Dual Immunotherapy a Winner for Melanoma Brain Mets

Megan Brooks

August 22, 2018

Combined immunotherapy with two checkpoint inhibitors — nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) — has shown "clinically meaningful" efficacy in patients with asymptomatic, untreated melanoma metastases to the brain, according to a report regarding new data from the CheckMate 204 open-label phase 2 study.

"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," write the authors.

Intracranial responses, which matched extracranial responses, were seen in more than half the patients and were detected at the first disease assessment, suggesting a rapid response. The reponses were also durable.

"Most importantly," the combination of nivolumab plus ipilimumab prevented intracranial progression for more than 6 months in 64% of patients, report Hussein Tawbi, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

Preliminary results from CheckMate 204 on 75 patients with median follow-up of 6.3 months were presented last year at the annual meeting of the American Society of Clinical Oncology and were reported at the time by Medscape Medical News.

These new data, on 94 patients with a median follow-up of 14.0 months, were published August 23 in the New England Journal of Medicine.

First-Line Therapy

"Although this was a relatively small, nonrandomized study, in our view, the data reported are relevant to clinical practice, given the high response rate, rapid time to response, and manageable side-effect profile," Samra Turajlic, MD, PhD, and James Larkin, PhD, from Royal Marsden National Health Service Foundation Trust in London, United Kingdom, write in a related editorial.

"Therefore, outside the context of clinical trials, we would suggest that this regimen be considered as first-line therapy for all patients with brain metastases who meet the inclusion criteria for this study," Turajlic and Larkin say.

The CheckMate 204 study enrolled patients with melanoma whose performance status was good and who had at least one measurable, nonirradiated asymptomatic brain metastasis measuring 0.5 to 3 cm in diameter. Patients with leptomeningeal disease, those with metastases larger than 3 cm in diameter, and those receiving glucocorticoid therapy were excluded from the study.

Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for up to four doses, followed by nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxic effects.

The primary outcome was the rate of intracranial clinical benefit, defined as the percentage of patients who had complete response, partial response, or stable disease for at least 6 months. The primary outcome was achieved by 57% of patients (95% confidence interval [CI], 47% to 68%), which was on par with the rate of extracranial clinical benefit, at 56% (95% CI, 46% to 67%).

More than a quarter of patients (26%) had a complete response, another 30% had a partial response, and 2% had stable disease for at least 6 months.

Treatment-related grade 3 or 4 side effects were reported in 55% of patients; the most common of these events was an increase in liver enzyme levels (alanine aminotransferase or aspartate aminotransferase).

Nineteen patients (20%) discontinued treatment because of an adverse event of grade 3 or 4. Treatment-related adverse events of any grade that affected the central nervous system (CNS) occurred in 34 patients (36%); grade 3 or 4 CNS events occurred in seven patients (7%).

The safety profile of the combination regimen was similar to that reported in patients with melanoma who do not have brain metastases, the researchers report.

Broader Implications?

Turajlic and Larkin caution against extrapolating these data to higher-risk patients, such as those excluded from the study (patients with leptomeningeal disease, low performance status, or large-volume or symptomatic CNS disease or those taking glucocorticoids).

"There are good data showing that patients with cerebral metastases can be stratified into groups that have very different survival and morbidity. Caution is necessary until we have data across all the groups," they write.

"Another major question regards the role and timing of radiotherapy, particularly stereotactic radiosurgery," they add. "This should be addressed by a randomized trial of immunotherapy with or without stereotactic radiosurgery in appropriate patients."

More broadly, they say, the data "unquestionably" show that checkpoint inhibitors can be as efficacious for CNS metastases as they are for extracranial metastases from melanoma. Therefore, they recommend additional, larger trials involving patients with CNS metastases not just from melanoma but also from kidney, lung, and other cancers in which checkpoint inhibitors are active. "Such patients should no longer generally be excluded from clinical trials," they comment.

The study was supported by Bristol-Myers Squibb and by a grant from the National Cancer Institute. Disclosures of relevant financial relationships for the study authors, Dr Larkin, and Dr Turajlic are available at NEJM.org.

N Engl J Med. 2018:379;722-730, 789-790. Abstract, Editorial

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