Real-life efficacy and safety of idelalisib in 55 double-refractory follicular lymphoma patients.

Idelalisib, a reversible inhibitor of PI3Kδ (phosphoinositide-3 kinase delta), showed remarkable activity in the phase II DELTA trial, leading to its approval by the European Medicines Agency (EMA) in patients with relapsed/refractory (R/R) follicular lymphoma (FL). However, real-life data on idelalisib are scarce. We treated 55 double-refractory FL patients with idelalisib in a real-life setting. With a median exposure to idelalisib of 10 months (range 1-43), overall response rate was 73%, the highest ever reported. Non-haematological toxicities were mild and manageable. At 12 months, 80% of patients were alive, and 72% disease-free. The efficacy and safety of idelalisib was confirmed in a real-life setting.

Results of a Prospective Non-Interventional Post-Authorization Safety Study of Idelalisib in Germany.

BACKGROUND: In pivotal studies, idelalisib demonstrated remarkable efficacy and manageable tolerability in patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This prospective, multicenter, non-interventional post-authorization study assessed the characteristics, clinical management, and outcome of CLL and FL patients receiving idelalisib in routine clinical practice in Germany. PATIENTS: Observational study in CLL and FL patients treated with idelalisib between September 2015 and December 2020. RESULTS: A total of 147 patients with CLL and FL were included with a median age of 75 and 71 years, respectively. More than 80% of patients presented with comorbidity and many CLL patients with documented high-risk genetic features, including del(17p)/TP53 mutation or unmutated IGHV. The median progression-free survival (PFS) and overall survival (OS) were not reached in the CLL cohort irrespective of del(17p)/TP53 or unmutated IGHV. The estimated 6-month PFS and OS rates in CLL were 82% and 92%. The estimated 6-month PFS and OS rates for FL were 32.2% and 77.2%. Overall response rates in the CLL and FL cohorts were 70.4% and 36.4%, with the presence of high-risk genetics having no negative impact. No unexpected adverse events were observed. Most frequently reported adverse drug reactions (ADRs) were diarrhea, nausea, pneumonia, rash, and fatigue. CONCLUSION: This real-world study shows that idelalisib is an effective therapy for CLL and FL, regardless of age and high-risk genetic features, consistent with results from previous clinical trials. Collected safety data and the pattern of ADRs reflect those from previous studies.

Rationale and design of a phase II trial of dacomitinib in advanced non-small cell lung cancer patients with uncommon epidermal growth factor receptor mutations: a prospective and single arm study (DANCE study).

BACKGROUND: Dacomitinib is a second-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). ARCHER-1050 showed that this agent can improve progression-free survival and overall survival in advanced non-small cell lung cancer patients with sensitive EGFR mutation compared to gefitinib. However, it is unclear whether dacomitinib is effective in patients with sensitizing uncommon EGFR mutations in exon 18-21. The aim of this study is to investigate the safety and efficacy of dacomitinib in these patients. METHODS: This is a single arm, prospective, open label and phase II trial. Sample size will be calculated by a minimax two-stage design method based on the following parameters: α = 0.075, 1-ß = 0.9, P0 = 0.20, P1 = 0.45 and a dropout rate of 10%. A total of 30 eligible patients will be included. Patients will receive continuous oral therapy with dacomitinib (45 mg/day) until disease progression, withdrawal of consent, or unacceptable toxicity, whichever occurs first. The primary endpoint is objective response rate (ORR) per RECIST version 1.1, as assessed by investigators' review. The second endpoint is disease control rate (DCR), PFS, OS, and safety. DISCUSSION: We conduct a single arm, phase II study to investigate the safety and efficacy of dacomitinib in advanced NSCLC patients with sensitizing uncommon EGFR mutations. The results of the DANCE study will provide new data regarding efficacy and safety of these patients. TRIAL REGISTRATION: NCT04504071.

The Effect of Hepatic Impairment on the Pharmacokinetics of Dacomitinib.

BACKGROUND AND OBJECTIVE: Dacomitinib is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations. To evaluate the effect of hepatic impairment on the pharmacokinetics of dacomitinib, two dedicated studies were conducted to inform optimal dosing. METHODS: Study 1 (NCT01571388) evaluated the effect of mild and moderate hepatic impairment on the plasma pharmacokinetics, safety, and tolerability after a single oral dose of dacomitinib 30 mg, and Study 2 (NCT03865446) evaluated the same endpoints in a severe hepatic impairment population. Both studies were phase I, open-label, parallel-group studies. A one-way analysis of variance (ANOVA) with unequal variance assumption and hepatic impairment group as a fixed effect was used to compare the natural log of area under the plasma concentration-time curve extrapolated to infinite time (AUCinf), AUC from time zero to the last quantifiable concentration (AUClast), and maximum plasma concentration (Cmax) for each hepatic impairment group to the respective normal hepatic function group. Since dacomitinib is a cytochrome P450 (CYP) 2D6 substrate, only participants with extensive or intermediate CYP2D6 phenotypes were included in the primary analysis. RESULTS: The AUCinf for participants with mild, moderate, or severe hepatic impairment decreased by 6%, decreased by 23%, and increased by 4%, respectively, compared with normal hepatic function, while the Cmax for participants with mild, moderate, or severe hepatic impairment increased by 3%, decreased by 20%, and increased by 31%, respectively, compared with normal hepatic function. A single oral dose of dacomitinib 30 mg was well tolerated in all participants. CONCLUSION: Based on these pharmacokinetic results, dacomitinib pharmacokinetics of participants with mild, moderate, or severe hepatic impairment were not statistically different relative to participants with normal hepatic function based on the ANOVA analysis. No dacomitinib dose adjustments for patients with hepatic impairment are recommended. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01571388, registered 5 April 2012; ClinicalTrials.gov NCT03865446, registered 6 March 2019.

Severe infections in patients with lymphoproliferative diseases treated with new targeted drugs: A multicentric real-world study.

BACKGROUND: Lymphoid neoplasms treatment has recently been renewed to increase antitumor efficacy and conventional chemotherapies toxicities. Limited data have been published about the infection risk associated with these new drugs, therefore this study analyzes the infectious complications in patients with lymphoproliferative diseases (LPD) treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab, or pembrolizumab), BTK inhibitors (ibrutinib and acalabrutinib), PI3K inhibitors (idelalisib) and BCL2 inhibitors (venetoclax). METHODS: Multicenter retrospective study of 458 LPD patients treated with targeted therapies in real-life setting, in 18 Spanish institutions, from the time of their commercial availability to August 2020. RESULTS: Severe infections incidence was 23% during 17-month median follow-up; cumulative incidence was higher in the first 3-6 months of targeted drug treatment and then decreased. The most frequent etiology was bacterial (54%). Nine (6%) Invasive fungal infections (IFI) were observed, in its majority in chronic lymphocytic leukemia (CLL) patients treated predominantly with ibrutinib. Significant risk factors for severe infection were: severe lymphopenia (p = 0.009, OR 4.7, range 1.3-1.7), combined targeted treatment vs single agent treatment (p = 0.014 OR 2.2 range 1.1-4.2) and previous rituximab (p = 0.03 OR 1.8, range 1.05-3.3). Infection-related mortality was 6%. In 22% of patients with severe infections, definitive discontinuation of the targeted drug was observed. CONCLUSION: A high proportion of patients presented severe infections during follow-up, with non-negligible attributable mortality, but infection incidence is not superior to the one observed during the chemotherapy era. In selected cases with specific risk factors for infection, antimicrobial prophylaxis should be considered.

Successful treatment of 2 patients with brain metastases from non-small cell lung cancer with epidermal growth factor receptor mutation receiving dacomitinib: A case report.

RATIONALE: Approximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with brain metastasis, which is related to poor survival outcomes. The ability of tyrosine kinase inhibitor drugs to penetrate the blood-brain barrier makes them a potential option for intracranial metastases. Dacomitinib, an irreversible second-generation pan-HER tyrosine kinase inhibitor, has become a standard therapy for patients with epidermal growth factor receptor mutations. However, its efficacy in patients with brain metastases (BMs) is not yet established. Here, we present 2 patients with epidermal growth factor receptor-mutant NSCLC with brain metastasis. After initiation of dacomitinib as first-line treatment, a significant clinical response was achieved, and a long-lasting complete remission was achieved in 1 patient up to this date. PATIENT CONCERN: Case 1 was a 47-year-old man who was admittedtothe hospital because of recurrent cough and expectoration for >1 year. Chest computed tomography scans revealed a high-density shadow in the left upper lobe. Cranial magnetic resonance imaging indicated an abnormal nodular enhancement in the right cerebellar hemisphere. Case 2 was a 55-year-old man with a chief complaint of intermittent cough and expectoration for >1 month. Chest computed tomography revealed a high-density mass in the left superior lobe. Magnetic resonance imaging of the central nervous system revealed 2 abnormal nodular enhancements in the left frontal lobe. DIAGNOSIS: Both patients were diagnosed with lung adenocarcinoma by bronchoscopy and lymph node biopsy. INTERVENTIONS: Both patients received dacomitinib 30 mg once daily as first-line therapy for 8 and 11 months, respectively until disease progression. OUTCOME: After treatment with dacomitinib, both patients achieved complete response in BMs. Progression-free survival was 11 and 8 months, respectively. LESSONS: Dacomitinib strongly controlled BMs in patients with advanced NSCLC, and the adverse reactions were tolerable. Dacomitinib may be considered a new treatment option for these patients. Further prospective studies are recommended to confirm this conclusion.

Quantitative Systems Pharmacology Modeling of Avadomide-Induced Neutropenia Enables Virtual Clinical Dose and Schedule Finding Studies.

Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia; however, the identification of optimal dosing schedules remains a clinical challenge. Quantitative systems pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development. We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage. The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort. Model utility was demonstrated by simulating the avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low-grade neutropenia.

Idelalisib immune-related toxicity is associated with improved treatment response.

Idelalisib is associated with increased occurrence of immune-related adverse events (irAEs). Clinical observations suggest a correlation between immune checkpoint inhibitor-induced irAEs and survival outcomes in patients with solid tumors; however, this relationship in hematologic malignancies is not well understood. In a post hoc analysis of 3 registrational trials, we explored the relationship between Grade ≥3 diarrhea/colitis and alanine/aspartate transaminase (ALT/AST) elevation incidences and efficacy endpoints in patients with indolent non-Hodgkin lymphoma (iNHL), follicular lymphoma (FL), and chronic lymphocytic leukemia treated with idelalisib. Grade ≥3 diarrhea/colitis was associated with higher overall response rate (ORR) and longer progression-free survival (PFS) for all subgroups. Grade ≥3 ALT/AST elevations were associated with improved duration of response and overall survival for all subgroups and improved ORR and PFS for patients with FL or iNHL. Our analysis in hematologic malignancies showed a trend correlating idelalisib-induced Grade ≥3 irAEs with improved efficacy.

A retrospective observational study to evaluate the clinical outcomes and routine management of patients with chronic lymphocytic leukaemia treated with idelalisib and rituximab in the UK and Ireland (RETRO-idel).

Idelalisib (IDL) is an oral first-in-class phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for chronic lymphocytic leukaemia (CLL) alongside rituximab (R) since 2014. However, little data exist on routine practice. The RETRO-idel was a protocol-led, retrospective study of 110 patients [n = 27 front-line (1L)] who received IDL-R. The primary end-point was clinical overall response rate (ORR). The median (range) follow-up of the whole cohort was 30·2 (0·1-51·9) months. The median (range) age was 72 (48-89) years. Tumour protein p53-disruption was common [100% 1L, 32·5% relapsed/refractory (R/R)]. The best ORR (intention-to-treat) was 88·2% (1L 96·3%, R/R 85·5%). Overall, the median event-free survival (mEFS) was 20·3 months and time-to-next treatment was 29·2 months. The mEFS for 1L patients was 18·7 months and R/R patients was 21·7 months. The 3-year overall survival was 56·1% (95% confidence interval 45·7-65·3). IDL was discontinued in 87·3% (n = 96). More patients discontinued due to adverse events in the front-line setting (1L 63·0% vs. R/R 44·6%) and due to progressive disease in R/R patients (20·5% vs. 3·7% in 1L). Lower respiratory tract infection/pneumonia were reported in 34·5% (Grade ≥3, 19·1%), diarrhoea in 30·9% (Grade ≥3, 6·4%), and colitis in 9·1% (Grade ≥3, 5·5%). Overall, these data describe clear efficacy for IDL-R in routine practice. No new safety signals were identified, although careful management of known toxicities is required.

Relation of insulin treatment for type 2 diabetes to the risk of major adverse cardiovascular events after acute coronary syndrome: an analysis of the BETonMACE randomized clinical trial.

BACKGROUND: In stable patients with type 2 diabetes (T2D), insulin treatment is associated with elevated risk for major adverse cardiovascular events (MACE). Patients with acute coronary syndrome (ACS) and T2D are at particularly high risk for recurrent MACE despite evidence-based therapies. It is uncertain to what extent this risk is further magnified in patients with recent ACS who are treated with insulin. We examined the relationship of insulin use to risk of MACE and modification of that risk by apabetalone, a bromodomain and extra-terminal (BET) protein inhibitor. METHODS: The analysis utilized data from the BETonMACE phase 3 trial that compared apabetalone to placebo in patients with T2D, low HDL cholesterol, andACS. The primary MACE outcome (cardiovascular death, myocardial infarction, or stroke) was examined according to insulin treatment and assigned study treatment. Multivariable Cox regression was used to determine whether insulin use was independently associated with the risk of MACE. RESULTS: Among 2418 patients followed for median 26.5 months, 829 (34.2%) were treated with insulin. Despite high utilization of evidence-based treatments including coronary revascularization, intensive statin treatment, and dual antiplatelet therapy, the 3-year incidence of MACE in the placebo group was elevated among insulin-treated patients (20.4%) compared to those not-treated with insulin (12.8%, P = 0.0001). Insulin treatment remained strongly associated with the risk of MACE (HR 2.10, 95% CI 1.42-3.10, P = 0.0002) after adjustment for demographic, clinical, and treatment variables. Apabetalone had a consistent, favorable effect on MACE in insulin-treated and not insulin-treated patients. CONCLUSION: Insulin-treated patients with T2D, low HDL cholesterol, and ACS are at high risk for recurrent MACE despite the use of evidence-based, contemporary therapies. A strong association of insulin treatment with risk of MACE persists after adjustment for other characteristics associated with MACE. There is unmet need for additional treatments to mitigate this risk. Trial registration ClinicalTrials.gov NCT02586155, registered October 26, 2015.

Epigenetic Therapies for Heart Failure: Current Insights and Future Potential.

Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy ("epidrugs") is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.

Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia.

We present the results of a phase 2 study evaluating the combination of obinutuzumab + idelalisib in relapsed/refractory (R/R) Waldenström macroglobulinemia (WM). The goal was to determine the safety and efficacy of a fixed-duration chemotherapy-free treatment. During the induction phase, patients received idelalisib + obinutuzumab for 6 cycles, followed by a maintenance phase with idelalisib alone for ≤2 years. Forty-eight patients with R/R WM were treated with the induction combination, and 27 patients participated in the maintenance phase. The best responses, reached after a median of 6.5 months (interquartile range, 3.4-7.1; range, 2.6-22.1 months), were very good partial response in 5 patients, partial response in 27 patients, and minor response in 3 patients, leading to overall response rate and major response rate estimates of 71.4% (95% confidence interval [CI], 56.7-83.4) and 65.3% (95% CI, 50.4-78.3), respectively. With a median follow-up of 25.9 months, median progression-free survival was 25.4 months (95% CI, 15.7-29.0). Univariate analysis focusing on molecular screening found no significant impact of CXCR4 genotypes on responses and survivals but a deleterious impact of TP53 mutations on survival. Although there was no grade 5 toxicity, 26 patients were removed from the study because of side effects; the most frequent were neutropenia (9.4%), diarrhea (8.6%), and liver toxicity (9.3%). The combination of idelalisib + obinutuzumab is effective in R/R WM. Nonetheless, the apparent lack of impact of genotype on outcome could give new meaning to targeting of the phosphatidylinositol 3-kinase pathway in WM. This trial was registered at www.clinicaltrials.gov as #NCT02962401.

Preexisting and treatment-emergent autoimmune cytopenias in patients with CLL treated with targeted drugs.

Autoimmune cytopenias (AICs) affect 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs-ibrutinib, idelalisib, and venetoclax-have a prominent role in the treatment of CLL, but their impact on CLL-associated AICs is largely unknown. In this study, we evaluated the characteristics and outcome of preexisting AICs and described the incidence, quality, and management of treatment-emergent AICs during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab, and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of preexisting AICs was reported in 104 (13%) of 815 patients. Interestingly, 80% of patients whose AICs had not resolved when treatment with a targeted drug was started experienced an improvement or a resolution during therapy. Treatment-emergent AICs occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib therapy, and in 7% during venetoclax therapy, with an estimated incidence rate of 5, 6, and 69 episodes per 1000 patients per year of exposure in the 3 treatment groups, respectively. The vast majority of patients who developed treatment-emergent AICs had unfavorable biological features such as an unmutated IGHV and a del(17p) and/or TP53 mutation. Notably, despite AICs, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib, or venetoclax seems to have a beneficial impact on CLL-associated AICs, inducing an improvement or even a resolution of preexisting AICs in most cases and eliciting treatment-emergent AICs in a negligible portion of patients.

Efficacy of idelalisib and rituximab in relapsed/refractory chronic lymphocytic leukemia treated outside of clinical trials. A report of the Gimema Working Group.

Because the efficacy of new drugs reported in trials may not translate into similar results when used in the real-life, we analyzed the efficacy of idelalisib and rituximab (IR) in 149 patients with relapsed/refractory chronic lymphocytic leukemia treated at 34 GIMEMA centers. Median progression-free survival (PFS) and overall survival were 22.9 and 44.5 months, respectively; performance status (PS) ≥2 and ≥3 previous lines of therapy were associated with shorter PFS and overall survival (OS). 48% of patients were on treatment at 12 months; the experience of the centers (≥5 treated patients) and PS 0-1 were associated with a significantly longer treatment duration (p = 0.015 and p = 0.002, respectively). TP53 disruption had no prognostic significance. The overall response rate to subsequent treatment was 49.2%, with median OS of 15.5 months and not reached in patients who discontinued, respectively, for progression and for toxicity (p < 0.01). Treatment breaks ≥14 days were recorded in 96% of patients and adverse events mirrored those reported in trials. In conclusion, this real-life analysis showed that IR treatment duration was longer at experienced centers, that the ECOG PS and ≥3 lines of previous therapy are strong prognostic factor and that the overall outcome with this regimen was superimposable to that reported in a randomized trial.

Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study.

BACKGROUND: Patients with diabetes and acute coronary syndrome (ACS) are at high risk for subsequent heart failure. Apabetalone is a selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. Preclinical data suggest that apabetalone exerts favorable effects on pathways related to myocardial structure and function and therefore could impact subsequent heart failure events. The effect of apabetalone on heart failure events after an ACS is not currently known. METHODS: The phase 3 BETonMACE trial was a double-blind, randomized comparison of apabetalone versus placebo on the incidence of major adverse cardiovascular events (MACE) in 2425 patients with a recent ACS and diabetes. This prespecified secondary analysis investigated the impact of apabetalone on hospitalization for congestive heart failure, not previously studied. RESULTS: Patients (age 62 years, 74.4% males, 90% high-intensity statin use, LDL-C 70.3 mg/dL, HDL-C 33.3 mg/dL and HbA1c 7.3%) were followed for an average 26 months. Apabetalone treated patients experienced the nominal finding of a lower rate of first hospitalization for heart failure (2.4% vs. 4.0%, HR 0.59 [95%CI 0.38-0.94], P = 0.03), total number of hospitalizations for heart failure (35 vs. 70, HR 0.47 [95%CI 0.27-0.83], P = 0.01) and the combination of cardiovascular death or hospitalization for heart failure (5.7% vs. 7.8%, HR 0.72 [95%CI 0.53-0.98], P = 0.04). CONCLUSION: Apabetalone treatment was associated with fewer hospitalizations for heart failure in patients with type 2 diabetes and recent ACS. Future studies are warranted to define the potential for BET inhibition with apabetalone to prevent heart failure in patients with diabetes and ACS.