Immune Checkpoint Inhibitors in Melanoma: New Directions

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…

More on the Use of Nivolumab and Ipilimumab in Melanoma

“As single agents, immune checkpoints blockers nivolumab (Opdivo) and ipilimumab (Yervoy) both have demonstrated improvements in overall survival for patients with metastatic melanoma. However, when taken together, these agents have demonstrated even more impressive findings.

“Earlier reported findings from a phase I dose-escalation study demonstrated that the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab demonstrated encouraging antitumor activity. Additionally, an ongoing phase III clinical trial is assessing nivolumab or ipilimumab plus nivolumab versus ipilimumab alone in previously untreated patients with advanced melanoma (CheckMate-067; NCT01844505).

“At the 2015 AACR Annual Meeting, F. Stephen Hodi, MD, presented findings from the phase II CheckMate-069 trial, further validating the efficacy seen with the combination in earlier studies and providing hints at what could be expected in the phase III trial. In this analysis, nivolumab plus ipilimumab delayed disease progression by 60% compared with 11% in patients who were given ipilimumab alone (HR = 0.40; 95% CI, 0.23-0.68; P .001). With the combination, the ORR was 61% in BRAF wild-type (WT) patients and 52% in BRAF-positive patients.

“Included in the phase II CheckMate-069 study were 142 treatment-naïve patients with advanced melanoma with a median patient age of 65 years. Patients were randomized to receive ipilimumab at 3 mg/kg with either nivolumab at 1 mg/kg (n = 95) or placebo (n = 47) every 3 weeks for four doses. This was followed by nivolumab or placebo every 2 weeks until progression or unacceptable toxicity.”

New Combo of Immunotherapy Drugs Is Safe, Shrinks Tumors in Metastatic Melanoma Patients

“Once again, researchers at Penn’s Abramson Cancer Center have extended the reach of the immune system in the fight against metastatic melanoma, this time by combining the checkpoint inhibitor tremelimumab with an anti-CD40 monoclonal antibody drug. The first-of-its-kind study found the dual treatments to be safe and elicit a clinical response in patients, according to new results from a phase I trial to be presented at the AACR Annual Meeting 2015 on Sunday, April 19.

“Researchers include first author David L. Bajor, MD, instructor of Medicine in the division of Hematology/Oncology, and senior author Robert H. Vonderheide, MD, DPhil the Hanna Wise Professor in Cancer Research.

” ‘We’ve had wonderful success with immunotherapies, but we are barely scratching the surface,’ Bajor said. ‘Checkpoint inhibitors are just the beginning. When they are thoughtfully combined with immune-stimulating compounds like CD40 or drugs targeting other facets of the immune system we hope to be able to increase the response rate to previously approved therapies.’

“Known as a checkpoint inhibitor, tremelimumab is an investigational monoclonal antibody that ‘cuts the brakes’ of the immune system by targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), a protein that can switch off a patient’s immune response. Anti-CD40 drugs (in this trial, CP- 870,893) antagonize the CD40 receptor, and effectively ‘push the gas’ on the immune system to make it work harder.”

Tremelimumab Granted Orphan Drug Designation by US FDA for Treatment of Malignant Mesothelioma

“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.”

Nivolumab Beats Chemotherapy in Melanoma That Has Not Responded to Ipilimumab

“In the phase III CheckMate 037 trial reported in The Lancet Oncology, Weber et al found that treatment with the PD-1 inhibitor nivolumab (Opdivo) resulted in a significantly greater response rate vs chemotherapy as second- or later-line treatment in patients with advanced melanoma progressing after anti–CTLA-4 treatment. Findings in this trial supported the accelerated approval of nivolumab in this setting in December 2014.

“In this open-label trial, 405 patients with unresectable or metastatic melanoma from 90 sites in 14 countries were randomly assigned 2:1 between December 2010 and January 2014 to receive nivolumab (n = 272) or chemotherapy (n = 133). Patients had to have progressed after treatment with ipilimumab (Yervoy) or with ipilimumab and a BRAF inhibitor if they were BRAF V600 mutation–positive. Nivolumab was given at 3 mg/kg intravenously every 2 weeks. Dose delay but not reduction was permitted in nivolumab patients. Investigator’s choice of chemotherapy consisted of dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 combined with carboplatin area under the curve = 6 every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoints of the trial are objective response and overall survival. In the current report of the first interim analysis, objective response was assessed after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks…

“The investigators concluded: ‘Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need.’ ”

Study Confirms Long-Term Benefits of Melanoma Immunotherapy

“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.”

Genetics of Melanoma Tumor Shape Immunotherapy Benefits

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.”

Memorial Sloan Kettering Team Makes Key Discovery in Understanding Immunotherapy’s Successes—And Its Failures

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.’ ”

Immune System-Activating Drugs in Combination Treatments May Be Next Big Thing for Melanoma

Among solid tumors, the curative potential of immunotherapies has been explored most in melanoma. One reason for this is that melanoma tumors often contain so-called immune infiltrates—patches of T cells, the killer cells of the immune system. It seems that these fighter cells arrive at the ‘battlefield’ to target tumor cells for killing, but instead become ‘frozen,’ unable to attack.  How to activate the tumor-killing potential of T cells has been an area of intense and fruitful research, leading to the development of several immunotherapy drugs. Continue reading…