Idelalisib for Treatment of Relapsed Follicular Lymphoma and Chronic Lymphocytic Leukemia: A Comparison of Treatment Outcomes in Clinical Trial Participants vs Medicare Beneficiaries.

Importance: Idelalisib (IDEL) is approved as monotherapy in relapsed follicular lymphoma (FL) and with rituximab (IDEL+R) for relapsed chronic lymphocytic leukemia (CLL). Toxic effects can be severe and treatment-limiting. Outcomes in a real-world population are not yet characterized. Objective: We compared IDEL treatment outcomes in the clinical setting with outcomes in clinical trial data. Design, Setting, and Participants: This cohort study compared clinical trial participants treated with IDEL, aged 65 years or older, in studies 101-09 and 312-0116 with Medicare beneficiaries treated with IDEL of the same disease state and treatment regimen. Study 101-09 was a phase 2, single-group, open-label trial supporting accelerated approval of IDEL for relapsed or refractory FL. Study 312-0116 was a phase 3, multicenter, randomized, double-blind trial supporting approval of IDEL+R for relapsed CLL. Analyses were conducted between February and December 2018. Main Outcomes and Measures: Treatment duration, on-treatment and overall mortality, and serious and fatal infections were compared between trial participants and Medicare beneficiaries. Cox proportional hazards models quantified differences by cohort. Results: We identified 26 trial participants (mean [SD] age, 73 [4.9] years; 12 [46.2%] women) and 305 Medicare beneficiaries (mean [SD] age, 76 [6.9] years; 103 [54.8%] women) receiving IDEL for FL and 89 trial participants (mean [SD] age, 74 [6.0] years; 30 [33.7%] women) and 294 Medicare beneficiaries (mean age, 76 [6.3] years; 111 [37.8%] women) receiving IDEL+R for CLL. Medicare beneficiaries were older with higher comorbidity; had a shorter median treatment duration for CLL (173 days vs 473 days, P < .001) but not FL (114, days vs 160 days, P = .38); a numerically higher mortality rate (CLL: HR, 1.40; 95% CI, 0.93-2.11; FL: HR, 1.39; 95% CI, 0.69-2.78); and a significantly higher fatal infection rate per 100 person-years for CLL (18.4 vs 9.8, P = .04) and a numerically higher rate for FL (27.6 vs 18.6, P = .54), compared with trial participants. Trial participants had approximately twice as many dose reductions (CLL: 32.6% vs 18.0%; P = .003; FL: 38.5% vs 16.1%; P = .02). Among Medicare beneficiaries, a hospitalized infection within 6 months prior to IDEL initiation was associated with a 2.11-fold increased risk for on-treatment fatal infections (95% CI, 1.44-3.10). Despite a March 2016 recommendation for Pneumocystis jirovecii pneumonia prophylaxis in patients treated with IDEL, prophylaxis rates were low after March 2016 (FL: 25%, CLL: 37%). Conclusions and Relevance: We observed substantial imbalances in baseline comorbidities and treatment outcomes between Medicare beneficiaries and trial participants aged 65 years or older. Immunosuppression-related toxic effects, including infections, may have been somewhat reduced in trials by more frequent dose reductions and exclusion of patients with ongoing infections. Selective eligibility criteria and closer monitoring of trial patients may be responsible for limited generalizability of trial data to clinical practice.

FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma.

On July 23, 2014, the FDA granted accelerated approval to idelalisib (Zydelig tablets; Gilead Sciences, Inc.) for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma or relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies. In a multicenter, single-arm trial, 123 patients with relapsed indolent non-Hodgkin lymphomas received idelalisib, 150 mg orally twice daily. In patients with follicular lymphoma, the overall response rate (ORR) was 54%, and the median duration of response (DOR) was not evaluable; median follow-up was 8.1 months. In patients with SLL, the ORR was 58% and the median DOR was 11.9 months. One-half of patients experienced a serious adverse reaction of pneumonia, pyrexia, sepsis, febrile neutropenia, diarrhea, or pneumonitis. Other common adverse reactions were abdominal pain, nausea, fatigue, cough, dyspnea, and rash. Common treatment-emergent laboratory abnormalities were elevations in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, absolute lymphocytes, and triglycerides. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia.

On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11-0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy-designated drug to receive FDA approval.