Upon primary study termination and unblinding, patients could transition to the extension study to receive open-label IDELA monotherapy. The focus of this report is the long-term efficacy and safety of IDELA in patients who received IDELA/R in the primary study and continued IDELA treatment in the extension study (IDELA/R-to-IDELA arm). In addition, we provide the final results from the primary, double-blinded study as an update to the previously published article. 7

Idelalisib (IDELA) is a small molecule that targets the delta isoform of phosphoinositol 3-kinase (PI3Kδ) and inhibits PI3Kδ-dependent signaling, which leads to decreased activity of the AKT and mammalian target of rapamycin pathways and reduced survival of malignant B cells. 5 , 6 A randomized, double-blind, placebo-controlled phase III study evaluated the efficacy and safety of rituximab in combination with IDELA or placebo in patients with relapsed and refractory CLL who had notable comorbidities (cumulative illness rating scale score > 6, renal insufficiency, and/or poor bone marrow reserve) that precluded use of standard chemoimmunotherapy. 7 In August 2013, at the first prespecified interim analysis, the study was terminated because of the superior efficacy of IDELA plus rituximab (IDELA/R). 7 These results led to approval of IDELA in combination with rituximab for the treatment of patients with relapsed CLL. 8 , 9

Chronic lymphocytic leukemia (CLL) is most prevalent in patients age 65 years or older, who often have comorbidities that include decreased renal or bone marrow function. 1 - 4 Treating such patients with chemotherapy is challenging because of an increased risk of toxicity that may complicate disease management. 2 - 4

Multivariable analyses were performed for PFS, ORR, and OS in the IDELA/R-to-IDELA group to explore the influences of several baseline variables. Stepwise regression method was used, and P was .2 for the entry level and .1 for the exit level.

Time-to-event end points were summarized using Kaplan-Meier methods. For Kaplan-Meier estimates, 95% CIs were calculated based on variances estimated using the Greenwood formula. Hazard ratios (HR) and 95% CIs were calculated, when appropriate, using the Cox proportional hazard model, and P values were calculated from the log-rank test. ORR were summarized using frequencies and percentages. Odds ratios and the corresponding 95% CI were presented for the between-arm comparisons.

Results from the randomized study were presented for the two treatment arms (IDELA/R and placebo/R) using the intent-to-treat (ITT) analysis set, which included all patients randomly assigned in the primary study. The safety analysis set included data from patients who received at least one dose of study treatment; treatment assignments were designated according to the actual treatment received. The full analysis set was used for the long-term efficacy and safety analyses of treatment with IDELA and included all patients in the ITT set who received at least one dose of IDELA, including patients who completed the primary study but decided not to enroll in the open extension study, as well as patients who received IDELA/R, with or without PD, who transitioned to the extension study. OS was analyzed using the ITT set, including data from both primary and extension studies for all randomly assigned patients (IDELA/R and placebo/R) without adjustment for the crossover.

Safety and treatment response assessments were performed as previously described. 7 Determination of CLL response and progression was based on International Workshop on Chronic Lymphocytic Leukemia 2008 criteria, 10 modified to reflect current recommendations that pertain to novel target agents in treatment of CLL. 11 Disease progression was adjudicated by a blinded independent review committee. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 4.03. Diarrhea and colitis were diagnosed by the investigator according to the Common Terminology Criteria for Adverse Events. The use of colonoscopy and/or biopsy was performed according to investigator discretion.

The primary end point of the randomized trial was progression-free survival (PFS). Key secondary objectives were overall response rate (ORR), overall survival (OS), efficacy in subgroups, and safety. 7 The objectives of the extension study were to evaluate the long-term efficacy and safety of IDELA maintenance. Thus, in the extension study, no formal comparisons of outcomes between groups were made.

Detailed patient eligibility criteria for the primary study have been reported previously. 7 Briefly, eligible patients had recurrent, previously treated CLL; experienced PD within 24 months of completion of the last line of therapy; and were unable to receive cytotoxic therapies on the basis of cumulative illness rating scale scores greater than 6 points, decreased renal function, or cumulative marrow toxicity from prior therapy. Prior therapies must have included either a CD20 antibody–based regimen or at least two previous cytotoxic regimens. 7 Patients who either experienced centrally confirmed PD during the study or were actively participating at the time of primary study termination could transition to a companion extension study. Patients with confirmed malignant transformation from CLL to an aggressive lymphoma during the primary study were excluded.

All study protocols were approved by the institutional review board at each participating center. Studies were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization guidelines for Good Clinical Practice.

The extension study (ClinicalTrials.gov identifier: NCT01539291) was designed as a blinded study in which patients who experienced PD on placebo/R could receive oral IDELA 150 mg and matched placebo (two tablets) twice daily, whereas patients who experienced PD not as a result of transformation on IDELA/R received dose-intensified treatment with IDELA 300 mg (two tablets) twice daily. After termination of the primary study, the extension study was unblinded and patients who remained on the primary study transitioned to the extension study to receive open-label IDELA monotherapy 150 mg twice daily ( Fig 1A ).

The primary study was a randomized, two-arm, double-blind, placebo-controlled, phase III study (ClinicalTrials.gov identifier: NCT01539512). Random assignment (1:1) was stratified by the presence of deletion 17p (del[17p]) and/or TP53 mutation status and immunoglobulin heavy-chain variable region gene ( IGHV ) mutation status. 7 Rituximab was administered intravenously at a dose of 375 mg/m 2 on day 1, week 0, and at 500 mg/m 2 on day 1 of weeks 2, 4, 6, 8, 12, 16, and 20 for a total of eight infusions. IDELA 150 mg twice daily was administered orally. 7 IDELA or placebo were given until progressive disease (PD), drug-related toxicity, or study discontinuation occurred.

RESULTS Section: Choose Top of page Abstract INTRODUCTION PATIENTS AND METHODS RESULTS << DISCUSSION REFERENCES

Baseline Characteristics, Demographics, and Disposition of the ITT Population As reported previously for the primary study,7 patient demographic and baseline characteristics were balanced across treatment arms. Baseline patient demographics and characteristics, along with the most common prior therapies, stratified by whether the patients enrolled in the extension study, are in the Data Supplement. Overall, 65% of patients were men, and 90% were white; the median age was 71 years (range, 47 to 92 years). Patients received a median of three prior lines of therapy and had median time from diagnosis to study entry of approximately 8.5 years (range, 0.6 to 26.6 years). Either del(17p) or TP53 gene mutation was present at screening in 43.2% of patients and 83.6% of patients had unmutated IGHV. The most common prior regimens included bendamustine with rituximab, fludarabine with cyclophosphamide and rituximab, and rituximab alone. A total of 220 patients were randomly assigned to IDELA/R or placebo/R (n = 110 in each group; Fig 1B) from May 2012 to August 2013.7 In the IDELA/R arm, 14 patients met the primary end point of PD or death; four of these patients transitioned to the blinded part of the extension study to receive IDELA 300 mg twice daily. Twenty-five patients discontinued the primary study, mostly because of AEs (n = 9) or withdrawal by patient (n = 12). The remaining 71 patients without PD completed the primary study and enrolled in the open-label part of the extension study (Figs 1A and 1B). Overall, 161 patients transitioned from the primary study to the extension study (n = 75 patients from the IDELA/R arm and n = 86 from the placebo/R arm; Fig 1B). Among the four patients with PD from the IDELA/R arm who received IDELA 300 mg twice daily, two patients died (pneumonia, underlying CLL disease) and two discontinued the study (diarrhea, other reason). Of 71 patients without PD who continued IDELA in the open-label extension study, 10 patients died; 20 experienced PD; and 41 discontinued the study, primarily as a result of AEs (n = 22; Fig 1B). As of August 16, 2018, no patients remained in the extension study.

Final Efficacy Results From the Primary Study Primary study results from the final data cutoff of October 15, 2014, are presented in Table 1 and Figure 2A. During the primary study, one patient in the IDELA/R group experienced Richter transformation, which led to study discontinuation. TABLE 1. Overall Response Rate by IRC Assessment

Long-Term Efficacy of IDELA The cumulative median follow-up for PFS in the IDELA/R-to-IDELA group was 18 months (range, 0.3 to 67.6 months), and the median Kaplan-Meier–determined PFS was 20.3 months (95% CI, 17.3 to 26.3 months; Fig 2B), as of the August 16, 2018, data cutoff. PFS rates for patients in the IDELA/R-to-IDELA arm were 92.4% and 76.7% at 24 and 48 weeks, respectively. The median PFS was 20.8 months (95% CI, 16.4 to 28.9 months) in patients with neither del(17p) nor TP53 mutation and was 18.7 months (95% CI, 16.6 to 32.4 months) in patients with either del(17p) or TP53 mutation (unadjusted HR, 1.03; 95% CI, 0.62 to 1.72; P = .9012 per unstratified log-rank test; Fig 2C). The median PFS was 22.1 months versus 19.4 months in patients with IGHV mutated versus unmutated statuses (unadjusted HR, 0.58; 95% CI, 0.28 to 1.19; P = .1327 per unstratified log-rank test; Fig 2D). For comparison, this analysis performed in patients treated with rituximab alone in the primary study revealed that the presence of del(17p) and TP53 mutation was associated with adverse outcomes, including a median PFS of 4.0 months (95% CI, 3.7 to 5.7 months) versus a median PFS of 8.1 months (95% CI, 5.1 to 8.2 months) for patients with neither genetic aberration (Data Supplement). In the same patient group, the median PFS was longer in patients with mutated IGHV (8.5 months) than in patients with unmutated IGHV (5.6 months). No patients in the IDELA/R-to-IDELA group experienced documented, confirmed Richter transformation during the extension study. The ORR for patients in the IDELA/R-to-IDELA arm was 85.5% (95% CI, 77.5% to 91.5%) and there was one complete response (Table 1). The median duration of response was 21.4 months (95% CI, 16.6 to 26.1 months). The median OS were 40.6 (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. The adjusted HR for OS was 0.8 (95% CI, 0.5 to 1.1) and favored IDELA/R treatment compared with placebo/R (P = .1343 per stratified log-rank test; Fig 3A). The survival rates at 12 and 24 months were 89.3% and 69.8% in the IDELA/R arm, respectively, compared with 68.1% and 51.5% in the placebo/R arm, respectively. Treatment with IDELA/R significantly prolonged survival in patients with either del(17p) or TP53 mutations compared with those treated with placebo/R (HR, 0.59; 95% CI, 0.35 to 1.01; P = .0504; Figs 3B and 3C). As of August 16, 2018, according to the OS analysis, 106 patients died; 50 (45.5%) were in the IDELA/R arm, and 56 (50.9%) were in the placebo/R arm. The main causes of death were largely consistent with advanced CLL and the underlying frailty, age, and poor prognosis of the population and AEs. Multivariable analyses revealed statistically significant improvement in clinical outcomes for patients in the IDELA/R-to-IDELA group who were age 70 years or older (ORR), had earlier tumor stages per Binet staging (PFS and OS), were men, had mutated IGHV, or had received less than three prior therapies (OS; Data Supplement).

Efficacy of IDELA Monotherapy in Patients Who Initially Received Placebo/R For patients randomly assigned to placebo/R in the primary study who transitioned to IDELA monotherapy in the extension study, the median PFS during IDELA treatment for those with (n = 42) and without PD (n = 44) was 6.9 months (95% CI, 4.1 to 10.7 months) and 16.2 months (95% CI, 8.8 to 26.2 months), respectively (Data Supplement). The ORR during the extension study was 47.6% (95% CI, 32.0% to 63.6%) for those with PD and was 68.2% (95% CI, 52.4% to 81.5%) for those without PD; all were partial responses (Table 1). For the 42 patients who experienced PD during the primary study, the median PFS during the primary study (while receiving placebo/R) was 3.8 months (95% CI, 2.9 to 5.7 months), and the ORR was 7.1% (95% CI, 1.5% to 19.5%). One patient randomly assigned to placebo/R developed Richter transformation after the transition to the extension study (IDELA 150 mg treatment). The OS data for patients in the placebo/R arm who did or did not enroll in the extension study are shown in the Data Supplement.