A team led by researchers at Brigham and Women's Hospital reports that checkpoint blockade immunotherapies provided significant improvements in overall survival for patients with melanoma brain metastases. Their results (“Improved Risk-Adjusted Survival for Melanoma Brain Metastases in the Era of Checkpoint Blockade Immunotherapies: Results from a National Cohort”) are published in Cancer Immunology Research.
“The successes of checkpoint blockade immunotherapy (CBI) and BRAFV600-targeted therapy trials have generated substantial promise for revolutionizing the management of patients with advanced melanoma. However, because early clinical trials of CBIs and BRAFV600-targeted therapy either excluded or included disproportionately fewer cases of melanoma brain metastases (MBMs), the survival benefit of these novel therapies for MBM remains unknown. We, therefore, evaluated the characteristics, management, and overall survival (OS) of patients who presented with cutaneous MBMs during 2010 to 2015 using the National Cancer Database, which comprises 70% of all newly diagnosed U.S. cancers. OS was analyzed with risk-adjusted proportional hazards and compared by Kaplan–Meier techniques. We found that 2,753 (36%) of patients presenting with stage 4 melanoma had MBMs. Following the 2011 FDA approvals for CBI and BRAFV600-targeted therapy, MBM patients demonstrated a 91% relative increase in 4-year OS to 14.1% from 7.4% preapproval (P < 0.001),” write the investigators.
“Postapproval, the proportion of MBM patients who received CBI rose from 10.5% in 2011 to 34.0% in 2015 (P < 0.001). Initial CBI in MBM patients displayed an improved median and 4-year OS of 12.4 months (compared with 5.2 months; P < 0.001) and 28.1% (compared with 11.1%), respectively. These benefits were pronounced in MBM patients without extracranial metastases, in which CBI demonstrated improved median and 4-year OS of 56.4 months (compared with 7.7 months; P < 0.001) and 51.5% (compared with 16.9%), respectively. Using a large national cohort composed of a “real-life” MBM treatment population, we demonstrated the dramatic OS improvements associated with novel checkpoint blockade immunotherapies.”
“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,” says corresponding author J. Bryan Iorgulescu, M.D., postdoctoral fellow in the Department of Pathology at Brigham and Women's Hospital/Harvard Medical School and Department of Medical Oncology at the Dana-Farber Cancer Institute.
Approximately 1 in 54 people will develop melanoma in their lifetime, most of whom will be diagnosed early and cured by having the tumor surgically removed. But for patients with advanced disease, the median overall survival rate is less than a year. Advanced melanoma tends to spread to the brain and is the third most common cause of metastatic brain cancer.
Recent FDA approval of checkpoint blockade immunotherapies and targeted therapies, such as BFAF inhibitors, have added new options for treating advanced melanoma. These therapeutics have produced promising preliminary results in clinical trials of patients with advanced melanoma. However, many trials to date have excluded patients whose skin cancer has spread to the brain, making it unclear if these benefits would extend to this patient population.
In the current study, a research team that included investigators from the Brigham and Dana-Farber Cancer Institute compiled data from more than 2,753 patients from cancer hospitals across the country. Patients who received checkpoint blockade immunotherapy had an average survival of 12.4 months (compared to 5.2 months for those who did not receive immunotherapy) and had a four-year survival rate of 28.1 percent (compared to 11.1 percent for those who did not receive immunotherapy). For patients whose cancer had not spread beyond the brain (to the lungs and/or liver, for instance), these improvements were even more dramatic.
“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,” says senior author Timothy Smith, M.D., Ph.D., MPH, director of the Computational Neuroscience Outcomes Center at the department of neurosurgery at Brigham and Women's Hospital/Harvard Medical School. “This highlights the power of population data to help answer critical, but previously unanswerable, questions that we face every day in clinical practice.”
“Historically, central nervous system metastases from melanoma as well as other solid tumor types have proven particularly challenging to treat, with most therapeutic approaches providing minimal clinical benefit for patients,” adds co-author David Reardon, M.D., clinical director of the Center for Neuro-Oncology at Dana-Farber and professor of medicine at Harvard Medical School. “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. 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.”
The authors note that insurance status was an important barrier to receiving checkpoint blockade immunotherapy in melanoma brain metastasis patients. Uninsured patients were significantly less likely to receive the treatment than those who were insured privately or through Medicare – a situation suggesting that additional efforts are needed to ensure patient access to these critical therapies.