Melanoma

On April 30, 2018, the US Food and Drug Administration expanded the indication for the combined use of dabrafenib and trametinib to include adjuvant treatment of BRAF-mutant melanoma following complete surgical resection. Dabrafenib is an inhibitor of the BRAF kinase, and trametinib is an inhibitor of the MEK kinase, both of which are components of the mitogen-activated protein kinase (MAPK) signaling pathway. The 2 drugs are already approved as both single agents and in combination for the treatment of BRAF-mutated metastatic melanoma.

The current approval was based on data from a phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial. The COMBI-AD trial was carried out from January 2013 through December 2014 at 169 sites in 26 countries. A total of 870 patients with stage III melanoma and BRAF V600E/K mutations and pathologic involvement of regional lymph nodes following complete resection were randomly assigned to receive dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily, or 2 matched placebos for up to 1 year. Randomization was stratified according to BRAF mutation status (V600E or V600K) and disease stage (IIIA, IIIB or IIIC).

Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (on a scale of 1-5, with higher scores indicating greater disability). Patients who had undergone previous systemic anticancer therapy or radiotherapy were excluded from the study.

The primary endpoint was relapse-free survival (RFS), defined as the time from randomization to disease recurrence or death from any cause. Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety. Clinical examination and imaging by computed tomography, magnetic resonance imaging, or both was performed every 3 months for the first 2 years and then every 6 months until disease recurrence or trial completion.

As of the data cut-off, the combination of dabrafenib and trametinib reduced the risk of disease recurrence or death by 53% compared with placebo (hazard ratio [HR], 0.47; P < .001). Median RFS was not yet reached in the combination arm, compared with 16.6 months in the placebo arm. The RFS benefit was observed across all prespecified subgroups, and the combination was also found to improve OS, DMFS, and FFR.

The most common adverse events (AEs) included pyrexia, fatigue, nausea, rash, vomiting, diarrhea, chills, and myalgia. Overall, 97% of patients experienced an AE, 41% experienced a grade 3/4 AE, and 26% had an AE that led to treatment discontinuation. In patients treated with placebo, those numbers were 88%, 14%, and 3%, respectively.

On April 30, 2018, the US Food and Drug Administration expanded the indication for the combined use of dabrafenib and trametinib to include adjuvant treatment of BRAF-mutant melanoma following complete surgical resection. Dabrafenib is an inhibitor of the BRAF kinase, and trametinib is an inhibitor of the MEK kinase, both of which are components of the mitogen-activated protein kinase (MAPK) signaling pathway. The 2 drugs are already approved as both single agents and in combination for the treatment of BRAF-mutated metastatic melanoma.

The current approval was based on data from a phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial. The COMBI-AD trial was carried out from January 2013 through December 2014 at 169 sites in 26 countries. A total of 870 patients with stage III melanoma and BRAF V600E/K mutations and pathologic involvement of regional lymph nodes following complete resection were randomly assigned to receive dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily, or 2 matched placebos for up to 1 year. Randomization was stratified according to BRAF mutation status (V600E or V600K) and disease stage (IIIA, IIIB or IIIC).

Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (on a scale of 1-5, with higher scores indicating greater disability). Patients who had undergone previous systemic anticancer therapy or radiotherapy were excluded from the study.

The primary endpoint was relapse-free survival (RFS), defined as the time from randomization to disease recurrence or death from any cause. Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety. Clinical examination and imaging by computed tomography, magnetic resonance imaging, or both was performed every 3 months for the first 2 years and then every 6 months until disease recurrence or trial completion.

As of the data cut-off, the combination of dabrafenib and trametinib reduced the risk of disease recurrence or death by 53% compared with placebo (hazard ratio [HR], 0.47; P < .001). Median RFS was not yet reached in the combination arm, compared with 16.6 months in the placebo arm. The RFS benefit was observed across all prespecified subgroups, and the combination was also found to improve OS, DMFS, and FFR.

The most common adverse events (AEs) included pyrexia, fatigue, nausea, rash, vomiting, diarrhea, chills, and myalgia. Overall, 97% of patients experienced an AE, 41% experienced a grade 3/4 AE, and 26% had an AE that led to treatment discontinuation. In patients treated with placebo, those numbers were 88%, 14%, and 3%, respectively.

On April 30, 2018, the US Food and Drug Administration expanded the indication for the combined use of dabrafenib and trametinib to include adjuvant treatment of BRAF-mutant melanoma following complete surgical resection. Dabrafenib is an inhibitor of the BRAF kinase, and trametinib is an inhibitor of the MEK kinase, both of which are components of the mitogen-activated protein kinase (MAPK) signaling pathway. The 2 drugs are already approved as both single agents and in combination for the treatment of BRAF-mutated metastatic melanoma.

The current approval was based on data from a phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial. The COMBI-AD trial was carried out from January 2013 through December 2014 at 169 sites in 26 countries. A total of 870 patients with stage III melanoma and BRAF V600E/K mutations and pathologic involvement of regional lymph nodes following complete resection were randomly assigned to receive dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily, or 2 matched placebos for up to 1 year. Randomization was stratified according to BRAF mutation status (V600E or V600K) and disease stage (IIIA, IIIB or IIIC).

Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (on a scale of 1-5, with higher scores indicating greater disability). Patients who had undergone previous systemic anticancer therapy or radiotherapy were excluded from the study.

The primary endpoint was relapse-free survival (RFS), defined as the time from randomization to disease recurrence or death from any cause. Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety. Clinical examination and imaging by computed tomography, magnetic resonance imaging, or both was performed every 3 months for the first 2 years and then every 6 months until disease recurrence or trial completion.

As of the data cut-off, the combination of dabrafenib and trametinib reduced the risk of disease recurrence or death by 53% compared with placebo (hazard ratio [HR], 0.47; P < .001). Median RFS was not yet reached in the combination arm, compared with 16.6 months in the placebo arm. The RFS benefit was observed across all prespecified subgroups, and the combination was also found to improve OS, DMFS, and FFR.

The most common adverse events (AEs) included pyrexia, fatigue, nausea, rash, vomiting, diarrhea, chills, and myalgia. Overall, 97% of patients experienced an AE, 41% experienced a grade 3/4 AE, and 26% had an AE that led to treatment discontinuation. In patients treated with placebo, those numbers were 88%, 14%, and 3%, respectively.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

Perusal of any lifestyle magazine reveals photographs of movie stars with sun-kissed skin. One can imagine their carefree lives afford ample time outdoors, a vast departure from the pasty masses trapped in their office cubicles. Our cultural norms dictate that a glowing look is a sign of health and attractiveness. Light-skinned individuals must receive regular exposure to sunlight to maintain their bronzed color. Over the last century, the indoor tanning industry has expanded to fill the niche created by the ceaseless pursuit of the ideal complexion.

Indoor tanning use causes up to 170,000 cases of skin cancer per year worldwide.¹ Accumulating sunburns early in life is a leading risk factor for melanoma, the deadliest form of skin cancer. Campaigns to spread awareness about the link between UV radiation and skin cancer are ubiquitous. The US Food and Drug Administration (FDA) recommends against the use of tanning beds by minors, and several states have passed laws restricting their access. However, adolescents continue to engage. White female high school students remain frequenters of this practice, with more than 15% reporting current use of indoor tanning facilities.² It seems targeted outreach and media campaigns are unsuccessful in influencing their behavior, and new approaches are needed.

Tanning-Related Injuries

Concentrated exposure to UV radiation during indoor tanning sessions carries the potential for immediate harm. Public health campaigns have focused on long-term skin cancer risk while overlooking thousands of injuries that occur annually at tanning salons across the country. The US Consumer Product Safety Commission first noted injuries associated with the largely unregulated tanning industry in 1974.³ In response, the FDA limited radiation levels, required indoor tanning devices to have timers and manual off switches, and mandated the use of protective eyewear. These changes sparked industry backlash due to the cost of compliance. The Indoor Tanning Association (no longer in operation) hired a lobbying firm in 2009 that successfully fought to resist further regulation.³

More than 3000 indoor tanning–related injuries are treated in emergency departments annually.⁴ White women aged 18 to 24 years who visit tanning salons are most likely to sustain injuries. In one study, severe skin burns accounted for 80% of emergency department visits, while the rest were due to fainting, eye injuries, and infections from unsanitary equipment.Timer malfunctions may play a role in tanning bed injuries, as several injured patients have reported falling asleep while tanning.⁴ Only 5% of tanning salons in North Carolina complied with FDA-recommended exposure schedules in 2003, suggesting that neglect or deliberate override of safety features also may contribute to injury.⁵

Challenges in Changing Tanning Behaviors

Use of indoor tanning facilities by adolescents is boosted by their misperceptions of peer engagement. Many teenagers overestimate the number of their peers who tan, which influences their own behavior.⁶ This phenomenon illustrates the importance of perceived social norms in this demographic group. Motivating adolescents to take actions that violate these norms poses a considerable challenge.

To teenagers, the perceived immediate benefits of indoor tanning far outweigh perceived costs. The immediate benefit of indoor tanning is having attractive skin, which may improve social standing and perceived self-worth. When adolescents weigh costs and benefits at different points in time, the present value of future events is discounted when compared to current events. For example, an immediate loss of $1000 is more impactful than losing $1000 ten years down the road. Adolescents are motivated to succeed in the short-term and may heavily discount future adverse effects such as the risk for developing cancer or premature aging of the skin. Therefore, getting a tan may be the “rational” decision even if there is an increased risk of future skin cancer.⁷

The addiction theory of tanning seeks to explain why individuals continue to tan despite knowledge of the associated risks. Exposure to UV radiation releases endorphins, producing a natural narcotic effect.⁸ The relaxing feeling sunbathers experience may lead to a phenomenon similar to addictions to opioids, alcohol, tobacco, and sugar. Behavior change is a process that unfolds over time. The 5 stages are precontemplation, contemplation, preparation, action, and maintenance.⁹ Education falls on deaf ears when the recipients are not ready to consider change. Individuals who are already thinking about cutting back on tanning fall into the category of contemplators and are the most open to educational techniques.⁹

Potential Solutions

Despite the dire long-term consequences of melanoma, warning adolescents of the increased cancer risk from tanning is an ineffective dissuasion strategy.¹⁰ Solutions that aim to limit tanning behaviors in this population should instead center on decreasing the present utility of a tan. Emphasis on the risk of immediate injury may be one effective route. The costs of potential damage to current appearance, vision, and overall health are not readily discounted by adolescents. Teens who devote time and money to the pursuit of a golden glow place high value on attractiveness. Such individuals respond best to loss-framed messages that focus on the impact of UV exposure on appearance, not just their health.¹¹ However, appearance-motivated individuals may feel threatened by interventions that aim to reduce their decision freedom and display high reactance, leading them to reassert their freedom by resisting antitanning messages.¹² Another strategy is altering media messaging to support a wider swathe of skin tones, reducing the social benefits of a tan. To swing the needle on our cultural norms, this intervention will require an enduring effort with backing from media outlets and celebrities.

Taxes on tanning salons and devices provide a basic economic disincentive to adolescents who typically have limited funds. State cigarette tax increases successfully reduced youth consumption of tobacco in the 1990s.¹³ A provision of the Patient Protection and Affordable Care Act levied a 10% excise tax on tanning salons with promising early results.¹⁴ Further taxation may generate revenue for educational campaigns on the injury risks of tanning. Continued safety improvements that limit user exposure to UV radiation and enforcement of FDA regulations also will decrease injury rates. Minimizing the UV output of tanning beds and designing protective equipment for tanners are 2 potential objectives. Improvement of over-the-counter sunless tanning agents also will provide alternatives to catching rays for adolescents who wish to attain a bronzed complexion.

Final Thoughts

Health care providers must assess a patient’s readiness for change and tailor interventions accordingly. Regardless of the method, new approaches to combat adolescent tanning injuries may reduce health care costs and minimize serious public health concerns for the next generation.

Perusal of any lifestyle magazine reveals photographs of movie stars with sun-kissed skin. One can imagine their carefree lives afford ample time outdoors, a vast departure from the pasty masses trapped in their office cubicles. Our cultural norms dictate that a glowing look is a sign of health and attractiveness. Light-skinned individuals must receive regular exposure to sunlight to maintain their bronzed color. Over the last century, the indoor tanning industry has expanded to fill the niche created by the ceaseless pursuit of the ideal complexion.

Indoor tanning use causes up to 170,000 cases of skin cancer per year worldwide.¹ Accumulating sunburns early in life is a leading risk factor for melanoma, the deadliest form of skin cancer. Campaigns to spread awareness about the link between UV radiation and skin cancer are ubiquitous. The US Food and Drug Administration (FDA) recommends against the use of tanning beds by minors, and several states have passed laws restricting their access. However, adolescents continue to engage. White female high school students remain frequenters of this practice, with more than 15% reporting current use of indoor tanning facilities.² It seems targeted outreach and media campaigns are unsuccessful in influencing their behavior, and new approaches are needed.

Tanning-Related Injuries

Concentrated exposure to UV radiation during indoor tanning sessions carries the potential for immediate harm. Public health campaigns have focused on long-term skin cancer risk while overlooking thousands of injuries that occur annually at tanning salons across the country. The US Consumer Product Safety Commission first noted injuries associated with the largely unregulated tanning industry in 1974.³ In response, the FDA limited radiation levels, required indoor tanning devices to have timers and manual off switches, and mandated the use of protective eyewear. These changes sparked industry backlash due to the cost of compliance. The Indoor Tanning Association (no longer in operation) hired a lobbying firm in 2009 that successfully fought to resist further regulation.³

More than 3000 indoor tanning–related injuries are treated in emergency departments annually.⁴ White women aged 18 to 24 years who visit tanning salons are most likely to sustain injuries. In one study, severe skin burns accounted for 80% of emergency department visits, while the rest were due to fainting, eye injuries, and infections from unsanitary equipment.Timer malfunctions may play a role in tanning bed injuries, as several injured patients have reported falling asleep while tanning.⁴ Only 5% of tanning salons in North Carolina complied with FDA-recommended exposure schedules in 2003, suggesting that neglect or deliberate override of safety features also may contribute to injury.⁵

Challenges in Changing Tanning Behaviors

Use of indoor tanning facilities by adolescents is boosted by their misperceptions of peer engagement. Many teenagers overestimate the number of their peers who tan, which influences their own behavior.⁶ This phenomenon illustrates the importance of perceived social norms in this demographic group. Motivating adolescents to take actions that violate these norms poses a considerable challenge.

To teenagers, the perceived immediate benefits of indoor tanning far outweigh perceived costs. The immediate benefit of indoor tanning is having attractive skin, which may improve social standing and perceived self-worth. When adolescents weigh costs and benefits at different points in time, the present value of future events is discounted when compared to current events. For example, an immediate loss of $1000 is more impactful than losing $1000 ten years down the road. Adolescents are motivated to succeed in the short-term and may heavily discount future adverse effects such as the risk for developing cancer or premature aging of the skin. Therefore, getting a tan may be the “rational” decision even if there is an increased risk of future skin cancer.⁷

The addiction theory of tanning seeks to explain why individuals continue to tan despite knowledge of the associated risks. Exposure to UV radiation releases endorphins, producing a natural narcotic effect.⁸ The relaxing feeling sunbathers experience may lead to a phenomenon similar to addictions to opioids, alcohol, tobacco, and sugar. Behavior change is a process that unfolds over time. The 5 stages are precontemplation, contemplation, preparation, action, and maintenance.⁹ Education falls on deaf ears when the recipients are not ready to consider change. Individuals who are already thinking about cutting back on tanning fall into the category of contemplators and are the most open to educational techniques.⁹

Potential Solutions

Despite the dire long-term consequences of melanoma, warning adolescents of the increased cancer risk from tanning is an ineffective dissuasion strategy.¹⁰ Solutions that aim to limit tanning behaviors in this population should instead center on decreasing the present utility of a tan. Emphasis on the risk of immediate injury may be one effective route. The costs of potential damage to current appearance, vision, and overall health are not readily discounted by adolescents. Teens who devote time and money to the pursuit of a golden glow place high value on attractiveness. Such individuals respond best to loss-framed messages that focus on the impact of UV exposure on appearance, not just their health.¹¹ However, appearance-motivated individuals may feel threatened by interventions that aim to reduce their decision freedom and display high reactance, leading them to reassert their freedom by resisting antitanning messages.¹² Another strategy is altering media messaging to support a wider swathe of skin tones, reducing the social benefits of a tan. To swing the needle on our cultural norms, this intervention will require an enduring effort with backing from media outlets and celebrities.

Taxes on tanning salons and devices provide a basic economic disincentive to adolescents who typically have limited funds. State cigarette tax increases successfully reduced youth consumption of tobacco in the 1990s.¹³ A provision of the Patient Protection and Affordable Care Act levied a 10% excise tax on tanning salons with promising early results.¹⁴ Further taxation may generate revenue for educational campaigns on the injury risks of tanning. Continued safety improvements that limit user exposure to UV radiation and enforcement of FDA regulations also will decrease injury rates. Minimizing the UV output of tanning beds and designing protective equipment for tanners are 2 potential objectives. Improvement of over-the-counter sunless tanning agents also will provide alternatives to catching rays for adolescents who wish to attain a bronzed complexion.

Final Thoughts

Health care providers must assess a patient’s readiness for change and tailor interventions accordingly. Regardless of the method, new approaches to combat adolescent tanning injuries may reduce health care costs and minimize serious public health concerns for the next generation.

Perusal of any lifestyle magazine reveals photographs of movie stars with sun-kissed skin. One can imagine their carefree lives afford ample time outdoors, a vast departure from the pasty masses trapped in their office cubicles. Our cultural norms dictate that a glowing look is a sign of health and attractiveness. Light-skinned individuals must receive regular exposure to sunlight to maintain their bronzed color. Over the last century, the indoor tanning industry has expanded to fill the niche created by the ceaseless pursuit of the ideal complexion.

Indoor tanning use causes up to 170,000 cases of skin cancer per year worldwide.¹ Accumulating sunburns early in life is a leading risk factor for melanoma, the deadliest form of skin cancer. Campaigns to spread awareness about the link between UV radiation and skin cancer are ubiquitous. The US Food and Drug Administration (FDA) recommends against the use of tanning beds by minors, and several states have passed laws restricting their access. However, adolescents continue to engage. White female high school students remain frequenters of this practice, with more than 15% reporting current use of indoor tanning facilities.² It seems targeted outreach and media campaigns are unsuccessful in influencing their behavior, and new approaches are needed.

Tanning-Related Injuries

Concentrated exposure to UV radiation during indoor tanning sessions carries the potential for immediate harm. Public health campaigns have focused on long-term skin cancer risk while overlooking thousands of injuries that occur annually at tanning salons across the country. The US Consumer Product Safety Commission first noted injuries associated with the largely unregulated tanning industry in 1974.³ In response, the FDA limited radiation levels, required indoor tanning devices to have timers and manual off switches, and mandated the use of protective eyewear. These changes sparked industry backlash due to the cost of compliance. The Indoor Tanning Association (no longer in operation) hired a lobbying firm in 2009 that successfully fought to resist further regulation.³

More than 3000 indoor tanning–related injuries are treated in emergency departments annually.⁴ White women aged 18 to 24 years who visit tanning salons are most likely to sustain injuries. In one study, severe skin burns accounted for 80% of emergency department visits, while the rest were due to fainting, eye injuries, and infections from unsanitary equipment.Timer malfunctions may play a role in tanning bed injuries, as several injured patients have reported falling asleep while tanning.⁴ Only 5% of tanning salons in North Carolina complied with FDA-recommended exposure schedules in 2003, suggesting that neglect or deliberate override of safety features also may contribute to injury.⁵

Challenges in Changing Tanning Behaviors

Use of indoor tanning facilities by adolescents is boosted by their misperceptions of peer engagement. Many teenagers overestimate the number of their peers who tan, which influences their own behavior.⁶ This phenomenon illustrates the importance of perceived social norms in this demographic group. Motivating adolescents to take actions that violate these norms poses a considerable challenge.

To teenagers, the perceived immediate benefits of indoor tanning far outweigh perceived costs. The immediate benefit of indoor tanning is having attractive skin, which may improve social standing and perceived self-worth. When adolescents weigh costs and benefits at different points in time, the present value of future events is discounted when compared to current events. For example, an immediate loss of $1000 is more impactful than losing $1000 ten years down the road. Adolescents are motivated to succeed in the short-term and may heavily discount future adverse effects such as the risk for developing cancer or premature aging of the skin. Therefore, getting a tan may be the “rational” decision even if there is an increased risk of future skin cancer.⁷

The addiction theory of tanning seeks to explain why individuals continue to tan despite knowledge of the associated risks. Exposure to UV radiation releases endorphins, producing a natural narcotic effect.⁸ The relaxing feeling sunbathers experience may lead to a phenomenon similar to addictions to opioids, alcohol, tobacco, and sugar. Behavior change is a process that unfolds over time. The 5 stages are precontemplation, contemplation, preparation, action, and maintenance.⁹ Education falls on deaf ears when the recipients are not ready to consider change. Individuals who are already thinking about cutting back on tanning fall into the category of contemplators and are the most open to educational techniques.⁹

Potential Solutions

Despite the dire long-term consequences of melanoma, warning adolescents of the increased cancer risk from tanning is an ineffective dissuasion strategy.¹⁰ Solutions that aim to limit tanning behaviors in this population should instead center on decreasing the present utility of a tan. Emphasis on the risk of immediate injury may be one effective route. The costs of potential damage to current appearance, vision, and overall health are not readily discounted by adolescents. Teens who devote time and money to the pursuit of a golden glow place high value on attractiveness. Such individuals respond best to loss-framed messages that focus on the impact of UV exposure on appearance, not just their health.¹¹ However, appearance-motivated individuals may feel threatened by interventions that aim to reduce their decision freedom and display high reactance, leading them to reassert their freedom by resisting antitanning messages.¹² Another strategy is altering media messaging to support a wider swathe of skin tones, reducing the social benefits of a tan. To swing the needle on our cultural norms, this intervention will require an enduring effort with backing from media outlets and celebrities.

Taxes on tanning salons and devices provide a basic economic disincentive to adolescents who typically have limited funds. State cigarette tax increases successfully reduced youth consumption of tobacco in the 1990s.¹³ A provision of the Patient Protection and Affordable Care Act levied a 10% excise tax on tanning salons with promising early results.¹⁴ Further taxation may generate revenue for educational campaigns on the injury risks of tanning. Continued safety improvements that limit user exposure to UV radiation and enforcement of FDA regulations also will decrease injury rates. Minimizing the UV output of tanning beds and designing protective equipment for tanners are 2 potential objectives. Improvement of over-the-counter sunless tanning agents also will provide alternatives to catching rays for adolescents who wish to attain a bronzed complexion.

Final Thoughts

Health care providers must assess a patient’s readiness for change and tailor interventions accordingly. Regardless of the method, new approaches to combat adolescent tanning injuries may reduce health care costs and minimize serious public health concerns for the next generation.

Patients who use indoor tanning beds are more likely to develop a second primary melanoma, and do it more quickly, than those who avoid indoor tanning, according to a retrospective study involving 434 melanoma patients.

rfranki@mdedge.com

SOURCE: Li Y et al. J Am Acad Dermatol. 2018;79(6):1101-8.

Patients who use indoor tanning beds are more likely to develop a second primary melanoma, and do it more quickly, than those who avoid indoor tanning, according to a retrospective study involving 434 melanoma patients.

rfranki@mdedge.com

SOURCE: Li Y et al. J Am Acad Dermatol. 2018;79(6):1101-8.

Patients who use indoor tanning beds are more likely to develop a second primary melanoma, and do it more quickly, than those who avoid indoor tanning, according to a retrospective study involving 434 melanoma patients.

rfranki@mdedge.com

SOURCE: Li Y et al. J Am Acad Dermatol. 2018;79(6):1101-8.

Stereotactic radiosurgery (SRS) provides better early local control of brain metastases than complete surgical resection, but this advantage fades with time, according to investigators.

By 6 months, lower risks associated with SRS shifted in favor of those who had surgical resection, reported lead author Thomas Churilla, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues.

“Outside recognized indications for surgery such as establishing diagnosis or relieving mass effect, little evidence is available to guide the therapeutic choice of SRS vs. surgical resection in the treatment of patients with limited brain metastases,” the investigators wrote in JAMA Oncology.

The investigators performed an exploratory analysis of data from the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial, which was designed to evaluate whole-brain radiotherapy for patients with one to three brain metastases who had undergone SRS or complete surgical resection. The present analysis involved 268 patients, of whom 154 had SRS and 114 had complete surgical resection.

Primary tumors included lung, breast, colorectum, kidney, and melanoma. Initial analysis showed that patients undergoing surgical resection, compared with those who had SRS, typically had larger brain metastases (median, 28 mm vs. 20 mm) and more often had 1 brain metastasis (98.2% vs. 74.0%). Mass locality also differed between groups; compared with patients receiving SRS, surgical patients more often had metastases in the posterior fossa (26.3% vs. 7.8%) and less often in the parietal lobe (18.4% vs. 39.6%).

After median follow-up of 39.9 months, risks of local recurrence were similar between surgical and SRS groups (hazard ratio, 1.15). Stratifying by interval, however, showed that surgical patients were at much higher risk of local recurrence in the first 3 months following treatment (HR for 0-3 months, 5.94). Of note, this risk faded with time (HR for 3-6 months, 1.37; HR for 6-9 months, 0.75; HR for 9 months or longer, 0.36). From the 6-9 months interval onward, surgical patients had lower risk of recurrence, compared with SRS patients, and the risk even decreased after the 6-9 month interval.

“Prospective controlled trials are warranted to direct the optimal local approach for patients with brain metastases and to define whether any population may benefit from escalation in local therapy,” the investigators concluded.

The study was funded by the National Cancer Institute, National Institutes of Health, and Fonds Cancer in Belgium. One author reported receiving financial compensation from Pfizer via her institution.

SOURCE: Churilla T et al. JAMA Onc. 2018. doi: 10.1001/jamaoncol.2018.4610.
 

Stereotactic radiosurgery (SRS) provides better early local control of brain metastases than complete surgical resection, but this advantage fades with time, according to investigators.

By 6 months, lower risks associated with SRS shifted in favor of those who had surgical resection, reported lead author Thomas Churilla, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues.

“Outside recognized indications for surgery such as establishing diagnosis or relieving mass effect, little evidence is available to guide the therapeutic choice of SRS vs. surgical resection in the treatment of patients with limited brain metastases,” the investigators wrote in JAMA Oncology.

The investigators performed an exploratory analysis of data from the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial, which was designed to evaluate whole-brain radiotherapy for patients with one to three brain metastases who had undergone SRS or complete surgical resection. The present analysis involved 268 patients, of whom 154 had SRS and 114 had complete surgical resection.

Primary tumors included lung, breast, colorectum, kidney, and melanoma. Initial analysis showed that patients undergoing surgical resection, compared with those who had SRS, typically had larger brain metastases (median, 28 mm vs. 20 mm) and more often had 1 brain metastasis (98.2% vs. 74.0%). Mass locality also differed between groups; compared with patients receiving SRS, surgical patients more often had metastases in the posterior fossa (26.3% vs. 7.8%) and less often in the parietal lobe (18.4% vs. 39.6%).

After median follow-up of 39.9 months, risks of local recurrence were similar between surgical and SRS groups (hazard ratio, 1.15). Stratifying by interval, however, showed that surgical patients were at much higher risk of local recurrence in the first 3 months following treatment (HR for 0-3 months, 5.94). Of note, this risk faded with time (HR for 3-6 months, 1.37; HR for 6-9 months, 0.75; HR for 9 months or longer, 0.36). From the 6-9 months interval onward, surgical patients had lower risk of recurrence, compared with SRS patients, and the risk even decreased after the 6-9 month interval.

“Prospective controlled trials are warranted to direct the optimal local approach for patients with brain metastases and to define whether any population may benefit from escalation in local therapy,” the investigators concluded.

The study was funded by the National Cancer Institute, National Institutes of Health, and Fonds Cancer in Belgium. One author reported receiving financial compensation from Pfizer via her institution.

SOURCE: Churilla T et al. JAMA Onc. 2018. doi: 10.1001/jamaoncol.2018.4610.
 

Stereotactic radiosurgery (SRS) provides better early local control of brain metastases than complete surgical resection, but this advantage fades with time, according to investigators.

By 6 months, lower risks associated with SRS shifted in favor of those who had surgical resection, reported lead author Thomas Churilla, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues.

“Outside recognized indications for surgery such as establishing diagnosis or relieving mass effect, little evidence is available to guide the therapeutic choice of SRS vs. surgical resection in the treatment of patients with limited brain metastases,” the investigators wrote in JAMA Oncology.

The investigators performed an exploratory analysis of data from the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial, which was designed to evaluate whole-brain radiotherapy for patients with one to three brain metastases who had undergone SRS or complete surgical resection. The present analysis involved 268 patients, of whom 154 had SRS and 114 had complete surgical resection.

Primary tumors included lung, breast, colorectum, kidney, and melanoma. Initial analysis showed that patients undergoing surgical resection, compared with those who had SRS, typically had larger brain metastases (median, 28 mm vs. 20 mm) and more often had 1 brain metastasis (98.2% vs. 74.0%). Mass locality also differed between groups; compared with patients receiving SRS, surgical patients more often had metastases in the posterior fossa (26.3% vs. 7.8%) and less often in the parietal lobe (18.4% vs. 39.6%).

After median follow-up of 39.9 months, risks of local recurrence were similar between surgical and SRS groups (hazard ratio, 1.15). Stratifying by interval, however, showed that surgical patients were at much higher risk of local recurrence in the first 3 months following treatment (HR for 0-3 months, 5.94). Of note, this risk faded with time (HR for 3-6 months, 1.37; HR for 6-9 months, 0.75; HR for 9 months or longer, 0.36). From the 6-9 months interval onward, surgical patients had lower risk of recurrence, compared with SRS patients, and the risk even decreased after the 6-9 month interval.

“Prospective controlled trials are warranted to direct the optimal local approach for patients with brain metastases and to define whether any population may benefit from escalation in local therapy,” the investigators concluded.

The study was funded by the National Cancer Institute, National Institutes of Health, and Fonds Cancer in Belgium. One author reported receiving financial compensation from Pfizer via her institution.

SOURCE: Churilla T et al. JAMA Onc. 2018. doi: 10.1001/jamaoncol.2018.4610.
 

Pregnancy does not necessarily increase a woman’s risk for melanoma, nor is it clear that becoming pregnant affects melanoma’s disease course, according to current evidence. This guidance is among several updates added to newly released guidelines for managing patients with primary cutaneous melanoma.

The American Academy of Dermatology, which formed a working group to develop the updated cutaneous melanoma (CM) treatment guidelines, also addressed the burgeoning field of genetic testing for cancer in the guidelines, which were published online on Nov. 1. Although there may be a hereditary component to some melanomas, genetic testing may not be appropriate for all patients, and any formal genetic testing should be carried out only after individualized education and counseling, according to the updates.

However, the guidelines make it clear that all patients whose family history includes melanoma should be counseled about their genetic risk.

As with genetic testing, counseling regarding future pregnancies for women with melanoma, or a history of melanoma, should be personalized and account for individual history and melanoma risk, according to the new guidelines. Since evidence is lacking that pregnancy affects the course of melanoma, physicians caring for pregnant women with melanoma should first look at patient and the disease characteristics. The addition of detailed guidance regarding pregnancy reflects research showing that CM is the most common malignancy seen in pregnancy, amounting to nearly one-third of the malignancies that arise in pregnancy. “Although the incidence of CM is generally higher in men, it is higher in younger women than in men, most notably during women’s reproductive years,” wrote Susan M. Swetter, MD, and her guideline coauthors.

The National Cancer Institute

“Melanoma is the deadliest form of skin cancer, and we hope these guidelines will help dermatologists and other physicians enhance their delivery of life-saving treatment to patients,” Dr. Swetter said in a press release announcing the guideline updates. Dr. Swetter, professor of dermatology and director of the pigmented lesion and melanoma program at Stanford (Calif.) University Medical Center and Cancer Institute, led the working group that developed the guidelines. “In order to provide the best possible resource for practitioners, we reviewed the latest scientific data and addressed certain topics that weren’t covered in the AAD’s previous melanoma guidelines,” she said.

A cornerstone of cutaneous melanoma care remains unchanged in the guidelines: Surgical excision is still the preferred method for treating melanoma. Adjuvant topical therapies or radiation, say the guidelines, can be considered as second-line care, but only in limited situations in which surgery is not feasible. Staged excision techniques, such as Mohs surgery, also may be considered for certain types of melanoma and in certain body areas.

koakes@mdedge.com

SOURCE: Swetter S. et al. J Am Acad Dermatol. 2011 Nov;65(5):1032-47.

Pregnancy does not necessarily increase a woman’s risk for melanoma, nor is it clear that becoming pregnant affects melanoma’s disease course, according to current evidence. This guidance is among several updates added to newly released guidelines for managing patients with primary cutaneous melanoma.

The American Academy of Dermatology, which formed a working group to develop the updated cutaneous melanoma (CM) treatment guidelines, also addressed the burgeoning field of genetic testing for cancer in the guidelines, which were published online on Nov. 1. Although there may be a hereditary component to some melanomas, genetic testing may not be appropriate for all patients, and any formal genetic testing should be carried out only after individualized education and counseling, according to the updates.

However, the guidelines make it clear that all patients whose family history includes melanoma should be counseled about their genetic risk.

As with genetic testing, counseling regarding future pregnancies for women with melanoma, or a history of melanoma, should be personalized and account for individual history and melanoma risk, according to the new guidelines. Since evidence is lacking that pregnancy affects the course of melanoma, physicians caring for pregnant women with melanoma should first look at patient and the disease characteristics. The addition of detailed guidance regarding pregnancy reflects research showing that CM is the most common malignancy seen in pregnancy, amounting to nearly one-third of the malignancies that arise in pregnancy. “Although the incidence of CM is generally higher in men, it is higher in younger women than in men, most notably during women’s reproductive years,” wrote Susan M. Swetter, MD, and her guideline coauthors.

The National Cancer Institute

“Melanoma is the deadliest form of skin cancer, and we hope these guidelines will help dermatologists and other physicians enhance their delivery of life-saving treatment to patients,” Dr. Swetter said in a press release announcing the guideline updates. Dr. Swetter, professor of dermatology and director of the pigmented lesion and melanoma program at Stanford (Calif.) University Medical Center and Cancer Institute, led the working group that developed the guidelines. “In order to provide the best possible resource for practitioners, we reviewed the latest scientific data and addressed certain topics that weren’t covered in the AAD’s previous melanoma guidelines,” she said.

A cornerstone of cutaneous melanoma care remains unchanged in the guidelines: Surgical excision is still the preferred method for treating melanoma. Adjuvant topical therapies or radiation, say the guidelines, can be considered as second-line care, but only in limited situations in which surgery is not feasible. Staged excision techniques, such as Mohs surgery, also may be considered for certain types of melanoma and in certain body areas.

koakes@mdedge.com

SOURCE: Swetter S. et al. J Am Acad Dermatol. 2011 Nov;65(5):1032-47.

Pregnancy does not necessarily increase a woman’s risk for melanoma, nor is it clear that becoming pregnant affects melanoma’s disease course, according to current evidence. This guidance is among several updates added to newly released guidelines for managing patients with primary cutaneous melanoma.

The American Academy of Dermatology, which formed a working group to develop the updated cutaneous melanoma (CM) treatment guidelines, also addressed the burgeoning field of genetic testing for cancer in the guidelines, which were published online on Nov. 1. Although there may be a hereditary component to some melanomas, genetic testing may not be appropriate for all patients, and any formal genetic testing should be carried out only after individualized education and counseling, according to the updates.

However, the guidelines make it clear that all patients whose family history includes melanoma should be counseled about their genetic risk.

As with genetic testing, counseling regarding future pregnancies for women with melanoma, or a history of melanoma, should be personalized and account for individual history and melanoma risk, according to the new guidelines. Since evidence is lacking that pregnancy affects the course of melanoma, physicians caring for pregnant women with melanoma should first look at patient and the disease characteristics. The addition of detailed guidance regarding pregnancy reflects research showing that CM is the most common malignancy seen in pregnancy, amounting to nearly one-third of the malignancies that arise in pregnancy. “Although the incidence of CM is generally higher in men, it is higher in younger women than in men, most notably during women’s reproductive years,” wrote Susan M. Swetter, MD, and her guideline coauthors.

The National Cancer Institute

“Melanoma is the deadliest form of skin cancer, and we hope these guidelines will help dermatologists and other physicians enhance their delivery of life-saving treatment to patients,” Dr. Swetter said in a press release announcing the guideline updates. Dr. Swetter, professor of dermatology and director of the pigmented lesion and melanoma program at Stanford (Calif.) University Medical Center and Cancer Institute, led the working group that developed the guidelines. “In order to provide the best possible resource for practitioners, we reviewed the latest scientific data and addressed certain topics that weren’t covered in the AAD’s previous melanoma guidelines,” she said.

A cornerstone of cutaneous melanoma care remains unchanged in the guidelines: Surgical excision is still the preferred method for treating melanoma. Adjuvant topical therapies or radiation, say the guidelines, can be considered as second-line care, but only in limited situations in which surgery is not feasible. Staged excision techniques, such as Mohs surgery, also may be considered for certain types of melanoma and in certain body areas.

koakes@mdedge.com

SOURCE: Swetter S. et al. J Am Acad Dermatol. 2011 Nov;65(5):1032-47.

Circulating tumor DNA could be effectively isolated from plasma by focusing on a particular range of fragment sizes, which paves the way for noninvasive genomic analysis of tumor DNA, new research suggests.

In a study of 344 plasma samples from 200 patients with 18 cancer types and 65 samples from healthy controls, DNA fragment length could be used to distinguish circulating tumor DNA (ctDNA) from other cell-free DNA (cfDNA), investigators reported in Science Translational Medicine.

“We hypothesized that we could improve the sensitivity for noninvasive cancer genomics by selective sequencing of ctDNA fragments and by leveraging differences in the biology that determine DNA fragmentation,” wrote Florent Mouliere, PhD, from the Cancer Research UK Cambridge Institute, and coauthors.

Cell-free plasma fragments are often cleaved at around 167 base pairs in length and differences in length between circulating fetal and maternal DNA are already used for noninvasive prenatal diagnosis. However, the authors said that only a few studies, with conflicting results, have looked at the size distribution of tumor-derived cfDNA.

The study used two approaches to determining the size profile of mutant ctDNA. The first looked at tumor and nontumor cfDNA in mice with human ovarian cancer xenografts and the second approach used deep sequencing in 19 cancer patients. This revealed that tumor-derived cfDNA was most commonly found in fragments between 90-150 base pairs or 250-320 base pairs in size.

The researchers also noted that mutant circulating tumor DNA was generally more fragmented than nonmutant cfDNA and that patients with untreated advanced cancer showed consistently shorter lengths of mutant DNA.

The next question was whether size selection and other biological properties – such as somatic alterations – of the cfDNA could be used to enhance detection of ctDNA via machine learning technology.

Two models, designed to distinguish between healthy and cancerous samples, were developed using 153 samples, then validated on two datasets of 94 and 83 samples.

One of these models correctly classified cancerous samples in 94% of samples from patients with cancers known to have high levels of ctDNA – colorectal, cholangiocarcinoma, ovarian, breast, and melanoma – and in 65% of samples from low-ctDNA cancers – pancreatic, renal, and glioma.

Another model focused just on fragmentation patterns and was still able to distinguish cancer samples from those of healthy controls, although with slightly reduced area under the curve.

“Our results indicate that exploiting fundamental properties of cfDNA with fragment-specific analyses can allow more sensitive evaluation of ctDNA,” the authors wrote. “We identified features that could determine the presence and amount of ctDNA in plasma samples, without a prior knowledge of somatic aberrations.”

The authors pointed out that size selection of DNA fragments was relatively simple and cheap, and was also compatible with other genome-wide and targeted genomic analyses, “greatly increasing the potential value and utility of liquid biopsies as well as the cost-effectiveness of cfDNA sequencing.”

However, they cautioned that their catalogue had focused solely on double-stranded DNA and was subject to potential biases from the DNA extraction and sequencing methods they used in the study. They also commented that other biological effects could help refine the analysis of ctDNA.

“Other bodily fluids [urine, cerebrospinal fluid, and saliva], different nucleic acids and structures, altered mechanisms of release into circulation, or sample processing methods could exhibit varying fragment size signatures and could offer additional exploitable biological patterns for selective sequencing,” they wrote.

The study was supported by the University of Cambridge, Cancer Research UK, and the Engineering and Physical Sciences Research Council. Research supporting the study was also funded by the European Research Council, the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre, Hutchison Whampoa, Target Ovarian Cancer, the Medical Research Council, and AstraZeneca. Three authors are cofounders, shareholders, and officers/consultants in a company specializing in ctDNA analysis. One author declared research funding and advisory board fees from private industry. Seven authors are listed on related patents.

SOURCE: Mouliere F et al. Sci Transl Med. 2018 Nov 7. doi: 10.1126/scitranslmed.aat4921.
 

Circulating tumor DNA could be effectively isolated from plasma by focusing on a particular range of fragment sizes, which paves the way for noninvasive genomic analysis of tumor DNA, new research suggests.

In a study of 344 plasma samples from 200 patients with 18 cancer types and 65 samples from healthy controls, DNA fragment length could be used to distinguish circulating tumor DNA (ctDNA) from other cell-free DNA (cfDNA), investigators reported in Science Translational Medicine.

“We hypothesized that we could improve the sensitivity for noninvasive cancer genomics by selective sequencing of ctDNA fragments and by leveraging differences in the biology that determine DNA fragmentation,” wrote Florent Mouliere, PhD, from the Cancer Research UK Cambridge Institute, and coauthors.

Cell-free plasma fragments are often cleaved at around 167 base pairs in length and differences in length between circulating fetal and maternal DNA are already used for noninvasive prenatal diagnosis. However, the authors said that only a few studies, with conflicting results, have looked at the size distribution of tumor-derived cfDNA.

The study used two approaches to determining the size profile of mutant ctDNA. The first looked at tumor and nontumor cfDNA in mice with human ovarian cancer xenografts and the second approach used deep sequencing in 19 cancer patients. This revealed that tumor-derived cfDNA was most commonly found in fragments between 90-150 base pairs or 250-320 base pairs in size.

The researchers also noted that mutant circulating tumor DNA was generally more fragmented than nonmutant cfDNA and that patients with untreated advanced cancer showed consistently shorter lengths of mutant DNA.

The next question was whether size selection and other biological properties – such as somatic alterations – of the cfDNA could be used to enhance detection of ctDNA via machine learning technology.

Two models, designed to distinguish between healthy and cancerous samples, were developed using 153 samples, then validated on two datasets of 94 and 83 samples.

One of these models correctly classified cancerous samples in 94% of samples from patients with cancers known to have high levels of ctDNA – colorectal, cholangiocarcinoma, ovarian, breast, and melanoma – and in 65% of samples from low-ctDNA cancers – pancreatic, renal, and glioma.

Another model focused just on fragmentation patterns and was still able to distinguish cancer samples from those of healthy controls, although with slightly reduced area under the curve.

“Our results indicate that exploiting fundamental properties of cfDNA with fragment-specific analyses can allow more sensitive evaluation of ctDNA,” the authors wrote. “We identified features that could determine the presence and amount of ctDNA in plasma samples, without a prior knowledge of somatic aberrations.”

The authors pointed out that size selection of DNA fragments was relatively simple and cheap, and was also compatible with other genome-wide and targeted genomic analyses, “greatly increasing the potential value and utility of liquid biopsies as well as the cost-effectiveness of cfDNA sequencing.”

However, they cautioned that their catalogue had focused solely on double-stranded DNA and was subject to potential biases from the DNA extraction and sequencing methods they used in the study. They also commented that other biological effects could help refine the analysis of ctDNA.

“Other bodily fluids [urine, cerebrospinal fluid, and saliva], different nucleic acids and structures, altered mechanisms of release into circulation, or sample processing methods could exhibit varying fragment size signatures and could offer additional exploitable biological patterns for selective sequencing,” they wrote.

The study was supported by the University of Cambridge, Cancer Research UK, and the Engineering and Physical Sciences Research Council. Research supporting the study was also funded by the European Research Council, the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre, Hutchison Whampoa, Target Ovarian Cancer, the Medical Research Council, and AstraZeneca. Three authors are cofounders, shareholders, and officers/consultants in a company specializing in ctDNA analysis. One author declared research funding and advisory board fees from private industry. Seven authors are listed on related patents.

SOURCE: Mouliere F et al. Sci Transl Med. 2018 Nov 7. doi: 10.1126/scitranslmed.aat4921.
 

Circulating tumor DNA could be effectively isolated from plasma by focusing on a particular range of fragment sizes, which paves the way for noninvasive genomic analysis of tumor DNA, new research suggests.

In a study of 344 plasma samples from 200 patients with 18 cancer types and 65 samples from healthy controls, DNA fragment length could be used to distinguish circulating tumor DNA (ctDNA) from other cell-free DNA (cfDNA), investigators reported in Science Translational Medicine.

“We hypothesized that we could improve the sensitivity for noninvasive cancer genomics by selective sequencing of ctDNA fragments and by leveraging differences in the biology that determine DNA fragmentation,” wrote Florent Mouliere, PhD, from the Cancer Research UK Cambridge Institute, and coauthors.

Cell-free plasma fragments are often cleaved at around 167 base pairs in length and differences in length between circulating fetal and maternal DNA are already used for noninvasive prenatal diagnosis. However, the authors said that only a few studies, with conflicting results, have looked at the size distribution of tumor-derived cfDNA.

The study used two approaches to determining the size profile of mutant ctDNA. The first looked at tumor and nontumor cfDNA in mice with human ovarian cancer xenografts and the second approach used deep sequencing in 19 cancer patients. This revealed that tumor-derived cfDNA was most commonly found in fragments between 90-150 base pairs or 250-320 base pairs in size.

The researchers also noted that mutant circulating tumor DNA was generally more fragmented than nonmutant cfDNA and that patients with untreated advanced cancer showed consistently shorter lengths of mutant DNA.

The next question was whether size selection and other biological properties – such as somatic alterations – of the cfDNA could be used to enhance detection of ctDNA via machine learning technology.

Two models, designed to distinguish between healthy and cancerous samples, were developed using 153 samples, then validated on two datasets of 94 and 83 samples.

One of these models correctly classified cancerous samples in 94% of samples from patients with cancers known to have high levels of ctDNA – colorectal, cholangiocarcinoma, ovarian, breast, and melanoma – and in 65% of samples from low-ctDNA cancers – pancreatic, renal, and glioma.

Another model focused just on fragmentation patterns and was still able to distinguish cancer samples from those of healthy controls, although with slightly reduced area under the curve.

“Our results indicate that exploiting fundamental properties of cfDNA with fragment-specific analyses can allow more sensitive evaluation of ctDNA,” the authors wrote. “We identified features that could determine the presence and amount of ctDNA in plasma samples, without a prior knowledge of somatic aberrations.”

The authors pointed out that size selection of DNA fragments was relatively simple and cheap, and was also compatible with other genome-wide and targeted genomic analyses, “greatly increasing the potential value and utility of liquid biopsies as well as the cost-effectiveness of cfDNA sequencing.”

However, they cautioned that their catalogue had focused solely on double-stranded DNA and was subject to potential biases from the DNA extraction and sequencing methods they used in the study. They also commented that other biological effects could help refine the analysis of ctDNA.

“Other bodily fluids [urine, cerebrospinal fluid, and saliva], different nucleic acids and structures, altered mechanisms of release into circulation, or sample processing methods could exhibit varying fragment size signatures and could offer additional exploitable biological patterns for selective sequencing,” they wrote.

The study was supported by the University of Cambridge, Cancer Research UK, and the Engineering and Physical Sciences Research Council. Research supporting the study was also funded by the European Research Council, the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre, Hutchison Whampoa, Target Ovarian Cancer, the Medical Research Council, and AstraZeneca. Three authors are cofounders, shareholders, and officers/consultants in a company specializing in ctDNA analysis. One author declared research funding and advisory board fees from private industry. Seven authors are listed on related patents.

SOURCE: Mouliere F et al. Sci Transl Med. 2018 Nov 7. doi: 10.1126/scitranslmed.aat4921.
 

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

For previously untreated patients with BRAF wild-type advanced melanoma, the antiprogrammed death-ligand 1 agent nivolumab dramatically improved overall survival (OS), compared with standard first-line chemotherapy, according to new data from the CheckMate 066 trial.

At the 3-year follow-up, more than twice as many nivolumab-treated patients were alive, compared with those who received dacarbazine, reported lead author Paolo A. Ascierto, MD, director of the unit of melanoma, cancer immunotherapy, and innovative therapy at the Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy, and his colleagues. Longer median progression-free survival (PFS) and higher complete response rates were also reported.

“The results of this 3-year follow-up analysis provided evidence for a durable survival benefit with nivolumab monotherapy in patients with previously untreated BRAF wild-type advanced melanoma,” the investigators wrote in JAMA Oncology.

The double-blind, phase 3 trial involved 418 patients with unresectable, previously untreated stage III or IV melanoma not exhibiting a BRAF mutation. Patients were randomized to receive either nivolumab (n = 210; 3 mg/kg every 2 weeks plus placebo every 3 weeks) or dacarbazine (n = 208; 1,000 mg/m2 every 3 weeks plus placebo every 2 weeks). Treatment continued until unacceptable toxicity or disease progression occurred.

The results showed dramatic benefits, measured by OS and PFS, when patients were treated with nivolumab. The 3-year OS rate was 51.2% in the nivolumab group, compared with 21.6% in the dacarbazine group, an approximate 130% difference. Median OS and median PFS were also multiplied by the checkpoint inhibitor, showing 230% and 130% improvements, respectively (OS, 37.5 months vs. 11.2 months; PFS, 5.1 months vs. 2.2 months; P less than .001). Grade 3 or higher treatment-related adverse events (AEs) were comparable between treatment arms (nivolumab, 15.0% vs. dacarbazine, 17.6%).

“Responses to nivolumab were long lasting in many patients who discontinued treatment, with most patients who stopped treatment still alive and without disease progression at the time of the last assessment,” the investigators wrote.

“Collectively, our results showed durable responses and long-term survival with nivolumab monotherapy, with no new AEs developing at late time points,” they concluded.

The study was funded by Bristol-Myers Squibb. The authors reported financial relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, Amgen, and others.

SOURCE: Ascierto PA et al. JAMA Oncol. 2018 Oct 25. doi: 10.1001/jamaoncol.2018.4514.

For previously untreated patients with BRAF wild-type advanced melanoma, the antiprogrammed death-ligand 1 agent nivolumab dramatically improved overall survival (OS), compared with standard first-line chemotherapy, according to new data from the CheckMate 066 trial.

At the 3-year follow-up, more than twice as many nivolumab-treated patients were alive, compared with those who received dacarbazine, reported lead author Paolo A. Ascierto, MD, director of the unit of melanoma, cancer immunotherapy, and innovative therapy at the Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy, and his colleagues. Longer median progression-free survival (PFS) and higher complete response rates were also reported.

“The results of this 3-year follow-up analysis provided evidence for a durable survival benefit with nivolumab monotherapy in patients with previously untreated BRAF wild-type advanced melanoma,” the investigators wrote in JAMA Oncology.

The double-blind, phase 3 trial involved 418 patients with unresectable, previously untreated stage III or IV melanoma not exhibiting a BRAF mutation. Patients were randomized to receive either nivolumab (n = 210; 3 mg/kg every 2 weeks plus placebo every 3 weeks) or dacarbazine (n = 208; 1,000 mg/m2 every 3 weeks plus placebo every 2 weeks). Treatment continued until unacceptable toxicity or disease progression occurred.

The results showed dramatic benefits, measured by OS and PFS, when patients were treated with nivolumab. The 3-year OS rate was 51.2% in the nivolumab group, compared with 21.6% in the dacarbazine group, an approximate 130% difference. Median OS and median PFS were also multiplied by the checkpoint inhibitor, showing 230% and 130% improvements, respectively (OS, 37.5 months vs. 11.2 months; PFS, 5.1 months vs. 2.2 months; P less than .001). Grade 3 or higher treatment-related adverse events (AEs) were comparable between treatment arms (nivolumab, 15.0% vs. dacarbazine, 17.6%).

“Responses to nivolumab were long lasting in many patients who discontinued treatment, with most patients who stopped treatment still alive and without disease progression at the time of the last assessment,” the investigators wrote.

“Collectively, our results showed durable responses and long-term survival with nivolumab monotherapy, with no new AEs developing at late time points,” they concluded.

The study was funded by Bristol-Myers Squibb. The authors reported financial relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, Amgen, and others.

SOURCE: Ascierto PA et al. JAMA Oncol. 2018 Oct 25. doi: 10.1001/jamaoncol.2018.4514.

For previously untreated patients with BRAF wild-type advanced melanoma, the antiprogrammed death-ligand 1 agent nivolumab dramatically improved overall survival (OS), compared with standard first-line chemotherapy, according to new data from the CheckMate 066 trial.

At the 3-year follow-up, more than twice as many nivolumab-treated patients were alive, compared with those who received dacarbazine, reported lead author Paolo A. Ascierto, MD, director of the unit of melanoma, cancer immunotherapy, and innovative therapy at the Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy, and his colleagues. Longer median progression-free survival (PFS) and higher complete response rates were also reported.

“The results of this 3-year follow-up analysis provided evidence for a durable survival benefit with nivolumab monotherapy in patients with previously untreated BRAF wild-type advanced melanoma,” the investigators wrote in JAMA Oncology.

The double-blind, phase 3 trial involved 418 patients with unresectable, previously untreated stage III or IV melanoma not exhibiting a BRAF mutation. Patients were randomized to receive either nivolumab (n = 210; 3 mg/kg every 2 weeks plus placebo every 3 weeks) or dacarbazine (n = 208; 1,000 mg/m2 every 3 weeks plus placebo every 2 weeks). Treatment continued until unacceptable toxicity or disease progression occurred.

The results showed dramatic benefits, measured by OS and PFS, when patients were treated with nivolumab. The 3-year OS rate was 51.2% in the nivolumab group, compared with 21.6% in the dacarbazine group, an approximate 130% difference. Median OS and median PFS were also multiplied by the checkpoint inhibitor, showing 230% and 130% improvements, respectively (OS, 37.5 months vs. 11.2 months; PFS, 5.1 months vs. 2.2 months; P less than .001). Grade 3 or higher treatment-related adverse events (AEs) were comparable between treatment arms (nivolumab, 15.0% vs. dacarbazine, 17.6%).

“Responses to nivolumab were long lasting in many patients who discontinued treatment, with most patients who stopped treatment still alive and without disease progression at the time of the last assessment,” the investigators wrote.

“Collectively, our results showed durable responses and long-term survival with nivolumab monotherapy, with no new AEs developing at late time points,” they concluded.

The study was funded by Bristol-Myers Squibb. The authors reported financial relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, Amgen, and others.

SOURCE: Ascierto PA et al. JAMA Oncol. 2018 Oct 25. doi: 10.1001/jamaoncol.2018.4514.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.