TY - JOUR
T1 - Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204)
T2 - final results of an open-label, multicentre, phase 2 study
AU - Tawbi, Hussein A.
AU - Forsyth, Peter A.
AU - Hodi, F. Stephen
AU - Algazi, Alain P.
AU - Hamid, Omid
AU - Lao, Christopher D.
AU - Moschos, Stergios J.
AU - Atkins, Michael B.
AU - Lewis, Karl
AU - Postow, Michael A.
AU - Thomas, Reena P.
AU - Glaspy, John
AU - Jang, Sekwon
AU - Khushalani, Nikhil I.
AU - Pavlick, Anna C.
AU - Ernstoff, Marc S.
AU - Reardon, David A.
AU - Kudchadkar, Ragini
AU - Tarhini, Ahmad
AU - Chung, Caroline
AU - Ritchings, Corey
AU - Durani, Piyush
AU - Askelson, Margarita
AU - Puzanov, Igor
AU - Margolin, Kim A.
N1 - Funding Information:
This study was supported by Bristol Myers Squibb. We thank the patients and investigators who participated in the CheckMate 204 trial. This research was supported in part through the US National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748 (to MAP) and P30 CA016056 (to IP). We acknowledge Ono Pharmaceutical Company (Osaka, Japan) for contributions to nivolumab development and Dako, an Agilent Technologies company (Santa Clara, CA, USA) for collaborative development of the PD-L1 immunohistochemistry 28-8 pharmDx assay. We acknowledge David Leung from Bristol Myers Squibb for contributions to the design of the study and blinded independent central review (BICR), and for support of the BICR data acquisition and analyses. Professional medical writing and editorial assistance were provided by Melissa Kirk and Michele Salernitano at Ashfield MedComms, an Ashfield Health Company, funded by Bristol Myers Squibb.
Funding Information:
This study was supported by Bristol Myers Squibb. We thank the patients and investigators who participated in the CheckMate 204 trial. This research was supported in part through the US National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748 (to MAP) and P30 CA016056 (to IP). We acknowledge Ono Pharmaceutical Company (Osaka, Japan) for contributions to nivolumab development and Dako, an Agilent Technologies company (Santa Clara, CA, USA) for collaborative development of the PD-L1 immunohistochemistry 28-8 pharmDx assay. We acknowledge David Leung from Bristol Myers Squibb for contributions to the design of the study and blinded independent central review (BICR), and for support of the BICR data acquisition and analyses. Professional medical writing and editorial assistance were provided by Melissa Kirk and Michele Salernitano at Ashfield MedComms, an Ashfield Health Company, funded by Bristol Myers Squibb.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/12
Y1 - 2021/12
N2 - Background: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. Methods: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5–3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0–2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058. Findings: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7–36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2–35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2–67·2]) of 101 patients in cohort A and three (16·7% [3·6–41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3–63·5]) patients in cohort A and three (16·7% [3·6–41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7–64·1) and overall survival was 71·9% (61·8–79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6–40·5) and overall survival was 36·6% (14·0–59·8). The most common grade 3–4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). Interpretation: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. Funding: Bristol Myers Squibb.
AB - Background: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. Methods: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5–3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0–2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058. Findings: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7–36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2–35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2–67·2]) of 101 patients in cohort A and three (16·7% [3·6–41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3–63·5]) patients in cohort A and three (16·7% [3·6–41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7–64·1) and overall survival was 71·9% (61·8–79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6–40·5) and overall survival was 36·6% (14·0–59·8). The most common grade 3–4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). Interpretation: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. Funding: Bristol Myers Squibb.
UR - http://www.scopus.com/inward/record.url?scp=85122490432&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122490432&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(21)00545-3
DO - 10.1016/S1470-2045(21)00545-3
M3 - Article
C2 - 34774225
AN - SCOPUS:85122490432
SN - 1470-2045
VL - 22
SP - 1692
EP - 1704
JO - The lancet oncology
JF - The lancet oncology
IS - 12
ER -