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NRAS mutations predict immunotherapy outcomes in melanoma patients
Patients with advanced melanoma who were treated with immunotherapy responded better if they harbored mutations in the NRAS gene, according to a study published March 3 in Cancer Immunology Research.
Out of 229 cases retrospectively analyzed, 26% had mutations in NRASG12/G13/Q61, 23% had BRAFV600, and 51% were wild type for NRAS and BRAF. Patients received first-line therapy with high-dose IL-2 (25%), ipilimumab (62%), or anti-PD-1/PD-L1 (12%), investigators reported (Cancer Immunol. Res. 2015 March 3).
Complete or partial responses were found in 32% of patients with NRAS-mutant melanomas, compared with 20% of those without NRAS mutations (P = .07). Clinical benefit (defined as complete response, partial response, or stable disease for 24 weeks or longer) was observed in 50% of the NRAS mutant group vs. 30% of the non–mutant NRAS group (P < .01), reported Dr. Douglas B. Johnson of Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tenn., and associates.
Although the numbers for individual agents were small, the NRAS-mutant benefit was most pronounced for immune checkpoint inhibitors, especially anti-PD-1/PD-L1 therapy, where clinical benefit was observed in 8 of 11 NRAS-mutant patients vs. 13 of 37 patients with wild-type NRAS.
“This finding could have implications for molecular testing and treatment decision making, and it provides early insights into the complex relationship between tumor genetics and the immune response,” Dr. Johnson and associates wrote.
Patients with NRAS-mutant melanoma account for 15%-20% of all melanomas, and the mutation is associated with a poorer prognosis. The authors speculate that elevated PD-1 expression may be a factor in inferior prognosis of NRAS-mutant phenotypes as well as the observed improved response to anti-PD-1.
“We studied a small group of patients, but the results were quite suggestive. Our findings need to be confirmed in a prospective study. This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy. Our study will hopefully lead to understanding the biological mechanisms that explain why NRAS mutations predict response,” Dr. Johnson and his associates said.
Patients with advanced melanoma who were treated with immunotherapy responded better if they harbored mutations in the NRAS gene, according to a study published March 3 in Cancer Immunology Research.
Out of 229 cases retrospectively analyzed, 26% had mutations in NRASG12/G13/Q61, 23% had BRAFV600, and 51% were wild type for NRAS and BRAF. Patients received first-line therapy with high-dose IL-2 (25%), ipilimumab (62%), or anti-PD-1/PD-L1 (12%), investigators reported (Cancer Immunol. Res. 2015 March 3).
Complete or partial responses were found in 32% of patients with NRAS-mutant melanomas, compared with 20% of those without NRAS mutations (P = .07). Clinical benefit (defined as complete response, partial response, or stable disease for 24 weeks or longer) was observed in 50% of the NRAS mutant group vs. 30% of the non–mutant NRAS group (P < .01), reported Dr. Douglas B. Johnson of Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tenn., and associates.
Although the numbers for individual agents were small, the NRAS-mutant benefit was most pronounced for immune checkpoint inhibitors, especially anti-PD-1/PD-L1 therapy, where clinical benefit was observed in 8 of 11 NRAS-mutant patients vs. 13 of 37 patients with wild-type NRAS.
“This finding could have implications for molecular testing and treatment decision making, and it provides early insights into the complex relationship between tumor genetics and the immune response,” Dr. Johnson and associates wrote.
Patients with NRAS-mutant melanoma account for 15%-20% of all melanomas, and the mutation is associated with a poorer prognosis. The authors speculate that elevated PD-1 expression may be a factor in inferior prognosis of NRAS-mutant phenotypes as well as the observed improved response to anti-PD-1.
“We studied a small group of patients, but the results were quite suggestive. Our findings need to be confirmed in a prospective study. This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy. Our study will hopefully lead to understanding the biological mechanisms that explain why NRAS mutations predict response,” Dr. Johnson and his associates said.
Patients with advanced melanoma who were treated with immunotherapy responded better if they harbored mutations in the NRAS gene, according to a study published March 3 in Cancer Immunology Research.
Out of 229 cases retrospectively analyzed, 26% had mutations in NRASG12/G13/Q61, 23% had BRAFV600, and 51% were wild type for NRAS and BRAF. Patients received first-line therapy with high-dose IL-2 (25%), ipilimumab (62%), or anti-PD-1/PD-L1 (12%), investigators reported (Cancer Immunol. Res. 2015 March 3).
Complete or partial responses were found in 32% of patients with NRAS-mutant melanomas, compared with 20% of those without NRAS mutations (P = .07). Clinical benefit (defined as complete response, partial response, or stable disease for 24 weeks or longer) was observed in 50% of the NRAS mutant group vs. 30% of the non–mutant NRAS group (P < .01), reported Dr. Douglas B. Johnson of Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tenn., and associates.
Although the numbers for individual agents were small, the NRAS-mutant benefit was most pronounced for immune checkpoint inhibitors, especially anti-PD-1/PD-L1 therapy, where clinical benefit was observed in 8 of 11 NRAS-mutant patients vs. 13 of 37 patients with wild-type NRAS.
“This finding could have implications for molecular testing and treatment decision making, and it provides early insights into the complex relationship between tumor genetics and the immune response,” Dr. Johnson and associates wrote.
Patients with NRAS-mutant melanoma account for 15%-20% of all melanomas, and the mutation is associated with a poorer prognosis. The authors speculate that elevated PD-1 expression may be a factor in inferior prognosis of NRAS-mutant phenotypes as well as the observed improved response to anti-PD-1.
“We studied a small group of patients, but the results were quite suggestive. Our findings need to be confirmed in a prospective study. This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy. Our study will hopefully lead to understanding the biological mechanisms that explain why NRAS mutations predict response,” Dr. Johnson and his associates said.
FROM CANCER IMMUNOLOGY RESEARCH
Key clinical point: Patients with advanced melanoma and mutations in the NRAS gene had better responses to immunotherapy than did those without NRAS mutations.
Major finding: Of the patients with mutated NRAS, 28% had complete or partial responses to first-line immunotherapy, compared with 16% of patients without NRAS mutations.
Data source: The retrospective study evaluated medical records from 229 patients with advanced melanoma who were treated with ipilimumab, IL-2, or anti-PD-1/PD-L1.
Disclosures: Dr. Johnson had no disclosures. Dr. Lovly received grants from AstraZeneca and Novartis. Dr. Iafrate has ownership in ArcherDx and an advisory role with BioReference Labs.
Ipilimumab’s survival benefit extends to 5 years
Among patients with advanced melanoma, twice as many survived to 5 years if they received ipilimumab plus dacarbazine than if they received placebo plus dacarbazine as part of a phase III randomized clinical trial, according to a report published online Feb. 23 in the Journal of Clinical Oncology.
The investigators described their analysis as the first examination of long-term survival after a course of ipilimumab therapy, as well as the first analysis of safety outcomes in a small subset of patients who continued to receive ipilimumab as maintenance therapy. They performed this milestone survival analysis “to confirm prior reports of long-term survival in a proportion of patients from nonrandomized phase II studies,” and their findings do in fact confirm those reports, said Dr. Michele Maio of University Hospital of Siena (Italy) and her associates.
The industry-sponsored study (CA184-024) involved 502 adults with treatment-naive unresectable stage III or IV melanoma who were randomly assigned to receive ipilimumab plus dacarbazine (250 patients) or placebo plus dacarbazine (252 patients) for 10 weeks. Those who showed stable disease, a partial response, or a complete response at week 24 were permitted to continue on ipilimumab or placebo as maintenance therapy every 12 weeks thereafter.
At a minimum follow-up of 5 years, 40 patients (18.2%) in the ipilimumab group and 20 (8.8%) in the placebo group were still alive. Five-year survival with ipilimumab was not only double that with placebo, it also was roughly double the historical survival rate of patients with stage IV melanoma, which is approximately 10%, Dr. Maio and her associates reported (J. Clin. Oncol. 2015 Feb. 23 [doi:10.1200/JCO.2014.56.6018]).
With ipilimumab, 3 long-term survivors (7.5%) achieved a complete response, 17 (42.5%) had a partial response, and 11 (27.5%) achieved stable disease. In contrast, with placebo no long-term survivors achieved a complete response, 7 (35%) had a partial response, and 8 (40%) had stable disease.
There were no grade 5 adverse events. Grade 3-4 adverse events were confined to the skin and comprised pruritus and rash. Low-grade adverse events included rash, vitiligo, pruritus, GI problems, and an increased ALT or AST level.
The subset of study participants who used ipilimumab maintenance therapy was small (seven patients) but “provides some insight into the safety profile of ipilimumab during extended treatment.” The only high-grade adverse events were pruritus and rash, which affected only one patient.
“This analysis demonstrates that a proportion of treatment-naive patients with advanced melanoma can achieve durable, long-term survival with ipilimumab therapy,” Dr. Maio and her associates wrote.
Among patients with advanced melanoma, twice as many survived to 5 years if they received ipilimumab plus dacarbazine than if they received placebo plus dacarbazine as part of a phase III randomized clinical trial, according to a report published online Feb. 23 in the Journal of Clinical Oncology.
The investigators described their analysis as the first examination of long-term survival after a course of ipilimumab therapy, as well as the first analysis of safety outcomes in a small subset of patients who continued to receive ipilimumab as maintenance therapy. They performed this milestone survival analysis “to confirm prior reports of long-term survival in a proportion of patients from nonrandomized phase II studies,” and their findings do in fact confirm those reports, said Dr. Michele Maio of University Hospital of Siena (Italy) and her associates.
The industry-sponsored study (CA184-024) involved 502 adults with treatment-naive unresectable stage III or IV melanoma who were randomly assigned to receive ipilimumab plus dacarbazine (250 patients) or placebo plus dacarbazine (252 patients) for 10 weeks. Those who showed stable disease, a partial response, or a complete response at week 24 were permitted to continue on ipilimumab or placebo as maintenance therapy every 12 weeks thereafter.
At a minimum follow-up of 5 years, 40 patients (18.2%) in the ipilimumab group and 20 (8.8%) in the placebo group were still alive. Five-year survival with ipilimumab was not only double that with placebo, it also was roughly double the historical survival rate of patients with stage IV melanoma, which is approximately 10%, Dr. Maio and her associates reported (J. Clin. Oncol. 2015 Feb. 23 [doi:10.1200/JCO.2014.56.6018]).
With ipilimumab, 3 long-term survivors (7.5%) achieved a complete response, 17 (42.5%) had a partial response, and 11 (27.5%) achieved stable disease. In contrast, with placebo no long-term survivors achieved a complete response, 7 (35%) had a partial response, and 8 (40%) had stable disease.
There were no grade 5 adverse events. Grade 3-4 adverse events were confined to the skin and comprised pruritus and rash. Low-grade adverse events included rash, vitiligo, pruritus, GI problems, and an increased ALT or AST level.
The subset of study participants who used ipilimumab maintenance therapy was small (seven patients) but “provides some insight into the safety profile of ipilimumab during extended treatment.” The only high-grade adverse events were pruritus and rash, which affected only one patient.
“This analysis demonstrates that a proportion of treatment-naive patients with advanced melanoma can achieve durable, long-term survival with ipilimumab therapy,” Dr. Maio and her associates wrote.
Among patients with advanced melanoma, twice as many survived to 5 years if they received ipilimumab plus dacarbazine than if they received placebo plus dacarbazine as part of a phase III randomized clinical trial, according to a report published online Feb. 23 in the Journal of Clinical Oncology.
The investigators described their analysis as the first examination of long-term survival after a course of ipilimumab therapy, as well as the first analysis of safety outcomes in a small subset of patients who continued to receive ipilimumab as maintenance therapy. They performed this milestone survival analysis “to confirm prior reports of long-term survival in a proportion of patients from nonrandomized phase II studies,” and their findings do in fact confirm those reports, said Dr. Michele Maio of University Hospital of Siena (Italy) and her associates.
The industry-sponsored study (CA184-024) involved 502 adults with treatment-naive unresectable stage III or IV melanoma who were randomly assigned to receive ipilimumab plus dacarbazine (250 patients) or placebo plus dacarbazine (252 patients) for 10 weeks. Those who showed stable disease, a partial response, or a complete response at week 24 were permitted to continue on ipilimumab or placebo as maintenance therapy every 12 weeks thereafter.
At a minimum follow-up of 5 years, 40 patients (18.2%) in the ipilimumab group and 20 (8.8%) in the placebo group were still alive. Five-year survival with ipilimumab was not only double that with placebo, it also was roughly double the historical survival rate of patients with stage IV melanoma, which is approximately 10%, Dr. Maio and her associates reported (J. Clin. Oncol. 2015 Feb. 23 [doi:10.1200/JCO.2014.56.6018]).
With ipilimumab, 3 long-term survivors (7.5%) achieved a complete response, 17 (42.5%) had a partial response, and 11 (27.5%) achieved stable disease. In contrast, with placebo no long-term survivors achieved a complete response, 7 (35%) had a partial response, and 8 (40%) had stable disease.
There were no grade 5 adverse events. Grade 3-4 adverse events were confined to the skin and comprised pruritus and rash. Low-grade adverse events included rash, vitiligo, pruritus, GI problems, and an increased ALT or AST level.
The subset of study participants who used ipilimumab maintenance therapy was small (seven patients) but “provides some insight into the safety profile of ipilimumab during extended treatment.” The only high-grade adverse events were pruritus and rash, which affected only one patient.
“This analysis demonstrates that a proportion of treatment-naive patients with advanced melanoma can achieve durable, long-term survival with ipilimumab therapy,” Dr. Maio and her associates wrote.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: The short-term survival benefit conferred by ipilimumab therapy in advanced melanoma extends to at least 5 years.
Major finding: Five-year survival with ipilimumab (18.2%) was double that with placebo (8.8%) and roughly double the historical survival rate of patients with stage IV melanoma (approximately 10%).
Data source: An industry-sponsored “milestone survival” analysis to capture 5-year mortality data for 502 adults with advanced melanoma who participated in a phase III clinical trial comparing ipilimumab with placebo.
Disclosures: This study (NCT 00324155) was sponsored by Bristol-Myers Squibb. Dr. Maio reported receiving honoraria, research funding, and other compensation and serving as a consultant/adviser to Bristol-Myers Squibb, GlaxoSmithKline, and Roche. Her associates reported ties to numerous industry sources.
UVA damage to skin DNA continues for hours after exposure
DNA damage to skin continues for hours after UVA exposure ceases, and melanin is a key culprit in the process, based on the results of cell cultures and studies in mice.
“What is extraordinary about this study is that it implicates melanin as a potential source of oxidative stress, [which can] lead to DNA damage and ultimately accelerate skin aging and skin cancer,” said Dr. Adam Friedman, director of dermatologic research at Albert Einstein College of Medicine, New York, who was not involved in the research. “For years, melanin was thought of as only a UV radiation protectant and antioxidant. Could this be a missing element in our fight to prevent skin cancer? The emphasis has always been on preventing the fire, not necessarily putting it out.”
The findings suggest that antioxidant-rich lotions might one day help prevent damage if users apply the “quenchers” soon after sun exposure, said lead author Sanjay Premi, Ph.D. at Yale University in New Haven, Conn., and his associates. Vitamin E and ethyl sorbate are two possible candidates for such “evening after” sunscreens, the researchers said (Science 2015 Feb. 20;347:842-7). For their study, the researchers exposed mouse fibroblasts and melanocytes to UVA, the main type of cancer-causing radiation from sunlight and tanning beds. Then they measured the accumulation of cyclobutane pyrimidine dimers (CPDs), a hallmark of UV-induced DNA damage. Levels of CPDs peaked immediately after UVA exposure in skin cells from albino mice, but kept rising for at least another 3 hours in melanocytes from pigmented mice, the investigators reported. Furthermore, 2 hours after live mice were exposed to UVA, their CPD levels were three times greater than just after UVA exposure, they said. “If the same holds for human skin, this would mean that past measurements of CPDs immediately after UV exposure have underestimated the consequences of UV exposure,” the researchers concluded.
They found similar results for human melanocytes, except that CPD levels varied more, probably because of genetic differences among human skin donors, Dr. Premi and his associates wrote. Further testing of melanin fragments revealed the process by which DNA damage accumulates, even after UVA exposures ends: Reactive oxygen and nitrogen species together excited an electron that in turn damaged DNA in the same way that UV radiation did. “A consequence of these events is that melanin may be carcinogenic as well as protective against cancer,” the researchers emphasized. “This double nature would explain the apparent cancer-facilitating effects of melanin seen in mice and in human epidemiology.”
Although “it is difficult to translate cell assays and mouse models to the human system,” the findings “no doubt raise important, paradigm-shifting ideas in terms of our understanding of UV-induced DNA damage,” said Dr. Friedman. For example, studies have shown that skin cells incur DNA damage even when individuals wear sunscreen as directed, he noted. “Are these cellular changes a result of sunscreen inefficiency, or is it delayed damage due to persistent melanin radicals?” he asked. “We see patients all the time who say, ‘I used sunscreen but I still got burned.’ Granted, there are likely many confounding factors, such as amount of sunscreen applied, frequency, clothing choice, and water exposure. However, maybe we can add progressive and persistent oxidative stress to the list.”
Developing effective “evening-after” lotions to halt UVA damage after exposure will take work, Dr. Friedman added. “The reality is that many, if not most, antioxidants are highly unstable, whether they oxidize easily when exposed to air, or are photo-labile, meaning they degrade upon exposure to sunlight,” he said. One solution is to encapsulate antioxidants within liposomes, solid lipid nanoparticles, or polymeric nanoparticles, but “skin penetration is not the only issue,” he added. “These antioxidants need to actually get into the cells to be effective.”
For that reason, researchers have explored systemic administration of agents such as polypodium leucotomos, which has antioxidant and anti-inflammatory properties, Dr. Friedman noted. “The clinical data available looks at using this natural ingredient to increase minimal erythemal dose, rather then postirradiation recovery,” he said. “Could postirradiation intake be effective? Possibly.”
The research was funded by the U.S. Department of Defense, the National Institutes of Health, the University of Veterinary Medicine in Vienna, Fundação de Amparo à Pesquisa do Estado de São Paulo, and INCT–Processos Redox em Biomedicina. The investigators declared having no conflicts of interest.
DNA damage to skin continues for hours after UVA exposure ceases, and melanin is a key culprit in the process, based on the results of cell cultures and studies in mice.
“What is extraordinary about this study is that it implicates melanin as a potential source of oxidative stress, [which can] lead to DNA damage and ultimately accelerate skin aging and skin cancer,” said Dr. Adam Friedman, director of dermatologic research at Albert Einstein College of Medicine, New York, who was not involved in the research. “For years, melanin was thought of as only a UV radiation protectant and antioxidant. Could this be a missing element in our fight to prevent skin cancer? The emphasis has always been on preventing the fire, not necessarily putting it out.”
The findings suggest that antioxidant-rich lotions might one day help prevent damage if users apply the “quenchers” soon after sun exposure, said lead author Sanjay Premi, Ph.D. at Yale University in New Haven, Conn., and his associates. Vitamin E and ethyl sorbate are two possible candidates for such “evening after” sunscreens, the researchers said (Science 2015 Feb. 20;347:842-7). For their study, the researchers exposed mouse fibroblasts and melanocytes to UVA, the main type of cancer-causing radiation from sunlight and tanning beds. Then they measured the accumulation of cyclobutane pyrimidine dimers (CPDs), a hallmark of UV-induced DNA damage. Levels of CPDs peaked immediately after UVA exposure in skin cells from albino mice, but kept rising for at least another 3 hours in melanocytes from pigmented mice, the investigators reported. Furthermore, 2 hours after live mice were exposed to UVA, their CPD levels were three times greater than just after UVA exposure, they said. “If the same holds for human skin, this would mean that past measurements of CPDs immediately after UV exposure have underestimated the consequences of UV exposure,” the researchers concluded.
They found similar results for human melanocytes, except that CPD levels varied more, probably because of genetic differences among human skin donors, Dr. Premi and his associates wrote. Further testing of melanin fragments revealed the process by which DNA damage accumulates, even after UVA exposures ends: Reactive oxygen and nitrogen species together excited an electron that in turn damaged DNA in the same way that UV radiation did. “A consequence of these events is that melanin may be carcinogenic as well as protective against cancer,” the researchers emphasized. “This double nature would explain the apparent cancer-facilitating effects of melanin seen in mice and in human epidemiology.”
Although “it is difficult to translate cell assays and mouse models to the human system,” the findings “no doubt raise important, paradigm-shifting ideas in terms of our understanding of UV-induced DNA damage,” said Dr. Friedman. For example, studies have shown that skin cells incur DNA damage even when individuals wear sunscreen as directed, he noted. “Are these cellular changes a result of sunscreen inefficiency, or is it delayed damage due to persistent melanin radicals?” he asked. “We see patients all the time who say, ‘I used sunscreen but I still got burned.’ Granted, there are likely many confounding factors, such as amount of sunscreen applied, frequency, clothing choice, and water exposure. However, maybe we can add progressive and persistent oxidative stress to the list.”
Developing effective “evening-after” lotions to halt UVA damage after exposure will take work, Dr. Friedman added. “The reality is that many, if not most, antioxidants are highly unstable, whether they oxidize easily when exposed to air, or are photo-labile, meaning they degrade upon exposure to sunlight,” he said. One solution is to encapsulate antioxidants within liposomes, solid lipid nanoparticles, or polymeric nanoparticles, but “skin penetration is not the only issue,” he added. “These antioxidants need to actually get into the cells to be effective.”
For that reason, researchers have explored systemic administration of agents such as polypodium leucotomos, which has antioxidant and anti-inflammatory properties, Dr. Friedman noted. “The clinical data available looks at using this natural ingredient to increase minimal erythemal dose, rather then postirradiation recovery,” he said. “Could postirradiation intake be effective? Possibly.”
The research was funded by the U.S. Department of Defense, the National Institutes of Health, the University of Veterinary Medicine in Vienna, Fundação de Amparo à Pesquisa do Estado de São Paulo, and INCT–Processos Redox em Biomedicina. The investigators declared having no conflicts of interest.
DNA damage to skin continues for hours after UVA exposure ceases, and melanin is a key culprit in the process, based on the results of cell cultures and studies in mice.
“What is extraordinary about this study is that it implicates melanin as a potential source of oxidative stress, [which can] lead to DNA damage and ultimately accelerate skin aging and skin cancer,” said Dr. Adam Friedman, director of dermatologic research at Albert Einstein College of Medicine, New York, who was not involved in the research. “For years, melanin was thought of as only a UV radiation protectant and antioxidant. Could this be a missing element in our fight to prevent skin cancer? The emphasis has always been on preventing the fire, not necessarily putting it out.”
The findings suggest that antioxidant-rich lotions might one day help prevent damage if users apply the “quenchers” soon after sun exposure, said lead author Sanjay Premi, Ph.D. at Yale University in New Haven, Conn., and his associates. Vitamin E and ethyl sorbate are two possible candidates for such “evening after” sunscreens, the researchers said (Science 2015 Feb. 20;347:842-7). For their study, the researchers exposed mouse fibroblasts and melanocytes to UVA, the main type of cancer-causing radiation from sunlight and tanning beds. Then they measured the accumulation of cyclobutane pyrimidine dimers (CPDs), a hallmark of UV-induced DNA damage. Levels of CPDs peaked immediately after UVA exposure in skin cells from albino mice, but kept rising for at least another 3 hours in melanocytes from pigmented mice, the investigators reported. Furthermore, 2 hours after live mice were exposed to UVA, their CPD levels were three times greater than just after UVA exposure, they said. “If the same holds for human skin, this would mean that past measurements of CPDs immediately after UV exposure have underestimated the consequences of UV exposure,” the researchers concluded.
They found similar results for human melanocytes, except that CPD levels varied more, probably because of genetic differences among human skin donors, Dr. Premi and his associates wrote. Further testing of melanin fragments revealed the process by which DNA damage accumulates, even after UVA exposures ends: Reactive oxygen and nitrogen species together excited an electron that in turn damaged DNA in the same way that UV radiation did. “A consequence of these events is that melanin may be carcinogenic as well as protective against cancer,” the researchers emphasized. “This double nature would explain the apparent cancer-facilitating effects of melanin seen in mice and in human epidemiology.”
Although “it is difficult to translate cell assays and mouse models to the human system,” the findings “no doubt raise important, paradigm-shifting ideas in terms of our understanding of UV-induced DNA damage,” said Dr. Friedman. For example, studies have shown that skin cells incur DNA damage even when individuals wear sunscreen as directed, he noted. “Are these cellular changes a result of sunscreen inefficiency, or is it delayed damage due to persistent melanin radicals?” he asked. “We see patients all the time who say, ‘I used sunscreen but I still got burned.’ Granted, there are likely many confounding factors, such as amount of sunscreen applied, frequency, clothing choice, and water exposure. However, maybe we can add progressive and persistent oxidative stress to the list.”
Developing effective “evening-after” lotions to halt UVA damage after exposure will take work, Dr. Friedman added. “The reality is that many, if not most, antioxidants are highly unstable, whether they oxidize easily when exposed to air, or are photo-labile, meaning they degrade upon exposure to sunlight,” he said. One solution is to encapsulate antioxidants within liposomes, solid lipid nanoparticles, or polymeric nanoparticles, but “skin penetration is not the only issue,” he added. “These antioxidants need to actually get into the cells to be effective.”
For that reason, researchers have explored systemic administration of agents such as polypodium leucotomos, which has antioxidant and anti-inflammatory properties, Dr. Friedman noted. “The clinical data available looks at using this natural ingredient to increase minimal erythemal dose, rather then postirradiation recovery,” he said. “Could postirradiation intake be effective? Possibly.”
The research was funded by the U.S. Department of Defense, the National Institutes of Health, the University of Veterinary Medicine in Vienna, Fundação de Amparo à Pesquisa do Estado de São Paulo, and INCT–Processos Redox em Biomedicina. The investigators declared having no conflicts of interest.
FROM SCIENCE
Key clinical point: Melanin played a key role in DNA damage to skin cells hours after UVA exposure.
Major finding: Melanocytes continued to form cyclobutane pyrimidine dimers for at least 3 hours after exposure to UVA radiation.
Data source: Histologic study of UV-exposed skin cells from mice and humans, and of in vivo mice.
Disclosures: The research was funded by the U.S. Department of Defense, the National Institutes of Health, the University of Veterinary Medicine in Vienna, Fundação de Amparo à Pesquisa do Estado de São Paulo, and INCT–Processos Redox em Biomedicina. The investigators declared having no conflicts of interest.
Diagnose Pediatric Melanoma Using the CUP Criteria
It is typically perceived that cutaneous malignancies in childhood and adolescence are uncommon, but the incidence of melanoma in this patient population is increasing. In 2014, the American Cancer Society estimated 310 cases of malignant melanoma in adolescents aged 15 to 19 years, making it the 8th most prevalent cancer in adolescents. Based on US data for pediatric patients aged 0 to 19 years (2006-2010), melanoma was reported to be more common in girls and non-Hispanic whites. For pediatric cases diagnosed in 2003-2009, the 5-year observed survival rate was 95%, an increase from 83% in 1975-1979. These findings serve as a reminder for practitioners to encourage young patients to practice good sun protection habits. Even if patients are careful, melanomas do occur in childhood and early diagnosis is key.
The ABCDE—asymmetry, border irregularity, color variegation, diameter, evolving—criteria have been used for melanoma screening in adults and may be helpful in detecting pediatric melanoma. However, Silverberg and McCuaig proposed a mnemonic specifically for screening children called the CUP criteria. Because melanomas of childhood do not necessarily arise in a preexisting nevus, the CUP criteria take into account melanomas that arise de novo and may present histologically as spitzoid neoplasms. The atypical presentation of melanomas in childhood includes color uniformity (pink/red), ulceration and upward thickening, and pyogenic granuloma–like lesions and pop-up of new lesions.
For more information on practice modifications from these screening criteria for pediatric melanoma, read Silverberg and McCuaig’s Cutis article “Melanoma in Childhood: Changing Our Mind-set.”
It is typically perceived that cutaneous malignancies in childhood and adolescence are uncommon, but the incidence of melanoma in this patient population is increasing. In 2014, the American Cancer Society estimated 310 cases of malignant melanoma in adolescents aged 15 to 19 years, making it the 8th most prevalent cancer in adolescents. Based on US data for pediatric patients aged 0 to 19 years (2006-2010), melanoma was reported to be more common in girls and non-Hispanic whites. For pediatric cases diagnosed in 2003-2009, the 5-year observed survival rate was 95%, an increase from 83% in 1975-1979. These findings serve as a reminder for practitioners to encourage young patients to practice good sun protection habits. Even if patients are careful, melanomas do occur in childhood and early diagnosis is key.
The ABCDE—asymmetry, border irregularity, color variegation, diameter, evolving—criteria have been used for melanoma screening in adults and may be helpful in detecting pediatric melanoma. However, Silverberg and McCuaig proposed a mnemonic specifically for screening children called the CUP criteria. Because melanomas of childhood do not necessarily arise in a preexisting nevus, the CUP criteria take into account melanomas that arise de novo and may present histologically as spitzoid neoplasms. The atypical presentation of melanomas in childhood includes color uniformity (pink/red), ulceration and upward thickening, and pyogenic granuloma–like lesions and pop-up of new lesions.
For more information on practice modifications from these screening criteria for pediatric melanoma, read Silverberg and McCuaig’s Cutis article “Melanoma in Childhood: Changing Our Mind-set.”
It is typically perceived that cutaneous malignancies in childhood and adolescence are uncommon, but the incidence of melanoma in this patient population is increasing. In 2014, the American Cancer Society estimated 310 cases of malignant melanoma in adolescents aged 15 to 19 years, making it the 8th most prevalent cancer in adolescents. Based on US data for pediatric patients aged 0 to 19 years (2006-2010), melanoma was reported to be more common in girls and non-Hispanic whites. For pediatric cases diagnosed in 2003-2009, the 5-year observed survival rate was 95%, an increase from 83% in 1975-1979. These findings serve as a reminder for practitioners to encourage young patients to practice good sun protection habits. Even if patients are careful, melanomas do occur in childhood and early diagnosis is key.
The ABCDE—asymmetry, border irregularity, color variegation, diameter, evolving—criteria have been used for melanoma screening in adults and may be helpful in detecting pediatric melanoma. However, Silverberg and McCuaig proposed a mnemonic specifically for screening children called the CUP criteria. Because melanomas of childhood do not necessarily arise in a preexisting nevus, the CUP criteria take into account melanomas that arise de novo and may present histologically as spitzoid neoplasms. The atypical presentation of melanomas in childhood includes color uniformity (pink/red), ulceration and upward thickening, and pyogenic granuloma–like lesions and pop-up of new lesions.
For more information on practice modifications from these screening criteria for pediatric melanoma, read Silverberg and McCuaig’s Cutis article “Melanoma in Childhood: Changing Our Mind-set.”
VIDEO: Biologics slowly taming metastatic melanoma
MAUI, HAWAII – Though costly, newer biologics increase 1-year survival with metastatic melanoma from perhaps 40% to more than 70%.
Among the latest are nivolumab and pembrolizumab, antibodies against PD-1 (programmed cell death) cell surface receptors that were approved in 2014 for unresectable melanoma no longer responding to other drugs; another anti-PD-1 is in development.
In this video interview at the 2015 Rheumatology Winter Clinical Symposium, Dr. George Martin of the Dermatology and Laser Center of Maui explains the latest developments and shares his excitement about them.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MAUI, HAWAII – Though costly, newer biologics increase 1-year survival with metastatic melanoma from perhaps 40% to more than 70%.
Among the latest are nivolumab and pembrolizumab, antibodies against PD-1 (programmed cell death) cell surface receptors that were approved in 2014 for unresectable melanoma no longer responding to other drugs; another anti-PD-1 is in development.
In this video interview at the 2015 Rheumatology Winter Clinical Symposium, Dr. George Martin of the Dermatology and Laser Center of Maui explains the latest developments and shares his excitement about them.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MAUI, HAWAII – Though costly, newer biologics increase 1-year survival with metastatic melanoma from perhaps 40% to more than 70%.
Among the latest are nivolumab and pembrolizumab, antibodies against PD-1 (programmed cell death) cell surface receptors that were approved in 2014 for unresectable melanoma no longer responding to other drugs; another anti-PD-1 is in development.
In this video interview at the 2015 Rheumatology Winter Clinical Symposium, Dr. George Martin of the Dermatology and Laser Center of Maui explains the latest developments and shares his excitement about them.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT RWCS 2015
Melanoma incidence highest in Oregon, lowest in Texas in 2015
Projections for the number of new melanoma cases in 2015 give Texas the lowest estimated incidence and Oregon the highest, according to a report from the American Cancer Society.
Texas is expected to have 2,410 new cases of melanoma this year, for an incidence of 8.9 cases per 100,000 people. Oregon’s projected 1,480 melanoma cases for 2015 results in an incidence of 37.3 cases per 100,000 population. (The ACS projected the number of new cases, so incidences here are calculated via recent Census Bureau population estimates.)
After Texas, Louisiana should have the lowest melanoma rate at 11.6 per 100,000, followed by Arkansas and the District of Columbia, both at 12.1 per 100,000. On the upper end of the scale, Oregon will likely be followed by Washington, where the incidence for 2015 is expected to be 34.8 per 100,000, the ACS data show.
Using incidences (1995-2011) reported by the North American Association of Central Cancer Registries, the ACS projected that 73,870 new cases of melanoma will be diagnosed in the United States this year – meaning an overall incidence of 23.2 per 100,000, based on the same Census Bureau figures.
The ACS estimated that there will be 9,940 deaths from melanoma in 2015 – an incidence of 3.1 per 100,000 population – as well as 3,400 deaths from other forms of skin cancer, not including basal cell and squamous cell carcinomas.
Projections for the number of new melanoma cases in 2015 give Texas the lowest estimated incidence and Oregon the highest, according to a report from the American Cancer Society.
Texas is expected to have 2,410 new cases of melanoma this year, for an incidence of 8.9 cases per 100,000 people. Oregon’s projected 1,480 melanoma cases for 2015 results in an incidence of 37.3 cases per 100,000 population. (The ACS projected the number of new cases, so incidences here are calculated via recent Census Bureau population estimates.)
After Texas, Louisiana should have the lowest melanoma rate at 11.6 per 100,000, followed by Arkansas and the District of Columbia, both at 12.1 per 100,000. On the upper end of the scale, Oregon will likely be followed by Washington, where the incidence for 2015 is expected to be 34.8 per 100,000, the ACS data show.
Using incidences (1995-2011) reported by the North American Association of Central Cancer Registries, the ACS projected that 73,870 new cases of melanoma will be diagnosed in the United States this year – meaning an overall incidence of 23.2 per 100,000, based on the same Census Bureau figures.
The ACS estimated that there will be 9,940 deaths from melanoma in 2015 – an incidence of 3.1 per 100,000 population – as well as 3,400 deaths from other forms of skin cancer, not including basal cell and squamous cell carcinomas.
Projections for the number of new melanoma cases in 2015 give Texas the lowest estimated incidence and Oregon the highest, according to a report from the American Cancer Society.
Texas is expected to have 2,410 new cases of melanoma this year, for an incidence of 8.9 cases per 100,000 people. Oregon’s projected 1,480 melanoma cases for 2015 results in an incidence of 37.3 cases per 100,000 population. (The ACS projected the number of new cases, so incidences here are calculated via recent Census Bureau population estimates.)
After Texas, Louisiana should have the lowest melanoma rate at 11.6 per 100,000, followed by Arkansas and the District of Columbia, both at 12.1 per 100,000. On the upper end of the scale, Oregon will likely be followed by Washington, where the incidence for 2015 is expected to be 34.8 per 100,000, the ACS data show.
Using incidences (1995-2011) reported by the North American Association of Central Cancer Registries, the ACS projected that 73,870 new cases of melanoma will be diagnosed in the United States this year – meaning an overall incidence of 23.2 per 100,000, based on the same Census Bureau figures.
The ACS estimated that there will be 9,940 deaths from melanoma in 2015 – an incidence of 3.1 per 100,000 population – as well as 3,400 deaths from other forms of skin cancer, not including basal cell and squamous cell carcinomas.
Overall survival plateaus at 3 years for ipilimumab-treated melanoma patients
Among patients with advanced melanoma who were treated with ipilimumab, about 20%-26% survived to 3 years, and these patients are likely to have a good long-term outcome, according to a pooled analysis of survival data published online Feb. 9 in the Journal of Clinical Oncology.
Investigators pooled data from ten prospective (including two phase III trials) and two retrospective studies with a total of 1,257 previously treated and 604 treatment-naive patients. At least 3 years after receiving ipilimumab, 254 patients were still alive, with a median follow up for this subset of 69 months. Around year 3, the Kaplan-Meier overall survival (OS) curve began to plateau and extended to 9.9 years for the longest survival follow-up.
“These results suggest that the majority of patients who reached this milestone time point had a low risk of death thereafter,” wrote Dr. Dirk Schadendorf and his associates (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]).
Compared with patients who were previously treated, treatment-naive patients had a higher median overall survival (13.5 months [95% confidence interval, 11.9-15.4] vs. 10.7 months [9.6-11.4]) and higher 3-year-survival rates (26% [21%-30%] vs. 20% [18%-23%]). No definitive conclusion could be drawn from this observation, however, since nonrandomized subsets were used for this analysis. Subset analysis by dose showed similar median OS and 3-year survival rates for ipilimumab 3 mg/kg, 10 mg/kg, and other dosing regimens.
The researchers expanded the study to include overall survival (OS) data from 2,985 patients enrolled in a U.S. multicenter, open-label, expanded-access treatment protocol (EAP). This group included patients with poorer prognostic factors, some of whom were ineligible for clinical trials. The expanded group showed a lower median OS of 9.5 months and 3 year–survival rate of 21%, with the familiar OS curve plateau around 3 years that extended up to 10 years in some patients.
While this analysis only examined overall survival rates, individual ipilimumab studies that tracked patient responses to the drug have shown that some proportion of long-term survivors did not achieve a response. Identifying the specific disease characteristics of the long-term survivors will require further study.
“Considering the historic median OS of approximately 8-10 months and a 5-year survival rate of approximately 10% in advanced melanoma, the results presented herein are encouraging for patients diagnosed with this aggressive disease,” the authors wrote.
Dr. Schadendorf and his associates demonstrate a plateau in the survival curve of ipilimumab-treated patients beginning at about 3 years and representing about 21% of the treatment group. The curve suggests that those who survive to 3 years are highly likely to have a good long-term outcome, which provides a strong motivating factor in the decision to consider ipilimumab treatment. While pooled data adds information far beyond individual trials, a major drawback lies in the loss of control data necessary to isolate the added benefit of the study drug.
An indirect comparison using historic control series, in this case a large cohort documented in the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, can substitute for missing control data in the pooled analysis. Reviewing data for stage IIIc and IV patients, the overall survival Kaplan-Meier curves in this population also show a plateau, but much later than that reported for ipilimumab, at beyond 8 years.
The AJCC melanoma classification gives survival rates at 3, 5, and 10 years of 19%, 13%, and 9%, respectively. Comparison with ipilimumab data suggests that survival at 3 years is similar, but thereafter improves with ipilimumab by 10% over other treatments that were available at the time. This difference is similar to the percentage of patients who achieved objective responses with ipilimumab. Although assessing response rate and progression-free survival in patients treated with ipilimumab presents challenges, the long-term benefits of ipilimumab could be better ascertained if information on the number of patients in the 21% plateau who were disease free or stably maintaining response had been collected.
Evaluation of long-term benefits of ipilimumab should consider toxicities and costs, as it is one of the most costly systemic therapies used for cancer treatment. The phase III trial using the drug at 3 mg/kg demonstrated that the large majority of patients had no serious adverse effects. If older patients and those with advanced disease are candidates, then the 10%-15% of grade 3 or 4 adverse events may translate to hospitalization and added expense, putting health regulatory systems in the position to deny widespread use of the agent despite proven benefit.
As the first agent to benefit overall survival of patients with advanced melanoma, ipilimumab may pave the way to broader improvements in a larger proportion of patients by combining with targeted therapies, such as BRAF and MEK inhibitors, and other new immunotherapies, such as anti-PD-1 antibodies.
Dr. Antoni Ribas is an oncologist with the Jonsson Comprehensive Cancer Center, Los Angles, and Dr. Keith T. Flaherty is an oncologist with Massachusetts General Hospital Cancer Center, Boston. These remarks were part of an editorial accompanying the report (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]). Dr. Ribas has an advisory role with Merck, Amgen, Novartis, GlaxoSmithKline, and Genentech/Roche. Dr. Flaherty has an advisory role with GlaxoSmithKline, Genentech/Roche, Novartis, and Merck.
Dr. Schadendorf and his associates demonstrate a plateau in the survival curve of ipilimumab-treated patients beginning at about 3 years and representing about 21% of the treatment group. The curve suggests that those who survive to 3 years are highly likely to have a good long-term outcome, which provides a strong motivating factor in the decision to consider ipilimumab treatment. While pooled data adds information far beyond individual trials, a major drawback lies in the loss of control data necessary to isolate the added benefit of the study drug.
An indirect comparison using historic control series, in this case a large cohort documented in the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, can substitute for missing control data in the pooled analysis. Reviewing data for stage IIIc and IV patients, the overall survival Kaplan-Meier curves in this population also show a plateau, but much later than that reported for ipilimumab, at beyond 8 years.
The AJCC melanoma classification gives survival rates at 3, 5, and 10 years of 19%, 13%, and 9%, respectively. Comparison with ipilimumab data suggests that survival at 3 years is similar, but thereafter improves with ipilimumab by 10% over other treatments that were available at the time. This difference is similar to the percentage of patients who achieved objective responses with ipilimumab. Although assessing response rate and progression-free survival in patients treated with ipilimumab presents challenges, the long-term benefits of ipilimumab could be better ascertained if information on the number of patients in the 21% plateau who were disease free or stably maintaining response had been collected.
Evaluation of long-term benefits of ipilimumab should consider toxicities and costs, as it is one of the most costly systemic therapies used for cancer treatment. The phase III trial using the drug at 3 mg/kg demonstrated that the large majority of patients had no serious adverse effects. If older patients and those with advanced disease are candidates, then the 10%-15% of grade 3 or 4 adverse events may translate to hospitalization and added expense, putting health regulatory systems in the position to deny widespread use of the agent despite proven benefit.
As the first agent to benefit overall survival of patients with advanced melanoma, ipilimumab may pave the way to broader improvements in a larger proportion of patients by combining with targeted therapies, such as BRAF and MEK inhibitors, and other new immunotherapies, such as anti-PD-1 antibodies.
Dr. Antoni Ribas is an oncologist with the Jonsson Comprehensive Cancer Center, Los Angles, and Dr. Keith T. Flaherty is an oncologist with Massachusetts General Hospital Cancer Center, Boston. These remarks were part of an editorial accompanying the report (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]). Dr. Ribas has an advisory role with Merck, Amgen, Novartis, GlaxoSmithKline, and Genentech/Roche. Dr. Flaherty has an advisory role with GlaxoSmithKline, Genentech/Roche, Novartis, and Merck.
Dr. Schadendorf and his associates demonstrate a plateau in the survival curve of ipilimumab-treated patients beginning at about 3 years and representing about 21% of the treatment group. The curve suggests that those who survive to 3 years are highly likely to have a good long-term outcome, which provides a strong motivating factor in the decision to consider ipilimumab treatment. While pooled data adds information far beyond individual trials, a major drawback lies in the loss of control data necessary to isolate the added benefit of the study drug.
An indirect comparison using historic control series, in this case a large cohort documented in the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, can substitute for missing control data in the pooled analysis. Reviewing data for stage IIIc and IV patients, the overall survival Kaplan-Meier curves in this population also show a plateau, but much later than that reported for ipilimumab, at beyond 8 years.
The AJCC melanoma classification gives survival rates at 3, 5, and 10 years of 19%, 13%, and 9%, respectively. Comparison with ipilimumab data suggests that survival at 3 years is similar, but thereafter improves with ipilimumab by 10% over other treatments that were available at the time. This difference is similar to the percentage of patients who achieved objective responses with ipilimumab. Although assessing response rate and progression-free survival in patients treated with ipilimumab presents challenges, the long-term benefits of ipilimumab could be better ascertained if information on the number of patients in the 21% plateau who were disease free or stably maintaining response had been collected.
Evaluation of long-term benefits of ipilimumab should consider toxicities and costs, as it is one of the most costly systemic therapies used for cancer treatment. The phase III trial using the drug at 3 mg/kg demonstrated that the large majority of patients had no serious adverse effects. If older patients and those with advanced disease are candidates, then the 10%-15% of grade 3 or 4 adverse events may translate to hospitalization and added expense, putting health regulatory systems in the position to deny widespread use of the agent despite proven benefit.
As the first agent to benefit overall survival of patients with advanced melanoma, ipilimumab may pave the way to broader improvements in a larger proportion of patients by combining with targeted therapies, such as BRAF and MEK inhibitors, and other new immunotherapies, such as anti-PD-1 antibodies.
Dr. Antoni Ribas is an oncologist with the Jonsson Comprehensive Cancer Center, Los Angles, and Dr. Keith T. Flaherty is an oncologist with Massachusetts General Hospital Cancer Center, Boston. These remarks were part of an editorial accompanying the report (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]). Dr. Ribas has an advisory role with Merck, Amgen, Novartis, GlaxoSmithKline, and Genentech/Roche. Dr. Flaherty has an advisory role with GlaxoSmithKline, Genentech/Roche, Novartis, and Merck.
Among patients with advanced melanoma who were treated with ipilimumab, about 20%-26% survived to 3 years, and these patients are likely to have a good long-term outcome, according to a pooled analysis of survival data published online Feb. 9 in the Journal of Clinical Oncology.
Investigators pooled data from ten prospective (including two phase III trials) and two retrospective studies with a total of 1,257 previously treated and 604 treatment-naive patients. At least 3 years after receiving ipilimumab, 254 patients were still alive, with a median follow up for this subset of 69 months. Around year 3, the Kaplan-Meier overall survival (OS) curve began to plateau and extended to 9.9 years for the longest survival follow-up.
“These results suggest that the majority of patients who reached this milestone time point had a low risk of death thereafter,” wrote Dr. Dirk Schadendorf and his associates (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]).
Compared with patients who were previously treated, treatment-naive patients had a higher median overall survival (13.5 months [95% confidence interval, 11.9-15.4] vs. 10.7 months [9.6-11.4]) and higher 3-year-survival rates (26% [21%-30%] vs. 20% [18%-23%]). No definitive conclusion could be drawn from this observation, however, since nonrandomized subsets were used for this analysis. Subset analysis by dose showed similar median OS and 3-year survival rates for ipilimumab 3 mg/kg, 10 mg/kg, and other dosing regimens.
The researchers expanded the study to include overall survival (OS) data from 2,985 patients enrolled in a U.S. multicenter, open-label, expanded-access treatment protocol (EAP). This group included patients with poorer prognostic factors, some of whom were ineligible for clinical trials. The expanded group showed a lower median OS of 9.5 months and 3 year–survival rate of 21%, with the familiar OS curve plateau around 3 years that extended up to 10 years in some patients.
While this analysis only examined overall survival rates, individual ipilimumab studies that tracked patient responses to the drug have shown that some proportion of long-term survivors did not achieve a response. Identifying the specific disease characteristics of the long-term survivors will require further study.
“Considering the historic median OS of approximately 8-10 months and a 5-year survival rate of approximately 10% in advanced melanoma, the results presented herein are encouraging for patients diagnosed with this aggressive disease,” the authors wrote.
Among patients with advanced melanoma who were treated with ipilimumab, about 20%-26% survived to 3 years, and these patients are likely to have a good long-term outcome, according to a pooled analysis of survival data published online Feb. 9 in the Journal of Clinical Oncology.
Investigators pooled data from ten prospective (including two phase III trials) and two retrospective studies with a total of 1,257 previously treated and 604 treatment-naive patients. At least 3 years after receiving ipilimumab, 254 patients were still alive, with a median follow up for this subset of 69 months. Around year 3, the Kaplan-Meier overall survival (OS) curve began to plateau and extended to 9.9 years for the longest survival follow-up.
“These results suggest that the majority of patients who reached this milestone time point had a low risk of death thereafter,” wrote Dr. Dirk Schadendorf and his associates (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]).
Compared with patients who were previously treated, treatment-naive patients had a higher median overall survival (13.5 months [95% confidence interval, 11.9-15.4] vs. 10.7 months [9.6-11.4]) and higher 3-year-survival rates (26% [21%-30%] vs. 20% [18%-23%]). No definitive conclusion could be drawn from this observation, however, since nonrandomized subsets were used for this analysis. Subset analysis by dose showed similar median OS and 3-year survival rates for ipilimumab 3 mg/kg, 10 mg/kg, and other dosing regimens.
The researchers expanded the study to include overall survival (OS) data from 2,985 patients enrolled in a U.S. multicenter, open-label, expanded-access treatment protocol (EAP). This group included patients with poorer prognostic factors, some of whom were ineligible for clinical trials. The expanded group showed a lower median OS of 9.5 months and 3 year–survival rate of 21%, with the familiar OS curve plateau around 3 years that extended up to 10 years in some patients.
While this analysis only examined overall survival rates, individual ipilimumab studies that tracked patient responses to the drug have shown that some proportion of long-term survivors did not achieve a response. Identifying the specific disease characteristics of the long-term survivors will require further study.
“Considering the historic median OS of approximately 8-10 months and a 5-year survival rate of approximately 10% in advanced melanoma, the results presented herein are encouraging for patients diagnosed with this aggressive disease,” the authors wrote.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Ipilimumab-treated advanced melanoma patients alive at 3 years tend to have good long-term outcomes.
Major finding: Around year 3, the Kaplan-Meier OS curve began to plateau and extended to 9.9 years for the longest survival follow-up.
Data source: Pooled overall survival data from 12 studies including 1,861 ipilimumab-treated patients with advanced melanoma.
Disclosures: Dr. Schadendorf disclosed that he is a consultant for Bristol-Myers Squibb. Bristol-Myers Squibb sponsored this study.
Melanoma pathogenesis in patient reveals phenotype-genotype paradox
A melanoma in a dysplastic nevus contained a phenotype-genotype disagreement confounding the exclusive significance of BRAF and NRAS mutations in melanoma pathogenesis, according to Dr. Jean-Marie Tan and associates.
A man in his 50s was diagnosed with a melanoma in a dysplastic nevus after being admitted with a irregularly pigmented melanocytic lesion. Microbiopsy specimens were taken across the lesion and genotyping was carried out on DNA samples for BRAF and NRAS mutations. The melanoma showed only BRAF wild-type, while the dysplastic nevus showed both BRAF wild-type and BRAF V600E mutations. Sequencing in all DNA samples revealed NRAS wild-type genotype, the researchers found.
These conflicting results indicate further studies are required to investigate the importance of other candidate genes linked to melanomagenesis, the investigators concluded.
Read the full article at JAMA Dermatology (doi:10.1001/jamadermatol.2014.3775).
A melanoma in a dysplastic nevus contained a phenotype-genotype disagreement confounding the exclusive significance of BRAF and NRAS mutations in melanoma pathogenesis, according to Dr. Jean-Marie Tan and associates.
A man in his 50s was diagnosed with a melanoma in a dysplastic nevus after being admitted with a irregularly pigmented melanocytic lesion. Microbiopsy specimens were taken across the lesion and genotyping was carried out on DNA samples for BRAF and NRAS mutations. The melanoma showed only BRAF wild-type, while the dysplastic nevus showed both BRAF wild-type and BRAF V600E mutations. Sequencing in all DNA samples revealed NRAS wild-type genotype, the researchers found.
These conflicting results indicate further studies are required to investigate the importance of other candidate genes linked to melanomagenesis, the investigators concluded.
Read the full article at JAMA Dermatology (doi:10.1001/jamadermatol.2014.3775).
A melanoma in a dysplastic nevus contained a phenotype-genotype disagreement confounding the exclusive significance of BRAF and NRAS mutations in melanoma pathogenesis, according to Dr. Jean-Marie Tan and associates.
A man in his 50s was diagnosed with a melanoma in a dysplastic nevus after being admitted with a irregularly pigmented melanocytic lesion. Microbiopsy specimens were taken across the lesion and genotyping was carried out on DNA samples for BRAF and NRAS mutations. The melanoma showed only BRAF wild-type, while the dysplastic nevus showed both BRAF wild-type and BRAF V600E mutations. Sequencing in all DNA samples revealed NRAS wild-type genotype, the researchers found.
These conflicting results indicate further studies are required to investigate the importance of other candidate genes linked to melanomagenesis, the investigators concluded.
Read the full article at JAMA Dermatology (doi:10.1001/jamadermatol.2014.3775).
Xerosis is significant risk during targeted anticancer treatments
Patients receiving targeted anticancer treatments are at a significant risk of developing xerosis, or abnormal dryness, according to Dr. Johannah Valentine and her associates.
In a systematic review and meta-analysis of clinical trials involving 58 targeted agents, nearly 18% of all patients developed xerosis, with 1% of patients developing high-grade xerosis. The incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions, and reporting may vary among physicians and institutions, the researchers said.
Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality-of-life impairment, the investigators recommended.
Read the full article at the Journal of the American Academy of Dermatology (doi:10.1016/j.jaad.2014.12.010).
Patients receiving targeted anticancer treatments are at a significant risk of developing xerosis, or abnormal dryness, according to Dr. Johannah Valentine and her associates.
In a systematic review and meta-analysis of clinical trials involving 58 targeted agents, nearly 18% of all patients developed xerosis, with 1% of patients developing high-grade xerosis. The incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions, and reporting may vary among physicians and institutions, the researchers said.
Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality-of-life impairment, the investigators recommended.
Read the full article at the Journal of the American Academy of Dermatology (doi:10.1016/j.jaad.2014.12.010).
Patients receiving targeted anticancer treatments are at a significant risk of developing xerosis, or abnormal dryness, according to Dr. Johannah Valentine and her associates.
In a systematic review and meta-analysis of clinical trials involving 58 targeted agents, nearly 18% of all patients developed xerosis, with 1% of patients developing high-grade xerosis. The incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions, and reporting may vary among physicians and institutions, the researchers said.
Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality-of-life impairment, the investigators recommended.
Read the full article at the Journal of the American Academy of Dermatology (doi:10.1016/j.jaad.2014.12.010).
Manage Your Dermatology Practice: Managing Difficult Patient Encounters
Difficult patient encounters in the dermatology office can be navigated through honest physician-patient communication regarding problems within the office and insurance coverage. Dr. Gary Goldenberg provides tips on communicating with patients about cosmetic procedures that may be noncovered services as well as diagnoses such as melanoma and psoriasis. He also advises how to work through a long list of questions patients may bring to their visit.
Difficult patient encounters in the dermatology office can be navigated through honest physician-patient communication regarding problems within the office and insurance coverage. Dr. Gary Goldenberg provides tips on communicating with patients about cosmetic procedures that may be noncovered services as well as diagnoses such as melanoma and psoriasis. He also advises how to work through a long list of questions patients may bring to their visit.
Difficult patient encounters in the dermatology office can be navigated through honest physician-patient communication regarding problems within the office and insurance coverage. Dr. Gary Goldenberg provides tips on communicating with patients about cosmetic procedures that may be noncovered services as well as diagnoses such as melanoma and psoriasis. He also advises how to work through a long list of questions patients may bring to their visit.
