Nivolumab effective against melanoma brain metastases


By Will Boggs MD

NEW YORK (Reuters Health) - Nivolumab, alone and in combination with ipilimumab, is active against melanoma brain metastases, researchers from Australia report.

Treatment with the anti-PD-1 monoclonal antibody improves response and survival rates in patients with metastatic melanoma, compared with ipilimumab, an anti-CTLA-4 monoclonal antibody. But nivolumab's efficacy in melanoma brain metastases is uncertain.

Dr. Georgina V. Long from the University of Sydney and colleagues at four cancer centers in Australia investigated the efficacy and safety of nivolumab monotherapy and nivolumab-ipilimumab combination therapy in their open-label randomized phase 2 study of three cohorts of patients with active melanoma brain metastases.

After median follow-ups ranging from 14 months to 31 months, investigator-assessed intracranial responses were achieved by 46% (16/35) of patients with asymptomatic melanoma brain metastases treated with nivolumab-ipilimumab (cohort A), 20% (5/25) of patients with asymptomatic melanoma brain metastases treated with nivolumab monotherapy (cohort B), and 6% (1/16) of patients with symptomatic melanoma brain metastases treated with nivolumab monotherapy (cohort C, nonrandomized).

Complete responses occurred in 17% of cohort A and 12% of cohort B, the researchers report in The Lancet Oncology, online March 27.

At data cutoff, 46% of cohort A and 80% of cohort B had an intracranial progression event. Thirty-seven percent of patients in cohort A, 48% of patients in cohort B and 81% of patients in cohort C had died.

Treatment-related serious adverse events occurred in 46% of cohort A patients, 4% of cohort B patients and 13% of cohort C patients, but there were no deaths because of study treatment.

"Our study showed that combination nivolumab and ipilimumab and nivolumab monotherapy are active in melanoma brain metastases, with durable responses in most patients who received combination therapy upfront," the researchers note. "Given the increasing evidence of efficacy of immunotherapy across many solid tumors, these results might have marked implications for the management of active brain metastases in other solid tumors."

"Patients with asymptomatic untreated melanoma brain metastases should be considered for combination nivolumab and ipilimumab in the first-line setting," they conclude.

"Combination ipilimumab and nivolumab should now be a first-line standard of care for melanoma patients with brain metastases who can tolerate the side-effects and are not on high-dose corticosteroids," writes Dr. Paul B. Chapman from Memorial Sloan Kettering Cancer Center, in New York, in a linked editorial. "In some patients, surgery or stereotactic radiosurgery will be appropriate, although whether combination ipilimumab and nivolumab should be used afterwards in the adjuvant setting in these patients is an appropriate topic for future investigation."

"A final suggestion is that not only should these results be considered important for changing clinical practice, but that patients with brain metastases should be included in future trials in which objective response is the primary endpoint - in light of the new evidence, there seems little justification for excluding them," he adds.

Dr. Paul W. Sperduto from the University of Minnesota, in Minneapolis, who has evaluated treatments for melanoma brain metastases, said, "Stereotactic radiosurgery (SRS) (a one-day outpatient procedure delivering a high dose of radiation to just the tumor) is the standard of care for these patients who are usually symptomatic. This study is interesting because it shows that, in patients without symptoms, two drugs (immune checkpoint inhibitors (ICI) nivolumab and ipilimumab) are better than one (nivolumab) in terms of intracranial response rate of the brain metastases. There is provocative preliminary data suggesting combined SRS and dual ICI may be better than either SRS alone or dual ICI alone."

"Phase III randomized clinical trials which include symptomatic patients are needed comparing SRS + dual ICI versus dual ICI alone versus SRS alone," Dr. Sperduto, who was not involved in the new work, told Reuters Health by email. "Another important question is whether dual ICI can prevent the development of brain metastases, not just generate a response of existing brain metastases."

Dr. Friedegund Meier from the University of Dresden and National Center for Tumor Diseases, in Germany, recently reviewed therapies for melanoma brain metastases. She told Reuters Health by email, "I agree with the authors: nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases. Taking into account retrospective analyses, additional stereotactic radiosurgery should be considered."

"Furthermore, the high toxicity of nivolumab combined with ipilimumab should be taken into account," she said. "In particular, for patients with BRAFV600mut melanoma with symptomatic brain metastases, dabrafenib combined with trametinib should be considered as a first-line therapy."

Bristol-Myers Squibb funded the study and had various relationships with several authors of the report and with Dr. Chapman.

Dr. Long did not respond to a request for comments.


Lancet Oncol 2018.

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