Melanoma Brain Metastases: Q&A With Keith Black, MD

“Malignant melanoma is one of the most common primary tumors to spread to the brain. In close to 50% of patients who have metastatic melanoma, the disease can be found in their brain.

“For example, in former President Carter’s case, the cancer was first found in his liver and later removed. During his press briefing last month, he announced that the melanoma had metastasized to his brain, and he was beginning treatment with pembrolizumab immediately.

“In order to learn more about melanoma metastases to the brain, Targeted Oncology interviewed Keith Black, MD, chairman and professor, Department of Neurosurgery, Cedars-Sinai Medical Center, director, Maxine Dunitz Neurosurgical Institute, director, Johnnie L. Cochran, Jr, Brain Tumor Center, and Ruth and Lawrence Harvey Chair in Neuroscience.”


Frequency of Certain Immune Cells in Blood May Predict Metastatic Melanoma Response to Pembrolizumab

“Among patients with metastatic melanoma treated with the immunotherapy drug pembrolizumab (Keytruda), those whose cancer responded to the treatment had a higher frequency of immune cells called T cells that were positive for the proteins CD8, PD-1, and Bim (CD8+PD-1+Bim+ T cells) in blood samples taken immediately before starting pembrolizumab than those who had disease progression, according to data presented at the CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference, held Sept. 16–19.

“Pembrolizumab, which targets the protein PD-1, was approved by the U.S. Food and Drug Administration for treating metastatic melanoma in September 2014. Some patients with metastatic melanoma have remarkable responses to pembrolizumab, whereas others do not respond at all, according to Roxana S. Dronca, MD, a medical oncology consultant and assistant professor of oncology at the Mayo Clinic in Rochester, Minnesota.”


Video: Efficacy of PD-1/PD-L1 Inhibitors in Melanoma

“Jason J. Luke, MD, FACP, assistant professor of medicine, The University of Chicago, discusses the efficacy of PD-1/PD-L1 inhibitors in melanoma. The combination of these inhibitors, nivolumab and ipilimumab, was used to treat patients with previously untreated, unresectable or metastatic melanoma, in the Checkmate 069 study.

“Luke says PD-L1 is very complex and difficult when developing immunohistochemical assays. Since several pharmaceutical companies conduct different assays that test various things, a particular patient may be positive in one case, but not in another. For this reason, patients become very confused.

“Luke also mentions that there is no validated method across the board, so it is difficult to determine the next steps going forward.”


What Determines Whether a Melanoma Patient Will Respond to Checkpoint Blockade Drugs?


Of all cancer types, melanoma is the most investigated in terms of its potential to be treated through immune system-based approaches. More immunotherapy drugs are approved for melanoma than for any other type of cancer, and more are in development. Recent additions to the immunotherapy arsenal are the ‘anti-PD-1’ immune checkpoint blockade drugs pembrolizumab (Keytruda) and nivolumab (Opdivo). Continue reading…


European Commission Approves Pembrolizumab for Advanced Melanoma

“The European Commission has approved the PD-1 inhibitor pembrolizumab (Keytruda) as a treatment for adult patients with unresectable or metastatic melanoma in the first-line and previously treated settings, based on data from 3 clinical trials that assessed the medication in more than 1500 patients.

“The European Commission decision follows a recommendation from Committee for Medicinal Products for Human Use, and allows for the medication to be marketed across 28 European Union member states. The medication is approved at a dose of 2 mg/kg every 3 weeks. In the 834-patient phase III KEYNOTE-006 study, pembrolizumab demonstrated an extension in overall survival (OS) and progression-free survival (PFS) compared with ipilimumab. Additionally, in the 540-patient phase II KEYNOTE-002 study, pembrolizumab improved PFS versus chemotherapy, with OS data pending maturity.

“ ‘Today’s European approval supports our goal of accelerating immuno-oncology research for the benefit of patients around the world,’ Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement. ‘We believe that the broad data set supporting this approval helps illustrate the significant potential of Keytruda to treat advanced melanoma, a devastating disease.’ “


New Collaboration Leads to Combo Experimental Therapy for Metastatic Melanoma

“Pharmaceutical companies are teaming up to combine experimental therapies that may help combat metastatic cutaneous and uveal melanomas in a whole new way. The novel international collaboration may bring new combined targeted therapies to the market much sooner.

“Eli Lilly and Immunocore Limited are collaborating in immunotherapy-based clinical trials to evaluate the utility of Immunocore’s lead T-cell receptor-based investigational drug IMCgp100. This agent will be combined with Lilly’s galunisertib (LY2157299) and merestinib (LY2801653) for melanoma treatment. The investigators will explore the durability and efficacy of potential combined regimens in patients with metastatic cutaneous and uveal melanomas.

“ ‘Combining our ImmTAC, IMCgp100 with Lilly’s galunisertib and merestinib has the potential to transform the treatment of metastatic cutaneous and uveal melanoma. Immunocore is committed to the development of IMCgp100 in metastatic uveal and cutaneous melanoma where there is such great unmet medical need,’ said Eliot Forster, who is chief executive officer of Immunocore, Oxford, England.”


Ignyta Announces Collaboration with UCSF For Clinical Trial of Entrectinib

“Ignyta, Inc. (Nasdaq: RXDX),a precision oncology biotechnology company, today announced a clinical collaboration with the University of California, San Francisco (UCSF), under which UCSF will study entrectinib in a proof-of-concept clinical trial in cancer patients with metastatic melanoma that is positive for activating alterations to NTRK1/2/3 (encoding TrkA/TrkB/TrkC) or ROS1.

“ ‘We are excited to collaborate with UCSF, a world-renowned academic research institution,’ said Jonathan Lim, M.D., Chairman and CEO of Ignyta. ‘The focus on melanoma in this study will complement the broader range of indications on which we are focused in our own clinical trials, and we expect the findings to accelerate our understanding of the potential role of entrectinib in treating patients with NTRK-positive and ROS1-positive cancers.’

“Under the terms of the collaboration agreement, Ignyta will contribute $1 million toward the funding of the clinical trial, as well as per-patient fees based on enrollment of NTRK-positive or ROS1-positive patients and their participation in the trial. Ignyta will also provide UCSF with sufficient supply of entrectinib for use in the clinical trial. In addition to the safety and efficacy data from the trial, UCSF will provide Ignyta with tumor samples and genetic sequencing data for patients screened for inclusion in the trial for further genomic analysis.”


New Type of Clinical Trial Launching for Advanced Melanoma

“Mayo Clinic and the Translational Genomics Research Institute (TGen) are helping launch a national clinical trial that will apply the latest in precision medicine to treat advanced melanoma skin cancer.

“The study leverages advances in genomics, informatics, and health information technology, yielding more precise medical treatments for patients with this devastating disease.

“Mayo Clinic is the only clinical site in Arizona to offer this new treatment, sponsored by Stand Up to Cancer (SU2C) and the Melanoma Research Alliance. These clinical trials are the culmination of nearly four years of research under an SU2C Melanoma Dream Team grant.

“Metastatic melanoma is a type of cancer that has spread from the skin to other parts of the body, most frequently the lungs, muscles, brain, and liver. Metastatic melanoma is responsible for more than 9,000 deaths a year in the United States, so there remains an urgent need for new treatment options.”


Surgery Followed by Ipilimumab in Melanoma Patients Improves Survival

“Melanoma is predicted to result in approximately 10,000 deaths in 2015. The majority of these deaths are due to advanced stage disease that has spread or metastasized to other sites. The prognosis for patients with metastatic melanoma remains poor, with 5-year survival rates of 63 percent in patients who have metastatic disease in regional lymph nodes, and only 17 percent in patients who have metastatic disease in distant sites. Moffitt Cancer Center researchers participated in an international phase 3 study that demonstrated that a drug called ipilimumab improves the relapse-free survival of advanced stage melanoma patients rendered free of disease surgically but at high risk for relapse.

“Ipilimumab is approved for the treatment of  that cannot be surgically removed or that has metastasized to different sites. Ipilimumab targets a protein called cytotoxic T lymphocytic antigen-4 (CTLA-4) that is found on a type of immune cell called a T cell. CTLA-4 keeps the immune system in check to avoid autoimmune disease by downregulating T cell activity. Tumors take advantage of CTLA-4 activity to avoid immune detection. By targeting CTLA-4, ipilimumab restimulates the immune system to target tumor cells.

“Researchers wanted to determine if ipilimumab could improve the survival of advanced-stage melanoma patients if it was given after the surgical removal of both their primary melanoma tumors and their  nodes.”