. 2021 Nov 2;23(11):1961-1973.

doi: 10.1093/neuonc/noab094.

Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204)

Hussein A Tawbi¹, Peter A Forsyth², F Stephen Hodi³, Christopher D Lao⁴, Stergios J Moschos⁵, Omid Hamid⁶, Michael B Atkins⁷, Karl Lewis⁸, Reena P Thomas⁹, John A Glaspy¹⁰, Sekwon Jang¹¹, Alain P Algazi¹², Nikhil I Khushalani¹³, Michael A Postow¹⁴, Anna C Pavlick¹⁵, Marc S Ernstoff¹⁶, David A Reardon¹⁷, Igor Puzanov¹⁸, Ragini R Kudchadkar¹⁹, Ahmad A Tarhini¹³, Anne Sumbul²⁰, Jasmine I Rizzo²¹, Kim A Margolin²²

Affiliations

¹ Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
² Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁴ Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Division of Hematology and Oncology, The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
⁶ Department of Translational Research & Immunotherapy, The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, California, USA.
⁷ Department of Medical Oncology, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.
⁸ Department of Medical Oncology, University of Colorado Comprehensive Cancer Center, Aurora, Colorado, USA.
⁹ Department of Neurology, Stanford University Cancer Center, Stanford, California, USA.
¹⁰ Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.
¹¹ Department of Medicine, Inova Schar Cancer Institute, Virginia Commonwealth University, Fairfax, Virginia, USA.
¹² Department of Hematology and Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
¹³ Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
¹⁴ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
¹⁵ Department of Medical Oncology, Weill Cornell Medicine, New York, New York, USA.
¹⁶ Department of Immuno-Oncology, Division of Cancer Treatment and Diagnosis, National Cancer Institute at the National Institutes of Health, Rockville, Maryland, USA.
¹⁷ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹⁸ Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
¹⁹ Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
²⁰ Biostatistics, Bristol Myers Squibb, Princeton, New Jersey, USA.
²¹ Oncology Clinical Development, Bristol Myers Squibb, Princeton, New Jersey, USA.
²² Department of Medical Oncology, City of Hope, Duarte, California, USA.

PMID: 33880555
PMCID: PMC8563325
DOI: 10.1093/neuonc/noab094

Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204)

Hussein A Tawbi et al. Neuro Oncol. 2021.

. 2021 Nov 2;23(11):1961-1973.

doi: 10.1093/neuonc/noab094.

Authors

Affiliations

¹ Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
² Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁴ Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Division of Hematology and Oncology, The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
⁶ Department of Translational Research & Immunotherapy, The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, California, USA.
⁷ Department of Medical Oncology, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.
⁸ Department of Medical Oncology, University of Colorado Comprehensive Cancer Center, Aurora, Colorado, USA.
⁹ Department of Neurology, Stanford University Cancer Center, Stanford, California, USA.
¹⁰ Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.
¹¹ Department of Medicine, Inova Schar Cancer Institute, Virginia Commonwealth University, Fairfax, Virginia, USA.
¹² Department of Hematology and Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
¹³ Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
¹⁴ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
¹⁵ Department of Medical Oncology, Weill Cornell Medicine, New York, New York, USA.
¹⁶ Department of Immuno-Oncology, Division of Cancer Treatment and Diagnosis, National Cancer Institute at the National Institutes of Health, Rockville, Maryland, USA.
¹⁷ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹⁸ Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
¹⁹ Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
²⁰ Biostatistics, Bristol Myers Squibb, Princeton, New Jersey, USA.
²¹ Oncology Clinical Development, Bristol Myers Squibb, Princeton, New Jersey, USA.
²² Department of Medical Oncology, City of Hope, Duarte, California, USA.

PMID: 33880555
PMCID: PMC8563325
DOI: 10.1093/neuonc/noab094

Abstract

Background: In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients.

Methods: Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months).

Results: Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed.

Conclusions: Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.

Keywords: checkpoint inhibitor; ipilimumab; melanoma; nivolumab; symptomatic brain metastases.

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Figures

**Fig.1**
Kaplan-Meier plot of (A) progression-free survival (PFS) as assessed by the investigators and (B) overall survival (OS) in symptomatic patients. Symbols indicate censored observations. Median PFS was 1.2 months (95% CI: 0.7-1.3) for intracranial disease, 2.2 months (95% CI: 0.8-not reached) for extracranial disease, and 1.2 months (95% CI: 0.8-not reached) for global disease. Median OS was 8.7 months (95% CI: 8.8-not reached).

**Fig. 2**
Kaplan-Meier plot of (A) progression-free survival (PFS) as assessed by the investigators and (B) overall survival (OS) in asymptomatic patients. Symbols indicate censored observations. Median PFS has not been reached for intracranial (95% CI: 6.5-not reached), extracranial (95% CI: 13.9-not reached), or global (95% CI: 6.5-not reached) disease. Median OS has not been reached. ^aIncludes 7 patients without extracranial disease at baseline.

See this image and copyright information in PMC

Comment in

The evolving role of systemic therapy and local, brain-directed treatment in patients with melanoma and brain metastases.
Lamba N, Aizer AA. Lamba N, et al. Neuro Oncol. 2021 Nov 2;23(11):1816-1817. doi: 10.1093/neuonc/noab194. Neuro Oncol. 2021. PMID: 34350960 Free PMC article. No abstract available.

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Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204)

Affiliations

Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204)

Authors

Affiliations

Abstract

Figures

Comment in

References

Publication types

MeSH terms

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Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

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