First-Line Nivolumab/Ipilimumab Yields Durable Survival Benefit in Asymptomatic Melanoma With Brain Mets


The combination of nivolumab plus ipilimumab demonstrated a survival benefit among patients with active melanoma and brain metastases.

First-line nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated durable responses in a population of asymptomatic patients with melanoma and brain metastases, according to findings from the phase 2 CheckMate 204 study (NCT02320058), published in The Lancet Oncology.1

In the asymptomatic cohort of patients (cohort A), investigators reported an overall survival (OS) of 71.9% at 3 years compared with 36.6% in the symptomatic cohort (cohort B). Patients that had symptomatic brain metastases or were receiving corticosteroid therapy had an OS of 36.6%. Moreover, the investigator assessed median intracranial progression-free survival (PFS) was not reached in cohort A, and was 39.3 months per blinded independent central review (BICR). PFS by intracranial-based assessment was 54.1% (95% CI, 42.7%-64.1%), and 52.5% (95% CI, 41.4-62.4) by BICR was. OS at 36 months was 73.0% for patients with BRAF-mutant and 68.8% for wild-type tumors.

“Inducing an intracranial response with combination immunotherapy has a direct and lasting impact on survival for patients whose melanoma has spread to the brain. We’ve shown that this treatment offers a chance of long-term survival to patients with a historically dire prognosis,” lead author Hussein Tawbi, MD, PhD, professor of Melanoma Medical Oncology and co-director of the Brain Metastasis Clinic at MD Anderson Cancer Center, said in a press release.

A total of 165 patients were enrolled in the study, 72% of whom were treated, including 101 patients from cohort A and 18 in cohort B. A total of 89% of patients in cohort B had neurological symptoms or signs at baseline.

The study’s minimum follow-up was 34.2 months, and median follow-up was 34.3 months. Investigators reported that 58% of patients in cohort A and 28% in cohort B remained in follow-up until database cutoff. In cohort A, the median duration of treatment was 3.4 months, and 57% of patients entered the maintenance phase of treatment. In cohort B, the median duration was 0.7 months and 22% patients entered the maintenance phase of treatment. Moreover, 19% of patients in cohort A and 22% in cohort B received subsequent systemic therapies.

Of those who were asymptomatic, 57.4% derived intracranial clinical benefit (95% CI, 47.2%-67.2%), and 53.5% achieved an objective response (95% CI, 43.3%-63.5%). Intracranial clinical benefit by BICR in cohort A was 53.5% (95% CI, 43.3%-63.5%) and 49.5% (95% CI, 39.4%-59.6%) experienced an intracranial objective response.

The BICR assessment indicated that patients in cohort A had a median reduction in tumor volume of -69.0% and 84% of patients had an ongoing intracranial response. The median duration of response had not been reached, and 58% of patients had responses lasting more than 2 years. The majority of patients experienced first responses at a median of 2.8 months per BICR, and 1.4 months per investigator.

In cohort B, 16.7% of patients had an intracranial response (95% CI, 3.6%-41.4%) and 22.2% had extracranial and global responses (95% CI, 6.4%-47.6%). The median duration of response had not yet been reached at the time of the data lock. An overall median increase in tumor volume of 23.0% was observed within cohort B by BICR assessment. In cohort B, the median time to response was 2.0 months per BICR and 5.5 months per the investigators, and responses lasted 2.5 years.

The median intracranial PFS for symptomatic patients was 1.2 months per BICR and investigator assessment. At 36 months, the PFS rate for intracranial disease was 18.9% (95% CI, 4.6%-40.5%) by investigator assessment and 28.2% (95% CI, 9.6%-50.5%) by BICR assessment. The 36-month OS was 36.6% (95% CI, 14.0%-59.8%).

A total of 2 of 12 patients who received corticosteroids at baseline achieved a response vs 2 of 6 patients who did not. The 24-month OS was 32.4% (95% CI, 8.0%-60.5%) for those with baseline dexamethasone use, and 66.7% (95% CI, 19.5%-90.4%) for those who did not receive the treatment.

Grade 3/4 treatment-related adverse effects (TRAEs) occurred in 55% of patients in cohort A and 67% in cohort B. In cohort A, the most common TRAE was increase alanine (15%) or aspartate aminotransferase (15%). In cohort B, there were no grade 3 TRAEs that occurred in more than 1 patient and no grade 4 toxicities.

Treatment discontinuation occurred in 29% of patients in cohort A because of any grade TRAEs, and in cohort B, 3 patients discontinued, due to pustular rash, nephritis, or pneumonitis. Grade 3/4 neurological TRAEs occurred in 7 patients in cohort A and 3 in cohort B.

Immune-mediated AEs were similar between cohorts, with the most common being hepatitis, rash, and hypothyroidism. Serious TRAEs included colitis, diarrhea, hypophysis, and increased alanine aminotransferase in cohort A.

There was 1 treatment-related death in cohort A due to grade 5 myocarditis. In cohort A, a total of 29 deaths were reported; 21 deaths were from disease, 1 from drug toxicity, and 7 were from unknown causes. A total of 10 deaths occurred in cohort B—8 from disease and 2 from unknown causes.


1. 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):1692-1704. doi:10.1016/S1470-2045(21)00545-3

2. Combination immunotherapy improves survival for patients with asymptomatic melanoma brain metastases. News Release. MD Anderson Cancer Center. November 10, 2021. Accessed December 15, 2021.

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