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Systemic therapy plays role in evolving paradigm for brain metastases
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NEW YORK — Effective targeted therapies and immunotherapies for melanoma are likely to also be effective for the treatment of brain metastases, according to a presenter at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.
“If we look at the incidence of brain metastases in melanoma, it’s an astronomical number,” Sanjiv S. Agarwala, MD, professor of medicine at Temple University School of Medicine, chief of hematology and oncology at St. Luke’s Cancer Center in Bethlehem, Pennsylvania, and a HemOnc Today Editorial Board member, said during his presentation. “There are between 170,000 and 300,000 cases of brain metastasis per year. Two-thirds of patients with melanoma have brain metastases at autopsy, and most were missed. Even the best MRI misses them.”
Sanjiv S. Agarwala
Surgery and radiation were common treatment approaches to brain metastases in the era before effective systemic therapies, Agarwala said. However, effective systemic therapies now include chemotherapy, immunotherapy and BRAF-targeted therapy.
Agarwala and colleagues conducted a study — published in 2004 in Journal of Clinical Oncology — of temozolomide in brain metastases prior to radiation therapy. The objective response rate was 7% in patients who had not received prior chemotherapy and 9% in patients who had.
Data exists also on ipilimumab (Yervoy, Bristol-Myers Squibb) for brain metastases. An analysis conducted by Margolin and colleagues, published in 2012 in Lancet Oncology, included patients who received 10 mg/kg induction and maintenance ipilimumab with or without steroids. The response rates in the brain were similar to response rates outside of the brain. Further, 2-year OS rates were 26% for patients not receiving steroids and 10% for patients who were.
“This curve reminds us of the overall curve for ipilimumab given systemically,” Agarwala said. “So I think it is fair to say that ipilimumab is a reasonable drug to use in the brain if you have to use it. I don’t think we should completely give up on local therapies, but this data is very important and I think as we get more information we can refine this even more.”
The ongoing ABC trial is evaluating nivolumab (Opdivo, Bristol-Myers Squibb) with or without ipilimumab in patients with brain metastases who were previously untreated and asymptomatic or previously treated and symptomatic.
Another study has been designed to look at pembrolizumab (Keytruda, Merck) in patients with at least two brain metastases.
More data exists on the treatment of brain metastases with BRAF-targeted therapies, Agarwala said.
A study published in 2012 in The Lancet Oncology by Long and colleagues showed dabrafenib (Tafinlar, GlaxoSmithKline) yielded a brain response rate of 39% in previously untreated patients and 31% in treated patients.
Compared with the earlier temozolomide data, these data show considerable advances, Agarwala said.
“I think the days of using temozolomide in the brain are over, although it is still used in the community,” Agarwala said. “If the patient is BRAF mutated, you should definitely not use it, and if they are BRAF wild type, I think you should make every effort to put them on a clinical trial of immunotherapy.”
Vemurafenib (Zelboraf; Genentech, Daiichi Sankyo) data have demonstrated similar response rates for brain metastases as dabrafenib.
However, dabrafenib and trametinib (Mekinist, GlaxoSmithKline) have replaced systemic therapy for BRAF-positive disease in metastatic disease, but studies on this combination in brain metastases have not yet been published.
Molecular tests are also being developed to evaluate the risk for brain metastases according to BRAF, NRAS, and PTEN status.
“Now, we are moving away from drugs that have never worked systemically … to drugs that actually work very well,” Agarwala said. “It is nice to know that if you pick a drug that works in melanoma, it is probably also going to work in the brain. It may not approach identical results, but is encouraging for patients. Brain metastases are no longer a death sentence.” — by Alexandra Todak
References:
Agarwala SS. Systemic management of brain metastases. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; April 10-11, 2015; New York.
Agarwala SS, et al. J Clin Oncol. 2004;22:2101-2107.
Long GV, et al. Lancet Oncol. 2012;doi:10.1016/S1470-2045(12)70431-X.
Margolin K, et al. Lancet Oncol. 2012;doi:10.1016/S1470-2045(12)70090-6.
Disclosure: Agarwala reports no relevant financial disclosures.