Melanoma

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

sworcester@mdedge.com

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

sworcester@mdedge.com

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

sworcester@mdedge.com

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

If by now you have not had a patient ask, “Doctor, what sunscreen should I use NOW?” you will soon.

The US Food and Drug Administration (FDA) recently published a press release detailing a proposed rule on how manufacturers will be required to test and label sunscreens in the United States.^1,2 Although the press release was complicated and contained much information, the media specifically latched onto the FDA’s consideration of only 2 active sunscreen ingredients—zinc oxide and titanium dioxide—as generally recognized as safe and effective (GRASE). In response, some patients may assume that most sunscreens on the market are dangerous.

How did this new proposed rule come about? To understand the process, it takes some explanation of the history of the FDA’s regulation of sunscreens.

How are sunscreens regulated by the FDA?

The regulatory process for sunscreens in the United States is complicated. The FDA regulates sunscreens as over-the-counter (OTC) drugs rather than as cosmetics, which is how they are regulated in most of the rest of the world.

The US sunscreen regulation process began in 1978 with an advance notice of proposed rulemaking from the FDA that included recommendations from an advisory review panel on the safe and effective use of OTC sunscreen products.³ At that time, 21 active sunscreen ingredients and their maximum use concentrations were listed and determined to be safe, or GRASE. It also gave manufacturers guidance on how to test for efficacy with the methodology for determining the sun protection factor (SPF) as well as various labeling requirements. Over the years, the FDA has issued a number of other sunscreen guidelines, such as removing padimate A and adding avobenzone and zinc oxide to the list of GRASE ingredients in the 1990s.^4,5

In 1999, the FDA issued a final rule that listed 16 active sunscreen ingredients and concentrations as GRASE.⁶ There were some restrictions as to certain combinations of ingredients that could not be used in a finished product. Labeling requirements, including a maximum SPF of 30, also were put in place. This final rule established a final sunscreen monograph that was supposed to have been effective by 2002; however, in 2001 the agency delayed the effective date indefinitely because they had not yet established broad-spectrum (UVA) protection testing and labeling.⁷

The FDA published a proposed rule in 2007 as well as a final rule in 2011 that again listed the same 16 ingredients as GRASE and specified labeling and testing methods for establishing SPF, broad-spectrum protection, and water-resistance claims.^8,9 The final rule limited product labels to a maximum SPF of 50+; provided directions for use with regard to other labeling elements (eg, warnings); and identified specific claims that would not be allowed on product labels, such as “waterproof” and “all-day protection.”⁹

Nevertheless, an effective final OTC monograph for sunscreen products has not yet been published.

What is the Sunscreen Innovation Act?

In 2014, the US Congress enacted the Sunscreen Innovation Act¹⁰ primarily to mandate that the FDA develop a more efficient way to determine the safety and efficacy of new active sunscreen ingredients that were commonly used in Europe and other parts of the world at the time. Many of these agents were thought to be more protective in the UVA and/or UVB spectrum, and if added to the list of GRASE ingredients available to US manufacturers, they would lead to the development of products that would improve the protection offered by sunscreens marketed to US consumers. The time and extent application (TEA) was established, a method that allowed manufacturers to apply for FDA approval of specific agents. The TEA also suggested allowing data generated in other countries where these agents were already in use for years to be considered in the FDA’s evaluation of the agents as GRASE. In addition, Congress mandated that a final monograph on OTC sunscreens be published by the end of 2019. A number of manufacturers have submitted TEAs for new active sunscreen ingredients, and so far, all have been rejected.

Why is the FDA interested in more safety data?

Since then, the FDA has become concerned not only with the safety and efficacy of newly proposed agents through the TEA but also with the original 16 active sunscreen ingredients listed as GRASE in the 2011 final rule. In the 1970s and 1980s, sunscreen use was limited to beach vacations or outdoor sporting events, but sun-protective behaviors have changed dramatically since that time, with health care providers now becoming cognizant of the growing threats of skin cancer and melanoma as well as the cosmetic concerns of photoaging, thereby recommending daily sunscreen use to their patients. In addition, the science behind sunscreens with higher concentrations of active ingredients intended to achieve higher and higher SPFs and their respective penetration of the skin has evolved, leading to new concerns about systemic toxicity. Early limited research frequently touted by the lay media has suggested that some of these agents might lead to hormonal changes, reproductive toxicity, and carcinogenicity.

In November 2016, the FDA issued a guidance for manufacturers that outlined the safety data that would be required to establish an OTC sunscreen active ingredient as GRASE.¹¹ It also provided detailed information about both clinical and nonclinical safety testing, including human irritation and sensitization studies as well as human photosafety studies. In vitro dermal and systemic carcinogenicity studies and animal developmental and reproductive toxicity studies also were required as well studies regarding safety in children.

Many of these recommendations were already being utilized by manufacturers; however, one important change was the requirement for human absorption studies by a maximal usage trial, which more accurately addresses the absorption of sunscreen agents according to actual use. Such studies will be required at the highest allowable concentration of an agent in multiple vehicles and over large body surface areas for considerable exposure times.

This guidance to sunscreen manufacturers was announced to the public in a press release in May 2018.¹²

What are the new regulations?

All of this has culminated in the recent proposed rule, which includes several important proposals²:

• Of the 16 currently marketed active sunscreen ingredients, only 2—zinc oxide and titanium dioxide—are considered GRASE. Two ingredients—trolamine salicylate and para-aminobenzoic acid—are considered non-GRASE, but there is not enough information at this time to determine if the remaining 12 ingredients are GRASE. The FDA is working with manufacturers to obtain sufficient information to make this determination.

• Approved dosage formulations include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. Further information is needed regarding powders before they can be considered.

• The maximum SPF will be increased from 50+ to 60+.

• Sunscreens with an SPF of 15 or higher are required to provide broad-spectrum protection commensurate with the SPF, expanding on critical wavelength testing.

• There are new labeling changes, including a requirement that active ingredients be listed on the front of the packaging.
• Sunscreen products that contain insect repellents are considered non-GRASE.

What’s next?

The process for the proposed final rule has now entered a 90-day public comment period that will end on May 27, 2019; however, it is unlikely that a final monograph as mandated by Congress will be produced by the end of this year.

Sunscreen manufacturers currently are coordinating a response to the proposed rule through the Personal Care Products Council and the Consumer Healthcare Products Association Sunscreen Task Force. It is likely that the new required testing will be costly, with estimates exceeding tens or even hundreds of millions of dollars. In all likelihood, the number of active ingredients that the industry will agree to support with costly testing will be fewer than the 12 that are now on the list. It also is likely that this process will lead to fewer sunscreen products for consumers to choose from and almost certainly at a higher cost.

What do we tell patients in the meantime?

According to the FDA’s rules, it was necessary that this process was made public, but it will almost certainly concern our patients as to the safety of the sunscreen products they have been using. We should be concerned that some of our patients may limit their use of sunscreens because of safety concerns.

There is no question that, as physicians, we want to “first, do no harm,” so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data. The good news is that when this process is completed, a large number of agents will likely be found to be GRASE. When the FDA finally gives its imprimatur to sunscreens, it will hopefully help to silence those naysayers who report that sunscreens are dangerous for consumers; however, it has been suggested by some in industry that the new testing required may take at least 5 years.

What should dermatologists do when we are asked, “What sunscreen should I use NOW?” For most patients, I would explain the regulatory process and assure them that the risk-benefit ratio at this point suggests they should continue using the same sunscreens that they are currently using. For special situations such as pregnant women and children, it may be best to suggest products that contain only the 2 GRASE inorganic agents.

If by now you have not had a patient ask, “Doctor, what sunscreen should I use NOW?” you will soon.

The US Food and Drug Administration (FDA) recently published a press release detailing a proposed rule on how manufacturers will be required to test and label sunscreens in the United States.^1,2 Although the press release was complicated and contained much information, the media specifically latched onto the FDA’s consideration of only 2 active sunscreen ingredients—zinc oxide and titanium dioxide—as generally recognized as safe and effective (GRASE). In response, some patients may assume that most sunscreens on the market are dangerous.

How did this new proposed rule come about? To understand the process, it takes some explanation of the history of the FDA’s regulation of sunscreens.

How are sunscreens regulated by the FDA?

The regulatory process for sunscreens in the United States is complicated. The FDA regulates sunscreens as over-the-counter (OTC) drugs rather than as cosmetics, which is how they are regulated in most of the rest of the world.

The US sunscreen regulation process began in 1978 with an advance notice of proposed rulemaking from the FDA that included recommendations from an advisory review panel on the safe and effective use of OTC sunscreen products.³ At that time, 21 active sunscreen ingredients and their maximum use concentrations were listed and determined to be safe, or GRASE. It also gave manufacturers guidance on how to test for efficacy with the methodology for determining the sun protection factor (SPF) as well as various labeling requirements. Over the years, the FDA has issued a number of other sunscreen guidelines, such as removing padimate A and adding avobenzone and zinc oxide to the list of GRASE ingredients in the 1990s.^4,5

In 1999, the FDA issued a final rule that listed 16 active sunscreen ingredients and concentrations as GRASE.⁶ There were some restrictions as to certain combinations of ingredients that could not be used in a finished product. Labeling requirements, including a maximum SPF of 30, also were put in place. This final rule established a final sunscreen monograph that was supposed to have been effective by 2002; however, in 2001 the agency delayed the effective date indefinitely because they had not yet established broad-spectrum (UVA) protection testing and labeling.⁷

The FDA published a proposed rule in 2007 as well as a final rule in 2011 that again listed the same 16 ingredients as GRASE and specified labeling and testing methods for establishing SPF, broad-spectrum protection, and water-resistance claims.^8,9 The final rule limited product labels to a maximum SPF of 50+; provided directions for use with regard to other labeling elements (eg, warnings); and identified specific claims that would not be allowed on product labels, such as “waterproof” and “all-day protection.”⁹

Nevertheless, an effective final OTC monograph for sunscreen products has not yet been published.

What is the Sunscreen Innovation Act?

In 2014, the US Congress enacted the Sunscreen Innovation Act¹⁰ primarily to mandate that the FDA develop a more efficient way to determine the safety and efficacy of new active sunscreen ingredients that were commonly used in Europe and other parts of the world at the time. Many of these agents were thought to be more protective in the UVA and/or UVB spectrum, and if added to the list of GRASE ingredients available to US manufacturers, they would lead to the development of products that would improve the protection offered by sunscreens marketed to US consumers. The time and extent application (TEA) was established, a method that allowed manufacturers to apply for FDA approval of specific agents. The TEA also suggested allowing data generated in other countries where these agents were already in use for years to be considered in the FDA’s evaluation of the agents as GRASE. In addition, Congress mandated that a final monograph on OTC sunscreens be published by the end of 2019. A number of manufacturers have submitted TEAs for new active sunscreen ingredients, and so far, all have been rejected.

Why is the FDA interested in more safety data?

Since then, the FDA has become concerned not only with the safety and efficacy of newly proposed agents through the TEA but also with the original 16 active sunscreen ingredients listed as GRASE in the 2011 final rule. In the 1970s and 1980s, sunscreen use was limited to beach vacations or outdoor sporting events, but sun-protective behaviors have changed dramatically since that time, with health care providers now becoming cognizant of the growing threats of skin cancer and melanoma as well as the cosmetic concerns of photoaging, thereby recommending daily sunscreen use to their patients. In addition, the science behind sunscreens with higher concentrations of active ingredients intended to achieve higher and higher SPFs and their respective penetration of the skin has evolved, leading to new concerns about systemic toxicity. Early limited research frequently touted by the lay media has suggested that some of these agents might lead to hormonal changes, reproductive toxicity, and carcinogenicity.

In November 2016, the FDA issued a guidance for manufacturers that outlined the safety data that would be required to establish an OTC sunscreen active ingredient as GRASE.¹¹ It also provided detailed information about both clinical and nonclinical safety testing, including human irritation and sensitization studies as well as human photosafety studies. In vitro dermal and systemic carcinogenicity studies and animal developmental and reproductive toxicity studies also were required as well studies regarding safety in children.

Many of these recommendations were already being utilized by manufacturers; however, one important change was the requirement for human absorption studies by a maximal usage trial, which more accurately addresses the absorption of sunscreen agents according to actual use. Such studies will be required at the highest allowable concentration of an agent in multiple vehicles and over large body surface areas for considerable exposure times.

This guidance to sunscreen manufacturers was announced to the public in a press release in May 2018.¹²

What are the new regulations?

All of this has culminated in the recent proposed rule, which includes several important proposals²:

• Of the 16 currently marketed active sunscreen ingredients, only 2—zinc oxide and titanium dioxide—are considered GRASE. Two ingredients—trolamine salicylate and para-aminobenzoic acid—are considered non-GRASE, but there is not enough information at this time to determine if the remaining 12 ingredients are GRASE. The FDA is working with manufacturers to obtain sufficient information to make this determination.

• Approved dosage formulations include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. Further information is needed regarding powders before they can be considered.

• The maximum SPF will be increased from 50+ to 60+.

• Sunscreens with an SPF of 15 or higher are required to provide broad-spectrum protection commensurate with the SPF, expanding on critical wavelength testing.

• There are new labeling changes, including a requirement that active ingredients be listed on the front of the packaging.
• Sunscreen products that contain insect repellents are considered non-GRASE.

What’s next?

The process for the proposed final rule has now entered a 90-day public comment period that will end on May 27, 2019; however, it is unlikely that a final monograph as mandated by Congress will be produced by the end of this year.

Sunscreen manufacturers currently are coordinating a response to the proposed rule through the Personal Care Products Council and the Consumer Healthcare Products Association Sunscreen Task Force. It is likely that the new required testing will be costly, with estimates exceeding tens or even hundreds of millions of dollars. In all likelihood, the number of active ingredients that the industry will agree to support with costly testing will be fewer than the 12 that are now on the list. It also is likely that this process will lead to fewer sunscreen products for consumers to choose from and almost certainly at a higher cost.

What do we tell patients in the meantime?

According to the FDA’s rules, it was necessary that this process was made public, but it will almost certainly concern our patients as to the safety of the sunscreen products they have been using. We should be concerned that some of our patients may limit their use of sunscreens because of safety concerns.

There is no question that, as physicians, we want to “first, do no harm,” so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data. The good news is that when this process is completed, a large number of agents will likely be found to be GRASE. When the FDA finally gives its imprimatur to sunscreens, it will hopefully help to silence those naysayers who report that sunscreens are dangerous for consumers; however, it has been suggested by some in industry that the new testing required may take at least 5 years.

What should dermatologists do when we are asked, “What sunscreen should I use NOW?” For most patients, I would explain the regulatory process and assure them that the risk-benefit ratio at this point suggests they should continue using the same sunscreens that they are currently using. For special situations such as pregnant women and children, it may be best to suggest products that contain only the 2 GRASE inorganic agents.

If by now you have not had a patient ask, “Doctor, what sunscreen should I use NOW?” you will soon.

The US Food and Drug Administration (FDA) recently published a press release detailing a proposed rule on how manufacturers will be required to test and label sunscreens in the United States.^1,2 Although the press release was complicated and contained much information, the media specifically latched onto the FDA’s consideration of only 2 active sunscreen ingredients—zinc oxide and titanium dioxide—as generally recognized as safe and effective (GRASE). In response, some patients may assume that most sunscreens on the market are dangerous.

How did this new proposed rule come about? To understand the process, it takes some explanation of the history of the FDA’s regulation of sunscreens.

How are sunscreens regulated by the FDA?

The regulatory process for sunscreens in the United States is complicated. The FDA regulates sunscreens as over-the-counter (OTC) drugs rather than as cosmetics, which is how they are regulated in most of the rest of the world.

The US sunscreen regulation process began in 1978 with an advance notice of proposed rulemaking from the FDA that included recommendations from an advisory review panel on the safe and effective use of OTC sunscreen products.³ At that time, 21 active sunscreen ingredients and their maximum use concentrations were listed and determined to be safe, or GRASE. It also gave manufacturers guidance on how to test for efficacy with the methodology for determining the sun protection factor (SPF) as well as various labeling requirements. Over the years, the FDA has issued a number of other sunscreen guidelines, such as removing padimate A and adding avobenzone and zinc oxide to the list of GRASE ingredients in the 1990s.^4,5

In 1999, the FDA issued a final rule that listed 16 active sunscreen ingredients and concentrations as GRASE.⁶ There were some restrictions as to certain combinations of ingredients that could not be used in a finished product. Labeling requirements, including a maximum SPF of 30, also were put in place. This final rule established a final sunscreen monograph that was supposed to have been effective by 2002; however, in 2001 the agency delayed the effective date indefinitely because they had not yet established broad-spectrum (UVA) protection testing and labeling.⁷

The FDA published a proposed rule in 2007 as well as a final rule in 2011 that again listed the same 16 ingredients as GRASE and specified labeling and testing methods for establishing SPF, broad-spectrum protection, and water-resistance claims.^8,9 The final rule limited product labels to a maximum SPF of 50+; provided directions for use with regard to other labeling elements (eg, warnings); and identified specific claims that would not be allowed on product labels, such as “waterproof” and “all-day protection.”⁹

Nevertheless, an effective final OTC monograph for sunscreen products has not yet been published.

What is the Sunscreen Innovation Act?

In 2014, the US Congress enacted the Sunscreen Innovation Act¹⁰ primarily to mandate that the FDA develop a more efficient way to determine the safety and efficacy of new active sunscreen ingredients that were commonly used in Europe and other parts of the world at the time. Many of these agents were thought to be more protective in the UVA and/or UVB spectrum, and if added to the list of GRASE ingredients available to US manufacturers, they would lead to the development of products that would improve the protection offered by sunscreens marketed to US consumers. The time and extent application (TEA) was established, a method that allowed manufacturers to apply for FDA approval of specific agents. The TEA also suggested allowing data generated in other countries where these agents were already in use for years to be considered in the FDA’s evaluation of the agents as GRASE. In addition, Congress mandated that a final monograph on OTC sunscreens be published by the end of 2019. A number of manufacturers have submitted TEAs for new active sunscreen ingredients, and so far, all have been rejected.

Why is the FDA interested in more safety data?

Since then, the FDA has become concerned not only with the safety and efficacy of newly proposed agents through the TEA but also with the original 16 active sunscreen ingredients listed as GRASE in the 2011 final rule. In the 1970s and 1980s, sunscreen use was limited to beach vacations or outdoor sporting events, but sun-protective behaviors have changed dramatically since that time, with health care providers now becoming cognizant of the growing threats of skin cancer and melanoma as well as the cosmetic concerns of photoaging, thereby recommending daily sunscreen use to their patients. In addition, the science behind sunscreens with higher concentrations of active ingredients intended to achieve higher and higher SPFs and their respective penetration of the skin has evolved, leading to new concerns about systemic toxicity. Early limited research frequently touted by the lay media has suggested that some of these agents might lead to hormonal changes, reproductive toxicity, and carcinogenicity.

In November 2016, the FDA issued a guidance for manufacturers that outlined the safety data that would be required to establish an OTC sunscreen active ingredient as GRASE.¹¹ It also provided detailed information about both clinical and nonclinical safety testing, including human irritation and sensitization studies as well as human photosafety studies. In vitro dermal and systemic carcinogenicity studies and animal developmental and reproductive toxicity studies also were required as well studies regarding safety in children.

Many of these recommendations were already being utilized by manufacturers; however, one important change was the requirement for human absorption studies by a maximal usage trial, which more accurately addresses the absorption of sunscreen agents according to actual use. Such studies will be required at the highest allowable concentration of an agent in multiple vehicles and over large body surface areas for considerable exposure times.

This guidance to sunscreen manufacturers was announced to the public in a press release in May 2018.¹²

What are the new regulations?

All of this has culminated in the recent proposed rule, which includes several important proposals²:

• Of the 16 currently marketed active sunscreen ingredients, only 2—zinc oxide and titanium dioxide—are considered GRASE. Two ingredients—trolamine salicylate and para-aminobenzoic acid—are considered non-GRASE, but there is not enough information at this time to determine if the remaining 12 ingredients are GRASE. The FDA is working with manufacturers to obtain sufficient information to make this determination.

• Approved dosage formulations include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. Further information is needed regarding powders before they can be considered.

• The maximum SPF will be increased from 50+ to 60+.

• Sunscreens with an SPF of 15 or higher are required to provide broad-spectrum protection commensurate with the SPF, expanding on critical wavelength testing.

• There are new labeling changes, including a requirement that active ingredients be listed on the front of the packaging.
• Sunscreen products that contain insect repellents are considered non-GRASE.

What’s next?

The process for the proposed final rule has now entered a 90-day public comment period that will end on May 27, 2019; however, it is unlikely that a final monograph as mandated by Congress will be produced by the end of this year.

Sunscreen manufacturers currently are coordinating a response to the proposed rule through the Personal Care Products Council and the Consumer Healthcare Products Association Sunscreen Task Force. It is likely that the new required testing will be costly, with estimates exceeding tens or even hundreds of millions of dollars. In all likelihood, the number of active ingredients that the industry will agree to support with costly testing will be fewer than the 12 that are now on the list. It also is likely that this process will lead to fewer sunscreen products for consumers to choose from and almost certainly at a higher cost.

What do we tell patients in the meantime?

According to the FDA’s rules, it was necessary that this process was made public, but it will almost certainly concern our patients as to the safety of the sunscreen products they have been using. We should be concerned that some of our patients may limit their use of sunscreens because of safety concerns.

There is no question that, as physicians, we want to “first, do no harm,” so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data. The good news is that when this process is completed, a large number of agents will likely be found to be GRASE. When the FDA finally gives its imprimatur to sunscreens, it will hopefully help to silence those naysayers who report that sunscreens are dangerous for consumers; however, it has been suggested by some in industry that the new testing required may take at least 5 years.

What should dermatologists do when we are asked, “What sunscreen should I use NOW?” For most patients, I would explain the regulatory process and assure them that the risk-benefit ratio at this point suggests they should continue using the same sunscreens that they are currently using. For special situations such as pregnant women and children, it may be best to suggest products that contain only the 2 GRASE inorganic agents.

WAIKOLOA, HAWAII – The widely utilized 5-mm surgical margins for excision of melanoma in situ are inadequate in many cases, Christopher B. Zachary, MD, said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

“You probably should be considering more like 9- or 10-mm margins for melanoma in situ,” advised Dr. Zachary, professor and chair of the department of dermatology at the University of California, Irvine.

This has been a controversial matter. The recommendation for the long-standard 5-mm margins for excision of melanoma in situ (MIS) date back to a 1992 consensus opinion. Since then, however, persuasive data have emerged showing that 5-mm margins are often inadequate for clearance, and the latest American Academy of Dermatology guidelines for the management of primary cutaneous melanoma recommend margins of 5-10 mm (J Am Acad Dermatol. 2019 Jan;80[1]:208-50).


Dr. Zachary’s advice to go on the high side of that 5- to 10-mm zone is based in large part on studies led by John A Zitelli, MD, of the University of Pittsburgh. More than 20 years ago, Dr. Zitelli and his coinvestigators published a provocative prospective series of 535 patients whose melanomas – in situ or invasive – were excised via Mohs micrographic surgery with frozen section examination of the margins. A 9-mm margin successfully removed 95% of the melanomas, a 12-mm margin removed 97%, and a 6-mm margin successfully excised only 83% of the lesions (J Am Acad Dermatol. 1997 Sep;37(3 Pt 1):422-9).

In a follow-up study, Dr. Zitelli and his colleagues reported on a prospective series of 1,072 patients with 1,120 MIS, all excised by Mohs micrographic surgery with frozen sections (J Am Acad Dermatol. 2012 Mar;66[3]:438-44). They determined that 86% of the MIS were completely cleared using a 6-mm margin, compared with 98.9% excised with a 9 mm margin, a statistically significant difference (P less than .001).

Support for Dr. Zitelli’s stance that 5-mm margins for MIS are inadequate was provided by dermatologic surgeons at the Mayo Clinic in Scottsdale, Ariz. Of 46 patients who underwent Mohs micrographic surgery with immunostaining for excision of MIS, margins of 6 mm achieved clearance in only half of them. Surgical excision margins of 15 mm were required to successfully clear 96% of the MIS (Dermatol Surg. 2000 Aug;26[8]:771-84).

Quite a few hands shot up when Dr. Zachary asked how many members of his audience utilize 5-mm margins for surgical excision of MIS.

“That had been my practice as well until quite recently,” he said.

Dr. Zachary reported having no financial conflicts of interest regarding his presentation.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com

WAIKOLOA, HAWAII – The widely utilized 5-mm surgical margins for excision of melanoma in situ are inadequate in many cases, Christopher B. Zachary, MD, said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

“You probably should be considering more like 9- or 10-mm margins for melanoma in situ,” advised Dr. Zachary, professor and chair of the department of dermatology at the University of California, Irvine.

This has been a controversial matter. The recommendation for the long-standard 5-mm margins for excision of melanoma in situ (MIS) date back to a 1992 consensus opinion. Since then, however, persuasive data have emerged showing that 5-mm margins are often inadequate for clearance, and the latest American Academy of Dermatology guidelines for the management of primary cutaneous melanoma recommend margins of 5-10 mm (J Am Acad Dermatol. 2019 Jan;80[1]:208-50).


Dr. Zachary’s advice to go on the high side of that 5- to 10-mm zone is based in large part on studies led by John A Zitelli, MD, of the University of Pittsburgh. More than 20 years ago, Dr. Zitelli and his coinvestigators published a provocative prospective series of 535 patients whose melanomas – in situ or invasive – were excised via Mohs micrographic surgery with frozen section examination of the margins. A 9-mm margin successfully removed 95% of the melanomas, a 12-mm margin removed 97%, and a 6-mm margin successfully excised only 83% of the lesions (J Am Acad Dermatol. 1997 Sep;37(3 Pt 1):422-9).

In a follow-up study, Dr. Zitelli and his colleagues reported on a prospective series of 1,072 patients with 1,120 MIS, all excised by Mohs micrographic surgery with frozen sections (J Am Acad Dermatol. 2012 Mar;66[3]:438-44). They determined that 86% of the MIS were completely cleared using a 6-mm margin, compared with 98.9% excised with a 9 mm margin, a statistically significant difference (P less than .001).

Support for Dr. Zitelli’s stance that 5-mm margins for MIS are inadequate was provided by dermatologic surgeons at the Mayo Clinic in Scottsdale, Ariz. Of 46 patients who underwent Mohs micrographic surgery with immunostaining for excision of MIS, margins of 6 mm achieved clearance in only half of them. Surgical excision margins of 15 mm were required to successfully clear 96% of the MIS (Dermatol Surg. 2000 Aug;26[8]:771-84).

Quite a few hands shot up when Dr. Zachary asked how many members of his audience utilize 5-mm margins for surgical excision of MIS.

“That had been my practice as well until quite recently,” he said.

Dr. Zachary reported having no financial conflicts of interest regarding his presentation.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com

WAIKOLOA, HAWAII – The widely utilized 5-mm surgical margins for excision of melanoma in situ are inadequate in many cases, Christopher B. Zachary, MD, said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

“You probably should be considering more like 9- or 10-mm margins for melanoma in situ,” advised Dr. Zachary, professor and chair of the department of dermatology at the University of California, Irvine.

This has been a controversial matter. The recommendation for the long-standard 5-mm margins for excision of melanoma in situ (MIS) date back to a 1992 consensus opinion. Since then, however, persuasive data have emerged showing that 5-mm margins are often inadequate for clearance, and the latest American Academy of Dermatology guidelines for the management of primary cutaneous melanoma recommend margins of 5-10 mm (J Am Acad Dermatol. 2019 Jan;80[1]:208-50).


Dr. Zachary’s advice to go on the high side of that 5- to 10-mm zone is based in large part on studies led by John A Zitelli, MD, of the University of Pittsburgh. More than 20 years ago, Dr. Zitelli and his coinvestigators published a provocative prospective series of 535 patients whose melanomas – in situ or invasive – were excised via Mohs micrographic surgery with frozen section examination of the margins. A 9-mm margin successfully removed 95% of the melanomas, a 12-mm margin removed 97%, and a 6-mm margin successfully excised only 83% of the lesions (J Am Acad Dermatol. 1997 Sep;37(3 Pt 1):422-9).

In a follow-up study, Dr. Zitelli and his colleagues reported on a prospective series of 1,072 patients with 1,120 MIS, all excised by Mohs micrographic surgery with frozen sections (J Am Acad Dermatol. 2012 Mar;66[3]:438-44). They determined that 86% of the MIS were completely cleared using a 6-mm margin, compared with 98.9% excised with a 9 mm margin, a statistically significant difference (P less than .001).

Support for Dr. Zitelli’s stance that 5-mm margins for MIS are inadequate was provided by dermatologic surgeons at the Mayo Clinic in Scottsdale, Ariz. Of 46 patients who underwent Mohs micrographic surgery with immunostaining for excision of MIS, margins of 6 mm achieved clearance in only half of them. Surgical excision margins of 15 mm were required to successfully clear 96% of the MIS (Dermatol Surg. 2000 Aug;26[8]:771-84).

Quite a few hands shot up when Dr. Zachary asked how many members of his audience utilize 5-mm margins for surgical excision of MIS.

“That had been my practice as well until quite recently,” he said.

Dr. Zachary reported having no financial conflicts of interest regarding his presentation.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com

WASHINGTON – Psoriasis induced by tumor necrosis factor (TNF) therapy is among the treatment-associated effects that involve the skin in patients with inflammatory bowel disease (IBD), Sophia Delano, MD, said during a session on the cutaneous effects of IBD at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

This is a paradoxical reaction, which can happen “weeks to years after starting a TNF blocker,” with about 70% of cases occurring during the first year of therapy, said Dr. Delano, an attending physician in the dermatology program at Boston Children’s Hospital.

Those receiving infliximab are more likely to develop TNF inhibitor–induced psoriasis, compared with those on adalimumab or etanercept. TNF inhibitor–induced psoriasis may not track with gastrointestinal activity, and some patients whose gastrointestinal disease is responding to treatment can begin to develop psoriasis, she noted.

The clinical presentation of TNF inhibitor–induced psoriasis can also vary. In one study of 216 cases, 26.9% of patients had a mixed morphology, with the most common presentations including plaque psoriasis (44.8%) and palmoplantar pustular psoriasis (36.3%). Other presentations were psoriasiform dermatitis (19.9%), scalp involvement with alopecia (7.5%), and generalized pustular psoriasis (10.9%). Locations affected were the soles of the feet (45.8%), extremities (45.4%), palms (44.9%), scalp (36.1%), and trunk (32.4%), Dr. Delano said.


TNF inhibitor–induced psoriasis is likely a class effect, she said, noting that, in the same review, symptoms resolved in 47.7% of patients who discontinued TNF inhibitors, in 36.7% of patients who switched to another TNF inhibitor, and in 32.9% of patients who continued their original therapy (J Am Acad Dermatol. 2017 Feb;76[2]:334-41). In the study, Crohn’s disease and RA were the most common diseases, in 40.7% and 37.0% of the patients, respectively.

There have been case reports of TNF antagonist–induced lupus-like syndrome (TAILS), which is more common in patients with RA and ulcerative colitis. TAILS occurs more often in women than in men; can present similarly to systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus; and resolves by stopping TNF inhibitor treatment, Dr. Delano said.

Skin cancer risk, infections, and injection site reactions

Both adult and pediatric patients treated with TNF inhibitors for IBD may be at increased risk for lymphoma, visceral tumors, melanoma, and nonmelanoma skin cancers. Dr. Delano referred to a study published in 2014, which identified 972 reports of melanoma in the Food and Drug Administration’s Adverse Event Reporting System database associated with TNF inhibitor use; of these, 69 cases involved patients using more than one TNF inhibitor. Infliximab, golimumab, etanercept, and adalimumab were associated with a safety signal for melanoma, but not certolizumab (Br J Dermatol. 2014 May;170[5]:1170-2).

Dr. Delano observed that thiopurines such as azathioprine are also associated with an increased cancer risk, as noted in one retrospective study that found that the risk of nonmelanoma skin cancer was 2.1 times higher in a mostly white male cohort with ulcerative colitis during treatment with thiopurines, compared with patients not treated with thiopurines (Am J Gastroenterol. 2014 Nov;109[11]:1781-93). A greater duration of treatment (more than 6 months) and higher doses were associated with higher risks.

Adalimumab, golimumab, and certolizumab can also cause injection site reactions, typically within 1- 2 days of injection, said Dr. Delano. In these cases, symptoms of erythema, warmth, burning, or pruritus are worse at the beginning of treatment and can be relieved by rotating the injection site as well as providing cool compresses, topical steroids, antihistamines, and supportive care.

“If you have a patient with a worsening reaction, consider it may represent the type 1 IgE-related hypersensitivity requiring desensitization to continue that systemic,” she noted.

Cutaneous bacterial, fungal, and viral infections such as molluscum contagiosum, verruca vulgaris, herpes simplex, and varicella zoster can occur as a result of TNF inhibition as well, and can be difficult to clear because of immunosuppression, she added.

Dr. Delano reported no relevant conflicts of interest.

WASHINGTON – Psoriasis induced by tumor necrosis factor (TNF) therapy is among the treatment-associated effects that involve the skin in patients with inflammatory bowel disease (IBD), Sophia Delano, MD, said during a session on the cutaneous effects of IBD at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

This is a paradoxical reaction, which can happen “weeks to years after starting a TNF blocker,” with about 70% of cases occurring during the first year of therapy, said Dr. Delano, an attending physician in the dermatology program at Boston Children’s Hospital.

Those receiving infliximab are more likely to develop TNF inhibitor–induced psoriasis, compared with those on adalimumab or etanercept. TNF inhibitor–induced psoriasis may not track with gastrointestinal activity, and some patients whose gastrointestinal disease is responding to treatment can begin to develop psoriasis, she noted.

The clinical presentation of TNF inhibitor–induced psoriasis can also vary. In one study of 216 cases, 26.9% of patients had a mixed morphology, with the most common presentations including plaque psoriasis (44.8%) and palmoplantar pustular psoriasis (36.3%). Other presentations were psoriasiform dermatitis (19.9%), scalp involvement with alopecia (7.5%), and generalized pustular psoriasis (10.9%). Locations affected were the soles of the feet (45.8%), extremities (45.4%), palms (44.9%), scalp (36.1%), and trunk (32.4%), Dr. Delano said.


TNF inhibitor–induced psoriasis is likely a class effect, she said, noting that, in the same review, symptoms resolved in 47.7% of patients who discontinued TNF inhibitors, in 36.7% of patients who switched to another TNF inhibitor, and in 32.9% of patients who continued their original therapy (J Am Acad Dermatol. 2017 Feb;76[2]:334-41). In the study, Crohn’s disease and RA were the most common diseases, in 40.7% and 37.0% of the patients, respectively.

There have been case reports of TNF antagonist–induced lupus-like syndrome (TAILS), which is more common in patients with RA and ulcerative colitis. TAILS occurs more often in women than in men; can present similarly to systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus; and resolves by stopping TNF inhibitor treatment, Dr. Delano said.

Skin cancer risk, infections, and injection site reactions

Both adult and pediatric patients treated with TNF inhibitors for IBD may be at increased risk for lymphoma, visceral tumors, melanoma, and nonmelanoma skin cancers. Dr. Delano referred to a study published in 2014, which identified 972 reports of melanoma in the Food and Drug Administration’s Adverse Event Reporting System database associated with TNF inhibitor use; of these, 69 cases involved patients using more than one TNF inhibitor. Infliximab, golimumab, etanercept, and adalimumab were associated with a safety signal for melanoma, but not certolizumab (Br J Dermatol. 2014 May;170[5]:1170-2).

Dr. Delano observed that thiopurines such as azathioprine are also associated with an increased cancer risk, as noted in one retrospective study that found that the risk of nonmelanoma skin cancer was 2.1 times higher in a mostly white male cohort with ulcerative colitis during treatment with thiopurines, compared with patients not treated with thiopurines (Am J Gastroenterol. 2014 Nov;109[11]:1781-93). A greater duration of treatment (more than 6 months) and higher doses were associated with higher risks.

Adalimumab, golimumab, and certolizumab can also cause injection site reactions, typically within 1- 2 days of injection, said Dr. Delano. In these cases, symptoms of erythema, warmth, burning, or pruritus are worse at the beginning of treatment and can be relieved by rotating the injection site as well as providing cool compresses, topical steroids, antihistamines, and supportive care.

“If you have a patient with a worsening reaction, consider it may represent the type 1 IgE-related hypersensitivity requiring desensitization to continue that systemic,” she noted.

Cutaneous bacterial, fungal, and viral infections such as molluscum contagiosum, verruca vulgaris, herpes simplex, and varicella zoster can occur as a result of TNF inhibition as well, and can be difficult to clear because of immunosuppression, she added.

Dr. Delano reported no relevant conflicts of interest.

WASHINGTON – Psoriasis induced by tumor necrosis factor (TNF) therapy is among the treatment-associated effects that involve the skin in patients with inflammatory bowel disease (IBD), Sophia Delano, MD, said during a session on the cutaneous effects of IBD at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

This is a paradoxical reaction, which can happen “weeks to years after starting a TNF blocker,” with about 70% of cases occurring during the first year of therapy, said Dr. Delano, an attending physician in the dermatology program at Boston Children’s Hospital.

Those receiving infliximab are more likely to develop TNF inhibitor–induced psoriasis, compared with those on adalimumab or etanercept. TNF inhibitor–induced psoriasis may not track with gastrointestinal activity, and some patients whose gastrointestinal disease is responding to treatment can begin to develop psoriasis, she noted.

The clinical presentation of TNF inhibitor–induced psoriasis can also vary. In one study of 216 cases, 26.9% of patients had a mixed morphology, with the most common presentations including plaque psoriasis (44.8%) and palmoplantar pustular psoriasis (36.3%). Other presentations were psoriasiform dermatitis (19.9%), scalp involvement with alopecia (7.5%), and generalized pustular psoriasis (10.9%). Locations affected were the soles of the feet (45.8%), extremities (45.4%), palms (44.9%), scalp (36.1%), and trunk (32.4%), Dr. Delano said.


TNF inhibitor–induced psoriasis is likely a class effect, she said, noting that, in the same review, symptoms resolved in 47.7% of patients who discontinued TNF inhibitors, in 36.7% of patients who switched to another TNF inhibitor, and in 32.9% of patients who continued their original therapy (J Am Acad Dermatol. 2017 Feb;76[2]:334-41). In the study, Crohn’s disease and RA were the most common diseases, in 40.7% and 37.0% of the patients, respectively.

There have been case reports of TNF antagonist–induced lupus-like syndrome (TAILS), which is more common in patients with RA and ulcerative colitis. TAILS occurs more often in women than in men; can present similarly to systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus; and resolves by stopping TNF inhibitor treatment, Dr. Delano said.

Skin cancer risk, infections, and injection site reactions

Both adult and pediatric patients treated with TNF inhibitors for IBD may be at increased risk for lymphoma, visceral tumors, melanoma, and nonmelanoma skin cancers. Dr. Delano referred to a study published in 2014, which identified 972 reports of melanoma in the Food and Drug Administration’s Adverse Event Reporting System database associated with TNF inhibitor use; of these, 69 cases involved patients using more than one TNF inhibitor. Infliximab, golimumab, etanercept, and adalimumab were associated with a safety signal for melanoma, but not certolizumab (Br J Dermatol. 2014 May;170[5]:1170-2).

Dr. Delano observed that thiopurines such as azathioprine are also associated with an increased cancer risk, as noted in one retrospective study that found that the risk of nonmelanoma skin cancer was 2.1 times higher in a mostly white male cohort with ulcerative colitis during treatment with thiopurines, compared with patients not treated with thiopurines (Am J Gastroenterol. 2014 Nov;109[11]:1781-93). A greater duration of treatment (more than 6 months) and higher doses were associated with higher risks.

Adalimumab, golimumab, and certolizumab can also cause injection site reactions, typically within 1- 2 days of injection, said Dr. Delano. In these cases, symptoms of erythema, warmth, burning, or pruritus are worse at the beginning of treatment and can be relieved by rotating the injection site as well as providing cool compresses, topical steroids, antihistamines, and supportive care.

“If you have a patient with a worsening reaction, consider it may represent the type 1 IgE-related hypersensitivity requiring desensitization to continue that systemic,” she noted.

Cutaneous bacterial, fungal, and viral infections such as molluscum contagiosum, verruca vulgaris, herpes simplex, and varicella zoster can occur as a result of TNF inhibition as well, and can be difficult to clear because of immunosuppression, she added.

Dr. Delano reported no relevant conflicts of interest.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

SAN FRANCISCO – Antibiotic exposure in the month before cancer immunotherapy starts may hamper the efficacy of immune checkpoint inhibitors, investigators caution.

Neil Osterweil/MDedge News

A prospective study of 196 patients treated with immune checkpoint inhibitors for various cancers showed that the 29 patients who received antibiotics within 30 days of starting immunotherapy had significantly worse overall survival than patients without antibiotic exposure; this effect was seen across cancer types, reported David James Pinato, MD, PhD, from Imperial College London.

In contrast, concurrent antibiotic and checkpoint inhibitor use was not significantly associated with overall survival differences, he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

“I think these data are quite interesting in showing an independent detrimental effect, both on response and survival, in unselected patients treated with immune checkpoint inhibitors in routine clinical practice,” Dr. Pinato said.

The data also suggest “the timing of antibiotic exposure is crucial,” he added. Antibiotic treatment concurrent with immunotherapy did not appear to affect prognosis. Alternatively, prior antibiotic therapy appeared to have “a sort of a priming effect towards the immune system.”

Broad-spectrum antibiotics can affect the diversity of the gut microbiome, which influences mucosal immunity, dendritic cell function, and antigen presentation. Alternatively, enrichment of the microbiome with several bacterial species can enhance the potency of checkpoint inhibitors by facilitating the process of tumor rejection, Dr. Pinato explained.

To see whether antibiotic disruption, or “dysbiosis” of the gut microbiome, could hinder responsiveness to checkpoint inhibitors regardless of the tumor site and whether there were time-dependent effects of antibiotic exposure on response to checkpoint inhibitors, the investigators conducted a prospective, observational study in 196 patients treated with checkpoint inhibitors for non–small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, head and neck cancer, transitional cell carcinoma of the bladder, and other cancers.

The researchers defined prior antibiotic exposure as more than 30 days before the start of checkpoint inhibitor therapy and concurrent exposure as antibiotics begun on the first day of the first cycle of checkpoint inhibitor dosing.

Of the 196 patients, 29 had previously received antibiotics, and 68 received them concurrently. The most frequently prescribed antibiotics were beta-lactam agents given in a single, short course. Other classes of drugs, used in eight or fewer patients each, included quinolones, macrolides, sulfonamides, tetracyclines, aminoglycosides, and nitroimidazole.

Median overall survival for the entire cohort, one of two primary outcomes, was 2 months for patients who had received prior antibiotics and 26 months for patients with no prior exposure. This difference was similar for patients with NSCLC (2.5 vs. 26 months), melanoma (3.9 vs. 14 months), and other cancers combined (1.1 vs. 11.0 months; log-rank P less than .01 for all comparisons).

In multivariate analysis, only response to checkpoints inhibitors (complete vs. partial response, stable disease, or progression) and prior antibiotic exposure were significantly associated with survival. The hazard ratio for survival for patients who had not previously received antibiotics was 3.5 (P less than .001).

In contrast, concurrent antibiotic and checkpoint inhibitor use did not have a significant effect on survival.

An analysis of radiologic responses also showed that patients with prior antibiotic exposure had a significantly higher probability of primary disease progression than those without (81% vs. 44%; P less than .001). There were no associations, however, between specific classes of antibiotics or corticosteroid use.

The findings indicate that “certainly, mechanistic studies are required here, not just to investigate the prognostic role of antibiotic-mediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity,” Dr. Pinato concluded.

The study was internally supported. Dr. Pinato reported receiving grant funding from Merck and Bristol-Myers Squibb unrelated to the study, as well as honoraria from ViiV Healthcare.

SOURCE: Pinato DJ et al. ASCO-SITC, Abstract 147.

SAN FRANCISCO – Antibiotic exposure in the month before cancer immunotherapy starts may hamper the efficacy of immune checkpoint inhibitors, investigators caution.

Neil Osterweil/MDedge News

A prospective study of 196 patients treated with immune checkpoint inhibitors for various cancers showed that the 29 patients who received antibiotics within 30 days of starting immunotherapy had significantly worse overall survival than patients without antibiotic exposure; this effect was seen across cancer types, reported David James Pinato, MD, PhD, from Imperial College London.

In contrast, concurrent antibiotic and checkpoint inhibitor use was not significantly associated with overall survival differences, he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

“I think these data are quite interesting in showing an independent detrimental effect, both on response and survival, in unselected patients treated with immune checkpoint inhibitors in routine clinical practice,” Dr. Pinato said.

The data also suggest “the timing of antibiotic exposure is crucial,” he added. Antibiotic treatment concurrent with immunotherapy did not appear to affect prognosis. Alternatively, prior antibiotic therapy appeared to have “a sort of a priming effect towards the immune system.”

Broad-spectrum antibiotics can affect the diversity of the gut microbiome, which influences mucosal immunity, dendritic cell function, and antigen presentation. Alternatively, enrichment of the microbiome with several bacterial species can enhance the potency of checkpoint inhibitors by facilitating the process of tumor rejection, Dr. Pinato explained.

To see whether antibiotic disruption, or “dysbiosis” of the gut microbiome, could hinder responsiveness to checkpoint inhibitors regardless of the tumor site and whether there were time-dependent effects of antibiotic exposure on response to checkpoint inhibitors, the investigators conducted a prospective, observational study in 196 patients treated with checkpoint inhibitors for non–small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, head and neck cancer, transitional cell carcinoma of the bladder, and other cancers.

The researchers defined prior antibiotic exposure as more than 30 days before the start of checkpoint inhibitor therapy and concurrent exposure as antibiotics begun on the first day of the first cycle of checkpoint inhibitor dosing.

Of the 196 patients, 29 had previously received antibiotics, and 68 received them concurrently. The most frequently prescribed antibiotics were beta-lactam agents given in a single, short course. Other classes of drugs, used in eight or fewer patients each, included quinolones, macrolides, sulfonamides, tetracyclines, aminoglycosides, and nitroimidazole.

Median overall survival for the entire cohort, one of two primary outcomes, was 2 months for patients who had received prior antibiotics and 26 months for patients with no prior exposure. This difference was similar for patients with NSCLC (2.5 vs. 26 months), melanoma (3.9 vs. 14 months), and other cancers combined (1.1 vs. 11.0 months; log-rank P less than .01 for all comparisons).

In multivariate analysis, only response to checkpoints inhibitors (complete vs. partial response, stable disease, or progression) and prior antibiotic exposure were significantly associated with survival. The hazard ratio for survival for patients who had not previously received antibiotics was 3.5 (P less than .001).

In contrast, concurrent antibiotic and checkpoint inhibitor use did not have a significant effect on survival.

An analysis of radiologic responses also showed that patients with prior antibiotic exposure had a significantly higher probability of primary disease progression than those without (81% vs. 44%; P less than .001). There were no associations, however, between specific classes of antibiotics or corticosteroid use.

The findings indicate that “certainly, mechanistic studies are required here, not just to investigate the prognostic role of antibiotic-mediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity,” Dr. Pinato concluded.

The study was internally supported. Dr. Pinato reported receiving grant funding from Merck and Bristol-Myers Squibb unrelated to the study, as well as honoraria from ViiV Healthcare.

SOURCE: Pinato DJ et al. ASCO-SITC, Abstract 147.

SAN FRANCISCO – Antibiotic exposure in the month before cancer immunotherapy starts may hamper the efficacy of immune checkpoint inhibitors, investigators caution.

Neil Osterweil/MDedge News

A prospective study of 196 patients treated with immune checkpoint inhibitors for various cancers showed that the 29 patients who received antibiotics within 30 days of starting immunotherapy had significantly worse overall survival than patients without antibiotic exposure; this effect was seen across cancer types, reported David James Pinato, MD, PhD, from Imperial College London.

In contrast, concurrent antibiotic and checkpoint inhibitor use was not significantly associated with overall survival differences, he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

“I think these data are quite interesting in showing an independent detrimental effect, both on response and survival, in unselected patients treated with immune checkpoint inhibitors in routine clinical practice,” Dr. Pinato said.

The data also suggest “the timing of antibiotic exposure is crucial,” he added. Antibiotic treatment concurrent with immunotherapy did not appear to affect prognosis. Alternatively, prior antibiotic therapy appeared to have “a sort of a priming effect towards the immune system.”

Broad-spectrum antibiotics can affect the diversity of the gut microbiome, which influences mucosal immunity, dendritic cell function, and antigen presentation. Alternatively, enrichment of the microbiome with several bacterial species can enhance the potency of checkpoint inhibitors by facilitating the process of tumor rejection, Dr. Pinato explained.

To see whether antibiotic disruption, or “dysbiosis” of the gut microbiome, could hinder responsiveness to checkpoint inhibitors regardless of the tumor site and whether there were time-dependent effects of antibiotic exposure on response to checkpoint inhibitors, the investigators conducted a prospective, observational study in 196 patients treated with checkpoint inhibitors for non–small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, head and neck cancer, transitional cell carcinoma of the bladder, and other cancers.

The researchers defined prior antibiotic exposure as more than 30 days before the start of checkpoint inhibitor therapy and concurrent exposure as antibiotics begun on the first day of the first cycle of checkpoint inhibitor dosing.

Of the 196 patients, 29 had previously received antibiotics, and 68 received them concurrently. The most frequently prescribed antibiotics were beta-lactam agents given in a single, short course. Other classes of drugs, used in eight or fewer patients each, included quinolones, macrolides, sulfonamides, tetracyclines, aminoglycosides, and nitroimidazole.

Median overall survival for the entire cohort, one of two primary outcomes, was 2 months for patients who had received prior antibiotics and 26 months for patients with no prior exposure. This difference was similar for patients with NSCLC (2.5 vs. 26 months), melanoma (3.9 vs. 14 months), and other cancers combined (1.1 vs. 11.0 months; log-rank P less than .01 for all comparisons).

In multivariate analysis, only response to checkpoints inhibitors (complete vs. partial response, stable disease, or progression) and prior antibiotic exposure were significantly associated with survival. The hazard ratio for survival for patients who had not previously received antibiotics was 3.5 (P less than .001).

In contrast, concurrent antibiotic and checkpoint inhibitor use did not have a significant effect on survival.

An analysis of radiologic responses also showed that patients with prior antibiotic exposure had a significantly higher probability of primary disease progression than those without (81% vs. 44%; P less than .001). There were no associations, however, between specific classes of antibiotics or corticosteroid use.

The findings indicate that “certainly, mechanistic studies are required here, not just to investigate the prognostic role of antibiotic-mediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity,” Dr. Pinato concluded.

The study was internally supported. Dr. Pinato reported receiving grant funding from Merck and Bristol-Myers Squibb unrelated to the study, as well as honoraria from ViiV Healthcare.

SOURCE: Pinato DJ et al. ASCO-SITC, Abstract 147.

WASHINGTON – The 31-gene expression profile test has met the highest level of evidence under the Strength of Recommendation Taxonomy (SORT) method as a prognostic marker for accurately predicting recurrence-free survival and distant metastasis-free survival and melanoma-specific survival, according to results presented by Bradley N. Greenhaw, MD, at a late-breaking research session at the annual meeting of the American Academy of Dermatology.

Dr. Greenhaw, a dermatologist affiliated with the North Mississippi Medical Center-Tupelo, and his colleagues pooled together 1,268 patients from the following studies that analyzed results from melanoma patients who had their disease classified with the 31-gene expression profile (31-GEP) test.

• A single-center study, conducted by Dr. Greenhaw and his associates (Greenhaw BN et al. Dermatol Surg. 2018 Dec. doi: 10.1097/DSS.0000000000001588.
• A multicenter prospective study (J Hematol Oncol. 2017 Aug. doi: 10.1186/s13045-017-0520-1.
• A retrospective archival study (J Am Acad Dermatol. 2019 Jan. doi: 10.1016/j.jaad.2018.07.028.

The 31-GEP test stratifies an individual’s likelihood of developing metastasis within 5 years as low and high risk. In the three studies, the test was used to identify tumors with low-risk (class 1A, class 1B), higher-risk (class 2A), and highest-risk (class 2B) melanoma based on tumor gene expression. In these individual studies, class 2B melanoma independently predicted recurrence-free survival (RFS), distant metastasis–free, and melanoma-specific survival.

Dr. Greenhaw and colleagues performed a meta-analysis of 1,268 patients with stage I through stage III melanoma from those three studies, using fixed and random effects weighting to account for study differences and heterogeneity, respectively. For class 2B tumors, they found a 2.96 increased risk for recurrent metastases and a 2.88 increased risk for distant metastases. The researchers also found no heterogeneity across the studies.

Melanoma-specific survival was not included in the meta-analysis because one paper did not contain any mortality events in class 1A melanoma patients.

“The meta-analysis demonstrated that the GEP test was able to accurately identify those melanoma patients who were at higher risk of metastasis, and we saw a consistent effect across multiple studies,” Dr. Greenhaw said.

Since publication of the 2019 JAAD paper, there were an additional 211 patients who met inclusion criteria and were included in an additional meta-analysis to determine whether inclusion of these patients affected the results. Dr. Greenhaw and colleagues found a 91.4% recurrence-free survival rate and a 94.1% distant metastasis–free survival rate for class 1A melanomas, compared with 45.7% and 55.5% , respectively, for class 2B tumors.

“You can see a big divergence,” Dr. Greenhaw said at the meeting. “Just by using this one test, it’s able to separate out melanomas that otherwise may be grouped in together under current AJCC [American Joint Committee on Cancer] staging,” he added. “The class 2B designation really did confirm a higher risk for recurrence in distant metastasis.”

The researchers used the SORT method to rate the quality of the data across all three studies. Level 1 evidence under the SORT method represents a systematic review or meta-analysis of good-quality studies and/or a prospective study with good follow-up, while an A-level recommendation represents good, quality evidence. Based on the meta-analysis results, the 31-GEP test meets level 1A evidence under the SORT method, Dr. Greenhaw said.

As a prognostic tool, 31-GEP has the potential to change how dermatologists manage their patients with regard to follow-up and adjuvant therapy. “It is being used not just as this novel test that gives us more information, it’s being used clinically,” said Dr. Greenhaw, who noted he regularly uses the 31-GEP test in his practice.

This is the first time that a meta-analysis has been performed for this test, he noted.

Dr. Greenhaw reports a pending relationship with Castle Biosciences.

SOURCE: Greenhaw BN et al. AAD 19. Session F055, Abstract 11370.

WASHINGTON – The 31-gene expression profile test has met the highest level of evidence under the Strength of Recommendation Taxonomy (SORT) method as a prognostic marker for accurately predicting recurrence-free survival and distant metastasis-free survival and melanoma-specific survival, according to results presented by Bradley N. Greenhaw, MD, at a late-breaking research session at the annual meeting of the American Academy of Dermatology.

Dr. Greenhaw, a dermatologist affiliated with the North Mississippi Medical Center-Tupelo, and his colleagues pooled together 1,268 patients from the following studies that analyzed results from melanoma patients who had their disease classified with the 31-gene expression profile (31-GEP) test.

• A single-center study, conducted by Dr. Greenhaw and his associates (Greenhaw BN et al. Dermatol Surg. 2018 Dec. doi: 10.1097/DSS.0000000000001588.
• A multicenter prospective study (J Hematol Oncol. 2017 Aug. doi: 10.1186/s13045-017-0520-1.
• A retrospective archival study (J Am Acad Dermatol. 2019 Jan. doi: 10.1016/j.jaad.2018.07.028.

The 31-GEP test stratifies an individual’s likelihood of developing metastasis within 5 years as low and high risk. In the three studies, the test was used to identify tumors with low-risk (class 1A, class 1B), higher-risk (class 2A), and highest-risk (class 2B) melanoma based on tumor gene expression. In these individual studies, class 2B melanoma independently predicted recurrence-free survival (RFS), distant metastasis–free, and melanoma-specific survival.

Dr. Greenhaw and colleagues performed a meta-analysis of 1,268 patients with stage I through stage III melanoma from those three studies, using fixed and random effects weighting to account for study differences and heterogeneity, respectively. For class 2B tumors, they found a 2.96 increased risk for recurrent metastases and a 2.88 increased risk for distant metastases. The researchers also found no heterogeneity across the studies.

Melanoma-specific survival was not included in the meta-analysis because one paper did not contain any mortality events in class 1A melanoma patients.

“The meta-analysis demonstrated that the GEP test was able to accurately identify those melanoma patients who were at higher risk of metastasis, and we saw a consistent effect across multiple studies,” Dr. Greenhaw said.

Since publication of the 2019 JAAD paper, there were an additional 211 patients who met inclusion criteria and were included in an additional meta-analysis to determine whether inclusion of these patients affected the results. Dr. Greenhaw and colleagues found a 91.4% recurrence-free survival rate and a 94.1% distant metastasis–free survival rate for class 1A melanomas, compared with 45.7% and 55.5% , respectively, for class 2B tumors.

“You can see a big divergence,” Dr. Greenhaw said at the meeting. “Just by using this one test, it’s able to separate out melanomas that otherwise may be grouped in together under current AJCC [American Joint Committee on Cancer] staging,” he added. “The class 2B designation really did confirm a higher risk for recurrence in distant metastasis.”

The researchers used the SORT method to rate the quality of the data across all three studies. Level 1 evidence under the SORT method represents a systematic review or meta-analysis of good-quality studies and/or a prospective study with good follow-up, while an A-level recommendation represents good, quality evidence. Based on the meta-analysis results, the 31-GEP test meets level 1A evidence under the SORT method, Dr. Greenhaw said.

As a prognostic tool, 31-GEP has the potential to change how dermatologists manage their patients with regard to follow-up and adjuvant therapy. “It is being used not just as this novel test that gives us more information, it’s being used clinically,” said Dr. Greenhaw, who noted he regularly uses the 31-GEP test in his practice.

This is the first time that a meta-analysis has been performed for this test, he noted.

Dr. Greenhaw reports a pending relationship with Castle Biosciences.

SOURCE: Greenhaw BN et al. AAD 19. Session F055, Abstract 11370.

WASHINGTON – The 31-gene expression profile test has met the highest level of evidence under the Strength of Recommendation Taxonomy (SORT) method as a prognostic marker for accurately predicting recurrence-free survival and distant metastasis-free survival and melanoma-specific survival, according to results presented by Bradley N. Greenhaw, MD, at a late-breaking research session at the annual meeting of the American Academy of Dermatology.

Dr. Greenhaw, a dermatologist affiliated with the North Mississippi Medical Center-Tupelo, and his colleagues pooled together 1,268 patients from the following studies that analyzed results from melanoma patients who had their disease classified with the 31-gene expression profile (31-GEP) test.

• A single-center study, conducted by Dr. Greenhaw and his associates (Greenhaw BN et al. Dermatol Surg. 2018 Dec. doi: 10.1097/DSS.0000000000001588.
• A multicenter prospective study (J Hematol Oncol. 2017 Aug. doi: 10.1186/s13045-017-0520-1.
• A retrospective archival study (J Am Acad Dermatol. 2019 Jan. doi: 10.1016/j.jaad.2018.07.028.

The 31-GEP test stratifies an individual’s likelihood of developing metastasis within 5 years as low and high risk. In the three studies, the test was used to identify tumors with low-risk (class 1A, class 1B), higher-risk (class 2A), and highest-risk (class 2B) melanoma based on tumor gene expression. In these individual studies, class 2B melanoma independently predicted recurrence-free survival (RFS), distant metastasis–free, and melanoma-specific survival.

Dr. Greenhaw and colleagues performed a meta-analysis of 1,268 patients with stage I through stage III melanoma from those three studies, using fixed and random effects weighting to account for study differences and heterogeneity, respectively. For class 2B tumors, they found a 2.96 increased risk for recurrent metastases and a 2.88 increased risk for distant metastases. The researchers also found no heterogeneity across the studies.

Melanoma-specific survival was not included in the meta-analysis because one paper did not contain any mortality events in class 1A melanoma patients.

“The meta-analysis demonstrated that the GEP test was able to accurately identify those melanoma patients who were at higher risk of metastasis, and we saw a consistent effect across multiple studies,” Dr. Greenhaw said.

Since publication of the 2019 JAAD paper, there were an additional 211 patients who met inclusion criteria and were included in an additional meta-analysis to determine whether inclusion of these patients affected the results. Dr. Greenhaw and colleagues found a 91.4% recurrence-free survival rate and a 94.1% distant metastasis–free survival rate for class 1A melanomas, compared with 45.7% and 55.5% , respectively, for class 2B tumors.

“You can see a big divergence,” Dr. Greenhaw said at the meeting. “Just by using this one test, it’s able to separate out melanomas that otherwise may be grouped in together under current AJCC [American Joint Committee on Cancer] staging,” he added. “The class 2B designation really did confirm a higher risk for recurrence in distant metastasis.”

The researchers used the SORT method to rate the quality of the data across all three studies. Level 1 evidence under the SORT method represents a systematic review or meta-analysis of good-quality studies and/or a prospective study with good follow-up, while an A-level recommendation represents good, quality evidence. Based on the meta-analysis results, the 31-GEP test meets level 1A evidence under the SORT method, Dr. Greenhaw said.

As a prognostic tool, 31-GEP has the potential to change how dermatologists manage their patients with regard to follow-up and adjuvant therapy. “It is being used not just as this novel test that gives us more information, it’s being used clinically,” said Dr. Greenhaw, who noted he regularly uses the 31-GEP test in his practice.

This is the first time that a meta-analysis has been performed for this test, he noted.

Dr. Greenhaw reports a pending relationship with Castle Biosciences.

SOURCE: Greenhaw BN et al. AAD 19. Session F055, Abstract 11370.

WASHINGTON – Noninvasive diagnostic devices may increasingly play a part in which lesions you choose to biopsy, Darrell S. Rigel, MD, said at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

“If you incorporate the data from these devices into the biopsy decision, you can improve biopsy sensitivity and accuracy of selection. I think there’s no question with these technologies that’s a true statement,” said Dr. Rigel, of New York University Langone Health.

When considering diagnostic devices, evaluate whether they produce results that outperform dermatologists, are low cost, user-friendly, time-efficient and have a high sensitivity and specificity, Dr. Rigel advised. But since no device has a perfect sensitivity and specificity, they cannot be followed blindly. The data from these devices should be used to inform, but not replace, clinical decisions made by dermatologists.

“They’re basically additional information to integrate into the biopsy decision,” he said. “At the end of the day, if you see something with a low score but it really looks funky, the reality is you have to really consider it for biopsy.”

Dr. Rigel discussed five device types that were used to analyze a number of preselected, noninvasive melanoma lesions. The devices required little training to use and a dermatologist would be required to correctly identify the lesions in a deeper analysis.

• Multispectral digital skin lesion analysis (MDSLA) uses 10 spectral wavelengths to measure the light reflected from the tissue, generating a score from a proprietary algorithm that predicts the risk of melanoma. Use of MDSLA improved the biopsy sensitivity for melanoma from 65% to 93% among 179 dermatologists who reviewed images of 24 lesions, 5 of which were melanoma (Arch Dermatol. 2012;148(4):541-3).
• Spectrophotometric intracutaneous analysis scope uses a similar analytic method as the MDSLA device but is difficult to find in the United States; however, one recent study cited a sensitivity of 81.4% and a specificity of 86.4%, indicating it has value for diagnosing melanoma.
• Raman spectroscopy uses monochromatic laser light to analyze the vibratory patterns of cells and examines the shifts in the light to identify a “molecular fingerprint” of potentially cancerous cells, has a high sensitivity and a “relatively reasonable specificity,” Dr. Rigel said.
• Elastic scattering spectroscopy, a newer technology that uses a smartphone-sized device to measure the difference in light scattered from different cellular structures, holds promise to reduce the number of negative biopsies when differentiating between malignant and benign skin conditions. It is currently pending approval with the Food and Drug Administration.
• Electrical impedance spectroscopy (EIS), which uses an electrical alternating current to detect the electrical resistance of potentially cancerous tissue, generates a score with a high negative predictive value and a higher positive predictive value as the score increases. In a study of melanoma diagnoses made by dermatology trainees, use of EIS decreased the number of missed melanomas by 23.4% and resulted in fewer benign biopsies. (J Amer Acad Dermatol. 2019;80:285-7).

All these technologies have been proven effective, but have encountered various economic roadblocks, including delays in regulatory approval, which are partly responsible for why some are no longer on the market, Dr. Rigel said. “If you have to wait 5 years or 7 years to get approval of these devices, by the time they’re approved, the technology is already passed by.”

There are also issues with reimbursements, Dr. Rigel noted, which can further reduce the clinical implementation of these technologies.

Dr. Rigel reported relationships with Derm Tech International, Scibase (maker of EIS) and a number of dermatologic drug companies.

WASHINGTON – Noninvasive diagnostic devices may increasingly play a part in which lesions you choose to biopsy, Darrell S. Rigel, MD, said at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

“If you incorporate the data from these devices into the biopsy decision, you can improve biopsy sensitivity and accuracy of selection. I think there’s no question with these technologies that’s a true statement,” said Dr. Rigel, of New York University Langone Health.

When considering diagnostic devices, evaluate whether they produce results that outperform dermatologists, are low cost, user-friendly, time-efficient and have a high sensitivity and specificity, Dr. Rigel advised. But since no device has a perfect sensitivity and specificity, they cannot be followed blindly. The data from these devices should be used to inform, but not replace, clinical decisions made by dermatologists.

“They’re basically additional information to integrate into the biopsy decision,” he said. “At the end of the day, if you see something with a low score but it really looks funky, the reality is you have to really consider it for biopsy.”

Dr. Rigel discussed five device types that were used to analyze a number of preselected, noninvasive melanoma lesions. The devices required little training to use and a dermatologist would be required to correctly identify the lesions in a deeper analysis.

• Multispectral digital skin lesion analysis (MDSLA) uses 10 spectral wavelengths to measure the light reflected from the tissue, generating a score from a proprietary algorithm that predicts the risk of melanoma. Use of MDSLA improved the biopsy sensitivity for melanoma from 65% to 93% among 179 dermatologists who reviewed images of 24 lesions, 5 of which were melanoma (Arch Dermatol. 2012;148(4):541-3).
• Spectrophotometric intracutaneous analysis scope uses a similar analytic method as the MDSLA device but is difficult to find in the United States; however, one recent study cited a sensitivity of 81.4% and a specificity of 86.4%, indicating it has value for diagnosing melanoma.
• Raman spectroscopy uses monochromatic laser light to analyze the vibratory patterns of cells and examines the shifts in the light to identify a “molecular fingerprint” of potentially cancerous cells, has a high sensitivity and a “relatively reasonable specificity,” Dr. Rigel said.
• Elastic scattering spectroscopy, a newer technology that uses a smartphone-sized device to measure the difference in light scattered from different cellular structures, holds promise to reduce the number of negative biopsies when differentiating between malignant and benign skin conditions. It is currently pending approval with the Food and Drug Administration.
• Electrical impedance spectroscopy (EIS), which uses an electrical alternating current to detect the electrical resistance of potentially cancerous tissue, generates a score with a high negative predictive value and a higher positive predictive value as the score increases. In a study of melanoma diagnoses made by dermatology trainees, use of EIS decreased the number of missed melanomas by 23.4% and resulted in fewer benign biopsies. (J Amer Acad Dermatol. 2019;80:285-7).

All these technologies have been proven effective, but have encountered various economic roadblocks, including delays in regulatory approval, which are partly responsible for why some are no longer on the market, Dr. Rigel said. “If you have to wait 5 years or 7 years to get approval of these devices, by the time they’re approved, the technology is already passed by.”

There are also issues with reimbursements, Dr. Rigel noted, which can further reduce the clinical implementation of these technologies.

Dr. Rigel reported relationships with Derm Tech International, Scibase (maker of EIS) and a number of dermatologic drug companies.

WASHINGTON – Noninvasive diagnostic devices may increasingly play a part in which lesions you choose to biopsy, Darrell S. Rigel, MD, said at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

“If you incorporate the data from these devices into the biopsy decision, you can improve biopsy sensitivity and accuracy of selection. I think there’s no question with these technologies that’s a true statement,” said Dr. Rigel, of New York University Langone Health.

When considering diagnostic devices, evaluate whether they produce results that outperform dermatologists, are low cost, user-friendly, time-efficient and have a high sensitivity and specificity, Dr. Rigel advised. But since no device has a perfect sensitivity and specificity, they cannot be followed blindly. The data from these devices should be used to inform, but not replace, clinical decisions made by dermatologists.

“They’re basically additional information to integrate into the biopsy decision,” he said. “At the end of the day, if you see something with a low score but it really looks funky, the reality is you have to really consider it for biopsy.”

Dr. Rigel discussed five device types that were used to analyze a number of preselected, noninvasive melanoma lesions. The devices required little training to use and a dermatologist would be required to correctly identify the lesions in a deeper analysis.

• Multispectral digital skin lesion analysis (MDSLA) uses 10 spectral wavelengths to measure the light reflected from the tissue, generating a score from a proprietary algorithm that predicts the risk of melanoma. Use of MDSLA improved the biopsy sensitivity for melanoma from 65% to 93% among 179 dermatologists who reviewed images of 24 lesions, 5 of which were melanoma (Arch Dermatol. 2012;148(4):541-3).
• Spectrophotometric intracutaneous analysis scope uses a similar analytic method as the MDSLA device but is difficult to find in the United States; however, one recent study cited a sensitivity of 81.4% and a specificity of 86.4%, indicating it has value for diagnosing melanoma.
• Raman spectroscopy uses monochromatic laser light to analyze the vibratory patterns of cells and examines the shifts in the light to identify a “molecular fingerprint” of potentially cancerous cells, has a high sensitivity and a “relatively reasonable specificity,” Dr. Rigel said.
• Elastic scattering spectroscopy, a newer technology that uses a smartphone-sized device to measure the difference in light scattered from different cellular structures, holds promise to reduce the number of negative biopsies when differentiating between malignant and benign skin conditions. It is currently pending approval with the Food and Drug Administration.
• Electrical impedance spectroscopy (EIS), which uses an electrical alternating current to detect the electrical resistance of potentially cancerous tissue, generates a score with a high negative predictive value and a higher positive predictive value as the score increases. In a study of melanoma diagnoses made by dermatology trainees, use of EIS decreased the number of missed melanomas by 23.4% and resulted in fewer benign biopsies. (J Amer Acad Dermatol. 2019;80:285-7).

All these technologies have been proven effective, but have encountered various economic roadblocks, including delays in regulatory approval, which are partly responsible for why some are no longer on the market, Dr. Rigel said. “If you have to wait 5 years or 7 years to get approval of these devices, by the time they’re approved, the technology is already passed by.”

There are also issues with reimbursements, Dr. Rigel noted, which can further reduce the clinical implementation of these technologies.

Dr. Rigel reported relationships with Derm Tech International, Scibase (maker of EIS) and a number of dermatologic drug companies.

Diet plays an important role in patient response to anti-programmed death-1 (PD-1) cancer immunotherapy, preliminary findings from a gut microbiome study involving 146 melanoma patients suggest.

Specifically, a high-fiber diet was associated with a more diverse gut microbiome and with improved response to anti-PD-1 therapy, whereas a diet high in sugar and processed meat was associated with fewer of the gut bacteria known to be associated with improved response, Christine Spencer, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research (AACR) annual meeting in Atlanta.

“We found that patients who reported eating high-fiber diets were about five times as likely to respond to anti-PD-1 checkpoint blockade immunotherapy (odds ratio vs. low-fiber diet, 5.3),” said Dr. Spencer, a research scientist at the Parker Institute for Cancer Immunotherapy.

Notably, more than 40% of patients reported taking probiotics, and those, surprisingly, were also associated with reduced gut microbiome diversity, she said.

For this study, Dr. Spencer and her colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed prospectively collected fecal samples from 146 melanoma patients, and collected baseline diet information via the National Cancer Institute dietary screener questionnaire, as well as information about probiotic and antibiotic use, in a subset of 113 who were initiating therapy at MD Anderson. Those patients were then followed to assess therapy response.

“Our early data suggest that different foods and supplements may impact response to cancer immunotherapy in patients, and we think this is likely mediated by the gut microbiome,” she said.

Since only 20%-30% of cancer patients respond to immunotherapy, the findings hint at potential approaches for improving gut microbiome diversity, and thus response to anti-PD-1 cancer immunotherapy.

“Eat your high-fiber foods: fruits, vegetables, and whole grains – lots of different kinds and lots of them,” she said. “High-fiber diets have been linked to health benefits in several other contexts, and this study, although preliminary, shows fiber is linked to more favorable gut microbiome in patients, and better response to cancer immunotherapy.”

Conversations about the use of probiotic supplements also are important, she said.

“A lot of people have the perception that probiotics will provide health benefits, but that might not be the case in cancer patients. We’re not saying all of them are bad, but the message is that these factors have never before been studied in patients on immunotherapy, and our data suggest for the first time that they could matter,” she said, noting that future directions include validation of the findings in larger cohorts.

SOURCE: Spencer C et al. AACR 2019, Abstract preview.

Diet plays an important role in patient response to anti-programmed death-1 (PD-1) cancer immunotherapy, preliminary findings from a gut microbiome study involving 146 melanoma patients suggest.

Specifically, a high-fiber diet was associated with a more diverse gut microbiome and with improved response to anti-PD-1 therapy, whereas a diet high in sugar and processed meat was associated with fewer of the gut bacteria known to be associated with improved response, Christine Spencer, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research (AACR) annual meeting in Atlanta.

“We found that patients who reported eating high-fiber diets were about five times as likely to respond to anti-PD-1 checkpoint blockade immunotherapy (odds ratio vs. low-fiber diet, 5.3),” said Dr. Spencer, a research scientist at the Parker Institute for Cancer Immunotherapy.

Notably, more than 40% of patients reported taking probiotics, and those, surprisingly, were also associated with reduced gut microbiome diversity, she said.

For this study, Dr. Spencer and her colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed prospectively collected fecal samples from 146 melanoma patients, and collected baseline diet information via the National Cancer Institute dietary screener questionnaire, as well as information about probiotic and antibiotic use, in a subset of 113 who were initiating therapy at MD Anderson. Those patients were then followed to assess therapy response.

“Our early data suggest that different foods and supplements may impact response to cancer immunotherapy in patients, and we think this is likely mediated by the gut microbiome,” she said.

Since only 20%-30% of cancer patients respond to immunotherapy, the findings hint at potential approaches for improving gut microbiome diversity, and thus response to anti-PD-1 cancer immunotherapy.

“Eat your high-fiber foods: fruits, vegetables, and whole grains – lots of different kinds and lots of them,” she said. “High-fiber diets have been linked to health benefits in several other contexts, and this study, although preliminary, shows fiber is linked to more favorable gut microbiome in patients, and better response to cancer immunotherapy.”

Conversations about the use of probiotic supplements also are important, she said.

“A lot of people have the perception that probiotics will provide health benefits, but that might not be the case in cancer patients. We’re not saying all of them are bad, but the message is that these factors have never before been studied in patients on immunotherapy, and our data suggest for the first time that they could matter,” she said, noting that future directions include validation of the findings in larger cohorts.

SOURCE: Spencer C et al. AACR 2019, Abstract preview.

Diet plays an important role in patient response to anti-programmed death-1 (PD-1) cancer immunotherapy, preliminary findings from a gut microbiome study involving 146 melanoma patients suggest.

Specifically, a high-fiber diet was associated with a more diverse gut microbiome and with improved response to anti-PD-1 therapy, whereas a diet high in sugar and processed meat was associated with fewer of the gut bacteria known to be associated with improved response, Christine Spencer, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research (AACR) annual meeting in Atlanta.

“We found that patients who reported eating high-fiber diets were about five times as likely to respond to anti-PD-1 checkpoint blockade immunotherapy (odds ratio vs. low-fiber diet, 5.3),” said Dr. Spencer, a research scientist at the Parker Institute for Cancer Immunotherapy.

Notably, more than 40% of patients reported taking probiotics, and those, surprisingly, were also associated with reduced gut microbiome diversity, she said.

For this study, Dr. Spencer and her colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed prospectively collected fecal samples from 146 melanoma patients, and collected baseline diet information via the National Cancer Institute dietary screener questionnaire, as well as information about probiotic and antibiotic use, in a subset of 113 who were initiating therapy at MD Anderson. Those patients were then followed to assess therapy response.

“Our early data suggest that different foods and supplements may impact response to cancer immunotherapy in patients, and we think this is likely mediated by the gut microbiome,” she said.

Since only 20%-30% of cancer patients respond to immunotherapy, the findings hint at potential approaches for improving gut microbiome diversity, and thus response to anti-PD-1 cancer immunotherapy.

“Eat your high-fiber foods: fruits, vegetables, and whole grains – lots of different kinds and lots of them,” she said. “High-fiber diets have been linked to health benefits in several other contexts, and this study, although preliminary, shows fiber is linked to more favorable gut microbiome in patients, and better response to cancer immunotherapy.”

Conversations about the use of probiotic supplements also are important, she said.

“A lot of people have the perception that probiotics will provide health benefits, but that might not be the case in cancer patients. We’re not saying all of them are bad, but the message is that these factors have never before been studied in patients on immunotherapy, and our data suggest for the first time that they could matter,” she said, noting that future directions include validation of the findings in larger cohorts.

SOURCE: Spencer C et al. AACR 2019, Abstract preview.

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the adjuvant treatment of patients with melanoma with lymph node involvement following resection.

FDA approval is based on results from the randomized, double-blind, placebo-controlled EORTC1325/KEYNOTE‑054 trial, in which 1,019 patients with completely resected stage III melanoma received either a placebo or 200 mg of pembrolizumab every 3 weeks for up to 1 year until disease recurrence or unacceptable toxicity.

Recurrence-free survival was significantly better in the pembrolizumab group than in the placebo group (hazard ratio, 0.57; 95% confidence interval, 0.46-0.70; P less than .001). The median recurrence-free survival time was 20.4 months in the placebo group and was not reached in the pembrolizumab group, the FDA said in a press release.

About three-quarters of patients received pembrolizumab for at least 6 months, while 14% of patients had to stop pembrolizumab treatment because of adverse events. The most common adverse events in pembrolizumab-treated patients included diarrhea, pruritus, nausea, arthralgia, hypothyroidism, cough, rash, asthenia, influenzalike illness, weight loss, and hyperthyroidism.

“The recommended pembrolizumab dose and schedule for the adjuvant treatment of melanoma is 200 mg administered as an IV infusion over 30 minutes every 3 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year,” the FDA said in the press release.

lfranki@mdedge.com

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the adjuvant treatment of patients with melanoma with lymph node involvement following resection.

FDA approval is based on results from the randomized, double-blind, placebo-controlled EORTC1325/KEYNOTE‑054 trial, in which 1,019 patients with completely resected stage III melanoma received either a placebo or 200 mg of pembrolizumab every 3 weeks for up to 1 year until disease recurrence or unacceptable toxicity.

Recurrence-free survival was significantly better in the pembrolizumab group than in the placebo group (hazard ratio, 0.57; 95% confidence interval, 0.46-0.70; P less than .001). The median recurrence-free survival time was 20.4 months in the placebo group and was not reached in the pembrolizumab group, the FDA said in a press release.

About three-quarters of patients received pembrolizumab for at least 6 months, while 14% of patients had to stop pembrolizumab treatment because of adverse events. The most common adverse events in pembrolizumab-treated patients included diarrhea, pruritus, nausea, arthralgia, hypothyroidism, cough, rash, asthenia, influenzalike illness, weight loss, and hyperthyroidism.

“The recommended pembrolizumab dose and schedule for the adjuvant treatment of melanoma is 200 mg administered as an IV infusion over 30 minutes every 3 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year,” the FDA said in the press release.

lfranki@mdedge.com

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the adjuvant treatment of patients with melanoma with lymph node involvement following resection.

FDA approval is based on results from the randomized, double-blind, placebo-controlled EORTC1325/KEYNOTE‑054 trial, in which 1,019 patients with completely resected stage III melanoma received either a placebo or 200 mg of pembrolizumab every 3 weeks for up to 1 year until disease recurrence or unacceptable toxicity.

Recurrence-free survival was significantly better in the pembrolizumab group than in the placebo group (hazard ratio, 0.57; 95% confidence interval, 0.46-0.70; P less than .001). The median recurrence-free survival time was 20.4 months in the placebo group and was not reached in the pembrolizumab group, the FDA said in a press release.

About three-quarters of patients received pembrolizumab for at least 6 months, while 14% of patients had to stop pembrolizumab treatment because of adverse events. The most common adverse events in pembrolizumab-treated patients included diarrhea, pruritus, nausea, arthralgia, hypothyroidism, cough, rash, asthenia, influenzalike illness, weight loss, and hyperthyroidism.

“The recommended pembrolizumab dose and schedule for the adjuvant treatment of melanoma is 200 mg administered as an IV infusion over 30 minutes every 3 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year,” the FDA said in the press release.

lfranki@mdedge.com