Tag: Malignant Melanoma of the Skin

SUMMARY: It is estimated that in the US, about 87,110 new cases of melanoma will be diagnosed in 2017 and about 9,730 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. A better understanding of Immune checkpoints has opened the doors for the discovery of novel immune targets. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoint proteins, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy to show prolonged Overall Survival (OS) among patients with advanced melanoma, in randomized phase III trials. YERVOY® in a pooled analysis of data from 12 studies showed a 3-year Overall Survival of 26% among treatment naive patients and survival up to 10 years in approximately 20% of all patients, with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies, which bind to the PD-1 receptor and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY®, in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA®, have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. OPDIVO® in combination with YERVOY® in a phase I study resulted in an Overall Survival of 68% at 3 years among patients with advanced melanoma, regardless of prior therapies.

CheckMate 067 is a phase III study which enrolled treatment naïve patients with advanced melanoma, and the authors in a previous publication reported significantly longer PFS and higher rates of ORR with OPDIVO® plus YERVOY® and with OPDIVO® alone, compared with single agent YERVOY®. In this publication, the authors provided the first analysis of 3-year OS data from the CheckMate 067 trial. In this double-blind, phase III study, patients with previously untreated advanced melanoma were randomly assigned in a 1:1:1 ratio to receive one of the three regimens: OPDIVO® 1 mg/kg every 3 weeks plus YERVOY® 3 mg/kg every 3 weeks for four doses, followed by OPDIVO® 3 mg/kg every 2 weeks (N=314); OPDIVO® 3 mg/kg every 2 weeks plus placebo (N=316); or YERVOY® 3 mg/kg every 3 weeks for four doses plus placebo (N=315). Randomization was stratified according to BRAF mutation status, metastasis stage, and Programmed cell Death Ligand 1 (PD-L1) status. Treatment was continued until disease progression or unacceptable toxicities. The two primary end points were PFS and OS in the OPDIVO® plus YERVOY® group and in the OPDIVO® group versus the YERVOY® group.

The median OS at a minimum follow up of 36 months, had not been reached in the OPDIVO® plus YERVOY® group and was 37.6 months in the OPDIVO® group, compared with 19.9 months in the YERVOY® group (Hazard Ratio for death with OPDIVO® plus YERVOY® versus YERVOY®=0.55 (P<0.001); Hazard Ratio for death with OPDIVO® versus YERVOY®=0.65 (P<0.001). The OS at 3 years in the OPDIVO® plus YERVOY® group was 58% and in the OPDIVO® group was 52%, as compared with 34% in the YERVOY® group. Grade 3 or 4 treatment-related toxicities, as expected were higher in the OPDIVO® plus YERVOY® group at 59% compared with 21% in the OPDIVO® group, and 28% in the YERVOY® group.

It was concluded that in patients with previously untreated advanced melanoma, significantly longer Overall Survival can be achieved with OPDIVO® plus YERVOY® combination therapy or with OPDIVO® alone, compared with single agent YERVOY®. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. N Engl J Med 2017; 377:1345-1356

SUMMARY: It is estimated that in the US, about 87,110 new cases of melanoma will be diagnosed in 2017 and about 9,730 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. A major risk factor for most skin cancers is exposure to UltraViolet (UV) radiation, which damages the DNA of skin cells. The main source of UV rays is sunlight, tanning lamps and tanning beds. UV exposure also can cause cataracts and ocular melanoma. Indoor tanning, exposes individuals to both UVA and UVB rays and is particularly dangerous for those who begin indoor tanning during adolescence or early adulthood, putting them at a higher risk of developing melanoma. The association between indoor tanning beds, including those with the newer tanning technology, and melanoma, has been well established with a 22-34% increase in the risk of developing melanoma with indoor tanning. The International Agency for Research on Cancer has classified indoor tanning as a Class I carcinogen, based on its significant association with malignant melanoma. Indoor tanning with resulting exposure to ultraviolet radiation is a potentially modifiable behavior. According to the 2015 Youth Risk Behavior Surveillance System, approximately 15% of the high school teens are indoor tanning and according to the 2010 National Health Interview Survey, indoor tanners tended to be young, non-Hispanic white women of whom 32% are aged 18 to 21 years.

The authors in this study estimated the health and economic benefits of reducing indoor tanning in the United States. Using a statistical model that takes into consideration risk, that continues over time (Markov model), the authors estimated the number of melanoma cases and deaths that could be prevented and melanoma treatment costs saved, by reducing indoor tanning among minors younger than 18 years. These estimations were based on a cohort of 61.2 million individuals aged 14 years or younger in the United States and the probability of these individuals using indoor tanning, based on data from the 2013 Youth Risk Behavior Survey. The prevalence of indoor tanning was based on a recent meta-analysis.

The researchers noted that restricting the use of indoor tanning among minors younger than 18 years was estimated to prevent 61,839 cases of melanoma (4.9% reduction) and 6,735 melanoma deaths (4.7% reduction), over the lifetime of this group of individuals. The treatment cost-savings from these reductions was estimated to be $342.9 million over the lifetime of these individuals. These health and economic benefits increased as indoor tanning was further reduced.

The authors concluded that reducing indoor tanning has the potential to reduce melanoma incidence, mortality, and treatment costs, emphasizing the importance of continued public health efforts to identify and implement effective strategies to prevent melanoma. The potential impact of reducing indoor tanning on melanoma prevention and treatment costs in the United States: An economic analysis. Guy GP, Zhang Y, Ekwueme DU, et al. Journal of the American Academy of Dermatology 2017;76:226-233

SUMMARY: It is estimated that in the US, about 87,110 new cases of melanoma will be diagnosed in 2017 and about 9,730 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. Alcohol related cancers account for 5.8% of all cancer deaths worldwide and there is compelling epidemiological evidence supporting that alcohol causes cancer of the oropharynx, larynx, oesophagus, liver, colon, rectum and breast (seven sites).

The mechanism of alcohol related carcinogenesis is not well understood and may vary from each target organ. Alcohol is predominantly metabolized in the liver to acetaldehyde, which is a carcinogen. Acetaldehyde is then converted into acetic acid radicals also known as acetyl radicals. There is strong evidence to suggest that acetaldehyde damages DNA. This mechanism of alcohol related carcinogenesis has been implicated in cancer of the oropharynx, larynx, esophagus and liver. With regards to breast cancer, breast tissue may be more susceptible to alcohol than other sites. Even moderate alcohol intake has been associated with increased levels of circulating sex hormones which in turn can activate cellular proliferation.

Even though the association between alcohol consumption and increased risk of numerous cancers is well known, there has been little or no evidence to associate alcohol consumption to melanoma. The authors in this study investigated whether alcohol intake was associated with risk of melanoma, by using data from three large prospective cohort studies, which included 210,252 participants. These individuals were followed for a mean of 18.3 years. The participants responded to questionnaires approximately every 4 years from 1984 to 2007 and provided information on their alcohol intake. A standard drink was defined at 12.8 grams of alcohol (one drink is considered to be 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of hard liquor).

In this pooled analysis, a total of 1,374 cases of invasive melanoma were documented during the follow up period. Higher alcohol intake was associated with an increased incidence of invasive melanoma (HR=1.14; P=0.04). When analyzed by the type of alcoholic beverages and after adjusting for other alcoholic beverages, white wine consumption was associated with an increased risk of melanoma (HR 1.13; P<0.01). It was also noted that alcohol consumption-related melanoma risk, was higher in the UV-spared sites such as the torso which receives less sun exposure, compared with UV-exposed sites such as head, neck, or extremities. Individuals who consumed 20 grams or more of alcohol a day were 73% more likely to be diagnosed with melanomas of the trunk compared to nondrinkers (HR=1.3;P=0.02), whereas only 2% of the individuals were more likely to be diagnosed with melanoma of the head, neck and extremities compared with non drinkers (HR=1.02; P=0.25).

The researchers noted that there was no evidence that age, smoking history, caffeine intake, physical activity, hair color, mole count or BMI, modified the association between alcohol intake and melanoma, when these results were stratified by those variables. It was hypothesized that white wine may have higher levels of pre-existing acetaldehyde (which gives the pleasant fruity aroma), than beer or hard liquors and the antioxidants in the red wine may offset the carcinogenic risks associated with acetaldehyde.

The authors concluded that these findings support the American Cancer Society Guidelines for Cancer Prevention, to limit alcohol intake, and alcohol consumption was associated with a modest increase in the risk of melanoma, particularly on parts of the body that are less sun exposed. Alcohol Intake and Risk of Incident Melanoma: A Pooled Analysis of Three Prospective Studies in the United States. Rivera A, Nan H, Li T, et al. Cancer Epidemiol Biomarkers Prev. 2016;25:1550-1558

SUMMARY: It is estimated that in the US, approximately 76,380 new cases of melanoma will be diagnosed in 2016 and approximately 10,130 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in the greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with stage IIIA disease have a disease-specific survival rate of 78%, whereas those with stage IIIB and stage IIIC disease have a disease-specific survival rates of 59% and 40% respectively. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. With the recognition of Immune checkpoint proteins (“gate keepers”) and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoint proteins, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

YERVOY® is a fully human immunoglobulin G1 monoclonal antibody, that blocks Immune checkpoint protein/receptor CTLA-4. YERVOY® was approved by the FDA in 2015 as adjuvant therapy for patients with malignant melanoma based on a phase III trial (EORTC 18071) in which adjuvant YERVOY® was compared with placebo in patients with resected stage III melanoma. At a median follow-up of 2.7 years, adjuvant YERVOY® was associated with significantly prolonged Recurrence Free Survival compared with placebo (HR=0.75; P=0.001). In this study, YERVOY® was dosed at 10 mg/kg and this dose was chosen based on a phase II trial that evaluated YERVOY® administered at three dose levels – 0.3 mg/kg, 3 mg/kg and 10 mg/kg. This trial demonstrated that the 10 mg/kg dose had the greatest efficacy for treatment of advanced melanoma, but had more toxicity.

The authors have now reported the efficacy of adjuvant therapy with YERVOY® in patients with high-risk stage III melanoma after complete lymph node dissection, at a median follow up of 5.3 years. EORTC 18071 is a randomized, double-blind, phase III trial in which patients who had undergone complete resection of stage III cutaneous melanoma were randomly assigned in a 1:1 ratio to receive YERVOY® at a dose of 10 mg/kg (N=475) or placebo (N=476), every 3 weeks for four doses and then every 3 months for up to 3 years or until disease recurrence or unacceptable toxicities. The Primary end point was Recurrence Free Survival and Secondary end points included Overall Survival, distant metastasis-free survival and safety.

At a median follow up of 5.3 years, the 5-year Recurrence Free Survival was 40.8% in the YERVOY® group compared with 30.3% in the placebo group (HR for recurrence or death = 0.76; P<0.001) and the 5-year Overall Survival was 65.4% in the YERVOY® group compared with 54.4% in the placebo group (HR for death = 0.72; P=0.001). The later meant a 28% reduction in the risk of death. The distant metastasis-free survival rate at 5 years was 48.3% in the YERVOY® group compared with 38.9% in the placebo group (HR for death or distant metastasis = 0.76; P=0.002). Grade 3 or 4 adverse events occurred in 54.1% of the patients in the YERVOY® group compared to 26.2% in the placebo group, and this was significant. Grade 3 or 4 Immune-related adverse events occurred in 41.6% of the patients in the YERVOY® group compared to 2.7% in the placebo group.

It was concluded that adjuvant therapy with YERVOY® at a dose of 10 mg/kg for high-risk stage III melanoma, significantly improves Recurrence Free Survival, Overall Survival, and distant metastasis-free survival, when compared to placebo. Given the potentially severe toxicities with this dose level of YERVOY®, the risks and benefits of this treatment has to be discussed with the patients and this treatment option should be reserved for experienced centers. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. Eggermont AM, Chiarion-Sileni V, Grob J-J, et al. October 8, 2016DOI: 10.1056/NEJMoa1611299

SUMMARY: It is estimated that in the US, approximately 76,380 new cases of melanoma will be diagnosed in 2016 and approximately 10,130 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. A better understanding of Immune checkpoints has opened the doors for the development of various immunotherapies. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoint proteins, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that targets PD-1 receptor. In 2014, Topalian and Colleagues reported their finding of an early phase I trial (J Clin Oncol 2014;32:1020-1030), in which patients with advanced Melanoma (N = 107) who had 1-5 prior systemic therapies received OPDIVO® monotherapy. The median age of patients in this study was 61 years and patients received OPDIVO® every 2 weeks for up to 96 weeks. The median Overall Survival for these patients was 16.8 months and 1 and 2 year survival rates were 62% and 43%, respectively. It was noted that some patients had durable responses that persisted even after treatment was discontinued. This patient group was followed for Overall Survival, Progression Free Survival (PFS), long term safety and response duration, after discontinuing treatment with OPDIVO®. The authors have now reported the results of this extended follow up, with 5 year Overall Survival (OS) data from this study.

The 5 year Overall Survival in all 107 patients was 34% and the median OS was 20.3 months for those who received the approved dose of 3 mg/kg of OPDIVO® and 17.3 months in all 107 patients. As a comparison, according to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data, the 5 year OS rate for metastatic Melanoma patients diagnosed during the study period was 16.6%. The OS rates in this study appeared to have plateaued at 48 months. The Progression Free Survival at 30 months following treatment was 25.7% for those who received the approved dose of 3 mg/kg of OPDIVO® and 18.6% for all patients. The most common side effects across the entire cohort included fatigue, rash, diarrhea, pruritus and nausea.

The authors concluded that this analysis represents the first and longest follow up to date, testing an anti–PD1 immunotherapy in any specific disease. Monotherapy with OPDIVO® in heavily pretreated advanced Melanoma patients can result in more than a third of patients (34%) being alive, 5 years after starting treatment. Durable, long-term survival in previously treated patients with advanced melanoma (MEL) who received nivolumab (NIVO) monotherapy in a phase I trial. Hodi FS, Kluger H, Sznol M, et al. 2016 AACR Annual Meeting. Abstract CT001