Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial.

This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n = 158) or CCR (n = 161). The median age was 71 years, median (range) enasidenib exposure was 142 days (3 to 1270), and CCR was 36 days (1 to 1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. The median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio], 0.86; P = .23); 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median, 4.9 vs 2.6 months with CCR; HR, 0.68; P = .008), TTF (median, 4.9 vs 1.9 months; HR, 0.53; P < .001), ORR (40.5% vs 9.9%; P <.001), HI (42.4% vs 11.2%), and red blood cell (RBC)-TI (31.7% vs 9.3%). Enasidenib safety was consistent with prior reports. The primary study endpoint was not met, but OS was confounded by early dropout and subsequent AML-directed therapies. Enasidenib provided meaningful benefits in EFS, TTF, ORR, HI, and RBC-TI in this heavily pretreated older mutant-IDH2 R/R AML population.

Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial.

BACKGROUND: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. METHODS: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of ß2 microglobulin at screening. Bortezomib (1·3 mg/m2) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. FINDINGS: Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). INTERPRETATION: Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. FUNDING: Celgene.

Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The efficacy and safety of lenalidomide as maintenance therapy after chemotherapy-based second-line therapy in patients with chronic lymphocytic leukaemia is unknown. Although kinase inhibitors can improve outcomes for some patients with relapsed and refractory disease, not all patients have access to these novel drugs. In this study, we aimed to assess the efficacy and safety of lenalidomide as maintenance therapy in patients with previously treated chronic lymphocytic leukaemia. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial (CONTINUUM) was done at 111 hospitals, medical centres, and clinics in 21 countries. Patients were eligible if they had chronic lymphocytic leukaemia; were aged 18 years or older; had been treated with two lines of therapy (with at least a partial response after second-line therapy); had received a purine analogue, bendamustine, anti-CD20 antibody, chlorambucil, or alemtuzumab as first-line or second-line treatment; and had an Eastern Cooperative Oncology Group performance score of 0-2. Eligible patients were randomly assigned (1:1) by an interactive voice-response system to receive either oral lenalidomide (2·5 mg/day) or matching oral placebo capsules (2·5 mg/day) for 28-day cycles, until disease progression or unacceptable toxicity. Lenalidomide dose escalation (to 5 mg or 10 mg per day) was permitted if the drug was well tolerated. Patients, investigators, and those completing data analyses were masked to treatment allocation. Randomisation was stratified by age, response to second-line therapy, and prognostic factors. Co-primary endpoints were progression-free survival and overall survival; the primary endpoint was later changed to overall survival after the data cutoff for this analysis. Secondary endpoints were time from randomisation to second disease progression or death (PFS2),32 tumour response (improvement in response and duration of response), safety, and health-related quality of life (HRQoL). Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00774345, and is closed to accrual, but follow-up is ongoing. FINDINGS: Between Feb 16, 2009 and Sept 29, 2015, 314 patients with chronic lymphocytic leukaemia were enrolled and randomly assigned to receive either lenalidomide (n=160) or placebo (n=154). With a median follow-up of 31·5 months (IQR 18·9-50·8), there was no significant difference in overall survival between the lenalidomide and the placebo groups (median 70·4 months, 95% CI 57·5-not estimable [NE] vs NE, 95% CI 62·8-NE; hazard ratio [HR] 0·96, 95% CI 0·63-1·48; p=0·86). Progression-free survival was significantly longer in the lenalidomide group (median 33·9 months, 95% CI 25·5-52·5) than in the placebo group (9·2 months, 7·4-13·6; HR 0·40, 95% CI 0·29-0·55; p<0·0001). PFS2 was significantly longer in the lenalidomide group than in the placebo group (median 57·5 months [47·7-NE] vs 32·7 months [26·4-49·0]; HR 0·46, 95% CI 0·29-0·70; p<0·01). Improved responses from baseline were observed in ten (6%) of 160 lenalidomide-treated patients versus four (3%) of 154 placebo-treated patients (p=0·12). Median time to improved response was 12·2 weeks (IQR 7·2-22·5) in the lenalidomide group versus 76·3 weeks (20·2-182·6) in the placebo group. Duration of improved response was not estimable in either group (95% CI 22·9-NE in the lenalidomide group vs NE-NE for placebo). There were no clinically meaningful differences in HRQoL between lenalidomide-treated patients and placebo-treated patients, as measured by FACT-Leu and EQ-5D, during maintenance treatment. In the safety population, the most common grade 3 or 4 adverse events included neutropenia (94 [60%] of 157 patients in the lenalidomide group vs 35 [23%] of 154 patients in the placebo group), thrombocytopenia (26 [17%] vs ten [6%]), and diarrhoea (13 [8%] vs one [<1%]). There were five fatal adverse events (three [2%] patients in the lenalidomide group and two [1%] patients in the placebo group). INTERPRETATION: Lenalidomide might delay time to subsequent therapy and does not adversely affect response to subsequent therapy. Chemoimmunotherapy followed by lenalidomide maintenance could be an effective treatment option for patients with chronic lymphocytic leukaemia who do not have access to kinase inhibitors. FUNDING: Celgene Corporation.