Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial

Achim Rittmeyer, Fabrice Barlesi, Daniel Waterkamp, Keunchil Park, Fortunato Ciardiello, Joachim von Pawel, Shirish M. Gadgeel, Toyoaki Hida, Dariusz M. Kowalski, Manuel Cobo Dols, Diego L. Cortinovis, Joseph Leach, Jonathan Polikoff, Carlos Barrios, Fairooz Kabbinavar, Osvaldo Arén Frontera, Filippo De Marinis, Hande Turna, Jong Seok Lee, Marcus BallingerMarcin Kowanetz, Pei He, Daniel S. Chen, Alan Sandler, David R. Gandara, for the, OAK Study Group

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Abstract

Background Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. Methods We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. Findings Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8–15·7] vs 9·6 months [8·6–11·2]; hazard ratio [HR] 0·73 [95% CI 0·62–0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6–18·0] with atezolizumab vs 10·3 months [8·8–12·0] with docetaxel; HR 0·74 [95% CI 0·58–0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59–0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54–0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60–0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. Interpretation To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. Funding F. Hoffmann-La Roche Ltd, Genentech, Inc.

Original languageEnglish
Pages (from-to)255-265
Number of pages11
JournalThe Lancet
Volume389
Issue number10066
DOIs
Publication statusPublished - Jan 21 2017

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docetaxel
Non-Small Cell Lung Carcinoma
Randomized Controlled Trials
Survival
Population
MPDL3280A
Therapeutics
Histology

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  • Medicine(all)

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Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK) : a phase 3, open-label, multicentre randomised controlled trial. / Rittmeyer, Achim; Barlesi, Fabrice; Waterkamp, Daniel; Park, Keunchil; Ciardiello, Fortunato; von Pawel, Joachim; Gadgeel, Shirish M.; Hida, Toyoaki; Kowalski, Dariusz M.; Dols, Manuel Cobo; Cortinovis, Diego L.; Leach, Joseph; Polikoff, Jonathan; Barrios, Carlos; Kabbinavar, Fairooz; Frontera, Osvaldo Arén; De Marinis, Filippo; Turna, Hande; Lee, Jong Seok; Ballinger, Marcus; Kowanetz, Marcin; He, Pei; Chen, Daniel S.; Sandler, Alan; Gandara, David R.; for the; OAK Study Group.

In: The Lancet, Vol. 389, No. 10066, 21.01.2017, p. 255-265.

Research output: Contribution to journalArticle

Rittmeyer, A, Barlesi, F, Waterkamp, D, Park, K, Ciardiello, F, von Pawel, J, Gadgeel, SM, Hida, T, Kowalski, DM, Dols, MC, Cortinovis, DL, Leach, J, Polikoff, J, Barrios, C, Kabbinavar, F, Frontera, OA, De Marinis, F, Turna, H, Lee, JS, Ballinger, M, Kowanetz, M, He, P, Chen, DS, Sandler, A, Gandara, DR, for the & OAK Study Group 2017, 'Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial', The Lancet, vol. 389, no. 10066, pp. 255-265. https://doi.org/10.1016/S0140-6736(16)32517-X
Rittmeyer, Achim ; Barlesi, Fabrice ; Waterkamp, Daniel ; Park, Keunchil ; Ciardiello, Fortunato ; von Pawel, Joachim ; Gadgeel, Shirish M. ; Hida, Toyoaki ; Kowalski, Dariusz M. ; Dols, Manuel Cobo ; Cortinovis, Diego L. ; Leach, Joseph ; Polikoff, Jonathan ; Barrios, Carlos ; Kabbinavar, Fairooz ; Frontera, Osvaldo Arén ; De Marinis, Filippo ; Turna, Hande ; Lee, Jong Seok ; Ballinger, Marcus ; Kowanetz, Marcin ; He, Pei ; Chen, Daniel S. ; Sandler, Alan ; Gandara, David R. ; for the ; OAK Study Group. / Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK) : a phase 3, open-label, multicentre randomised controlled trial. In: The Lancet. 2017 ; Vol. 389, No. 10066. pp. 255-265.
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abstract = "Background Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. Methods We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1{\%} PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. Findings Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95{\%} CI 11·8–15·7] vs 9·6 months [8·6–11·2]; hazard ratio [HR] 0·73 [95{\%} CI 0·62–0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95{\%} CI 12·6–18·0] with atezolizumab vs 10·3 months [8·8–12·0] with docetaxel; HR 0·74 [95{\%} CI 0·58–0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95{\%} CI 0·59–0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95{\%} CI 0·54–0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60–0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15{\%}] of 609 patients) versus docetaxel (247 [43{\%}] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. Interpretation To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. Funding F. Hoffmann-La Roche Ltd, Genentech, Inc.",
author = "Achim Rittmeyer and Fabrice Barlesi and Daniel Waterkamp and Keunchil Park and Fortunato Ciardiello and {von Pawel}, Joachim and Gadgeel, {Shirish M.} and Toyoaki Hida and Kowalski, {Dariusz M.} and Dols, {Manuel Cobo} and Cortinovis, {Diego L.} and Joseph Leach and Jonathan Polikoff and Carlos Barrios and Fairooz Kabbinavar and Frontera, {Osvaldo Ar{\'e}n} and {De Marinis}, Filippo and Hande Turna and Lee, {Jong Seok} and Marcus Ballinger and Marcin Kowanetz and Pei He and Chen, {Daniel S.} and Alan Sandler and Gandara, {David R.} and {for the} and {OAK Study Group}",
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month = "1",
day = "21",
doi = "10.1016/S0140-6736(16)32517-X",
language = "English",
volume = "389",
pages = "255--265",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Lancet Publishing Group",
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TY - JOUR

T1 - Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK)

T2 - a phase 3, open-label, multicentre randomised controlled trial

AU - Rittmeyer, Achim

AU - Barlesi, Fabrice

AU - Waterkamp, Daniel

AU - Park, Keunchil

AU - Ciardiello, Fortunato

AU - von Pawel, Joachim

AU - Gadgeel, Shirish M.

AU - Hida, Toyoaki

AU - Kowalski, Dariusz M.

AU - Dols, Manuel Cobo

AU - Cortinovis, Diego L.

AU - Leach, Joseph

AU - Polikoff, Jonathan

AU - Barrios, Carlos

AU - Kabbinavar, Fairooz

AU - Frontera, Osvaldo Arén

AU - De Marinis, Filippo

AU - Turna, Hande

AU - Lee, Jong Seok

AU - Ballinger, Marcus

AU - Kowanetz, Marcin

AU - He, Pei

AU - Chen, Daniel S.

AU - Sandler, Alan

AU - Gandara, David R.

AU - for the

AU - OAK Study Group

PY - 2017/1/21

Y1 - 2017/1/21

N2 - Background Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. Methods We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. Findings Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8–15·7] vs 9·6 months [8·6–11·2]; hazard ratio [HR] 0·73 [95% CI 0·62–0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6–18·0] with atezolizumab vs 10·3 months [8·8–12·0] with docetaxel; HR 0·74 [95% CI 0·58–0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59–0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54–0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60–0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. Interpretation To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. Funding F. Hoffmann-La Roche Ltd, Genentech, Inc.

AB - Background Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. Methods We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. Findings Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8–15·7] vs 9·6 months [8·6–11·2]; hazard ratio [HR] 0·73 [95% CI 0·62–0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6–18·0] with atezolizumab vs 10·3 months [8·8–12·0] with docetaxel; HR 0·74 [95% CI 0·58–0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59–0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54–0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60–0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. Interpretation To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. Funding F. Hoffmann-La Roche Ltd, Genentech, Inc.

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