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Tawbi HA, Forsyth PA, Hodi FS, et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 2021;22(12):1692-1704doi: 10.1016/S1470-2045(21)00545-3.
Tawbi, H. A., Forsyth, P. A., Hodi, F. S., Algazi, A. P., Hamid, O., Lao, C. D., Moschos, S. J., Atkins, M. B., Lewis, K., Postow, M. A., Thomas, R. P., Glaspy, J., Jang, S., Khushalani, N. I., Pavlick, A. C., Ernstoff, M. S., Reardon, D. A., Kudchadkar, R., Tarhini, A., Chung, C., Ritchings, C., Durani, P., Askelson, M., Puzanov, I., & Margolin, K. A. (2021). Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. The Lancet. Oncology, 22(12), 1692-1704. https://doi.org/10.1016/S1470-2045(21)00545-3
Tawbi, Hussein A, et al. "Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study." The Lancet. Oncology vol. 22,12 (2021): 1692-1704. doi: https://doi.org/10.1016/S1470-2045(21)00545-3
Tawbi HA, Forsyth PA, Hodi FS, Algazi AP, Hamid O, Lao CD, Moschos SJ, Atkins MB, Lewis K, Postow MA, Thomas RP, Glaspy J, Jang S, Khushalani NI, Pavlick AC, Ernstoff MS, Reardon DA, Kudchadkar R, Tarhini A, Chung C, Ritchings C, Durani P, Askelson M, Puzanov I, Margolin KA. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 2021 Dec;22(12):1692-1704. doi: 10.1016/S1470-2045(21)00545-3. Epub 2021 Nov 10. PMID: 34774225.
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Lancet Oncol. 2021 Dec;22(12):1692-1704. doi: 10.1016/S1470-2045(21)00545-3. Epub 2021 Nov 10.

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study.

The Lancet. Oncology

Hussein A Tawbi, Peter A Forsyth, F Stephen Hodi, Alain P Algazi, Omid Hamid, Christopher D Lao, Stergios J Moschos, Michael B Atkins, Karl Lewis, Michael A Postow, Reena P Thomas, John Glaspy, Sekwon Jang, Nikhil I Khushalani, Anna C Pavlick, Marc S Ernstoff, David A Reardon, Ragini Kudchadkar, Ahmad Tarhini, Caroline Chung, Corey Ritchings, Piyush Durani, Margarita Askelson, Igor Puzanov, Kim A Margolin

Affiliations

  1. University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected].
  2. Department of Neuro-Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
  3. Dana-Farber Cancer Institute, Boston, MA, USA.
  4. Melanoma Center, University of California-San Francisco, San Francisco, CA, USA.
  5. Melanoma Center, The Angeles Clinic and Research Institute, Los Angeles, CA, USA.
  6. Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
  7. Division of Hematology & Oncology, The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
  8. Department of Medical Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington DC, USA.
  9. Department of Medical Oncology, University of Colorado Comprehensive Cancer Center, Aurora, CO, USA.
  10. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  11. Department of Neurology, Stanford University Cancer Center, Stanford, CA, USA.
  12. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
  13. Inova Schar Cancer Institute, Fairfax, VA, USA.
  14. Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL USA.
  15. Department of Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
  16. Department of Immuno-Oncology, Division of Cancer Treatment and Diagnosis, National Cancer Institute at the National Institutes of Health, Rockville, MD, USA.
  17. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  18. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
  19. Departments of Cutaneous Oncology and Immunology, Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
  20. University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  21. Bristol Myers Squibb, Princeton, NJ, USA.
  22. Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  23. Department of Medical Oncology, City of Hope, Duarte, CA, USA.

PMID: 34774225 DOI: 10.1016/S1470-2045(21)00545-3

Abstract

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.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Conflict of interest statement

Declaration of interests HAT worked in a consulting/advisory role for Array BioPharma, Bristol Myers Squibb (BMS), Genentech/Roche, Merck, and Novartis; participated in a scientific advisory board for

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