TY - JOUR
T1 - Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial
AU - Peters, S.
AU - Pujol, J.L.
AU - Dafni, U.
AU - Domine, M.
AU - Popat, S.
AU - Reck, M.
AU - Andrade, J.
AU - Becker, A.
AU - Moro-Sibilot, D.
AU - Curioni-Fontecedro, A.
AU - Molinier, O.
AU - Nackaerts, K.
AU - Molla, A.I.
AU - Gervais, R.
AU - Vivanco, G.L.
AU - Madelaine, J.
AU - Mazieres, J.
AU - Faehling, M.
AU - Griesinger, F.
AU - Majem, M.
AU - Larriba, J.L.G.
AU - Pulla, M.P.
AU - Vervita, K.
AU - Roschitzki-Voser, H.
AU - Ruepp, B.
AU - Mitchell, P.
AU - Stahel, R.A.
AU - Le Pechoux, C.
AU - De Ruysscher, D.
AU - ETOP/IFCT 4-12 STIMULI Collaborators
N1 - Funding Information:
We thank the 222 patients who participated in the trial and their families, the STIMULI investigators at the 62 clinical sites and their teams, the French Cooperative Thoracic Intergroup (IFCT; Franck Morrin and Elodie Amour), the Spanish Lung Cancer Group (SLCG), the Australasian Lung Cancer Clinical Trials Group (ALTG), the Central laboratory in Lausanne, the European Thoracic Oncology Platform Independent Data Monitoring Committee (IDMC), the staff at the ETOP Coordinating Office and at the ETOP Statistical Office for supporting the trial. S. Popat acknowledges NHS funding to the Royal Marsden-ICR NIHR Biomedical Research Centre. This work was supported by the European Thoracic Oncology Platform (ETOP) and coordinated in collaboration with the French Cooperative Thoracic Intergroup (IFCT);, the Spanish Lung Cancer Group (SLCG); the Australasian Lung Cancer Clinical Trials Group (ALTG) (no grant numbers) and financed by a grant from Bristol Myers Squibb International Corporation, Brussels ([grant number CA184-310]. SP reports personal fees from Abbvie, Bayer, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffman–La Roche, Foundations Medicine, Janssen, Pharma Mar, Regeneron, Sanofi, Seattle Genetics, Takeda, Merck Serono, Merrimack, Medscape, Phosphoplatin Therapeutics, Beigene, Imedex and grants and personal fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Illumina, Novartis, Pfizer, Merck Sharp and Dohme, outside the submitted work; all fees to the institution. UD reports personal fees from F. Hoffman–La Roche, outside the submitted work. MD reports personal fees from AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, F. Hoffman–La Roche, Merck Sharp and Dohme, Pfizer, and Takeda, outside the submitted work. SP reports personal fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, F. Hoffman–La Roche, GlaxoSmithKline, Guardant Health, Incyte, Janssen, Lilly, Merck KGaA, and Takeda, outside the submitted work. MR reports personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Lilly, Merck KGaA, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, F. Hoffman–La Roche, and Regeneron, outside the submitted work. DMS reports grants, personal fees and non-financial support from AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, F. Hoffman–La Roche, during the conduct of the study; grants, personal fees and non-financial support from Boehringer-Ingelheim, Pfizer, and Takeda, grants and non-financial support from Lilly, outside the submitted work. OM reports personal fees from AstraZeneca, Merck Sharp and Dohme, Bristol-Myers Squibb, and Takeda, outside the submitted work. KN reports personal fees from Amgen, AbbVie, AstraZeneca, Bristol-Myers Squibb Belgium, and F. Hoffman–La Roche Belgium, outside the submitted work. AIM reports personal fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol, F. Hoffman–La Roche, Merck Sharp and Dohme, Pfizer, and Takeda, outside the submitted work. JM reports other from Boehringer-Ingelheim, Bristol-Myers Squibb, F. Hoffman–La Roche, and Pfizer, outside the submitted work. JM reports grants and personal fees from AstraZeneca, F. Hoffman–La Roche, Pierre Fabre and personal fees from Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Hengrui, Merck, Merck Sharp and Dohme, and Pfizer, outside the submitted work. MF reports personal fees from AstraZeneca, Bristol-Myers Squibb, F. Hoffman–La Roche, and Merck Sharp and Dohme, outside the submitted work. FG reports grants and personal fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, F. Hoffman–La Roche, Lilly, Merck Sharp and Dohme, Novartis, Pfizer, Siemens, and Takeda, and personal fees from Abbvie, outside the submitted work. MM reports grants and personal fees from Bristol-Myers Squibb, Pierre Fabre, personal fees and non-financial support from AstraZeneca, Boehringer-Ingelheim, F. Hoffman–La Roche, Merck Sharp and Dohme, and personal fees from Kyowa Kirin, outside the submitted work. MPP reports grants, personal fees and non-financial support from AstraZeneca, Bristol-Myers Squibb, and F. Hoffman–La Roche, personal fees from Merck Sharp and Dohme, and Takeda, outside the submitted work. PM reports personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, F. Hoffman–La Roche, Merck Sharp and Dohme, Puma Biotechnology, Specialised Therapeutics and grants from AstraZeneca, and Bristol-Myers Squibb, outside the submitted work. RAS reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, F. Hoffman–La Roche, Merck Sharp and Dohme, Pfizer, and Novartis, grants from F. Hoffman–La Roche, Ipsen, Pierre Fabre, personal fees from Amgen, Blueprint, Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Regeneron, Seattle Genetics, and Sandoz, personal fees and other from Genentech/F. Hoffman–La Roche, Lung Cancer, Takeda, and other from CTR, outside the submitted work. CLP reports other from Amgen, AstraZeneca, F. Hoffman–La Roche, Lilly, Medscape, and Nanobiotix, and personal fees from PrimeOncology, outside the submitted work. DDR reports grants from AstraZeneca, Bristol-Myers Squibb, Olink, Philips Health, and Seattle Genetics, and outside the submitted work. All other authors have declared no conflicts of interest.
Publisher Copyright:
© 2021 European Society for Medical Oncology
PY - 2022/1/1
Y1 - 2022/1/1
N2 - Background: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (ID-SCLC), with 5-year overall survival (OS) of only 25% to 33%.Patients and methods: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment dosed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint.Results: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR) = 1.02 (0.66-1.58), two-sided P = 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR = 0.95 (0.59-1.52), P = 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade >= 3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively.Conclusions: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.
AB - Background: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (ID-SCLC), with 5-year overall survival (OS) of only 25% to 33%.Patients and methods: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment dosed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint.Results: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR) = 1.02 (0.66-1.58), two-sided P = 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR = 0.95 (0.59-1.52), P = 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade >= 3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively.Conclusions: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.
KW - nivolumab
KW - ipilimumab
KW - small-cell lung cancer
KW - SCLC
KW - limited disease
KW - randomised clinical trial
KW - OPEN-LABEL
KW - PLUS IPILIMUMAB
KW - 1ST-LINE NIVOLUMAB
KW - CHECKMATE 032
KW - RECURRENT
KW - MULTICENTER
U2 - 10.1016/j.annonc.2021.09.011
DO - 10.1016/j.annonc.2021.09.011
M3 - Article
C2 - 34562610
SN - 0923-7534
VL - 33
SP - 67
EP - 79
JO - Annals of Oncology
JF - Annals of Oncology
IS - 1
ER -