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Watch for the skin side effects of novel melanoma therapies
WAIKOLOA, HAWAII – The spectacular developments in the treatment of advanced melanoma that began with approval of ipilimumab in 2011 continue to accelerate, and these advances promise to keep dermatologists quite busy for the foreseeable future in treating the cutaneous side effects of these targeted therapies.
Cutaneous toxicities requiring medical attention are extremely common with the new therapeutic agents. The key to minimizing their effects is proactive management, Dr. James E. Sligh emphasized at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.
"The message is that people are living longer with advanced melanoma, but you really need to work with your oncologists to get the absolute benefit patients deserve out of these advanced drugs," he said. "All patients on any of the BRAF inhibitors should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and for 6 months following treatment discontinuation. And while I use this as a guide, there are definitely patients I see for whom 2 months is way too long between visits," he added. "If they’re growing squamous cell carcinomas or verrucous keratoses at a good clip, they need to be seen more often. I’ll see them every other week if need be," said Dr. Sligh, chief of the dermatology division at the University of Arizona, Tucson.
"This is a plea to dermatologists," he continued. "If you have a patient who’s going on a BRAF inhibitor, they need to be seen in your office regularly. And if your next available appointment isn’t until 4 months down the road, you absolutely need to make room for these patients, because after 4 months they may have very large squamous cell carcinomas."
One in four advanced melanoma patients on a BRAF inhibitor – vemurafenib and dabrenafib are the two available thus far – will develop squamous cell carcinomas, Dr. Sligh said. If it’s going to happen, it typically begins in the first month or two of therapy. Caught early, the treatment is simple removal. The same goes for verrucous keratoses, which occur in close to half of treated patients.
"I use cryotherapy in the office, and I give patients 5-FU [5-fluorouracil] so they can start treating a lesion the day they see it, rather than waiting to show it to me a couple of months later," explained Dr. Sligh.
Other common cutaneous adverse events seen as a class effect with the BRAF inhibitors include photosensitivity reactions, seen in approximately one-third of patients in the phase III clinical trials; pruritus, seen in 23%; plantar hyperkeratosis in 10%-20%; and maculopapular rash in 9%.
The pretreatment dermatologic visit is an ideal time for patient education regarding sunscreen use, protective clothing, and the necessity to stay indoors in the event a photosensitivity rash emerges, Dr. Sligh noted. These are issues medical oncologists typically won’t counsel patients about, he said.
"The real advantage to doing this is you want these patients to maintain their optimal dose. For vemurafenib, it’s 960 mg b.i.d. There are very few things that will cause a dose reduction with these drugs, so if cutaneous toxicity is something patients are having a difficult time with, it’s our job as dermatologists to ensure that they have the best chance to make those side effects tolerable. Remaining on the drug is absolutely their best chance for survival," Dr. Sligh continued.
Serious hypersensitivity reactions, including anaphylaxis, as well as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients on a BRAF inhibitor. Such events do require permanent discontinuation of therapy. But that’s not necessarily the end of the road. "There are fantastic new options coming on board each year as alternatives for these people," according to Dr. Sligh.
New primary melanomas can arise while a patient is on BRAF inhibitor therapy. If they are detected early through those bimonthly office visits, the treatment is excision with no dosage adjustment.
Ipilimumab, which targets cytotoxic T-lymphocyte antigen 4, differs from the BRAF inhibitors in that its cutaneous adverse effects can emerge long after the drug is stopped.
"If you see a rash that’s not typical in a patient even 1 or 2 years after they were on ipilimumab, you should still consider that drug to be a likely culprit," Dr. Sligh said.
Trametinib, a MEK inhibitor, was approved last year for the treatment of melanomas with BRAF V600E or V600K mutations. Cutaneous toxicity occurs in close to 90% of patients on the drug, including a 12% rate of severe, grade 3 skin reactions. When trametinib is given in combination with vemurafenib or dabrafenib in an effort to delay emergence of tumor resistance, the result is longer progression-free survival than with either agent alone, and with a lower rate of squamous cell carcinomas and other cutaneous adverse events than with either agent as monotherapy. However, the question of whether or not combination therapy improves overall survival remains unclear, and is the subject of ongoing trials.
Close to half of melanoma patients have a BRAF mutation that makes them a potential candidate for BRAF inhibitor therapy. But in a separate presentation at the meeting, Dr. Michael Postow, an oncologist at Memorial Sloan Kettering Cancer Center in New York, urged dermatologists not to think only of the FDA-approved BRAF test when they have a patient diagnosed with melanoma.
"It’s really worthwhile to do more extensive molecular profiling of those patients, because you may find another targetable mutation," said Dr. Postow. "I would encourage you to refer any patients you have that are being diagnosed with melanoma for a larger institutional evaluation where more extensive molecular characterization of the tumor can be performed," he added.
Dr. Sligh is on the advisory board for and a consultant to Genentech, and he has received research grants from DermSpectra and SciBase. Dr. Postow reported serving as an unpaid adviser to Bristol-Myers Squibb.
SDEF and this news organization are owned by the same parent company.
WAIKOLOA, HAWAII – The spectacular developments in the treatment of advanced melanoma that began with approval of ipilimumab in 2011 continue to accelerate, and these advances promise to keep dermatologists quite busy for the foreseeable future in treating the cutaneous side effects of these targeted therapies.
Cutaneous toxicities requiring medical attention are extremely common with the new therapeutic agents. The key to minimizing their effects is proactive management, Dr. James E. Sligh emphasized at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.
"The message is that people are living longer with advanced melanoma, but you really need to work with your oncologists to get the absolute benefit patients deserve out of these advanced drugs," he said. "All patients on any of the BRAF inhibitors should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and for 6 months following treatment discontinuation. And while I use this as a guide, there are definitely patients I see for whom 2 months is way too long between visits," he added. "If they’re growing squamous cell carcinomas or verrucous keratoses at a good clip, they need to be seen more often. I’ll see them every other week if need be," said Dr. Sligh, chief of the dermatology division at the University of Arizona, Tucson.
"This is a plea to dermatologists," he continued. "If you have a patient who’s going on a BRAF inhibitor, they need to be seen in your office regularly. And if your next available appointment isn’t until 4 months down the road, you absolutely need to make room for these patients, because after 4 months they may have very large squamous cell carcinomas."
One in four advanced melanoma patients on a BRAF inhibitor – vemurafenib and dabrenafib are the two available thus far – will develop squamous cell carcinomas, Dr. Sligh said. If it’s going to happen, it typically begins in the first month or two of therapy. Caught early, the treatment is simple removal. The same goes for verrucous keratoses, which occur in close to half of treated patients.
"I use cryotherapy in the office, and I give patients 5-FU [5-fluorouracil] so they can start treating a lesion the day they see it, rather than waiting to show it to me a couple of months later," explained Dr. Sligh.
Other common cutaneous adverse events seen as a class effect with the BRAF inhibitors include photosensitivity reactions, seen in approximately one-third of patients in the phase III clinical trials; pruritus, seen in 23%; plantar hyperkeratosis in 10%-20%; and maculopapular rash in 9%.
The pretreatment dermatologic visit is an ideal time for patient education regarding sunscreen use, protective clothing, and the necessity to stay indoors in the event a photosensitivity rash emerges, Dr. Sligh noted. These are issues medical oncologists typically won’t counsel patients about, he said.
"The real advantage to doing this is you want these patients to maintain their optimal dose. For vemurafenib, it’s 960 mg b.i.d. There are very few things that will cause a dose reduction with these drugs, so if cutaneous toxicity is something patients are having a difficult time with, it’s our job as dermatologists to ensure that they have the best chance to make those side effects tolerable. Remaining on the drug is absolutely their best chance for survival," Dr. Sligh continued.
Serious hypersensitivity reactions, including anaphylaxis, as well as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients on a BRAF inhibitor. Such events do require permanent discontinuation of therapy. But that’s not necessarily the end of the road. "There are fantastic new options coming on board each year as alternatives for these people," according to Dr. Sligh.
New primary melanomas can arise while a patient is on BRAF inhibitor therapy. If they are detected early through those bimonthly office visits, the treatment is excision with no dosage adjustment.
Ipilimumab, which targets cytotoxic T-lymphocyte antigen 4, differs from the BRAF inhibitors in that its cutaneous adverse effects can emerge long after the drug is stopped.
"If you see a rash that’s not typical in a patient even 1 or 2 years after they were on ipilimumab, you should still consider that drug to be a likely culprit," Dr. Sligh said.
Trametinib, a MEK inhibitor, was approved last year for the treatment of melanomas with BRAF V600E or V600K mutations. Cutaneous toxicity occurs in close to 90% of patients on the drug, including a 12% rate of severe, grade 3 skin reactions. When trametinib is given in combination with vemurafenib or dabrafenib in an effort to delay emergence of tumor resistance, the result is longer progression-free survival than with either agent alone, and with a lower rate of squamous cell carcinomas and other cutaneous adverse events than with either agent as monotherapy. However, the question of whether or not combination therapy improves overall survival remains unclear, and is the subject of ongoing trials.
Close to half of melanoma patients have a BRAF mutation that makes them a potential candidate for BRAF inhibitor therapy. But in a separate presentation at the meeting, Dr. Michael Postow, an oncologist at Memorial Sloan Kettering Cancer Center in New York, urged dermatologists not to think only of the FDA-approved BRAF test when they have a patient diagnosed with melanoma.
"It’s really worthwhile to do more extensive molecular profiling of those patients, because you may find another targetable mutation," said Dr. Postow. "I would encourage you to refer any patients you have that are being diagnosed with melanoma for a larger institutional evaluation where more extensive molecular characterization of the tumor can be performed," he added.
Dr. Sligh is on the advisory board for and a consultant to Genentech, and he has received research grants from DermSpectra and SciBase. Dr. Postow reported serving as an unpaid adviser to Bristol-Myers Squibb.
SDEF and this news organization are owned by the same parent company.
WAIKOLOA, HAWAII – The spectacular developments in the treatment of advanced melanoma that began with approval of ipilimumab in 2011 continue to accelerate, and these advances promise to keep dermatologists quite busy for the foreseeable future in treating the cutaneous side effects of these targeted therapies.
Cutaneous toxicities requiring medical attention are extremely common with the new therapeutic agents. The key to minimizing their effects is proactive management, Dr. James E. Sligh emphasized at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.
"The message is that people are living longer with advanced melanoma, but you really need to work with your oncologists to get the absolute benefit patients deserve out of these advanced drugs," he said. "All patients on any of the BRAF inhibitors should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and for 6 months following treatment discontinuation. And while I use this as a guide, there are definitely patients I see for whom 2 months is way too long between visits," he added. "If they’re growing squamous cell carcinomas or verrucous keratoses at a good clip, they need to be seen more often. I’ll see them every other week if need be," said Dr. Sligh, chief of the dermatology division at the University of Arizona, Tucson.
"This is a plea to dermatologists," he continued. "If you have a patient who’s going on a BRAF inhibitor, they need to be seen in your office regularly. And if your next available appointment isn’t until 4 months down the road, you absolutely need to make room for these patients, because after 4 months they may have very large squamous cell carcinomas."
One in four advanced melanoma patients on a BRAF inhibitor – vemurafenib and dabrenafib are the two available thus far – will develop squamous cell carcinomas, Dr. Sligh said. If it’s going to happen, it typically begins in the first month or two of therapy. Caught early, the treatment is simple removal. The same goes for verrucous keratoses, which occur in close to half of treated patients.
"I use cryotherapy in the office, and I give patients 5-FU [5-fluorouracil] so they can start treating a lesion the day they see it, rather than waiting to show it to me a couple of months later," explained Dr. Sligh.
Other common cutaneous adverse events seen as a class effect with the BRAF inhibitors include photosensitivity reactions, seen in approximately one-third of patients in the phase III clinical trials; pruritus, seen in 23%; plantar hyperkeratosis in 10%-20%; and maculopapular rash in 9%.
The pretreatment dermatologic visit is an ideal time for patient education regarding sunscreen use, protective clothing, and the necessity to stay indoors in the event a photosensitivity rash emerges, Dr. Sligh noted. These are issues medical oncologists typically won’t counsel patients about, he said.
"The real advantage to doing this is you want these patients to maintain their optimal dose. For vemurafenib, it’s 960 mg b.i.d. There are very few things that will cause a dose reduction with these drugs, so if cutaneous toxicity is something patients are having a difficult time with, it’s our job as dermatologists to ensure that they have the best chance to make those side effects tolerable. Remaining on the drug is absolutely their best chance for survival," Dr. Sligh continued.
Serious hypersensitivity reactions, including anaphylaxis, as well as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients on a BRAF inhibitor. Such events do require permanent discontinuation of therapy. But that’s not necessarily the end of the road. "There are fantastic new options coming on board each year as alternatives for these people," according to Dr. Sligh.
New primary melanomas can arise while a patient is on BRAF inhibitor therapy. If they are detected early through those bimonthly office visits, the treatment is excision with no dosage adjustment.
Ipilimumab, which targets cytotoxic T-lymphocyte antigen 4, differs from the BRAF inhibitors in that its cutaneous adverse effects can emerge long after the drug is stopped.
"If you see a rash that’s not typical in a patient even 1 or 2 years after they were on ipilimumab, you should still consider that drug to be a likely culprit," Dr. Sligh said.
Trametinib, a MEK inhibitor, was approved last year for the treatment of melanomas with BRAF V600E or V600K mutations. Cutaneous toxicity occurs in close to 90% of patients on the drug, including a 12% rate of severe, grade 3 skin reactions. When trametinib is given in combination with vemurafenib or dabrafenib in an effort to delay emergence of tumor resistance, the result is longer progression-free survival than with either agent alone, and with a lower rate of squamous cell carcinomas and other cutaneous adverse events than with either agent as monotherapy. However, the question of whether or not combination therapy improves overall survival remains unclear, and is the subject of ongoing trials.
Close to half of melanoma patients have a BRAF mutation that makes them a potential candidate for BRAF inhibitor therapy. But in a separate presentation at the meeting, Dr. Michael Postow, an oncologist at Memorial Sloan Kettering Cancer Center in New York, urged dermatologists not to think only of the FDA-approved BRAF test when they have a patient diagnosed with melanoma.
"It’s really worthwhile to do more extensive molecular profiling of those patients, because you may find another targetable mutation," said Dr. Postow. "I would encourage you to refer any patients you have that are being diagnosed with melanoma for a larger institutional evaluation where more extensive molecular characterization of the tumor can be performed," he added.
Dr. Sligh is on the advisory board for and a consultant to Genentech, and he has received research grants from DermSpectra and SciBase. Dr. Postow reported serving as an unpaid adviser to Bristol-Myers Squibb.
SDEF and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM SDEF HAWAII DERMATOLOGY SEMINAR
Consumer Reports: Sunscreen SPF claims largely inaccurate
An analysis of 20 sunscreens by Consumer Reports found that only two provided the SPF protection claimed on the label.
The analysis – and rating of overall performance of those sunscreens – was released by the advocacy organization just ahead of Memorial Day weekend, the unofficial start of summer.
According to a survey of 1,000 adults conducted by the Consumer Reports National Research Center, a product’s sun protection factor (SPF) was the most important factor in determining what sunscreen to purchase.
Consumer Reports decided to put those SPF claims to the test in its own labs. The only two that tested at the SPF level claimed were BullFrog WaterArmor Sport InstaCool SPF 50-plus and Coppertone Sensitive Skin SPF 50. One product, Beyond Coastal Natural SPF 30, tested at half its claim. The other products tested at 4%-40% below the claimed SPF.
"We can’t say why our test results differ from the manufacturers’ claims, but they show that SPF isn’t always carved in stone," the Consumer Reports authors wrote.
The group also debunked some of what it called the "myths" about sunscreens, including that sprays provide the best coverage, and that "natural" sunscreens are safer than other sunscreens. In addition, mineral-based sunscreens are no more effective than other sunscreens, says Consumer Reports.
Also, the article said that there is no practical or meaningful difference between a sunscreen labeled for children and one for adults. In most cases, the active ingredients and the concentration of those ingredients are exactly the same. Some of the kids’ sunscreens contain only zinc oxide or titanium dioxide, which may be less irritating than products that contain chemical sunscreens such as avobenzone, according to the article.
The organization tested UVB protection by spreading a standard amount of sunscreen on a volunteer’s back, immersing them in a tub of water for a bit, and then exposing them to six intensities of UVB light from a sun simulator for a standard period of time. The skin patches were examined the next day for redness and the measured SPF was used to calculate the UVB scores.
For UVA, Consumer Reports conducted a critical wavelength test similar to what the Food and Drug Administration requires of manufacturers. The test assesses how well UV rays are absorbed by clear plastic plates that have been treated with the sunscreen.
The overall performance score was based on both the UVA and UVB results.
Among lotions, the best-performing product was Coppertone’s Water Babies SPF 50. Walmart’s less-expensive Equate Ultra Protection SPF 50 was the second-best performer. BullFrog’s WaterArmor Sport InstaCool SPF 50-plus was the top performing spray, followed by Target’s Up & Up Sport SPF 50. Banana Boat Ultra Defense Max Skin Protect SPF 110 spray and Neutrogena Ultimate Sport SPF 70-plus lotion were the highest-performing products with ultra-high SPFs.
The article and ratings are available online to subscribers and will be published in the group’s July 2014 print publication, Consumer Reports.
On Twitter @aliciaault
An analysis of 20 sunscreens by Consumer Reports found that only two provided the SPF protection claimed on the label.
The analysis – and rating of overall performance of those sunscreens – was released by the advocacy organization just ahead of Memorial Day weekend, the unofficial start of summer.
According to a survey of 1,000 adults conducted by the Consumer Reports National Research Center, a product’s sun protection factor (SPF) was the most important factor in determining what sunscreen to purchase.
Consumer Reports decided to put those SPF claims to the test in its own labs. The only two that tested at the SPF level claimed were BullFrog WaterArmor Sport InstaCool SPF 50-plus and Coppertone Sensitive Skin SPF 50. One product, Beyond Coastal Natural SPF 30, tested at half its claim. The other products tested at 4%-40% below the claimed SPF.
"We can’t say why our test results differ from the manufacturers’ claims, but they show that SPF isn’t always carved in stone," the Consumer Reports authors wrote.
The group also debunked some of what it called the "myths" about sunscreens, including that sprays provide the best coverage, and that "natural" sunscreens are safer than other sunscreens. In addition, mineral-based sunscreens are no more effective than other sunscreens, says Consumer Reports.
Also, the article said that there is no practical or meaningful difference between a sunscreen labeled for children and one for adults. In most cases, the active ingredients and the concentration of those ingredients are exactly the same. Some of the kids’ sunscreens contain only zinc oxide or titanium dioxide, which may be less irritating than products that contain chemical sunscreens such as avobenzone, according to the article.
The organization tested UVB protection by spreading a standard amount of sunscreen on a volunteer’s back, immersing them in a tub of water for a bit, and then exposing them to six intensities of UVB light from a sun simulator for a standard period of time. The skin patches were examined the next day for redness and the measured SPF was used to calculate the UVB scores.
For UVA, Consumer Reports conducted a critical wavelength test similar to what the Food and Drug Administration requires of manufacturers. The test assesses how well UV rays are absorbed by clear plastic plates that have been treated with the sunscreen.
The overall performance score was based on both the UVA and UVB results.
Among lotions, the best-performing product was Coppertone’s Water Babies SPF 50. Walmart’s less-expensive Equate Ultra Protection SPF 50 was the second-best performer. BullFrog’s WaterArmor Sport InstaCool SPF 50-plus was the top performing spray, followed by Target’s Up & Up Sport SPF 50. Banana Boat Ultra Defense Max Skin Protect SPF 110 spray and Neutrogena Ultimate Sport SPF 70-plus lotion were the highest-performing products with ultra-high SPFs.
The article and ratings are available online to subscribers and will be published in the group’s July 2014 print publication, Consumer Reports.
On Twitter @aliciaault
An analysis of 20 sunscreens by Consumer Reports found that only two provided the SPF protection claimed on the label.
The analysis – and rating of overall performance of those sunscreens – was released by the advocacy organization just ahead of Memorial Day weekend, the unofficial start of summer.
According to a survey of 1,000 adults conducted by the Consumer Reports National Research Center, a product’s sun protection factor (SPF) was the most important factor in determining what sunscreen to purchase.
Consumer Reports decided to put those SPF claims to the test in its own labs. The only two that tested at the SPF level claimed were BullFrog WaterArmor Sport InstaCool SPF 50-plus and Coppertone Sensitive Skin SPF 50. One product, Beyond Coastal Natural SPF 30, tested at half its claim. The other products tested at 4%-40% below the claimed SPF.
"We can’t say why our test results differ from the manufacturers’ claims, but they show that SPF isn’t always carved in stone," the Consumer Reports authors wrote.
The group also debunked some of what it called the "myths" about sunscreens, including that sprays provide the best coverage, and that "natural" sunscreens are safer than other sunscreens. In addition, mineral-based sunscreens are no more effective than other sunscreens, says Consumer Reports.
Also, the article said that there is no practical or meaningful difference between a sunscreen labeled for children and one for adults. In most cases, the active ingredients and the concentration of those ingredients are exactly the same. Some of the kids’ sunscreens contain only zinc oxide or titanium dioxide, which may be less irritating than products that contain chemical sunscreens such as avobenzone, according to the article.
The organization tested UVB protection by spreading a standard amount of sunscreen on a volunteer’s back, immersing them in a tub of water for a bit, and then exposing them to six intensities of UVB light from a sun simulator for a standard period of time. The skin patches were examined the next day for redness and the measured SPF was used to calculate the UVB scores.
For UVA, Consumer Reports conducted a critical wavelength test similar to what the Food and Drug Administration requires of manufacturers. The test assesses how well UV rays are absorbed by clear plastic plates that have been treated with the sunscreen.
The overall performance score was based on both the UVA and UVB results.
Among lotions, the best-performing product was Coppertone’s Water Babies SPF 50. Walmart’s less-expensive Equate Ultra Protection SPF 50 was the second-best performer. BullFrog’s WaterArmor Sport InstaCool SPF 50-plus was the top performing spray, followed by Target’s Up & Up Sport SPF 50. Banana Boat Ultra Defense Max Skin Protect SPF 110 spray and Neutrogena Ultimate Sport SPF 70-plus lotion were the highest-performing products with ultra-high SPFs.
The article and ratings are available online to subscribers and will be published in the group’s July 2014 print publication, Consumer Reports.
On Twitter @aliciaault
Drugs approved in 2013
In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [223Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.
There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.
The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.
Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.
There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.
The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.
Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.
Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.
Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).
Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.
Technetium (99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (99mTc). Animal reproduction studies have not been conducted. 99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.
The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.
Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta2-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.
There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at [email protected].
In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [223Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.
There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.
The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.
Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.
There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.
The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.
Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.
Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.
Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).
Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.
Technetium (99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (99mTc). Animal reproduction studies have not been conducted. 99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.
The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.
Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta2-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.
There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at [email protected].
In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [223Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.
There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.
The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.
Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.
There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.
The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.
Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.
Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.
Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).
Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.
Technetium (99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (99mTc). Animal reproduction studies have not been conducted. 99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.
The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.
Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta2-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.
There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at [email protected].
Nonmelanoma skin cancer linked to increased fracture risk in postmenopausal women
ALBUQUERQUE – Postmenopausal women who reported a history of nonmelanoma skin cancer were almost 16% more likely to sustain a lower arm fracture than were women without a skin cancer history, according to a large, prospective, longitudinal study.
Women with prior nonmelanoma skin cancers (NMSCs) also were more likely to suffer a subsequent hip fracture, although the association did not reach statistical significance, said Eric Anderson of the dermatology department at Stanford (Calif.) University School of Medicine.
"These results suggest that prior history of NMSC is associated with an increased risk of subsequent bone fracture, contrary to our hypothesis," noted Mr. Anderson. He presented the findings at the annual meeting of the Society for Investigational Dermatology.
Nonmelanoma skin cancer has been correlated with decreased fracture risk in at least one small cohort study, Mr. Anderson said (Osteoporos. Int. 2007;18:687-92). However, patients with NMSC also have been shown to wear more sunscreen and limit their sun exposure after diagnosis, which might lower their vitamin D levels and increase their fracture risk, Mr. Anderson noted (Cancer Causes Control 2012;23:133-40).
To better clarify the relationship between NMSC and fracture risk, Mr. Anderson and his associates compared prospective data from 4,289 women with self-reported NMSC and 67,470 women who did not report a history of NMSC at baseline. The participants were from the Womens Health Initiative, a prospective longitudinal cohort study of postmenopausal women aged 50-79 years who were enrolled at 40 centers in the United States. Participants were followed for more than 10 years, and new spine, hip, and lower arm fractures were recorded, Mr. Anderson said.
In age-adjusted Cox proportional hazards models, women with a history of NMSC were 1.55 times more likely to sustain a hip fracture (95% confidence interval, 1.31-1.85; P < 0.0001), 1.29 times more likely to suffer a spine fracture (95% CI, 1.10-1.51; P = 0.0018), and 1.28 times more likely to sustain a lower arm fracture (95% CI, 1.13-1.45; P < 0.0001) than were women who did not report a history of NMSC at baseline, Mr. Anderson and his associates reported.
After adjusting for sun exposure, sunscreen use, vitamin D intake, physical activity, and other risk factors for fracture, only lower arm fracture remained statistically significant (hazard ratio, 1.16; 95% CI, 1.31-1.85; P = 0.02), although hip fracture was borderline significant (HR, 1.18; 95% CI, 0.99-1.41; P = 0.06), the investigators reported. Baseline hip bone marrow density was not associated with risk of NMSC in a subgroup analysis of 4,267 women with available data, Mr. Anderson said.
"We’re inclined to believe that this increased fracture risk may be due to sun exposure avoidance after NMSC diagnosis," said Mr. Anderson. He added that, in future studies, the investigators would compare serum vitamin D levels between participants with and without a history of NMSC, and explore temporal relationships between diagnosis of NMSC and fracture occurrence.
The National Institutes of Health and the Medical Scholars Research Program at Stanford University funded the research. Mr. Anderson reported no conflicts of interest.
ALBUQUERQUE – Postmenopausal women who reported a history of nonmelanoma skin cancer were almost 16% more likely to sustain a lower arm fracture than were women without a skin cancer history, according to a large, prospective, longitudinal study.
Women with prior nonmelanoma skin cancers (NMSCs) also were more likely to suffer a subsequent hip fracture, although the association did not reach statistical significance, said Eric Anderson of the dermatology department at Stanford (Calif.) University School of Medicine.
"These results suggest that prior history of NMSC is associated with an increased risk of subsequent bone fracture, contrary to our hypothesis," noted Mr. Anderson. He presented the findings at the annual meeting of the Society for Investigational Dermatology.
Nonmelanoma skin cancer has been correlated with decreased fracture risk in at least one small cohort study, Mr. Anderson said (Osteoporos. Int. 2007;18:687-92). However, patients with NMSC also have been shown to wear more sunscreen and limit their sun exposure after diagnosis, which might lower their vitamin D levels and increase their fracture risk, Mr. Anderson noted (Cancer Causes Control 2012;23:133-40).
To better clarify the relationship between NMSC and fracture risk, Mr. Anderson and his associates compared prospective data from 4,289 women with self-reported NMSC and 67,470 women who did not report a history of NMSC at baseline. The participants were from the Womens Health Initiative, a prospective longitudinal cohort study of postmenopausal women aged 50-79 years who were enrolled at 40 centers in the United States. Participants were followed for more than 10 years, and new spine, hip, and lower arm fractures were recorded, Mr. Anderson said.
In age-adjusted Cox proportional hazards models, women with a history of NMSC were 1.55 times more likely to sustain a hip fracture (95% confidence interval, 1.31-1.85; P < 0.0001), 1.29 times more likely to suffer a spine fracture (95% CI, 1.10-1.51; P = 0.0018), and 1.28 times more likely to sustain a lower arm fracture (95% CI, 1.13-1.45; P < 0.0001) than were women who did not report a history of NMSC at baseline, Mr. Anderson and his associates reported.
After adjusting for sun exposure, sunscreen use, vitamin D intake, physical activity, and other risk factors for fracture, only lower arm fracture remained statistically significant (hazard ratio, 1.16; 95% CI, 1.31-1.85; P = 0.02), although hip fracture was borderline significant (HR, 1.18; 95% CI, 0.99-1.41; P = 0.06), the investigators reported. Baseline hip bone marrow density was not associated with risk of NMSC in a subgroup analysis of 4,267 women with available data, Mr. Anderson said.
"We’re inclined to believe that this increased fracture risk may be due to sun exposure avoidance after NMSC diagnosis," said Mr. Anderson. He added that, in future studies, the investigators would compare serum vitamin D levels between participants with and without a history of NMSC, and explore temporal relationships between diagnosis of NMSC and fracture occurrence.
The National Institutes of Health and the Medical Scholars Research Program at Stanford University funded the research. Mr. Anderson reported no conflicts of interest.
ALBUQUERQUE – Postmenopausal women who reported a history of nonmelanoma skin cancer were almost 16% more likely to sustain a lower arm fracture than were women without a skin cancer history, according to a large, prospective, longitudinal study.
Women with prior nonmelanoma skin cancers (NMSCs) also were more likely to suffer a subsequent hip fracture, although the association did not reach statistical significance, said Eric Anderson of the dermatology department at Stanford (Calif.) University School of Medicine.
"These results suggest that prior history of NMSC is associated with an increased risk of subsequent bone fracture, contrary to our hypothesis," noted Mr. Anderson. He presented the findings at the annual meeting of the Society for Investigational Dermatology.
Nonmelanoma skin cancer has been correlated with decreased fracture risk in at least one small cohort study, Mr. Anderson said (Osteoporos. Int. 2007;18:687-92). However, patients with NMSC also have been shown to wear more sunscreen and limit their sun exposure after diagnosis, which might lower their vitamin D levels and increase their fracture risk, Mr. Anderson noted (Cancer Causes Control 2012;23:133-40).
To better clarify the relationship between NMSC and fracture risk, Mr. Anderson and his associates compared prospective data from 4,289 women with self-reported NMSC and 67,470 women who did not report a history of NMSC at baseline. The participants were from the Womens Health Initiative, a prospective longitudinal cohort study of postmenopausal women aged 50-79 years who were enrolled at 40 centers in the United States. Participants were followed for more than 10 years, and new spine, hip, and lower arm fractures were recorded, Mr. Anderson said.
In age-adjusted Cox proportional hazards models, women with a history of NMSC were 1.55 times more likely to sustain a hip fracture (95% confidence interval, 1.31-1.85; P < 0.0001), 1.29 times more likely to suffer a spine fracture (95% CI, 1.10-1.51; P = 0.0018), and 1.28 times more likely to sustain a lower arm fracture (95% CI, 1.13-1.45; P < 0.0001) than were women who did not report a history of NMSC at baseline, Mr. Anderson and his associates reported.
After adjusting for sun exposure, sunscreen use, vitamin D intake, physical activity, and other risk factors for fracture, only lower arm fracture remained statistically significant (hazard ratio, 1.16; 95% CI, 1.31-1.85; P = 0.02), although hip fracture was borderline significant (HR, 1.18; 95% CI, 0.99-1.41; P = 0.06), the investigators reported. Baseline hip bone marrow density was not associated with risk of NMSC in a subgroup analysis of 4,267 women with available data, Mr. Anderson said.
"We’re inclined to believe that this increased fracture risk may be due to sun exposure avoidance after NMSC diagnosis," said Mr. Anderson. He added that, in future studies, the investigators would compare serum vitamin D levels between participants with and without a history of NMSC, and explore temporal relationships between diagnosis of NMSC and fracture occurrence.
The National Institutes of Health and the Medical Scholars Research Program at Stanford University funded the research. Mr. Anderson reported no conflicts of interest.
AT THE 2014 SID ANNUAL MEETING
Key clinical point: A history of nonmelanoma skin cancer may predispose patients to bone fractures.
Major finding: Incident lower arm fracture was significantly associated with a self-reported history of nonmelanoma skin cancer (hazard ratio, 1.16; P = 0.02).
Data source: Ten-year prospective cohort study of 4,289 women who self-reported a history of nonmelanoma skin cancer and 67,470 women who reported no history of NMSC.
Disclosures: The National Institutes of Health and the Medical Scholars Research Program at Stanford University funded the research. Mr. Anderson reported no conflicts of interest.
Topical tazarotene did not improve response to imiquimod 5% in lentigo maligna
ALBUQUERQUE – Adding topical tazarotene did not improve response to 5% imiquimod in lentigo maligna, based on data from nearly 300 patients.
But patients with higher levels of inflammation in response to topical therapy had significantly smaller surgical defects, required fewer surgical stages, and had improved clearance rates, said Nicholas Blickenstaff, a third-year medical student at the University of Utah and a former researcher at the Huntsman Cancer Institute, both in Salt Lake City.
Surgical excision with negative margins is the standard treatment for lentigo maligna, but the cancer’s predilection for the head and neck can cause disfigurement, especially with large tumors. Patients sometimes elect nonsurgical treatment because of cosmetic concerns, comorbidities, or both, Mr. Blickenstaff said at the annual meeting of the Society for Investigative Dermatology.
A prior study found that adding the topical retinoid tazarotene to 5% imiquimod showed a trend toward improved clearance in lentigo maligna, but the association did not reach statistical significance (Arch. Dermatol. 2012;148:592-6).
Based on those data, "we looked at a larger treatment cohort to determine if adding tazarotene to topical imiquimod increased clearance rates of lentigo maligna, as defined by the presence or absence of residual tumor at the time of surgical removal," said Mr. Blickenstaff.
He and his associates at the Huntsman Cancer Institute and the University of Utah School of Medicine conducted a retrospective chart study of 282 patients with an average age of 68 years and biopsy-confirmed lentigo maligna.
A total of 188 patients with 194 lesions received imiquimod 5% cream 5 days a week for 1-3 months, depending on the amount of inflammation observed, said Mr. Blickenstaff. Another group of 94 patients with 98 lesions received the same treatment plus tazarotene 0.1% gel twice weekly. Patients then underwent conservative staged excisions using Melan-A immunostaining on frozen sections to confirm negative margins. The investigators followed patients for an average of 43 months.
Using chart data, the investigators graded patients’ inflammatory responses to topical therapy on a 0-3 scale, with 0 interpreted as no erythema, 1 as mild erythema, 2 as moderate erythema, and 3 as severe erythema with possible surface erosions, said Mr. Blickenstaff.
The researchers found no difference between the two topical regimens in terms of presurgical clearance (P = 0.97). However, patients with higher levels of inflammation (scores of 2 or 3) were significantly more likely to be free of tumor at surgery than were other patients (odds ratio, 2.8; P = 0.002). Patients with more inflammation also had decreased postsurgical defect sizes (P = 0.023), and needed fewer stages to achieve clear margins (P = 0.015), Mr. Blickenstaff and his associates reported.
Patients required an average of 1.5 stages and a maximum of five stages to achieve clearance, Mr. Blickenstaff added. A total of four patients (1.4%) had a recurrence of lentigo maligna, and there were no deaths related to treatment or lentigo maligna, he said.
Based on the findings, "studies should evaluate whether the quality of the inflammatory response with 5% imiquimod is unique and required for efficacy," said Mr. Blickenstaff.
He is now a research fellow at UCSF Medical Center in San Francisco. He reported no conflicts of interest. The Huntsman Cancer Institute funded the study.
ALBUQUERQUE – Adding topical tazarotene did not improve response to 5% imiquimod in lentigo maligna, based on data from nearly 300 patients.
But patients with higher levels of inflammation in response to topical therapy had significantly smaller surgical defects, required fewer surgical stages, and had improved clearance rates, said Nicholas Blickenstaff, a third-year medical student at the University of Utah and a former researcher at the Huntsman Cancer Institute, both in Salt Lake City.
Surgical excision with negative margins is the standard treatment for lentigo maligna, but the cancer’s predilection for the head and neck can cause disfigurement, especially with large tumors. Patients sometimes elect nonsurgical treatment because of cosmetic concerns, comorbidities, or both, Mr. Blickenstaff said at the annual meeting of the Society for Investigative Dermatology.
A prior study found that adding the topical retinoid tazarotene to 5% imiquimod showed a trend toward improved clearance in lentigo maligna, but the association did not reach statistical significance (Arch. Dermatol. 2012;148:592-6).
Based on those data, "we looked at a larger treatment cohort to determine if adding tazarotene to topical imiquimod increased clearance rates of lentigo maligna, as defined by the presence or absence of residual tumor at the time of surgical removal," said Mr. Blickenstaff.
He and his associates at the Huntsman Cancer Institute and the University of Utah School of Medicine conducted a retrospective chart study of 282 patients with an average age of 68 years and biopsy-confirmed lentigo maligna.
A total of 188 patients with 194 lesions received imiquimod 5% cream 5 days a week for 1-3 months, depending on the amount of inflammation observed, said Mr. Blickenstaff. Another group of 94 patients with 98 lesions received the same treatment plus tazarotene 0.1% gel twice weekly. Patients then underwent conservative staged excisions using Melan-A immunostaining on frozen sections to confirm negative margins. The investigators followed patients for an average of 43 months.
Using chart data, the investigators graded patients’ inflammatory responses to topical therapy on a 0-3 scale, with 0 interpreted as no erythema, 1 as mild erythema, 2 as moderate erythema, and 3 as severe erythema with possible surface erosions, said Mr. Blickenstaff.
The researchers found no difference between the two topical regimens in terms of presurgical clearance (P = 0.97). However, patients with higher levels of inflammation (scores of 2 or 3) were significantly more likely to be free of tumor at surgery than were other patients (odds ratio, 2.8; P = 0.002). Patients with more inflammation also had decreased postsurgical defect sizes (P = 0.023), and needed fewer stages to achieve clear margins (P = 0.015), Mr. Blickenstaff and his associates reported.
Patients required an average of 1.5 stages and a maximum of five stages to achieve clearance, Mr. Blickenstaff added. A total of four patients (1.4%) had a recurrence of lentigo maligna, and there were no deaths related to treatment or lentigo maligna, he said.
Based on the findings, "studies should evaluate whether the quality of the inflammatory response with 5% imiquimod is unique and required for efficacy," said Mr. Blickenstaff.
He is now a research fellow at UCSF Medical Center in San Francisco. He reported no conflicts of interest. The Huntsman Cancer Institute funded the study.
ALBUQUERQUE – Adding topical tazarotene did not improve response to 5% imiquimod in lentigo maligna, based on data from nearly 300 patients.
But patients with higher levels of inflammation in response to topical therapy had significantly smaller surgical defects, required fewer surgical stages, and had improved clearance rates, said Nicholas Blickenstaff, a third-year medical student at the University of Utah and a former researcher at the Huntsman Cancer Institute, both in Salt Lake City.
Surgical excision with negative margins is the standard treatment for lentigo maligna, but the cancer’s predilection for the head and neck can cause disfigurement, especially with large tumors. Patients sometimes elect nonsurgical treatment because of cosmetic concerns, comorbidities, or both, Mr. Blickenstaff said at the annual meeting of the Society for Investigative Dermatology.
A prior study found that adding the topical retinoid tazarotene to 5% imiquimod showed a trend toward improved clearance in lentigo maligna, but the association did not reach statistical significance (Arch. Dermatol. 2012;148:592-6).
Based on those data, "we looked at a larger treatment cohort to determine if adding tazarotene to topical imiquimod increased clearance rates of lentigo maligna, as defined by the presence or absence of residual tumor at the time of surgical removal," said Mr. Blickenstaff.
He and his associates at the Huntsman Cancer Institute and the University of Utah School of Medicine conducted a retrospective chart study of 282 patients with an average age of 68 years and biopsy-confirmed lentigo maligna.
A total of 188 patients with 194 lesions received imiquimod 5% cream 5 days a week for 1-3 months, depending on the amount of inflammation observed, said Mr. Blickenstaff. Another group of 94 patients with 98 lesions received the same treatment plus tazarotene 0.1% gel twice weekly. Patients then underwent conservative staged excisions using Melan-A immunostaining on frozen sections to confirm negative margins. The investigators followed patients for an average of 43 months.
Using chart data, the investigators graded patients’ inflammatory responses to topical therapy on a 0-3 scale, with 0 interpreted as no erythema, 1 as mild erythema, 2 as moderate erythema, and 3 as severe erythema with possible surface erosions, said Mr. Blickenstaff.
The researchers found no difference between the two topical regimens in terms of presurgical clearance (P = 0.97). However, patients with higher levels of inflammation (scores of 2 or 3) were significantly more likely to be free of tumor at surgery than were other patients (odds ratio, 2.8; P = 0.002). Patients with more inflammation also had decreased postsurgical defect sizes (P = 0.023), and needed fewer stages to achieve clear margins (P = 0.015), Mr. Blickenstaff and his associates reported.
Patients required an average of 1.5 stages and a maximum of five stages to achieve clearance, Mr. Blickenstaff added. A total of four patients (1.4%) had a recurrence of lentigo maligna, and there were no deaths related to treatment or lentigo maligna, he said.
Based on the findings, "studies should evaluate whether the quality of the inflammatory response with 5% imiquimod is unique and required for efficacy," said Mr. Blickenstaff.
He is now a research fellow at UCSF Medical Center in San Francisco. He reported no conflicts of interest. The Huntsman Cancer Institute funded the study.
AT THE 2014 SID ANNUAL MEETING
Key clinical point: Patients with higher levels of inflammation in response to topical therapy were more likely not to have residual tumor at surgery than were other patients (odds ratio, 2.8).
Major finding: Adding topical tazarotene did not improve response to 5% imiquimod in lentigo maligna (P = 0.97).
Data source: A chart review of 188 patients with 194 lesions of lentigo maligna who received imiquimod 5% cream 5 days a week for 1-3 months, and 94 patients with 98 lesions who received the same treatment plus tazarotene 0.1% gel twice weekly.
Disclosures: The Huntsman Cancer Institute funded the study. Mr. Blickenstaff reported no conflicts of interest.
Infrared detector distinguished malignant and benign skin lesions
ALBUQUERQUE – A long-wave infrared system distinguished malignant and benign skin lesions with a sensitivity of 96.97% and a specificity of 78.05%, with skin biopsies used as a benchmark, in a pilot study of 74 patients.
The results "suggest the technique is promising as a noninvasive screening tool" and merits continued research and development to improve sensitivity, specificity, and statistical confidence, reported Stephen Myers, Ph.D., of Skinfrared, and his associates.
Recent advances in infrared technology have led to the development of imaging devices that noninvasively detect tumors, based on differential thermal properties of malignant versus healthy tissue. The long-wave infrared detection device used in the pilot study was designed to identify thermal signatures of suspicious lesions and surrounding skin after the application of a temperature stimulus, Dr. Myers said at the annual conference of the Society for Investigative Dermatology.
In the United States skin cancers are diagnosed more often than all other cancers combined, noted Dr. Myers, but screening for them "requires the skill of a highly trained dermatologist," who must assess a range of morphologic characteristics. "This is a rather subjective approach that causes many biopsies to be performed on benign lesions," Dr. Myers added.
To test the device, investigators at the University of New Mexico, Albuquerque, Dermatology Clinic offered patients with suspicious skin lesions the option of being evaluated with the infrared device before undergoing biopsy.
The device has infrared and visible cameras, as well as a registration marker, a cold air source, and a computer and software to guide image acquisition and analysis, Dr. Myers said. Investigators placed the registration marker near the skin lesion of interest, captured a visible image of the lesion, and then took a 15-second baseline thermal image sequence. After cooling the lesions and surrounding skin to 10° C, they measured and compared 3-minute thermal recovery rates for the lesion and surrounding skin.
Participants averaged 55 years of age, and 53% were male. A total of 102 suspicious lesions were tested. Based on biopsy results, 55% were benign, 34% were basal cell carcinomas, 7% were squamous cell carcinomas, and 4% were melanomas, Dr. Myers reported. The receiver operating curve – calculated to assess the test’s ability to classify skin lesions – had an area under the curve of 95.3% (95% confidence interval, 90.0-99.0). Using biopsy results as a benchmark, the infrared device had a sensitivity of 96.97% and a specificity of 78.05%, Dr. Myers said.
The study was supported by the National Science Foundation and Skinfrared, which makes the device. Dr. Myers is an employee of Skinfrared.
ALBUQUERQUE – A long-wave infrared system distinguished malignant and benign skin lesions with a sensitivity of 96.97% and a specificity of 78.05%, with skin biopsies used as a benchmark, in a pilot study of 74 patients.
The results "suggest the technique is promising as a noninvasive screening tool" and merits continued research and development to improve sensitivity, specificity, and statistical confidence, reported Stephen Myers, Ph.D., of Skinfrared, and his associates.
Recent advances in infrared technology have led to the development of imaging devices that noninvasively detect tumors, based on differential thermal properties of malignant versus healthy tissue. The long-wave infrared detection device used in the pilot study was designed to identify thermal signatures of suspicious lesions and surrounding skin after the application of a temperature stimulus, Dr. Myers said at the annual conference of the Society for Investigative Dermatology.
In the United States skin cancers are diagnosed more often than all other cancers combined, noted Dr. Myers, but screening for them "requires the skill of a highly trained dermatologist," who must assess a range of morphologic characteristics. "This is a rather subjective approach that causes many biopsies to be performed on benign lesions," Dr. Myers added.
To test the device, investigators at the University of New Mexico, Albuquerque, Dermatology Clinic offered patients with suspicious skin lesions the option of being evaluated with the infrared device before undergoing biopsy.
The device has infrared and visible cameras, as well as a registration marker, a cold air source, and a computer and software to guide image acquisition and analysis, Dr. Myers said. Investigators placed the registration marker near the skin lesion of interest, captured a visible image of the lesion, and then took a 15-second baseline thermal image sequence. After cooling the lesions and surrounding skin to 10° C, they measured and compared 3-minute thermal recovery rates for the lesion and surrounding skin.
Participants averaged 55 years of age, and 53% were male. A total of 102 suspicious lesions were tested. Based on biopsy results, 55% were benign, 34% were basal cell carcinomas, 7% were squamous cell carcinomas, and 4% were melanomas, Dr. Myers reported. The receiver operating curve – calculated to assess the test’s ability to classify skin lesions – had an area under the curve of 95.3% (95% confidence interval, 90.0-99.0). Using biopsy results as a benchmark, the infrared device had a sensitivity of 96.97% and a specificity of 78.05%, Dr. Myers said.
The study was supported by the National Science Foundation and Skinfrared, which makes the device. Dr. Myers is an employee of Skinfrared.
ALBUQUERQUE – A long-wave infrared system distinguished malignant and benign skin lesions with a sensitivity of 96.97% and a specificity of 78.05%, with skin biopsies used as a benchmark, in a pilot study of 74 patients.
The results "suggest the technique is promising as a noninvasive screening tool" and merits continued research and development to improve sensitivity, specificity, and statistical confidence, reported Stephen Myers, Ph.D., of Skinfrared, and his associates.
Recent advances in infrared technology have led to the development of imaging devices that noninvasively detect tumors, based on differential thermal properties of malignant versus healthy tissue. The long-wave infrared detection device used in the pilot study was designed to identify thermal signatures of suspicious lesions and surrounding skin after the application of a temperature stimulus, Dr. Myers said at the annual conference of the Society for Investigative Dermatology.
In the United States skin cancers are diagnosed more often than all other cancers combined, noted Dr. Myers, but screening for them "requires the skill of a highly trained dermatologist," who must assess a range of morphologic characteristics. "This is a rather subjective approach that causes many biopsies to be performed on benign lesions," Dr. Myers added.
To test the device, investigators at the University of New Mexico, Albuquerque, Dermatology Clinic offered patients with suspicious skin lesions the option of being evaluated with the infrared device before undergoing biopsy.
The device has infrared and visible cameras, as well as a registration marker, a cold air source, and a computer and software to guide image acquisition and analysis, Dr. Myers said. Investigators placed the registration marker near the skin lesion of interest, captured a visible image of the lesion, and then took a 15-second baseline thermal image sequence. After cooling the lesions and surrounding skin to 10° C, they measured and compared 3-minute thermal recovery rates for the lesion and surrounding skin.
Participants averaged 55 years of age, and 53% were male. A total of 102 suspicious lesions were tested. Based on biopsy results, 55% were benign, 34% were basal cell carcinomas, 7% were squamous cell carcinomas, and 4% were melanomas, Dr. Myers reported. The receiver operating curve – calculated to assess the test’s ability to classify skin lesions – had an area under the curve of 95.3% (95% confidence interval, 90.0-99.0). Using biopsy results as a benchmark, the infrared device had a sensitivity of 96.97% and a specificity of 78.05%, Dr. Myers said.
The study was supported by the National Science Foundation and Skinfrared, which makes the device. Dr. Myers is an employee of Skinfrared.
AT THE 2014 SID ANNUAL MEETING
Major finding: Malignant skin lesions (basal cell carcinomas, squamous cell carcinomas, and malignant melanomas) were distinguished from benign lesions with a sensitivity of 96.97% and a specificity of 78.05%.
Data source: Observational pilot study of 74 patients with 102 suspicious skin lesions who underwent infrared imaging followed by biopsy.
Disclosures: The study was supported by the National Science Foundation and Skinfrared, which makes the device. Dr. Myers is an employee of Skinfrared.
Single-fraction radiation therapy showed promise in metastatic Merkel cell carcinoma
ALBUQUERQUE – Single-fraction radiotherapy of distant metastatic Merkel cell carcinomas led to complete response rates ranging from 52% to 81%, and caused no adverse effects except rare transient pain flares, according to a single-center, single-arm study of 26 patients.
The rate of initial response was 94%, and three-quarters of responders never progressed during the study period, Dr. Paul Nghiem said at the annual meeting of the Society for Investigative Dermatology.
Merkel cell carcinoma (MCC) creates a "terribly frustrating situation" when it metastasizes because although two-thirds of patients initially respond to chemotherapy, the effect is short-lived, with a median progression-free survival of only 94 days, said Dr. Nghiem, professor of dermatology at the University of Washington, Seattle.
Radiation therapy is often used as an adjuvant or palliative treatment in MCC, but it is almost always fractionated, requiring multiple visits and potentially killing T cells that function in tumor immunity, Dr. Nghiem said. In light of evidence that single-fraction radiotherapy (SFRT) enhanced tumor immunity in mice, he and his colleagues at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle decided to "think outside the box and do something different."
Therefore, in 2010, the researchers began using 8-Gy SFRT on distant MCC metastases. In all, they targeted 93 tumors in 26 patients (median age, 68 years). Survivors were followed for a median of 252 days (range, 76-699 days). The median tumor size was 4 cm (range, 1-19 cm), and patients had 1-28 tumors, with an average of 3.5 tumors per patient.
The investigators classified half of patients (n = 13) as high risk because they were immunosuppressed and/or had prior chemotherapy. Other patients were categorized as low risk. High-risk patients had 60 tumors and a 3.5-month median interval from chemotherapy to start of SFRT. The low-risk group had 33 tumors.
A complete response was seen in 81% of tumors in low-risk patients and 52% of tumors in high-risk patients (P = .008), Dr. Nghiem reported. No tumor that completely responded ever recurred, regardless of risk, he said. In one case, a patient with a 5-cm metastasis compressing the trachea reported greater ease of breathing several days after SFRT, and subsequent imaging studies showed complete response with no recurrence at 20 months, he said, adding that the patient remained on an immunostimulant.
The rate of recurrence also was significantly lower in low-risk (9%) versus high-risk patients (30%; P = .02), Dr. Nghiem said. The P value "was statistically significant in this midsize trial, suggesting that the immune system really matters in controlling these lesions," he said, adding that Merkel cell carcinoma, "maybe more than most other cancers, is extremely linked to immune function. As we increase radiation dose, we see more cancer killing [activity], and more immune cell activation at lower doses."
The investigators did not perform post-treatment biopsies to quantify abscopal effects, Dr. Nghiem noted.
The National Cancer Institute, the American Cancer Society, and the National Institutes of Health funded the research. Dr. Nghiem reported no relevant conflicts of interest.
ALBUQUERQUE – Single-fraction radiotherapy of distant metastatic Merkel cell carcinomas led to complete response rates ranging from 52% to 81%, and caused no adverse effects except rare transient pain flares, according to a single-center, single-arm study of 26 patients.
The rate of initial response was 94%, and three-quarters of responders never progressed during the study period, Dr. Paul Nghiem said at the annual meeting of the Society for Investigative Dermatology.
Merkel cell carcinoma (MCC) creates a "terribly frustrating situation" when it metastasizes because although two-thirds of patients initially respond to chemotherapy, the effect is short-lived, with a median progression-free survival of only 94 days, said Dr. Nghiem, professor of dermatology at the University of Washington, Seattle.
Radiation therapy is often used as an adjuvant or palliative treatment in MCC, but it is almost always fractionated, requiring multiple visits and potentially killing T cells that function in tumor immunity, Dr. Nghiem said. In light of evidence that single-fraction radiotherapy (SFRT) enhanced tumor immunity in mice, he and his colleagues at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle decided to "think outside the box and do something different."
Therefore, in 2010, the researchers began using 8-Gy SFRT on distant MCC metastases. In all, they targeted 93 tumors in 26 patients (median age, 68 years). Survivors were followed for a median of 252 days (range, 76-699 days). The median tumor size was 4 cm (range, 1-19 cm), and patients had 1-28 tumors, with an average of 3.5 tumors per patient.
The investigators classified half of patients (n = 13) as high risk because they were immunosuppressed and/or had prior chemotherapy. Other patients were categorized as low risk. High-risk patients had 60 tumors and a 3.5-month median interval from chemotherapy to start of SFRT. The low-risk group had 33 tumors.
A complete response was seen in 81% of tumors in low-risk patients and 52% of tumors in high-risk patients (P = .008), Dr. Nghiem reported. No tumor that completely responded ever recurred, regardless of risk, he said. In one case, a patient with a 5-cm metastasis compressing the trachea reported greater ease of breathing several days after SFRT, and subsequent imaging studies showed complete response with no recurrence at 20 months, he said, adding that the patient remained on an immunostimulant.
The rate of recurrence also was significantly lower in low-risk (9%) versus high-risk patients (30%; P = .02), Dr. Nghiem said. The P value "was statistically significant in this midsize trial, suggesting that the immune system really matters in controlling these lesions," he said, adding that Merkel cell carcinoma, "maybe more than most other cancers, is extremely linked to immune function. As we increase radiation dose, we see more cancer killing [activity], and more immune cell activation at lower doses."
The investigators did not perform post-treatment biopsies to quantify abscopal effects, Dr. Nghiem noted.
The National Cancer Institute, the American Cancer Society, and the National Institutes of Health funded the research. Dr. Nghiem reported no relevant conflicts of interest.
ALBUQUERQUE – Single-fraction radiotherapy of distant metastatic Merkel cell carcinomas led to complete response rates ranging from 52% to 81%, and caused no adverse effects except rare transient pain flares, according to a single-center, single-arm study of 26 patients.
The rate of initial response was 94%, and three-quarters of responders never progressed during the study period, Dr. Paul Nghiem said at the annual meeting of the Society for Investigative Dermatology.
Merkel cell carcinoma (MCC) creates a "terribly frustrating situation" when it metastasizes because although two-thirds of patients initially respond to chemotherapy, the effect is short-lived, with a median progression-free survival of only 94 days, said Dr. Nghiem, professor of dermatology at the University of Washington, Seattle.
Radiation therapy is often used as an adjuvant or palliative treatment in MCC, but it is almost always fractionated, requiring multiple visits and potentially killing T cells that function in tumor immunity, Dr. Nghiem said. In light of evidence that single-fraction radiotherapy (SFRT) enhanced tumor immunity in mice, he and his colleagues at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle decided to "think outside the box and do something different."
Therefore, in 2010, the researchers began using 8-Gy SFRT on distant MCC metastases. In all, they targeted 93 tumors in 26 patients (median age, 68 years). Survivors were followed for a median of 252 days (range, 76-699 days). The median tumor size was 4 cm (range, 1-19 cm), and patients had 1-28 tumors, with an average of 3.5 tumors per patient.
The investigators classified half of patients (n = 13) as high risk because they were immunosuppressed and/or had prior chemotherapy. Other patients were categorized as low risk. High-risk patients had 60 tumors and a 3.5-month median interval from chemotherapy to start of SFRT. The low-risk group had 33 tumors.
A complete response was seen in 81% of tumors in low-risk patients and 52% of tumors in high-risk patients (P = .008), Dr. Nghiem reported. No tumor that completely responded ever recurred, regardless of risk, he said. In one case, a patient with a 5-cm metastasis compressing the trachea reported greater ease of breathing several days after SFRT, and subsequent imaging studies showed complete response with no recurrence at 20 months, he said, adding that the patient remained on an immunostimulant.
The rate of recurrence also was significantly lower in low-risk (9%) versus high-risk patients (30%; P = .02), Dr. Nghiem said. The P value "was statistically significant in this midsize trial, suggesting that the immune system really matters in controlling these lesions," he said, adding that Merkel cell carcinoma, "maybe more than most other cancers, is extremely linked to immune function. As we increase radiation dose, we see more cancer killing [activity], and more immune cell activation at lower doses."
The investigators did not perform post-treatment biopsies to quantify abscopal effects, Dr. Nghiem noted.
The National Cancer Institute, the American Cancer Society, and the National Institutes of Health funded the research. Dr. Nghiem reported no relevant conflicts of interest.
AT THE 2014 SID ANNUAL MEETING
Major finding: Complete response was seen in 52% of tumors in high-risk patients and 81% of tumors in low-risk patients (P = .008). No adverse effects were observed except pain flares in two patients.
Data source: Single-arm study of 26 patients with distant metastases of Merkel cell carcinoma treated with 8-Gy single-fraction radiotherapy.
Disclosures: The National Cancer Institute, the American Cancer Society, and the National Institutes of Health funded the research. Dr. Nghiem reported no relevant conflicts of interest.
AUDIO: Chemotherapy toxicities masquerade as skin disease
PALM BEACH, ARUBA – Chemotherapy can trigger a host of skin presentations, the specific histologies of which may not be as recognizable to oncologists and hematologists as they would be to dermatologists and primary care physicians. Dr. Jean L. Bolognia, professor of dermatology and vice chair of clinical affairs at Yale University, New Haven, Conn., suggests that by using the all-encompassing clinical term "toxic erythema of chemotherapy," a common ground can be established between all members of a patient’s cancer treatment team, and better outcomes achieved.
In this podcast, Dr. Bolognia offers clinicians specifics for determining when a patient is experiencing a cutaneous reaction to chemotherapy or biologics vs. other skin diseases, and suggests ways to adjust treatment to lessen skin reactions. "It requires adjusting some of the misconceptions about drug eruptions," advises Dr. Bolognia. "This is a toxic reaction, not an allergic one." The distinction is important, according to Dr. Bolognia, especially if the patient is responding to their primary treatment; rather than stop a medication, the timing and dosage can be changed.
Among other tips, such as which drugs create certain drug eruptions, Dr. Bolognia reminds dermatologists and primary care clinicians including physician’s assistants that even a month after treatment, cutaneous reactions are possible.
On Twitter @whitneymcknight
PALM BEACH, ARUBA – Chemotherapy can trigger a host of skin presentations, the specific histologies of which may not be as recognizable to oncologists and hematologists as they would be to dermatologists and primary care physicians. Dr. Jean L. Bolognia, professor of dermatology and vice chair of clinical affairs at Yale University, New Haven, Conn., suggests that by using the all-encompassing clinical term "toxic erythema of chemotherapy," a common ground can be established between all members of a patient’s cancer treatment team, and better outcomes achieved.
In this podcast, Dr. Bolognia offers clinicians specifics for determining when a patient is experiencing a cutaneous reaction to chemotherapy or biologics vs. other skin diseases, and suggests ways to adjust treatment to lessen skin reactions. "It requires adjusting some of the misconceptions about drug eruptions," advises Dr. Bolognia. "This is a toxic reaction, not an allergic one." The distinction is important, according to Dr. Bolognia, especially if the patient is responding to their primary treatment; rather than stop a medication, the timing and dosage can be changed.
Among other tips, such as which drugs create certain drug eruptions, Dr. Bolognia reminds dermatologists and primary care clinicians including physician’s assistants that even a month after treatment, cutaneous reactions are possible.
On Twitter @whitneymcknight
PALM BEACH, ARUBA – Chemotherapy can trigger a host of skin presentations, the specific histologies of which may not be as recognizable to oncologists and hematologists as they would be to dermatologists and primary care physicians. Dr. Jean L. Bolognia, professor of dermatology and vice chair of clinical affairs at Yale University, New Haven, Conn., suggests that by using the all-encompassing clinical term "toxic erythema of chemotherapy," a common ground can be established between all members of a patient’s cancer treatment team, and better outcomes achieved.
In this podcast, Dr. Bolognia offers clinicians specifics for determining when a patient is experiencing a cutaneous reaction to chemotherapy or biologics vs. other skin diseases, and suggests ways to adjust treatment to lessen skin reactions. "It requires adjusting some of the misconceptions about drug eruptions," advises Dr. Bolognia. "This is a toxic reaction, not an allergic one." The distinction is important, according to Dr. Bolognia, especially if the patient is responding to their primary treatment; rather than stop a medication, the timing and dosage can be changed.
Among other tips, such as which drugs create certain drug eruptions, Dr. Bolognia reminds dermatologists and primary care clinicians including physician’s assistants that even a month after treatment, cutaneous reactions are possible.
On Twitter @whitneymcknight
EXPERT ANALYSIS FROM CARIBBEAN DERMATOLOGY SYMPOSIUM 2014
An unusual presentation of an aggressive spindle cell skin cancer
Click on the PDF icon at the top of this introduction to read the full article.
Click on the PDF icon at the top of this introduction to read the full article.
Click on the PDF icon at the top of this introduction to read the full article.
Two investigational immunotherapies show promise in advanced melanoma
SAN DIEGO – DEDN6526A, a new anti–endothelin B receptor antibody-drug conjugate, demonstrated safety, tolerability, and hints of clinical efficacy against different types of metastatic or unresectable melanoma, results from a phase I trial showed.
During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. Jeffrey R. Infante said that anti–endothelin B receptor (ETBR), a G-protein–coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma, compared with normal skin. Developed by Genentech using Seattle Genetics antibody-drug conjugate (ADC) technology, DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin E (MMAE) linked to the humanized IgG1 anti-ETBR antibody and represents a targeted chemotherapy to melanoma. ETBR "regulates migration and proliferation of melanocyte precursors from the neural crest during embryonic development," explained Dr. Infante, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tenn. "It is associated with malignant transformation of melanocytes and with potentiation of metastatic spread."
A prototype ETBR assay is being developed as a potential comparison diagnostic in melanoma. The assay is used on formalin-fixed, paraffin-embedded melanoma.
In an effort to determine the maximum tolerated dose of DEDN6526A, 28 patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma received the intravenous agent every 3 weeks. The researchers collected pharmacokinetic samples and assessed tumor tissue for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1. (Response Evaluation Criteria in Solid Tumors version 1.1).
Dr. Infante reported that more than half of study participants had more than three prior therapies and 70% had two or more prior therapies. Eight of the patients had ocular melanoma and three of them had mucosal melanoma. Dose escalation started at 0.3 mg/kg and patients received a median of six doses of the agent. The maximum tolerated dose was determined to be 2.4 mg/kg, which is currently being tested in the expansion phase of the trial.
The most common adverse event of any grade was fatigue (57%), followed by chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), and infusion-related reaction (25%). Neutropenia was the most frequent grade 3 or 4 event. "It often did not require a dose reduction, so it was manageable," Dr. Infante said.
Complete radiographic data were available on 24 patients. Among these, clinical benefit was observed in 12 of the 19 patients who were assigned to a dosing regimen of 1.8 g/kg of DEDN6526A or more. Four of the 12 patients achieved complete response (two were cases of cutaneous melanoma and two were cases of mucosal melanoma). "It did not seem to depend on whether they had a BRAF mutation or had prior treatment with ipilimumab," Dr. Infante said. The other eight patients had stable disease for at least 6 months. "If you can stay on drug for 6 months, that’s probably meaningful benefit in an early phase I trial," he commented.
Dr. Thomas Lynch, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital at Yale University, New Haven, Conn., who moderated the press briefing, noted that while antibody-drug conjugates such as DEDN6526A "look very promising," the biomarker used in the trial is not fully developed yet. "It may well be that with a mature biomarker, it turns out to have good predictive value," he said.
In an unrelated presentation at the meeting, Dr. Mark Middleton presented findings from a phase I trial of IMCgp100, an investigational agent being developed by Immunocore that is comprised of an affinity-enhanced T-cell receptor specific for the HLA-A2 restricted melanoma gp100 peptide fused to an anti-CD3 antibody fragment. "What’s important about this method of targeting is that it’s very different from a lot of immunotherapies that have been reported," said Dr. Middleton, the study’s principal investigator who is professor of experimental cancer medicine at the University of Oxford (England). "Rather than targeting cell surface proteins, this is targeting the peptide HLA complex, and therefore brings in intracellular protein targets. The premise is that high affinity binding of the T-cell receptor portions of the cancer cell then leads to recruitment of T cells, formation of an immune synapse, and the release of lytic granules leading to apoptotic cell death of the cancer cell."
He and his associates conducted a phase I dose-escalation study using a standard 3+3 cohort design in melanoma patients who had disease in a variety of sites, including the lung, liver, lymphatic system, and various soft tissues. All patients received a single, 5 ng/kg dose of IMCgp100 followed by 30 days of observation. After this 30-day observation period patients could go on to have six weekly infusions followed by 4 weeks of rest if they continued to derive clinical benefit. "On establishment of the maximum tolerated dose, we specified that we would conduct an expansion cohort to explore pharmacodynamics, clinical efficacy, and safety in more detail," Dr. Middleton said, noting that a total of eight cohorts were studied. Patients had to have stage 4 or unresectable stage 3 melanoma, had to be HLA-A2 positive and have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.
The researchers administered IMCgp100 as a 4-hour infusion followed by 48 hours of in-patient observation. Over that 48-hour period they conducted extensive safety evaluations and pharmacokinetic and pharmacodynamic analysis, including detailed audiometric and ophthalmic review. "Because we started with such a low dose we said that we would triple the dose in the absence of toxicity, moving to smaller increments according to safety and pharmacokinetic profile," he said.
Dose-limiting toxicities were defined as drug-related toxicities that occurred within 8 days of drug administration. Anything grade 3 or higher would be deemed as a dose-limiting toxicity.
Among the 40 patients in the trial, the mean age was 59 years and 23 were male. The researchers started to see toxicity at a dose of 45 ng/kg, "which would manifest as a rash that would endure for a few hours, perhaps into the next day," Dr. Middleton said. "At a dose of 135 ng/kg this became more widespread, albeit transient, and we therefore slowed the rate of increase between cohorts." One patient in the 405 ng/kg cohort and two patients in the 900 ng/kg cohort developed grade 3 hypotension 10-12 hours after drug administration. This in part led the researchers to declare a nontolerated dose of 900 ng/kg and a maximum tolerated dose of 600 ng/kg.
Among the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg, the most common adverse event was an itchy rash, "which is often widespread, and associated with edema, which can be periorbital and more widespread," Dr. Middleton said. "This is transient; it usually settles down within 48-72 hours and is not as severe with subsequent administration of the drug." One case of hypotension occurred. The patient recovered after intensive supportive care. Evaluation of pharmacokinetics showed evidence of lymphocyte trafficking, neutrophilia, and a rise in C-reactive protein.
Efficacy results from 10 of the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg showed evidence of "significant and durable clinical responses, particularly in two patients who were treated in the dose escalation phase," he said. Those two patients met the RECIST criteria for response.
Dr. Middleton and his associates are continuing study expansion at the current dose level, with mandated tumor biopsies before treatment, and testing a weekly dosing arm. The goal is to identify the optimal dosing regimen for IMCgp100. The trial is expected to be complete in 2015.
The study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium, and Roche.
The study of DEDN6526A was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose.
Dr. Lynch disclosed that he is on the board of directors for Bristol Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and he receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation–testing patent and receives royalties.
SAN DIEGO – DEDN6526A, a new anti–endothelin B receptor antibody-drug conjugate, demonstrated safety, tolerability, and hints of clinical efficacy against different types of metastatic or unresectable melanoma, results from a phase I trial showed.
During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. Jeffrey R. Infante said that anti–endothelin B receptor (ETBR), a G-protein–coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma, compared with normal skin. Developed by Genentech using Seattle Genetics antibody-drug conjugate (ADC) technology, DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin E (MMAE) linked to the humanized IgG1 anti-ETBR antibody and represents a targeted chemotherapy to melanoma. ETBR "regulates migration and proliferation of melanocyte precursors from the neural crest during embryonic development," explained Dr. Infante, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tenn. "It is associated with malignant transformation of melanocytes and with potentiation of metastatic spread."
A prototype ETBR assay is being developed as a potential comparison diagnostic in melanoma. The assay is used on formalin-fixed, paraffin-embedded melanoma.
In an effort to determine the maximum tolerated dose of DEDN6526A, 28 patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma received the intravenous agent every 3 weeks. The researchers collected pharmacokinetic samples and assessed tumor tissue for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1. (Response Evaluation Criteria in Solid Tumors version 1.1).
Dr. Infante reported that more than half of study participants had more than three prior therapies and 70% had two or more prior therapies. Eight of the patients had ocular melanoma and three of them had mucosal melanoma. Dose escalation started at 0.3 mg/kg and patients received a median of six doses of the agent. The maximum tolerated dose was determined to be 2.4 mg/kg, which is currently being tested in the expansion phase of the trial.
The most common adverse event of any grade was fatigue (57%), followed by chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), and infusion-related reaction (25%). Neutropenia was the most frequent grade 3 or 4 event. "It often did not require a dose reduction, so it was manageable," Dr. Infante said.
Complete radiographic data were available on 24 patients. Among these, clinical benefit was observed in 12 of the 19 patients who were assigned to a dosing regimen of 1.8 g/kg of DEDN6526A or more. Four of the 12 patients achieved complete response (two were cases of cutaneous melanoma and two were cases of mucosal melanoma). "It did not seem to depend on whether they had a BRAF mutation or had prior treatment with ipilimumab," Dr. Infante said. The other eight patients had stable disease for at least 6 months. "If you can stay on drug for 6 months, that’s probably meaningful benefit in an early phase I trial," he commented.
Dr. Thomas Lynch, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital at Yale University, New Haven, Conn., who moderated the press briefing, noted that while antibody-drug conjugates such as DEDN6526A "look very promising," the biomarker used in the trial is not fully developed yet. "It may well be that with a mature biomarker, it turns out to have good predictive value," he said.
In an unrelated presentation at the meeting, Dr. Mark Middleton presented findings from a phase I trial of IMCgp100, an investigational agent being developed by Immunocore that is comprised of an affinity-enhanced T-cell receptor specific for the HLA-A2 restricted melanoma gp100 peptide fused to an anti-CD3 antibody fragment. "What’s important about this method of targeting is that it’s very different from a lot of immunotherapies that have been reported," said Dr. Middleton, the study’s principal investigator who is professor of experimental cancer medicine at the University of Oxford (England). "Rather than targeting cell surface proteins, this is targeting the peptide HLA complex, and therefore brings in intracellular protein targets. The premise is that high affinity binding of the T-cell receptor portions of the cancer cell then leads to recruitment of T cells, formation of an immune synapse, and the release of lytic granules leading to apoptotic cell death of the cancer cell."
He and his associates conducted a phase I dose-escalation study using a standard 3+3 cohort design in melanoma patients who had disease in a variety of sites, including the lung, liver, lymphatic system, and various soft tissues. All patients received a single, 5 ng/kg dose of IMCgp100 followed by 30 days of observation. After this 30-day observation period patients could go on to have six weekly infusions followed by 4 weeks of rest if they continued to derive clinical benefit. "On establishment of the maximum tolerated dose, we specified that we would conduct an expansion cohort to explore pharmacodynamics, clinical efficacy, and safety in more detail," Dr. Middleton said, noting that a total of eight cohorts were studied. Patients had to have stage 4 or unresectable stage 3 melanoma, had to be HLA-A2 positive and have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.
The researchers administered IMCgp100 as a 4-hour infusion followed by 48 hours of in-patient observation. Over that 48-hour period they conducted extensive safety evaluations and pharmacokinetic and pharmacodynamic analysis, including detailed audiometric and ophthalmic review. "Because we started with such a low dose we said that we would triple the dose in the absence of toxicity, moving to smaller increments according to safety and pharmacokinetic profile," he said.
Dose-limiting toxicities were defined as drug-related toxicities that occurred within 8 days of drug administration. Anything grade 3 or higher would be deemed as a dose-limiting toxicity.
Among the 40 patients in the trial, the mean age was 59 years and 23 were male. The researchers started to see toxicity at a dose of 45 ng/kg, "which would manifest as a rash that would endure for a few hours, perhaps into the next day," Dr. Middleton said. "At a dose of 135 ng/kg this became more widespread, albeit transient, and we therefore slowed the rate of increase between cohorts." One patient in the 405 ng/kg cohort and two patients in the 900 ng/kg cohort developed grade 3 hypotension 10-12 hours after drug administration. This in part led the researchers to declare a nontolerated dose of 900 ng/kg and a maximum tolerated dose of 600 ng/kg.
Among the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg, the most common adverse event was an itchy rash, "which is often widespread, and associated with edema, which can be periorbital and more widespread," Dr. Middleton said. "This is transient; it usually settles down within 48-72 hours and is not as severe with subsequent administration of the drug." One case of hypotension occurred. The patient recovered after intensive supportive care. Evaluation of pharmacokinetics showed evidence of lymphocyte trafficking, neutrophilia, and a rise in C-reactive protein.
Efficacy results from 10 of the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg showed evidence of "significant and durable clinical responses, particularly in two patients who were treated in the dose escalation phase," he said. Those two patients met the RECIST criteria for response.
Dr. Middleton and his associates are continuing study expansion at the current dose level, with mandated tumor biopsies before treatment, and testing a weekly dosing arm. The goal is to identify the optimal dosing regimen for IMCgp100. The trial is expected to be complete in 2015.
The study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium, and Roche.
The study of DEDN6526A was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose.
Dr. Lynch disclosed that he is on the board of directors for Bristol Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and he receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation–testing patent and receives royalties.
SAN DIEGO – DEDN6526A, a new anti–endothelin B receptor antibody-drug conjugate, demonstrated safety, tolerability, and hints of clinical efficacy against different types of metastatic or unresectable melanoma, results from a phase I trial showed.
During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. Jeffrey R. Infante said that anti–endothelin B receptor (ETBR), a G-protein–coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma, compared with normal skin. Developed by Genentech using Seattle Genetics antibody-drug conjugate (ADC) technology, DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin E (MMAE) linked to the humanized IgG1 anti-ETBR antibody and represents a targeted chemotherapy to melanoma. ETBR "regulates migration and proliferation of melanocyte precursors from the neural crest during embryonic development," explained Dr. Infante, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tenn. "It is associated with malignant transformation of melanocytes and with potentiation of metastatic spread."
A prototype ETBR assay is being developed as a potential comparison diagnostic in melanoma. The assay is used on formalin-fixed, paraffin-embedded melanoma.
In an effort to determine the maximum tolerated dose of DEDN6526A, 28 patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma received the intravenous agent every 3 weeks. The researchers collected pharmacokinetic samples and assessed tumor tissue for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1. (Response Evaluation Criteria in Solid Tumors version 1.1).
Dr. Infante reported that more than half of study participants had more than three prior therapies and 70% had two or more prior therapies. Eight of the patients had ocular melanoma and three of them had mucosal melanoma. Dose escalation started at 0.3 mg/kg and patients received a median of six doses of the agent. The maximum tolerated dose was determined to be 2.4 mg/kg, which is currently being tested in the expansion phase of the trial.
The most common adverse event of any grade was fatigue (57%), followed by chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), and infusion-related reaction (25%). Neutropenia was the most frequent grade 3 or 4 event. "It often did not require a dose reduction, so it was manageable," Dr. Infante said.
Complete radiographic data were available on 24 patients. Among these, clinical benefit was observed in 12 of the 19 patients who were assigned to a dosing regimen of 1.8 g/kg of DEDN6526A or more. Four of the 12 patients achieved complete response (two were cases of cutaneous melanoma and two were cases of mucosal melanoma). "It did not seem to depend on whether they had a BRAF mutation or had prior treatment with ipilimumab," Dr. Infante said. The other eight patients had stable disease for at least 6 months. "If you can stay on drug for 6 months, that’s probably meaningful benefit in an early phase I trial," he commented.
Dr. Thomas Lynch, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital at Yale University, New Haven, Conn., who moderated the press briefing, noted that while antibody-drug conjugates such as DEDN6526A "look very promising," the biomarker used in the trial is not fully developed yet. "It may well be that with a mature biomarker, it turns out to have good predictive value," he said.
In an unrelated presentation at the meeting, Dr. Mark Middleton presented findings from a phase I trial of IMCgp100, an investigational agent being developed by Immunocore that is comprised of an affinity-enhanced T-cell receptor specific for the HLA-A2 restricted melanoma gp100 peptide fused to an anti-CD3 antibody fragment. "What’s important about this method of targeting is that it’s very different from a lot of immunotherapies that have been reported," said Dr. Middleton, the study’s principal investigator who is professor of experimental cancer medicine at the University of Oxford (England). "Rather than targeting cell surface proteins, this is targeting the peptide HLA complex, and therefore brings in intracellular protein targets. The premise is that high affinity binding of the T-cell receptor portions of the cancer cell then leads to recruitment of T cells, formation of an immune synapse, and the release of lytic granules leading to apoptotic cell death of the cancer cell."
He and his associates conducted a phase I dose-escalation study using a standard 3+3 cohort design in melanoma patients who had disease in a variety of sites, including the lung, liver, lymphatic system, and various soft tissues. All patients received a single, 5 ng/kg dose of IMCgp100 followed by 30 days of observation. After this 30-day observation period patients could go on to have six weekly infusions followed by 4 weeks of rest if they continued to derive clinical benefit. "On establishment of the maximum tolerated dose, we specified that we would conduct an expansion cohort to explore pharmacodynamics, clinical efficacy, and safety in more detail," Dr. Middleton said, noting that a total of eight cohorts were studied. Patients had to have stage 4 or unresectable stage 3 melanoma, had to be HLA-A2 positive and have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.
The researchers administered IMCgp100 as a 4-hour infusion followed by 48 hours of in-patient observation. Over that 48-hour period they conducted extensive safety evaluations and pharmacokinetic and pharmacodynamic analysis, including detailed audiometric and ophthalmic review. "Because we started with such a low dose we said that we would triple the dose in the absence of toxicity, moving to smaller increments according to safety and pharmacokinetic profile," he said.
Dose-limiting toxicities were defined as drug-related toxicities that occurred within 8 days of drug administration. Anything grade 3 or higher would be deemed as a dose-limiting toxicity.
Among the 40 patients in the trial, the mean age was 59 years and 23 were male. The researchers started to see toxicity at a dose of 45 ng/kg, "which would manifest as a rash that would endure for a few hours, perhaps into the next day," Dr. Middleton said. "At a dose of 135 ng/kg this became more widespread, albeit transient, and we therefore slowed the rate of increase between cohorts." One patient in the 405 ng/kg cohort and two patients in the 900 ng/kg cohort developed grade 3 hypotension 10-12 hours after drug administration. This in part led the researchers to declare a nontolerated dose of 900 ng/kg and a maximum tolerated dose of 600 ng/kg.
Among the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg, the most common adverse event was an itchy rash, "which is often widespread, and associated with edema, which can be periorbital and more widespread," Dr. Middleton said. "This is transient; it usually settles down within 48-72 hours and is not as severe with subsequent administration of the drug." One case of hypotension occurred. The patient recovered after intensive supportive care. Evaluation of pharmacokinetics showed evidence of lymphocyte trafficking, neutrophilia, and a rise in C-reactive protein.
Efficacy results from 10 of the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg showed evidence of "significant and durable clinical responses, particularly in two patients who were treated in the dose escalation phase," he said. Those two patients met the RECIST criteria for response.
Dr. Middleton and his associates are continuing study expansion at the current dose level, with mandated tumor biopsies before treatment, and testing a weekly dosing arm. The goal is to identify the optimal dosing regimen for IMCgp100. The trial is expected to be complete in 2015.
The study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium, and Roche.
The study of DEDN6526A was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose.
Dr. Lynch disclosed that he is on the board of directors for Bristol Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and he receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation–testing patent and receives royalties.
AT THE AACR ANNUAL MEETING
Major finding: Two investigational immunotherapies for advanced melanoma, one an antibody-drug conjugate, the other directing patients’ immune responses toward tumor cell killing, demonstrated safety and signs of clinical efficacy.
Data source: Two phase I studies, one of DEDN6526A, a new anti-endothelin B receptor antibody-drug conjugate, and one of IMCgp100, composed of an affinity-enhanced T-cell receptor specific for the HLA-A2 restricted melanoma gp100 peptide fused to an anti-CD3 antibody fragment.
Disclosures: The first study was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose. The second study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium and Roche.
