“Treating metastatic melanoma with a triple threat—including radiation therapy and two immunotherapies that target the CTLA4 and PD-1 pathways—could elicit an optimal response in more patients, one that will boost the immune system’s attack on the disease, suggests a new study from a multidisciplinary team of researchers from Penn’s Abramson Cancer Center published today in Nature.
“The study, led by senior authors Andy J. Minn, MD, PhD, assistant professor of Radiation Oncology, Robert Vonderheide, MD, DPhil, the Hanna Wise Professor in Cancer Research, Amit Maity, MD, PhD, professor of Radiation Oncology, and E. John Wherry, PhD, professor of Microbiology and director of the Institute for Immunology at the Perelman School of Medicine at the University of Pennsylvania, reports for the first time on the response and resistance to radiation combined with ipilimumab (an antibody against CTLA4) in both patients and mice.
“In the phase I clinical study, known as the ‘RadVax’ trial, the team found that combining ipilimumab with radiation was safe and shrank tumors in a subset of 22 metastatic melanoma patients (18 percent). The concurrent mouse study shed light on a mechanism of resistance, known as the PD-L1 pathway, found in many patients whose cancers progressed, suggesting that an antibody against PD-L1 or its partner PD-1 is an ideal third treatment to improve response and immunity.”
“The FDA has accepted a supplemental Biologics License Application (sBLA) for ipilimumab (Yervoy) as an adjuvant treatment of patients with stage III melanoma at high risk of recurrence following complete resection, according to Bristol-Myers Squibb, the company developing the drug. The FDA is scheduled to make a decision on adjuvant ipilimumab by October 28, 2015.
“The acceptance of the sBLA is based on results from the phase III EORTC 18071 trial, which was presented at the 2014 ASCO Annual Meeting. This study showed a 25% improvement in recurrence-free survival (RFS) in patients treated with ipilimumab versus placebo (HR = 0.75; 95% CI, 0.64–0.90).
“ ‘This is a promising treatment—we saw substantially fewer recurrences among patients who are at high risk of relapse,’ Alexander Eggermont, MD, PhD, director general of the Gustave Roussy Cancer Campus Grand Paris in France, said in an 2014 ASCO Annual Meeting press release. ‘We’ve seen many impressive new treatments for advanced melanoma in recent years. This trial with ipilimumab is the first to show we may be able to give these new drugs earlier in the course of disease, where they can do more good and potentially cure more patients.’ ”
“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.”
“An experimental therapeutic vaccine from Danish drugmaker Bavarian Nordic helped significantly extend survival in patients with advanced prostate cancer, according to results of a small early-stage trial conducted by the U.S. National Cancer Institute.
“Shares of Bavarian Nordic closed up almost 12 percent in Copenhagen after the company released the data on Tuesday.
“The study involved 30 patients with prostate cancer that had failed to benefit from standard treatments that reduce levels of testosterone, the male hormone that fuels the cancer.
“Patients were treated with the company’s Prostvac vaccine, in addition to escalating doses of Bristol-Myers Squibb Co’s Yervoy, an approved injectable treatment for advanced melanoma that works by taking the brakes off the body’s immune system.”
“Some patients with advanced melanoma treated with ipilimumab continued to derive a survival benefit at least 5 years after treatment, according to study results.
“The results showed that, for certain patients, retreatment with ipilimumab (Yervoy, Bristol-Myers Squibb) can re-establish disease control while demonstrating a safety profile comparable to that observed during ipilimumab induction, researchers wrote.
“The analysis included patients treated with ipilimumab in one of six phase 2 clinical trials. In those trials, ipilimumab was administered in doses of 0.3 mg/kg, 3 mg/kg or 10 mg/kg.
“In the current companion study — conducted by Celeste Lebbé, MD, PhD, professor of dermatology at Hôpital Saint-Louis in Paris, and colleagues — patients underwent ipilimumab retreatment, extended maintenance therapy or follow-up for survival only.”
“The U.S. Food and Drug Administration today granted accelerated approval to Opdivo (nivolumab), a new treatment for patients with unresectable (cannot be removed by surgery) or metastatic (advanced) melanoma who no longer respond to other drugs.
“Melanoma is the fifth most common type of cancer in the United States. It forms in the body’s melanocyte cells, which develop the skin’s pigment. The National Cancer Institute estimates that 76,100 Americans will be diagnosed with melanoma and 9,710 will die from the disease this year.
“Opdivo works by inhibiting the PD-1 protein on cells, which blocks the body’s immune system from attacking melanoma tumors. Opdivo is intended for patients who have been previously treated with ipilimumab and, for melanoma patients whose tumors express a gene mutation called BRAF V600, for use after treatment with ipilimumab and a BRAF inhibitor.”
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: The drug ipilimumab showed promise for people with metastatic uveal melanoma in a recent clinical trial that tested it in volunteer patients. Ipilimumab (aka Zelboraf) has shown some success in treating cutaneous melanoma, but had not yet been tested in uveal melanoma. In the trial, ipilimumab was effective for some patients, and almost 25% are still alive two years after treatment; an encouraging outcome for the disease. More uveal melanoma patients will be given ipilimumab in clinical trials as research continues. One of the trials is currently recruiting patients.
“The first trial of the immunomodulator ipilimumab (Yervoy, Bristol-Myers Squibb Company) conducted in patients with malignant uveal melanoma has shown efficacy in some patients.
” ‘After almost 2 years’ follow-up, we can see that almost 25% of patients are still alive, and that is very encouraging in this population of patients with very bad outcome,’ lead investigator Josep Piulats, MD, PhD, from the Institut Catala d’Oncologia and L’Hospitalet del Llobregat in Spain, told Medscape Medical News.
“The results from the study, known as GEM1, were presented in a poster at the recent Society of Melanoma Research (SMR) 2014 International Congress, in Zurich, Switzerland.
“Although the study was small (only 32 patients) and open-label, and although it just missed its primary endpoint of improving overall survival, the researchers say they are encouraged by finding “objective responses in a population of highly metastatic patients.”