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

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 CifkovaRiina 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, Peter Libby, Monica Ligueros, Tom Thuren, Erin Bohula, Bindu Charmarthi, Susan Cheng, Sherry Chou, Jacqueline Danik, Graham McMahon, Bradley Maron, Ming Ming 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, Tom Thuren, Monica Ligueros, 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, Kent R Bailey, Pravin Jirvankar, Shankar Lal, Deepak Nema, Jaison Jose, Rory Collins, Kent Bailey, Roger Blumenthal, Helen Colhoun, Bernard Gersh, Robert J. Glynn

Research output: Contribution to journalArticle

271 Citations (Scopus)

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 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. Methods 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). 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 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% (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 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]; 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 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). Interpretation 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. Funding Novartis Pharmaceuticals.

Original languageEnglish (US)
Pages (from-to)1833-1842
Number of pages10
JournalThe Lancet
Volume390
Issue number10105
DOIs
StatePublished - Oct 21 2017

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Interleukin-1
Lung Neoplasms
Atherosclerosis
Placebos
C-Reactive Protein
Neoplasms
Mortality
Interleukin-6
canakinumab
Anti-Inflammatory Agents
Inflammasomes
Intention to Treat Analysis
Tumor Microenvironment
Early Detection of Cancer
Innate Immunity
Pharmaceutical Preparations
Sepsis
Thrombosis
Myocardial Infarction
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Medicine(all)

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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. / Ridker, Paul M.; MacFadyen, Jean G.; Thuren, Tom; Everett, Brendan M.; Libby, Peter; Glynn, Robert J.; Ridker, Paul; Lorenzatti, Alberto; Krum, Henry; Varigos, John; Siostrzonek, Peter; Sinnaeve, Peter; Fonseca, Francisco; Nicolau, Jose; Gotcheva, Nina; Genest, Jacques; Yong, Huo; Urina-Triana, Miguel; Milicic, Davor; Cifkova, Renata; Vettus, Riina; Koenig, Wolfgang; Anker, Stephan D.; Manolis, Athanasios J.; Wyss, Fernando; Forster, Tamas; Sigurdsson, Axel; Pais, Prem; Fucili, Alessandro; Ogawa, Hisao; Shimokawa, Hiroaki; Veze, Irina; Petrauskiene, Birute; Salvador, Leon; Kastelein, John; Cornel, Jan Hein; Klemsdal, Tor Ole; Medina, Felix; Budaj, Andrzej; Vida-Simiti, Luminita; Kobalava, Zhanna; Otasevic, Petar; Pella, Daniel; Lainscak, Mitja; Seung, Ki Bae; Commerford, Patrick; Dellborg, Mikael; Donath, Marc; Hwang, Juey Jen; Kultursay, Hakan; Flather, Marcus; Ballantyne, Christie; Bilazarian, Seth; Chang, William; East, Cara; Everett, Brendan; Forgosh, Les; Glynn, Robert; Harris, Barry; Libby, Peter; Ligueros, Monica; Thuren, Tom; Bohula, Erin; Charmarthi, Bindu; Cheng, Susan; Chou, Sherry; Danik, Jacqueline; McMahon, Graham; Maron, Bradley; Ning, Ming Ming; Olenchock, Benjamin; Pande, Reena; Perlstein, Todd; Pradhan, Aruna; Rost, Natalia; Singhal, Aneesh; Taqueti, Viviany; Wei, Nancy; Burris, Howard; Cioffi, Angela; Dalseg, Anne Marie; Ghosh, Nilanjan; Gralow, Julie; Mayer, Tina; Rugo, Hope; Fowler, Vance; Limaye, Ajit P.; Cosgrove, Sara; Levine, Donald; Lopes, Renato; Scott, John; Thuren, Tom; Ligueros, Monica; Hilkert, Robert; Tamesby, Georgia; Mickel, Carolyn; Manning, Brian; Woelcke, Julian; Tan, Monique; Manfreda, Sheryl; Ponce, Tom; Kam, Jane; Saini, Ravinder; Banker, Kehur; Salko, Thomas; Nandy, Panjat; Tawfik, Ronda; O'Neil, Greg; Bailey, Kent R; Jirvankar, Pravin; Lal, Shankar; Nema, Deepak; Jose, Jaison; Collins, Rory; Bailey, Kent; Blumenthal, Roger; Colhoun, Helen; Gersh, Bernard; Glynn, Robert J.

In: The Lancet, Vol. 390, No. 10105, 21.10.2017, p. 1833-1842.

Research output: Contribution to journalArticle

Ridker, PM, MacFadyen, JG, Thuren, T, Everett, BM, Libby, P, Glynn, RJ, Ridker, P, Lorenzatti, A, Krum, H, Varigos, J, Siostrzonek, P, Sinnaeve, P, Fonseca, F, Nicolau, J, Gotcheva, N, Genest, J, Yong, H, Urina-Triana, M, Milicic, D, Cifkova, R, Vettus, R, Koenig, W, Anker, SD, Manolis, AJ, Wyss, F, Forster, T, Sigurdsson, A, Pais, P, Fucili, A, Ogawa, H, Shimokawa, H, Veze, I, Petrauskiene, B, Salvador, L, Kastelein, J, Cornel, JH, Klemsdal, TO, Medina, F, Budaj, A, Vida-Simiti, L, Kobalava, Z, Otasevic, P, Pella, D, Lainscak, M, Seung, KB, Commerford, P, Dellborg, M, Donath, M, Hwang, JJ, Kultursay, H, Flather, M, Ballantyne, C, Bilazarian, S, Chang, W, East, C, Everett, B, Forgosh, L, Glynn, R, Harris, B, Libby, P, Ligueros, M, Thuren, T, Bohula, E, Charmarthi, B, Cheng, S, Chou, S, Danik, J, McMahon, G, Maron, B, Ning, MM, Olenchock, B, Pande, R, Perlstein, T, Pradhan, A, Rost, N, Singhal, A, Taqueti, V, Wei, N, Burris, H, Cioffi, A, Dalseg, AM, Ghosh, N, Gralow, J, Mayer, T, Rugo, H, Fowler, V, Limaye, AP, Cosgrove, S, Levine, D, Lopes, R, Scott, J, Thuren, T, Ligueros, M, Hilkert, R, Tamesby, G, Mickel, C, Manning, B, Woelcke, J, Tan, M, Manfreda, S, Ponce, T, Kam, J, Saini, R, Banker, K, Salko, T, Nandy, P, Tawfik, R, O'Neil, G, Bailey, KR, Jirvankar, P, Lal, S, Nema, D, Jose, J, Collins, R, Bailey, K, Blumenthal, R, Colhoun, H, Gersh, B & Glynn, RJ 2017, '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', The Lancet, vol. 390, no. 10105, pp. 1833-1842. https://doi.org/10.1016/S0140-6736(17)32247-X
Ridker, Paul M. ; MacFadyen, Jean G. ; Thuren, Tom ; Everett, Brendan M. ; Libby, Peter ; Glynn, Robert J. ; Ridker, Paul ; Lorenzatti, Alberto ; Krum, Henry ; Varigos, John ; Siostrzonek, Peter ; Sinnaeve, Peter ; Fonseca, Francisco ; Nicolau, Jose ; Gotcheva, Nina ; Genest, Jacques ; Yong, Huo ; Urina-Triana, Miguel ; Milicic, Davor ; Cifkova, Renata ; Vettus, Riina ; Koenig, Wolfgang ; Anker, Stephan D. ; Manolis, Athanasios J. ; Wyss, Fernando ; Forster, Tamas ; Sigurdsson, Axel ; Pais, Prem ; Fucili, Alessandro ; Ogawa, Hisao ; Shimokawa, Hiroaki ; Veze, Irina ; Petrauskiene, Birute ; Salvador, Leon ; Kastelein, John ; Cornel, Jan Hein ; Klemsdal, Tor Ole ; Medina, Felix ; Budaj, Andrzej ; Vida-Simiti, Luminita ; Kobalava, Zhanna ; Otasevic, Petar ; Pella, Daniel ; Lainscak, Mitja ; Seung, Ki Bae ; Commerford, Patrick ; Dellborg, Mikael ; Donath, Marc ; Hwang, Juey Jen ; Kultursay, Hakan ; Flather, Marcus ; Ballantyne, Christie ; Bilazarian, Seth ; Chang, William ; East, Cara ; Everett, Brendan ; Forgosh, Les ; Glynn, Robert ; Harris, Barry ; Libby, Peter ; Ligueros, Monica ; Thuren, Tom ; Bohula, Erin ; Charmarthi, Bindu ; Cheng, Susan ; Chou, Sherry ; Danik, Jacqueline ; McMahon, Graham ; Maron, Bradley ; Ning, Ming Ming ; Olenchock, Benjamin ; Pande, Reena ; Perlstein, Todd ; Pradhan, Aruna ; Rost, Natalia ; Singhal, Aneesh ; Taqueti, Viviany ; Wei, Nancy ; Burris, Howard ; Cioffi, Angela ; Dalseg, Anne Marie ; Ghosh, Nilanjan ; Gralow, Julie ; Mayer, Tina ; Rugo, Hope ; Fowler, Vance ; Limaye, Ajit P. ; Cosgrove, Sara ; Levine, Donald ; Lopes, Renato ; Scott, John ; Thuren, Tom ; Ligueros, Monica ; Hilkert, Robert ; Tamesby, Georgia ; Mickel, Carolyn ; Manning, Brian ; Woelcke, Julian ; Tan, Monique ; Manfreda, Sheryl ; Ponce, Tom ; Kam, Jane ; Saini, Ravinder ; Banker, Kehur ; Salko, Thomas ; Nandy, Panjat ; Tawfik, Ronda ; O'Neil, Greg ; Bailey, Kent R ; Jirvankar, Pravin ; Lal, Shankar ; Nema, Deepak ; Jose, Jaison ; Collins, Rory ; Bailey, Kent ; Blumenthal, Roger ; Colhoun, Helen ; Gersh, Bernard ; Glynn, Robert J. / 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. In: The Lancet. 2017 ; Vol. 390, No. 10105. pp. 1833-1842.
@article{64d2910dbf0346b68edfb0310aebaa0a,
title = "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",
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 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. Methods 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). 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 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{\%} (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 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]; 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 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). Interpretation 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. Funding Novartis Pharmaceuticals.",
author = "Ridker, {Paul M.} and MacFadyen, {Jean G.} and Tom Thuren and Everett, {Brendan M.} and Peter Libby and Glynn, {Robert J.} and Paul Ridker and Alberto Lorenzatti and Henry Krum and John Varigos and Peter Siostrzonek and Peter Sinnaeve and Francisco Fonseca and Jose Nicolau and Nina Gotcheva and Jacques Genest and Huo Yong and Miguel Urina-Triana and Davor Milicic and Renata Cifkova and Riina Vettus and Wolfgang Koenig and Anker, {Stephan D.} and Manolis, {Athanasios J.} and Fernando Wyss and Tamas Forster and Axel Sigurdsson and Prem Pais and Alessandro Fucili and Hisao Ogawa and Hiroaki Shimokawa and Irina Veze and Birute Petrauskiene and Leon Salvador and John Kastelein and Cornel, {Jan Hein} and Klemsdal, {Tor Ole} and Felix Medina and Andrzej Budaj and Luminita Vida-Simiti and Zhanna Kobalava and Petar Otasevic and Daniel Pella and Mitja Lainscak and Seung, {Ki Bae} and Patrick Commerford and Mikael Dellborg and Marc Donath and Hwang, {Juey Jen} and Hakan Kultursay and Marcus Flather and Christie Ballantyne and Seth Bilazarian and William Chang and Cara East and Brendan Everett and Les Forgosh and Robert Glynn and Barry Harris and Peter Libby and Monica Ligueros and Tom Thuren and Erin Bohula and Bindu Charmarthi and Susan Cheng and Sherry Chou and Jacqueline Danik and Graham McMahon and Bradley Maron and Ning, {Ming Ming} and Benjamin Olenchock and Reena Pande and Todd Perlstein and Aruna Pradhan and Natalia Rost and Aneesh Singhal and Viviany Taqueti and Nancy Wei and Howard Burris and Angela Cioffi and Dalseg, {Anne Marie} and Nilanjan Ghosh and Julie Gralow and Tina Mayer and Hope Rugo and Vance Fowler and Limaye, {Ajit P.} and Sara Cosgrove and Donald Levine and Renato Lopes and John Scott and Tom Thuren and Monica Ligueros and Robert Hilkert and Georgia Tamesby and Carolyn Mickel and Brian Manning and Julian Woelcke and Monique Tan and Sheryl Manfreda and Tom Ponce and Jane Kam and Ravinder Saini and Kehur Banker and Thomas Salko and Panjat Nandy and Ronda Tawfik and Greg O'Neil and Bailey, {Kent R} and Pravin Jirvankar and Shankar Lal and Deepak Nema and Jaison Jose and Rory Collins and Kent Bailey and Roger Blumenthal and Helen Colhoun and Bernard Gersh and Glynn, {Robert J.}",
year = "2017",
month = "10",
day = "21",
doi = "10.1016/S0140-6736(17)32247-X",
language = "English (US)",
volume = "390",
pages = "1833--1842",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "10105",

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TY - JOUR

T1 - Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis

T2 - exploratory results from a randomised, double-blind, placebo-controlled trial

AU - Ridker, Paul M.

AU - MacFadyen, Jean G.

AU - Thuren, Tom

AU - Everett, Brendan M.

AU - Libby, Peter

AU - Glynn, Robert J.

AU - Ridker, Paul

AU - Lorenzatti, Alberto

AU - Krum, Henry

AU - Varigos, John

AU - Siostrzonek, Peter

AU - Sinnaeve, Peter

AU - Fonseca, Francisco

AU - Nicolau, Jose

AU - Gotcheva, Nina

AU - Genest, Jacques

AU - Yong, Huo

AU - Urina-Triana, Miguel

AU - Milicic, Davor

AU - Cifkova, Renata

AU - Vettus, Riina

AU - Koenig, Wolfgang

AU - Anker, Stephan D.

AU - Manolis, Athanasios J.

AU - Wyss, Fernando

AU - Forster, Tamas

AU - Sigurdsson, Axel

AU - Pais, Prem

AU - Fucili, Alessandro

AU - Ogawa, Hisao

AU - Shimokawa, Hiroaki

AU - Veze, Irina

AU - Petrauskiene, Birute

AU - Salvador, Leon

AU - Kastelein, John

AU - Cornel, Jan Hein

AU - Klemsdal, Tor Ole

AU - Medina, Felix

AU - Budaj, Andrzej

AU - Vida-Simiti, Luminita

AU - Kobalava, Zhanna

AU - Otasevic, Petar

AU - Pella, Daniel

AU - Lainscak, Mitja

AU - Seung, Ki Bae

AU - Commerford, Patrick

AU - Dellborg, Mikael

AU - Donath, Marc

AU - Hwang, Juey Jen

AU - Kultursay, Hakan

AU - Flather, Marcus

AU - Ballantyne, Christie

AU - Bilazarian, Seth

AU - Chang, William

AU - East, Cara

AU - Everett, Brendan

AU - Forgosh, Les

AU - Glynn, Robert

AU - Harris, Barry

AU - Libby, Peter

AU - Ligueros, Monica

AU - Thuren, Tom

AU - Bohula, Erin

AU - Charmarthi, Bindu

AU - Cheng, Susan

AU - Chou, Sherry

AU - Danik, Jacqueline

AU - McMahon, Graham

AU - Maron, Bradley

AU - Ning, Ming Ming

AU - Olenchock, Benjamin

AU - Pande, Reena

AU - Perlstein, Todd

AU - Pradhan, Aruna

AU - Rost, Natalia

AU - Singhal, Aneesh

AU - Taqueti, Viviany

AU - Wei, Nancy

AU - Burris, Howard

AU - Cioffi, Angela

AU - Dalseg, Anne Marie

AU - Ghosh, Nilanjan

AU - Gralow, Julie

AU - Mayer, Tina

AU - Rugo, Hope

AU - Fowler, Vance

AU - Limaye, Ajit P.

AU - Cosgrove, Sara

AU - Levine, Donald

AU - Lopes, Renato

AU - Scott, John

AU - Thuren, Tom

AU - Ligueros, Monica

AU - Hilkert, Robert

AU - Tamesby, Georgia

AU - Mickel, Carolyn

AU - Manning, Brian

AU - Woelcke, Julian

AU - Tan, Monique

AU - Manfreda, Sheryl

AU - Ponce, Tom

AU - Kam, Jane

AU - Saini, Ravinder

AU - Banker, Kehur

AU - Salko, Thomas

AU - Nandy, Panjat

AU - Tawfik, Ronda

AU - O'Neil, Greg

AU - Bailey, Kent R

AU - Jirvankar, Pravin

AU - Lal, Shankar

AU - Nema, Deepak

AU - Jose, Jaison

AU - Collins, Rory

AU - Bailey, Kent

AU - Blumenthal, Roger

AU - Colhoun, Helen

AU - Gersh, Bernard

AU - Glynn, Robert J.

PY - 2017/10/21

Y1 - 2017/10/21

N2 - 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 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. Methods 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). 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 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% (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 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]; 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 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). Interpretation 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. Funding Novartis Pharmaceuticals.

AB - 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 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. Methods 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). 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 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% (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 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]; 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 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). Interpretation 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. Funding Novartis Pharmaceuticals.

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U2 - 10.1016/S0140-6736(17)32247-X

DO - 10.1016/S0140-6736(17)32247-X

M3 - Article

C2 - 28855077

AN - SCOPUS:85028364235

VL - 390

SP - 1833

EP - 1842

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10105

ER -