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Nivolumab plus Ipilimumab Combo Controls Brain Metastases in Patients with Skin Cancer

Web Exclusives - Immunotherapy

The combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) achieved clinically meaningful control of brain metastases in a substantial proportion of patients with metastatic melanoma, according to the recently published results of the phase 2 clinical trial known as CheckMate-204.1 The combination of these 2 immunotherapies is already approved by the FDA as first-line treatment for patients with unresectable or metastatic melanoma.

This clinical trial is the first study to show that this immunotherapy combination is as beneficial in controlling brain metastases as it is in treating extracranial metastases.

“These results are relevant in a population in whom progression [of cancer] can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,”1 wrote lead author Hussein A. Tawbi, MD, PhD, MSc, Director, Melanoma Clinical Research and Early Drug Development, Department of Melanoma Medical Oncology, M.D. Anderson Cancer Center, Houston, TX, and colleagues.

“Although current practice is to start with surgery, stereotactic radiotherapy, or both followed by immunotherapy or targeted agents, our results support the initiation of immunotherapy to achieve prompt control of both extracranial and brain metastases,”1 they added.

“This study is a fantastic advance for patients with brain metastases from melanoma. It shows that combination immunotherapy can shrink brain metastases in a substantial proportion of patients. Since the study did not include patients who were on corticosteroids or neurologically symptomatic, additional research is needed to know how well combination immunotherapy works in that group of patients,” co­-author Michael A. Postow, MD, a med­­ical oncologist at Memorial Sloan Kettering Cancer Center, New York City, said in an interview with Value-Based Cancer Care.

Brain metastases are a major cause of death in patients with cancer. Melanoma has a high likelihood of metastasizing to the brain. Up to 33% of patients with advanced melanoma have brain metastases at diagnosis, and up to 75% have brain metastases at the time of death.1

The investigators suggest that up-front use of the immunotherapy combination could reduce or prevent complications—including cognitive decline and radiation necrosis—associated with standard treatment for brain metastases in patients with advanced melanoma.

Study Details

This multicenter, open-label, phase 2 clinical trial enrolled 94 patients (median age, 59 years) with metastatic melanoma and ≥1 measurable nonirradiated asymptomatic brain metastases. Overall, 52% of all patients had 1 brain metastasis, 24% had 2 lesions, and 22% had ≥3 lesions at study entry.

Patients received nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses during induction. This was followed by maintenance with nivolumab 3 mg/kg every 2 weeks. Treatment was continued for a maximum of 24 months or until disease progression or unacceptable toxicity.

The primary end point was the rate of intracranial benefit, defined as the percentage of patients who had stable disease for at least 6 months after treatment initiation, complete response, or partial response. The minimum follow-up for the 94 patients was 6 months, and the median follow-up was 14 months.

The median overall duration of treatment was 3.4 months. The median number of doses received during induction was 3, and 35% of patients received all 4 scheduled doses of the combination. During the maintenance phase, 59% of patients received nivolumab therapy, with a median of 15 doses.

At the study cutoff date for analysis, 74% of patients were no longer receiving treatment, and 26% were still receiving treatment. The death rate was 22%.

Impressive Response Rates

The rate of intracranial benefit was 57%, the rate of complete responses was 26%, and 30% of patients had partial responses. An additional 2 (2%) patients had stable disease for ≥6 months. Extracranial lesions had a similar objective response rate. Among patients with an intracranial objective response, 90% were ongoing at the data cutoff, and the median time to response was 2.3 months.

A subgroup analysis showed that the immunotherapy combination achieved a higher rate of clinical benefit among patients whose tumor had PD-L1 expression of at least 5%, for ­­a total of 76% for those with high PD-L1 expression versus 48% for those with no PD-L1 expression. This finding is consistent with other studies in extracranial disease, according to the investigators.

The 6-month and 9-month rates of progression-free survival were 64.2% and 59.5%, respectively, for intracranial assessments; 75.9% and 70.4%, respectively, for extracranial assessments; and 61.1% and 56.6% for global assessments.

Preliminary assessment of overall survival (OS) rates showed that 92.3% of patients were alive at 6 months and 82.8% were alive at 9 months. The estimated 12-month OS rate was 81.5%, which is better than the median OS of 4 to 5 months with conventional therapy.

Safety Profile

The safety profile of nivolumab plus ipilimumab in this study was consistent with findings from earlier studies of this combination in patients with melanoma who did not have brain metastases.

Overall, 55% of patients had treatment-related grade 3 or 4 adverse events, including 7% with central nervous system events. Increases in liver enzymes were the most often reported grade 3 and 4 events. In addition, 19 (20%) patients discontinued treatment because of adverse events, and 1 patient died from immune-related myocarditis.


  1. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379:722-730.
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