The drugs pembrolizumab (Keytruda) and nivolumab (Opdivo) were approved by the U.S. Food and Drug Administration (FDA) in 2014 and 2015, respectively. These two competing blockbuster drugs are already changing the outlook in metastatic melanoma, previously considered to be a fatal disease. Known as ‘immune checkpoint inhibitors,’ they work by releasing ‘brakes’ on a patient’s own immune system, freeing it to attack tumors. In the wake of their success, researchers are now taking immune checkpoint inhibition in new directions. Continue reading…
“AstraZeneca today announced that the US Food and Drug Administration has granted Orphan Drug Designation for the anti-CTLA-4 monoclonal antibody, tremelimumab, for the treatment of malignant mesothelioma.
“Mesothelioma is a rare, aggressive cancer that most often affects the lining of the lungs and abdomen. Available treatments for mesothelioma are very limited, particularly for patients with advanced disease.
“ ‘There is a significant need for new treatment options for patients with mesothelioma because fewer than five percent of patients currently survive beyond five years, even when they receive timely diagnosis and care. Our aim is to rapidly advance the development of tremelimumab as a potential new treatment option for these patients,’ said Robert Iannone, Senior Vice President, Head of Immuno-oncology, Global Medicines Development at AstraZeneca.
“The Orphan Drug Designation programme provides orphan status to drugs and biologics, which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the US1.”
“A long-term follow up of people on an international clinical trial has confirmed the benefit of immunotherapy for certain patients with advanced (stage 3 or 4) melanoma.
“More than 18 per cent of patients were still alive five years after being treated with ipilimumab (Yervoy) in combination with a chemotherapy drug called dacarbazine.
“This compared to fewer than nine per cent who were treated with chemo alone.
“Ipilimumab is one of a new class of cancer treatments that target the immune system, and works by homing in on a molecule found on immune cells called CTLA-4. This relieves the molecular ‘brakes’ on a patient’s immune system, allowing it to attack their cancer.
“The study, which began recruiting patients 2006 – including several from the UK – also confirmed low rates of serious side-effects among patients who took the drug long-term.”
The gist: Sometimes, researchers can use a patient’s tumor genetics to predict how well that patient might respond to different cancer treatments. Now, new research might open the door for doctors to use tumor genetics to predict how well melanoma patients might respond to certain drugs known as CTLA-4 blockers, such as ipilimumab and tremelimumab. The researchers found that patients whose tumors have more mutations might respond better to CTLA-4 blockers. More research will be needed to better understand the association. CTLA-4 blockers are a type of immunotherapy—treatment that boosts a patient’s own immune system to fight cancer.
“Using whole-exome sequencing, researchers were able to define the genetic basis for deriving benefit from treatments that block cytotoxic T-lymphocyte antigen 4 (CTLA-4) in melanoma, results of a study published in the New England Journal of Medicine indicate.
“ ‘Our use of whole-exome sequencing to identify a genetic basis associated with a benefit from CTLA-4 blockade provides proof of principle that tumor genomics can inform responses to immunotherapy,’ wrote Alexandra Snyder, MD, from Memorial Sloan Kettering Cancer Center, and colleagues.
“Snyder and colleagues used tumor tissue for patients with melanoma who had been treated with the CTLA-4 blocking drugs ipilimumab and tremelimumab. They characterized somatic mutations and candidate neoantigens generated from the mutations, and tested neoantigen peptides for the ability to activate lymphocytes.”
The gist: Some melanoma patients benefit from treatment with the drug ipilimumab (Yervoy), but others don’t. New research has found that people who benefit from ipilimumab tend to have certain genetic mutations in their tumor cells. This research could be used to develop a diagnostic test that could help doctors predict whether ipilimumab will work or not for a particular patient.
“A collaborative team of leaders in the field of cancer immunology from Memorial Sloan Kettering Cancer Center has made a key discovery that advances the understanding of why some patients respond to ipilimumab, an immunotherapy drug, while others do not. MSK was at the forefront of the clinical research that brought this CTLA-4 blocking antibody to melanoma patients.
“A report published online first today in the New England Journal of Medicine shows that in patients who respond to ipilimumab, their cancer cells carry a high number of gene mutations—some of which make tumors more visible to the immune system, and therefore easier to fight. The research was led by Vice Chair of Radiation Oncology and cancer genomics researcher Timothy Chan, MD, PhD ; oncology fellow Alexandra Snyder Charen, MD; and Chief of the Melanoma and Immunotherapeutics Service and the Lloyd J. Old Chair for Clinical Investigation Jedd Wolchok, MD, PhD.
“ ‘We are learning that there are few treatments that don’t have some footprint in the cancer genome,’ says Dr. Chan. ‘For the first time, it might be feasible to develop a reliable diagnostic test to help guide treatment decisions by predicting who will respond…’
“Eventually, these findings could translate into a diagnostic test to detect the mutations in melanoma patients. Results could help doctors and patients make more-informed treatment choices. In addition, the MSK team plans to investigate whether specific tumor mutations influence the effectiveness of other immunotherapy drugs. Dr. Chan says, ‘If we know a patient won’t respond to ipilimumab, we may be able to identify other drugs that are more likely to be effective against this person’s tumor.’ ”