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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 - 30/11/21

Doi : 10.1016/S1470-2045(21)00545-3 
Hussein A Tawbi, ProfMD a, ⁎ , Peter A Forsyth, ProfMD b, F Stephen Hodi, ProfMD c, Alain P Algazi, MD d, Omid Hamid, MD e, Christopher D Lao, ProfMD f, Stergios J Moschos, MD g, Michael B Atkins, ProfMD h, Karl Lewis, MD i, Michael A Postow, MD j, Reena P Thomas, MD k, John Glaspy, ProfMD l, Sekwon Jang, MD m, Nikhil I Khushalani, MD n, Anna C Pavlick, DO o, Marc S Ernstoff, ProfMD p, David A Reardon, ProfMD q, Ragini Kudchadkar, MD r, Ahmad Tarhini, ProfMD s, Caroline Chung, MD a, Corey Ritchings, PharmD t, Piyush Durani, MD t, Margarita Askelson, MSc t, Igor Puzanov, ProfMD u, Kim A Margolin, ProfMD v
a University of Texas MD Anderson Cancer Center, Houston, TX, USA 
b Department of Neuro-Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL, USA 
c Dana-Farber Cancer Institute, Boston, MA, USA 
d Melanoma Center, University of California—San Francisco, San Francisco, CA, USA 
e Melanoma Center, The Angeles Clinic and Research Institute, Los Angeles, CA, USA 
f Department of Dermatology, University of Michigan, Ann Arbor, MI, USA 
g Division of Hematology & Oncology, The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA 
h Department of Medical Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington DC, USA 
i Department of Medical Oncology, University of Colorado Comprehensive Cancer Center, Aurora, CO, USA 
j Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 
k Department of Neurology, Stanford University Cancer Center, Stanford, CA, USA 
l Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA 
m Inova Schar Cancer Institute, Fairfax, VA, USA 
n Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL USA 
o Department of Medical Oncology, Weill Cornell Medicine, New York, NY, USA 
p Department of Immuno-Oncology, Division of Cancer Treatment and Diagnosis, National Cancer Institute at the National Institutes of Health, Rockville, MD, USA 
q Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 
r Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA 
s Departments of Cutaneous Oncology and Immunology, Moffitt Cancer Center & Research Institute, Tampa, FL, USA 
t Bristol Myers Squibb, Princeton, NJ, USA 
u Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA 
v Department of Medical Oncology, City of Hope, Duarte, CA, USA 

* Correspondence to: Prof Hussein A Tawbi, Melanoma Medical Oncology, Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Melanoma Medical Oncology Investigational Cancer Therapeutics University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Summary

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.

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Vol 22 - N° 12

P. 1692-1704 - décembre 2021 Retour au numéro
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