Practice Update: Oncology

EDITOR’S PICKS 11

Abstract BACKGROUND Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of inter- leukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter can- cer incidence. METHODS We did a randomised, double-blind, pla- cebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myo- cardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose-response effects, patients were ran- domly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or pla- cebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. FINDINGS Baseline concentrations of hsCRP (median 6•0 mg/L vs 4•2 mg/L; p<0•0001) and interleukin 6 (3•2 vs 2•6 ng/L; p<0•0001) were significantly higher among participants subse- quently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3•7 years, compared with placebo, canakinumab was associated with dose-depend- ent reductions in concentrations of hsCRP of 26-41% and of interleukin 6 of 25-43% (p<0•0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0•0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individ- ually (hazard ratio [HR] 0•49 [95% CI 0•31-0•75]; p=0•0009). Incident lung cancer (n=129) was sig- nificantly less frequent in the 150 mg (HR 0•61 [95% CI 0•39-0•97]; p=0•034) and 300 mg groups (HR 0•33 [95% CI 0•18-0•59]; p<0•0001; p<0•0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0•23 [95% CI 0•10-0•54]; p=0•0002) and in the pooled canakinumab population than in the pla- cebo group (p=0•0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and pla- cebo groups (HR 0•94 [95% CI 0•83-1•06]; p=0•31). INTERPRETATION Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleu- kin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mor- tality. Replication of these data in formal settings of cancer screening and treatment is required. Effect of interleukin-1 β inhibition with canaki- numab on incident lung cancer in patients with atherosclerosis: exploratory results from a ran- domised, double-blind, placebo-controlled trial. Lancet 2017 Aug 25;[EPub Ahead of Print], PM Ridker, JG MacFadyen, T Thuren, et al. www.practiceupdate.com/c/57597

LenalidomideMaintenance After First-Line Therapy for High-Risk Chronic Lymphocytic Leukemia The Lancet Haematology Take-home message • This phase III study was designed to evaluate use of lenalidomide mainte- nance vs placebo in 89 patients with CLL who achieved at least a partial response after first-line chemoimmunotherapy. Patients were randomized to receive lenalidomide (n = 60) or placebo (n = 29). Median progression-free survival was 13.3 months vs not-reached, favoring lenalidomide. Frequently reported adverse events included skin disorders, gastrointestinal disorders, hematological toxicity, and infections. • The efficacy of lenalidomide maintenance therapy was demonstrated, with acceptable toxicity, in patients with CLL following chemoimmunotherapy.

Abstract BACKGROUND The combined use of genetic markers and detectable minimal residual disease identifies patients with chronic lym- phocytic leukaemia with poor outcome after first-line chemoimmunotherapy. We aimed to assess lenalidomide maintenance therapy in these high-risk patients. METHODS In this randomised, double-blind, phase 3 study (CLLM1; CLL Maintenance 1 of the German CLL Study Group), patients older than 18 years and diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia with active disease, who responded to chemoimmunotherapy 2-5 months after completion of first-line therapy and who were assessed as having a high risk for an early progression with at least a partial response after four or more cycles of first-line chemoimmunotherapy, were eligible if they had high minimal residual disease lev- els or intermediate levels combined with an unmutated IGHV gene status or TP53 alter- ations. Patients were randomly assigned (2:1) to receive either lenalidomide (5 mg) or placebo. Randomisation was done with a fixed block size of three, and was stratified according to the minimal residual disease level achieved after first-line therapy. Main- tenance was started with 5 mg daily, and was escalated to the target dose of 15 mg. If tol- erated, medication was administered until disease progression. The primary endpoint was progression-free survival according to an independent review. The pre-planned interim analysis done by intention to treat was done after 20% of the calculated progression-free survival events. FINDINGS Between July 5, 2012, and March 15, 2016, 468 previously untreated patients with chronic lymphocytic leukaemia were screened for the study; 379 (81%) were not eligible. Recruitment was closed prematurely due to poor accrual after 89 of 200 planned patients were randomly assigned: 60 (67%) enrolled patients were assigned to the lena- lidomide group and 29 (33%) to the placebo

group, of whom 56 (63%) received lenalido- mide and 29 (33%) placebo, with a median of 11·0 (IQR 4·5-20·5) treatment cycles at data cutoff. After a median observation time of 17·9 months (IQR 9·1-28·1), the hazard ratio for progression-free survival assessed by an independent review was 0·168 (95% CI 0·074-0·379). Median progression-free sur- vival was 13·3 months (95% CI 9·9-19·7) in the placebo group and not reached (95% CI 32·3- not evaluable) in the lenalidomide group. The most frequent adverse events were skin dis- orders (35 patients [63%] in the lenalidomide group vs eight patients [28%] in the placebo group), gastrointestinal disorders (34 [61%] vs eight [28%]), infections (30 [54%] vs 19 [66%]), haematological toxicity (28 [50%] vs five [17%]), and general disorders (28 [50%] vs nine [31%]). One fatal adverse event was reported in each of the treatment groups (one [2%] patient with fatal acute lymphocytic leu- kaemia in the lenalidomide group and one patient (3%) with fatal multifocal leukoenceph- alopathy in the placebo group). INTERPRETATION Lenalidomide is an efficacious maintenance therapy reducing the relative risk of progression in first-line patients with chronic lymphocytic leukaemia who do not achieve minimal residual disease negative disease state following chemoimmunother- apy approaches. The toxicity seems to be acceptable considering the poor prognosis of the eligible patients. The trial independently confirms the clinical significance of a novel, minimal residual disease-based algorithm to predict short progression-free survival, which might be incorporated in future clinical trials to identify candidates for additional mainte- nance treatment. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a ran- domised, double-blind, phase 3 study. Lancet Haematol 2017 Sep 12;[EPub Ahead of Print], AM Fink, J Bahlo, S Robrecht, et al. www.practiceupdate.com/c/58261

VOL. 1 • NO. 3 • 2017