1. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial
- Author
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Paul M Ridker, Jean G MacFadyen, Tom Thuren, Brendan M Everett, Peter Libby, Robert J Glynn, Paul Ridker, Alberto Lorenzatti, Henry Krum, John Varigos, Peter Siostrzonek, Peter Sinnaeve, Francisco Fonseca, Jose Nicolau, Nina Gotcheva, Jacques Genest, Huo Yong, Miguel Urina-Triana, Davor Milicic, Renata Cifkova, Riina Vettus, Wolfgang Koenig, Stephan D Anker, Athanasios J Manolis, Fernando Wyss, Tamas Forster, Axel Sigurdsson, Prem Pais, Alessandro Fucili, Hisao Ogawa, Hiroaki Shimokawa, Irina Veze, Birute Petrauskiene, Leon Salvador, John Kastelein, Jan Hein Cornel, Tor Ole Klemsdal, Felix Medina, Andrzej Budaj, Luminita Vida-Simiti, Zhanna Kobalava, Petar Otasevic, Daniel Pella, Mitja Lainscak, Ki-Bae Seung, Patrick Commerford, Mikael Dellborg, Marc Donath, Juey-Jen Hwang, Hakan Kultursay, Marcus Flather, Christie Ballantyne, Seth Bilazarian, William Chang, Cara East, Brendan Everett, Les Forgosh, Robert Glynn, Barry Harris, Monica Ligueros, Erin Bohula, Bindu Charmarthi, Susan Cheng, Sherry Chou, Jacqueline Danik, Graham McMahon, Bradley Maron, MingMing Ning, Benjamin Olenchock, Reena Pande, Todd Perlstein, Aruna Pradhan, Natalia Rost, Aneesh Singhal, Viviany Taqueti, Nancy Wei, Howard Burris, Angela Cioffi, Anne Marie Dalseg, Nilanjan Ghosh, Julie Gralow, Tina Mayer, Hope Rugo, Vance Fowler, Ajit P Limaye, Sara Cosgrove, Donald Levine, Renato Lopes, John Scott, Robert Hilkert, Georgia Tamesby, Carolyn Mickel, Brian Manning, Julian Woelcke, Monique Tan, Sheryl Manfreda, Tom Ponce, Jane Kam, Ravinder Saini, Kehur Banker, Thomas Salko, Panjat Nandy, Ronda Tawfik, Greg O'Neil, Shobha Manne, Pravin Jirvankar, Shankar Lal, Deepak Nema, Jaison Jose, Rory Collins, Kent Bailey, Roger Blumenthal, Helen Colhoun, and Bernard Gersh
- Subjects
0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Lung Neoplasms ,Neutropenia ,Interleukin-1beta ,Placebo-controlled study ,Anti-Inflammatory Agents ,Myocardial Infarction ,Placebo ,Antibodies, Monoclonal, Humanized ,law.invention ,03 medical and health sciences ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,Sepsis ,Cancer screening ,medicine ,Humans ,Lung cancer ,Aged ,biology ,Dose-Response Relationship, Drug ,business.industry ,Interleukin-6 ,Incidence ,C-reactive protein ,Smoking ,Cancer ,Antibodies, Monoclonal ,General Medicine ,Middle Aged ,medicine.disease ,Atherosclerosis ,Thrombocytopenia ,Surgery ,Canakinumab ,030104 developmental biology ,C-Reactive Protein ,Cell Transformation, Neoplastic ,Editorial ,biology.protein ,Female ,business ,medicine.drug - Abstract
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 interleukin-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 cancer incidence.We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial 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 randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. 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. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017).Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p0·0001) were significantly higher among participants subsequently 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-dependent reductions in concentrations of hsCRP of 26-41% and of interleukin 6 of 25-43% (p0·0001 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 individually (hazard ratio [HR] 0·49 [95% CI 0·31-0·75]; p=0·0009). Incident lung cancer (n=129) was significantly 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]; p0·0001; p0·0001 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 placebo 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 placebo groups (HR 0·94 [95% CI 0·83-1·06]; p=0·31).Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required.Novartis Pharmaceuticals.
- Published
- 2017