Melanoma patients with brain metastasis have seen significant improvements in their survival rates since immune checkpoint inhibitors like Yervoy (ipilimumab) came into treatment use, a study based on “real-life” data covering more than 2,500 patients found.
Patients whose metastasis were restricted to the brain benefitted the most, the researchers found, living a median of 4.7 years — four years longer than those who were not treated with immune checkpoint blockers.
“Our findings build on the revolutionary success of checkpoint blockade immunotherapy clinical trials for advanced melanoma and demonstrate that their substantial survival benefits also extend to melanoma patients with brain metastases,” J. Bryan Iorgulescu, MD, postdoctoral fellow at Brigham and Women’s Hospital, Boston, and the study’s first author, said in a press release.
The study, “Improved Risk-Adjusted Survival for Melanoma Brain Metastases in the Era of Checkpoint Blockade Immunotherapies: Results from a National Cohort,” was published in Cancer Immunology Research.
Projections point to about 1 in every 54 people developing melanoma in their lifetime. While most are diagnosed early and cured with surgery, the picture is not so bright for patients with advanced disease — often marked by brain metastasis. People diagnosed with advanced melanoma who have limited responses to conventional chemotherapies typically survive less than one year.
Two medicines were approved in 2011 for melanoma patients whose disease had spread to distant organs: the immune checkpoint inhibitor Yervoy, and the BRAF inhibitor Zelboraf (vemurafenib).
Yervoy binds to the CTLA-4 surface molecule and works to boost the immune system’s activity. Zelboraf targets the BRAF protein, which is unusually activated in most melanomas and supports cancer cell growth and division.
Other checkpoint inhibitors — Opdivo (nivolumab) and Keytruda (pembrolizumab) — and targeted therapies — Tafinlar (dabrafenib), Mekinist (trametinib), and Cotellic (cobimetinib) — were approved in subsequent years.
These approvals came to revolutionize advanced melanoma treatment, eliminating the need for damaging chemotherapies as first-line therapy.
But while clinical trials have shown promise in metastatic patients, those with brain metastasis have been disproportionately excluded because of concerns as to an investigational therapy’s ability to cross the brain-blood barrier. The result is that efficacy outcomes in these patients are not established.
Researchers at Brigham and Women’s evaluated data from metastatic melanoma patients using the National Cancer Database, a database that comprises 70 percent of all newly diagnosed cancers in the U.S.
They compared the survival rates for patients diagnosed before and after 2011. Among those with later diagnosis, researchers also evaluated the differences in survival between patients given immune checkpoint inhibitors and those who were not.
“Through the use of nationwide cancer data, for the first time we can evaluate the impacts on survival that these exciting new therapies have for patients with melanoma brain metastases,” said Timothy Smith, MD, PhD, the study’s lead author. Smith is director of the Computational Neuroscience Outcomes Center affiliated with Brigham and Women’s Hospital and Harvard Medical School.
Among the 7,689 patients diagnosed with metastatic melanoma between 2010 and 2015, 2,753 — or 35.8 percent — had metastases in the brain.
These patients lived for a median of 5.1 months if diagnosed before 2011, a median that increased to 6.2 months after 2011. Survival rate at four years also increased from 7.4 percent prior to the approval to 14.1 percent between 2011 and 2015.
Patients being treated with immune checkpoint inhibitors also increased, from 10.5 percent in 2011 to 34 percent in 2015.
In the post-approval era, patients taking immune checkpoint inhibitors survived significantly longer – 12.4 months versus 5.2 months in those receiving other therapies. And while only 11 percent of patients receiving targeted therapies reached the four-year mark, 28 percent of those receiving the immunotherapies did.
Benefits were even better for melanoma patients whose metastasis was restricted to the brain. These people lived four years longer if they took immune checkpoint inhibitors, compared to patients who did not.
More than half of these patients survived for four years or longer, a mark reached by only 16.9 percent of patients using other treatment approaches.
Insurance coverage could determine treatment, the study also found. Patients with private insurance or on Medicare were significantly more likely to receive treatment with checkpoint blockade immunotherapies than those who were uninsured.
“The results of our analyses indicate that immune checkpoint inhibitors can achieve a meaningful therapeutic benefit for metastatic melanoma, including spread to the central nervous system,” said David Reardon, MD, professor of medicine at Harvard Medical School and study author.
“At the same time, not all patients benefit, indicating that much research is still required to optimize the potential of anti-tumor immune responses for CNS metastatic disease,” Reardon added.
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