study provides an estimate of potential final study findings. The AE profile from this study appears to corroborate the known safety profile of idelalisib. No new safety signals were detected. Disclosures Salles: Bristol Myers Squibb: Consultancy, Other; Genmab: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Epizyme: Consultancy; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Debiopharm: Consultancy; Takeda: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Kite: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other. Pettengell:Celgene: Honoraria; MEI Pharma: Honoraria; Roche Ltd: Honoraria; Takeda: Honoraria. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Abbvie: Other: travel grants, Research Funding; Gilead: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Corradini:Kiowakirin: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other; BMS: Other; Servier: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other. De Belder:Gilead Sciences Europe, Ltd.: Current Employment. Shah Gupta:Gilead Sciences, Ltd.: Current Employment. van Troostenburg:Gilead Sciences GmbH: Current Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Current Employment. Ramroth:Gilead Sciences, Ltd.: Current Employment.

Abstract PO-46: Mechanisms of resistance to the PI3K inhibitor copanlisib in marginal zone lymphoma

Abstract Background: PI3Kδ is expressed in B cells and has a central role in the B-cell receptor signaling. Copanlisib is a highly selective PI3Kδ and PI3Kα inhibitor, and it is currently under clinical development in indolent lymphomas including marginal zone lymphoma (MZL). Copanlisib is Food and Drug Administration (FDA) approved for the treatment of patients with relapsed or refractory follicular lymphoma. Nevertheless, a subset of patients can eventually relapse due to acquired resistance. A better understanding of resistance mechanisms could help to design improved therapies; hence, we generated MZL cell lines resistant to copanlisib. Materials and Methods: Cells were kept on copanlisib (IC90) until acquisition of resistance (RES) or with no drug (parental, PAR). Stable resistance was confirmed by MTT assay after 3 weeks of drug-free culture. Multidrug resistance phenotype was ruled out by confirming sensitivity to vincristine. Cells underwent transcriptome profiling (RNA-Seq) and immunophenotypic analysis. Results: The RES models were obtained from VL51 cell line with over 50-fold times higher IC50s than PAR counterparts. Of note, the copanlisib-resistant lines showed decreased sensitivity to other PI3K inhibitors such as duvelisib (50-fold) and idelalisib (5-fold) and to the BTK inhibitor ibrutinib (15-fold), suggesting that the mechanism observed here might drive resistance to other downstream B-cell receptor inhibitors. Gene expression profiles of RES showed the upregulation of cytokine signaling (IL1A, IL1B, CXCR4), NFkB (LTA, TNF), MAPK (RASGRP4, RASGRP2), and JAK-STAT (STAT3, JAK3) signaling pathways and negative regulators of apoptosis (CD44, JUN). Conversely, repressed genes in RES were involved in cell adhesion (ITGA4, ITGB1), antigen presentation (HLAs), and IFN response (PARP12, GBP6). Consistent with the overexpression of antiapoptotic signaling genes, RES cells exhibited also resistance to the BCL2-inhibitor venetoclax, either as a single as in combination with copanlisib. Flow cytometry confirmed the CXCR4 upregulation and the downregulation of CD49d (ITGA4), paired with reduced CD20 and CD81 surface expression. In accordance, addition of a CXCR4 inhibitor overcame resistance to copanlisib. Conclusions: We created a model of secondary resistance to the PI3K inhibitor copanlisib, derived from an MZL cell line. This model will help in clarifying mechanisms of resistance to the drug and to evaluate alternative therapeutic approaches. Indeed, we already identified novel potential targets, such as IL1 and CXCR4, that might be exploited in overcoming resistance to copanlisib and are worthy of further investigation. Citation Format: Alberto J. Arribas, Sara Napoli, Luciano Cascione, Eugenio Gaudio, Roberta Bordone-Pittau, Marilia Barreca, Giulio Sartori, Chiara Tarantelli, Filippo Spriano, Andrea Rinaldi, Anastasios Stathis, Georg Stussi, Davide Rossi, Emanuele Zucca, Francesco Bertoni. Mechanisms of resistance to the PI3K inhibitor copanlisib in marginal zone lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-46.

SHC014748M, a novel selective inhi-bitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia

PI3Kδ (phosphatidylinositol 3-kinase-δ), one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ for patients with indolent non-Hodgkin lymphomas. Here in this paper, we comprehensively evaluated the in vitro and in vivo antitumor activity of SHC014748M, an oral selective inhibitor of PI3Kδ under Phase I clinical evaluation. Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary chronic lymphocytic leukemia (CLL) cells. Scid mice were subcutaneously inoculated with the SU-DHL-6 cell line. SHC014748M was more selective for PI3Kδ inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines and primary CLL cells. SHC014748M also inhibited phosphorylation of AKT, targets downstream of PI3Kδ, in both lymphoma cells and primary CLL cells. In vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 in patient serum decreased sharply after SHC014748M treatment. According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL.