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Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential.

ABSTRACT: Idelalisib is a first-in-class, oral, selective phosphatidylinositol 3-kinase ? inhibitor that offers a chemotherapy-free option for patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Clinical trials in iNHL have evaluated idelalisib as monotherapy and as combination therapy with rituximab, bendamustine, and rituximab + bendamustine. When administered to heavily pretreated patients with R/R iNHL, idelalisib monotherapy or combination therapy showed durable antitumor activity accompanied by sustained or improved quality-of-life outcomes. Idelalisib has an acceptable safety profile; however, serious or fatal diarrhea/colitis, hepatoxicity, pneumonitis, and intestinal perforation have occurred in treated patients. Selective inhibition of phosphatidylinositol 3-kinase ? with idelalisib is a valuable addition to available treatment options for patients with iNHL, many of whom do not respond to or cannot tolerate chemoimmunotherapy. Two Phase III, randomized, placebo-controlled trials of idelalisib as combination therapy with rituximab or bendamustine + rituximab and a Phase I trial of idelalisib in combination with the Bruton's tyrosine kinase inhibitor ONO/GS-4059 in R/R B-cell malignancies are currently ongoing. A Phase III monotherapy trial in previously treated follicular lymphoma or small lymphocytic lymphoma is planned. The development of other kinase inhibitors for the treatment of iNHL raises the potential for new treatment combinations. Additional research is needed to determine optimal therapy (monotherapy vs combination regimens), treatment sequencing, and long-term management.

SUBMITTER: Barrientos JC

PROVIDER: S-EPMC4876096 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential.

Barrientos Jacqueline C JC

OncoTargets and therapy 20160518

Idelalisib is a first-in-class, oral, selective phosphatidylinositol 3-kinase δ inhibitor that offers a chemotherapy-free option for patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Clinical trials in iNHL have evaluated idelalisib as monotherapy and as combination therapy with rituximab, bendamustine, and rituximab + bendamustine. When administered to heavily pretreated patients with R/R iNHL, idelalisib monotherapy or combination therapy showed durable antitumor ...[more]

PMID: 27274288

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Project description:ImportanceIdelalisib is a first-in-class phosphatidylinositol 3-kinase inhibitor that received US Food and Drug Administration accelerated approval in July 2014 as a single-agent treatment for relapsed follicular lymphoma (FL) and small lymphocytic lymphoma (SLL). Serious adverse effects were reported in 2016 leading to termination of postmarketing registry trials. However, idelalisib remained on the market until 2022 when Gilead voluntarily withdrew the drug for the accelerated approval indication.ObjectiveEvaluate the regulatory oversight of the accelerated approval pathway and evidence generation for idelalisib during premarketing (2008-2014), postmarketing (2014-2016), and premarketing withdrawal periods (2016-2022).Data sourcesClinicalTrials.gov, FDA.gov, PubMed database.Study selectionClinical trials investigating the safety and effectiveness of idelalisib.Data extraction and synthesisStudy characteristics and relative risk (RR) of safety outcomes were abstracted. Data were pooled using random effects meta-analysis. The analysis was performed in October of 2022.Main outcomes and measuresTrial status, recruitment status, publication status, serious adverse events (SAEs), fatal adverse events (FAEs), and all-cause mortality.ResultsOverall, 31 idelalisib trials met selection criteria. In total, 20 of 30 (65%) included SLL and/or FL; 13 (42%) trials were completed, 13 (42%) had published results, and 7 (23%) were randomized clinical trials (RCTs). Overall, 6 RCTs of idelalisib had publicly available data on safety outcomes. By the initial postmarketing period (2016), the cumulative RR for SAEs was 1.86 (95% CI, 1.63-2.11), for FAEs was 3.30 (95% CI, 1.56-7.00), and for death was 1.35 (95% CI, 0.85-2.12). In the premarketing withdrawal period, only a single phase 3 trial was enrolling patients for FL and was terminated. However, idelalisib was not withdrawn from the market until 2022. Gilead reported cumulative sales revenue of $842 million during market authorization (2014-2022) and annual sales had a steady decline from $168 million to $62 million during the premarketing withdrawal period (2016-2021).Conclusions and relevanceFindings of this systematic review and meta-analysis show that serious risks of SAE, FAE, and death with idelalisib treatment were evident by 2016. However, idelalisib remained on the market for another 6 years, with minimal evidence generation. It was voluntarily withdrawn for FL and SLL accelerated approval indications coinciding with decreasing revenue generation. Closer attention for safety and effectiveness of drugs reaching market by accelerated approval is needed.

Project description:BackgroundPhosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas.MethodsIn this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety.ResultsThe median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%).ConclusionsIn this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.).

Project description:BackgroundBendamustine was approved in China on May 26th, 2019 by the National Medical Product Administration for the treatment of indolent B-cell non-Hodgkin lymphoma (NHL). The current study was the registration trial and the first reported evaluation of the efficacy, safety, and pharmacokinetics of bendamustine in Chinese adult patients with indolent B-cell NHL following relapse after chemotherapy and rituximab treatment.MethodsThis was a prospective, multicenter, open-label, single-arm, phase 3 study (NCT01596621; C18083/3076) with a 2-year follow-up period. Eligible patients received bendamustine hydrochloride 120 mg/m2 infused intravenously on days 1 and 2 of each 21-day treatment cycle for at least six planned cycles (and up to eight cycles). The primary endpoint was the overall response rate (ORR); and secondary endpoints were duration of response (DoR), progression-free survival (PFS), safety, and pharmacokinetics. Patients were classified according to their best overall response after initiation of therapy. Proportions of patients in each response category (complete response [CR], partial response [PR], stable disease, or progressive disease) were summarized along with a two-sided binomial exact 95% confidence intervals (CIs) for the ORR.ResultsA total of 102 patients were enrolled from 20 centers between August 6th, 2012, and June 18th, 2015. At the time of the primary analysis, the ORR was 73% (95% CI: 63%-81%) per Independent Review Committee (IRC) including 19% CR and 54% PR. With the follow-up period, the median DoR was 16.2 months by IRC and 13.4 months by investigator assessment; the median PFS was 18.6 months and 15.3 months, respectively. The most common non-hematologic adverse events (AEs) were gastrointestinal toxicity, pyrexia, and rash. Grade 3/4 neutropenia was reported in 76% of patients. Serious AEs were reported in 29 patients and five patients died during the study. Pharmacokinetic analysis indicated that the characteristics of bendamustine and its metabolites M3 and M4 were generally consistent with those reported for other ethnicities.ConclusionBendamustine is an active and effective therapy in Chinese patients with relapsed, indolent B-cell NHL, with a comparable risk/benefit relationship to that reported in North American patients.Clinical trial registrationClinicalTrials.gov, No. NCT01596621; https://clinicaltrials.gov/ct2/show/NCT01596621.

Dataset Information

Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential.

Publications

Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential.

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