TY - JOUR
T1 - Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505)
T2 - an open-label, multicentre, randomised, phase 3 trial
AU - Wakelee, Heather A.
AU - Dahlberg, Suzanne E.
AU - Keller, Steven M.
AU - Tester, William J.
AU - Gandara, David R.
AU - Graziano, Stephen L.
AU - Adjei, Alex A.
AU - Leighl, Natasha B.
AU - Aisner, Seena C.
AU - Rothman, Jan M.
AU - Patel, Jyoti D.
AU - Sborov, Mark D.
AU - McDermott, Sean R.
AU - Perez-Soler, Roman
AU - Traynor, Anne M.
AU - Butts, Charles
AU - Evans, Tracey
AU - Shafqat, Atif
AU - Chapman, Andrew E.
AU - Kasbari, Samer S.
AU - Horn, Leora
AU - Ramalingam, Suresh S.
AU - Schiller, Joan H.
N1 - Funding Information:
HAW has received honoraria from Peregrine, ACEA, and Helsinn; grants and honoraria from Pfizer and Genentech–Roche; and research support from Clovis, Exelixis, AstraZeneca–Medimmune, Bristol-Myers Squibb, Gilead, Novartis, Xcovery, Celgene, Pharmacyclics, and Lilly, outside the submitted work. SED has received research grants from the National Cancer Institute of the National Institutes of Health and Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network; and grants from Genentech during this study; and personal fees from AstraZeneca, outside the submitted work. Additionally, SED has a pending patent, Methods of Assessing Tumor Growth, for the Dana-Farber Cancer Institute (patent application number PCT/US2014/054821). Following completion of the study and presentation at the World Lung Conference, SMK left the clinical practice of Thoracic Surgery at the Montefiore Medical Center (NY, USA) and joined Merck on Nov 28, 2016, as a Senior Principal Scientist in the Lung Oncology Group. SRM has received personal fees from Clovis; grants and personal fees from Pfizer; grants from Amgen and Celgene; personal fees and research funding from Bristol-Myers Squibb; research funding from Merck, Bayer, and Janssen, outside the submitted work. RP-S has received honoraria from Roche–Genentech for advisory boards and educational speaking engagements. TE has received personal fees from Genentech, outside the submitted work. LH has received personal fees from AbbVie advisory board; pro bono from Bristol-Myers Squibb advisory board, Boehringer Ingelheim advisory board, Xcovery consulting, and Bayer consulting; personal fees from Lilly advisory board and Genentech–Roche advisory board; and payment to institution from Merck advisory board, outside the submitted work. SSR has served on advisory boards for Amgen, AstraZeneca, AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Celgene, Genentech, and Novartis, outside the submitted work. JH Prof J S has received research grants from the National Cancer Institute of the National Institutes of Health during the conduct of the study; and grants and personal fees from Genentech and Lilly, outside the submitted work. All other authors declare no competing interests.
Funding Information:
This trial was funded by the National Cancer Institute of the National Institutes of Health of the USA (grants CA180820, CA180794, CA180790, CA180799, CA180816, CA180821, CA180866, CA180844, CA180846, CA180847, CA180863, CA180864, CA180870, CA180888, CA189830, CA189858, CA189859, CA189863, and Canadian Research Grant 021039) and was coordinated by the Eastern Cooperative Oncology Group?American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group (Peter J O'Dwyer and Mitchell D Schnall are group co-chairs). We thank all patients who participated in the trial and their families and caregivers, the ECOG-ACRIN coordinating centre, in particular Jeanne Sheehan (ECOG-ACRIN Medical Research Foundation, Philadelphia, PA, USA), and all investigators and staff involved in this effort at the participating sites. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government.
Funding Information:
This trial was funded by the National Cancer Institute of the National Institutes of Health of the USA ( grants CA180820, CA180794, CA180790, CA180799, CA180816, CA180821, CA180866, CA180844, CA180846, CA180847, CA180863, CA180864, CA180870, CA180888, CA189830, CA189858, CA189859, CA189863 , and Canadian Research Grant 021039 ) and was coordinated by the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group (Peter J O'Dwyer and Mitchell D Schnall are group co-chairs). We thank all patients who participated in the trial and their families and caregivers, the ECOG-ACRIN coordinating centre, in particular Jeanne Sheehan (ECOG-ACRIN Medical Research Foundation, Philadelphia, PA, USA), and all investigators and staff involved in this effort at the participating sites. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government.
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/12
Y1 - 2017/12
N2 - Background Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC. Methods We did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6–12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805. Findings Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9–68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82–1·19; p=0·90). Grade 3–5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3–5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment. Interpretation Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC. Funding National Cancer Institute of the National Institutes of Health.
AB - Background Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC. Methods We did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6–12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805. Findings Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9–68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82–1·19; p=0·90). Grade 3–5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3–5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment. Interpretation Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC. Funding National Cancer Institute of the National Institutes of Health.
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U2 - 10.1016/S1470-2045(17)30691-5
DO - 10.1016/S1470-2045(17)30691-5
M3 - Article
AN - SCOPUS:85033451535
VL - 18
SP - 1610
EP - 1623
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 12
ER -