Melanoma

NATIONAL HARBOR, MD. – The combination of bempegaldesleukin and nivolumab produced durable responses in a phase 1/2 trial of patients with previously untreated metastatic melanoma.

Jennifer Smith/MDedge News

The overall response rate was 53%, and most responders were still in response at a median follow-up of about 19 months. The median progression-free survival was not reached, and the combination was considered well tolerated.

Adi Diab, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented these results from the PIVOT-02 study at the annual meeting of the Society for Immunotherapy of Cancer.

Dr. Diab explained that bempegaldesleukin (bempeg) is a CD122-preferential interleukin-2 pathway agonist, and earlier results from the PIVOT-02 trial showed that adding bempeg to nivolumab can convert baseline tumors from programmed death–ligand 1 (PD-L1) negative to PD-L1 positive (SITC 2018, Abstract O4).

Dr. Diab presented updated results from PIVOT-02 (NCT02983045) in 41 patients with metastatic melanoma who received bempeg plus nivolumab as first-line treatment. The patients had a median age of 63 years (range, 22-80 years) at baseline, and 58.5% were male. Most patients (58.5%) were PD-L1 positive, although PD-L1 status was unknown in 7.3% of patients.

Patients received bempeg at 0.006 mg/kg and nivolumab at 360 mg every 3 weeks. They received a median of nine cycles (range, 1-34), and the median follow-up was 18.6 months.

Efficacy

In the 38 patients who were evaluable for efficacy, the overall response rate was 53% (n = 20), and the complete response rate was 34% (n = 13). The median time to response was 2.0 months, and the median time to complete response was 7.9 months.

Dr. Diab noted that responses were seen regardless of PD-L1 expression at baseline. The response rate was 39% among PD-L1-negative patients, 64% among PD-L1-positive patients, and 33% among patients whose PD-L1 status was unknown.

Dr. Diab also pointed out that responses were durable and deepened over time. The median duration of response was not reached, and 17 of the 20 responders had ongoing responses at last follow-up. The median progression-free survival has not been reached.

Safety

“This combination is safe and tolerable, there’s no overlapping immune-related adverse events, and the most common side effects are grade 1/2 flu-like symptoms,” Dr. Diab said.

The most common grade 1/2 treatment-related adverse events (AEs) were flu-like symptoms (80.5%), rash (70.7%), fatigue (65.9%), pruritus (48.8%), nausea (46.3%), arthralgia (43.9%), decreased appetite (36.6%), and myalgia (36.6%).

Dr. Diab noted that cytokine-related AEs (flu-like symptoms, rash, and pruritus) were easily managed with NSAIDs; decreased with subsequent cycles of treatment; and did not necessitate dose delays, reductions, or discontinuations.

Grade 3/4 treatment-related AEs included two cases of acute kidney injury, two cases of atrial fibrillation, one case of dizziness, one case of dyspnea, one case of hypoxia, one case of hyperglycemia, and one case of hypernatremia.

Five patients discontinued treatment because of related AEs, including cerebrovascular accident, peripheral edema, blood creatinine increase, malaise, and pharyngitis. There were no treatment-related deaths.

Dr. Diab said these results were used to support the recent breakthrough therapy designation granted to bempeg in combination with nivolumab. The results have also prompted a phase 3 trial in which researchers are comparing the combination with nivolumab alone (NCT03635983).

The phase 1/2 trial is sponsored by Nektar Therapeutics in collaboration with Bristol-Myers Squibb. Dr. Diab reported relationships with Nektar, Celgene, CureVac, Idera, and Pfizer.

SOURCE: Diab A et al. SITC 2019, Abstract O35.

NATIONAL HARBOR, MD. – The combination of bempegaldesleukin and nivolumab produced durable responses in a phase 1/2 trial of patients with previously untreated metastatic melanoma.

Jennifer Smith/MDedge News

The overall response rate was 53%, and most responders were still in response at a median follow-up of about 19 months. The median progression-free survival was not reached, and the combination was considered well tolerated.

Adi Diab, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented these results from the PIVOT-02 study at the annual meeting of the Society for Immunotherapy of Cancer.

Dr. Diab explained that bempegaldesleukin (bempeg) is a CD122-preferential interleukin-2 pathway agonist, and earlier results from the PIVOT-02 trial showed that adding bempeg to nivolumab can convert baseline tumors from programmed death–ligand 1 (PD-L1) negative to PD-L1 positive (SITC 2018, Abstract O4).

Dr. Diab presented updated results from PIVOT-02 (NCT02983045) in 41 patients with metastatic melanoma who received bempeg plus nivolumab as first-line treatment. The patients had a median age of 63 years (range, 22-80 years) at baseline, and 58.5% were male. Most patients (58.5%) were PD-L1 positive, although PD-L1 status was unknown in 7.3% of patients.

Patients received bempeg at 0.006 mg/kg and nivolumab at 360 mg every 3 weeks. They received a median of nine cycles (range, 1-34), and the median follow-up was 18.6 months.

Efficacy

In the 38 patients who were evaluable for efficacy, the overall response rate was 53% (n = 20), and the complete response rate was 34% (n = 13). The median time to response was 2.0 months, and the median time to complete response was 7.9 months.

Dr. Diab noted that responses were seen regardless of PD-L1 expression at baseline. The response rate was 39% among PD-L1-negative patients, 64% among PD-L1-positive patients, and 33% among patients whose PD-L1 status was unknown.

Dr. Diab also pointed out that responses were durable and deepened over time. The median duration of response was not reached, and 17 of the 20 responders had ongoing responses at last follow-up. The median progression-free survival has not been reached.

Safety

“This combination is safe and tolerable, there’s no overlapping immune-related adverse events, and the most common side effects are grade 1/2 flu-like symptoms,” Dr. Diab said.

The most common grade 1/2 treatment-related adverse events (AEs) were flu-like symptoms (80.5%), rash (70.7%), fatigue (65.9%), pruritus (48.8%), nausea (46.3%), arthralgia (43.9%), decreased appetite (36.6%), and myalgia (36.6%).

Dr. Diab noted that cytokine-related AEs (flu-like symptoms, rash, and pruritus) were easily managed with NSAIDs; decreased with subsequent cycles of treatment; and did not necessitate dose delays, reductions, or discontinuations.

Grade 3/4 treatment-related AEs included two cases of acute kidney injury, two cases of atrial fibrillation, one case of dizziness, one case of dyspnea, one case of hypoxia, one case of hyperglycemia, and one case of hypernatremia.

Five patients discontinued treatment because of related AEs, including cerebrovascular accident, peripheral edema, blood creatinine increase, malaise, and pharyngitis. There were no treatment-related deaths.

Dr. Diab said these results were used to support the recent breakthrough therapy designation granted to bempeg in combination with nivolumab. The results have also prompted a phase 3 trial in which researchers are comparing the combination with nivolumab alone (NCT03635983).

The phase 1/2 trial is sponsored by Nektar Therapeutics in collaboration with Bristol-Myers Squibb. Dr. Diab reported relationships with Nektar, Celgene, CureVac, Idera, and Pfizer.

SOURCE: Diab A et al. SITC 2019, Abstract O35.

NATIONAL HARBOR, MD. – The combination of bempegaldesleukin and nivolumab produced durable responses in a phase 1/2 trial of patients with previously untreated metastatic melanoma.

Jennifer Smith/MDedge News

The overall response rate was 53%, and most responders were still in response at a median follow-up of about 19 months. The median progression-free survival was not reached, and the combination was considered well tolerated.

Adi Diab, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented these results from the PIVOT-02 study at the annual meeting of the Society for Immunotherapy of Cancer.

Dr. Diab explained that bempegaldesleukin (bempeg) is a CD122-preferential interleukin-2 pathway agonist, and earlier results from the PIVOT-02 trial showed that adding bempeg to nivolumab can convert baseline tumors from programmed death–ligand 1 (PD-L1) negative to PD-L1 positive (SITC 2018, Abstract O4).

Dr. Diab presented updated results from PIVOT-02 (NCT02983045) in 41 patients with metastatic melanoma who received bempeg plus nivolumab as first-line treatment. The patients had a median age of 63 years (range, 22-80 years) at baseline, and 58.5% were male. Most patients (58.5%) were PD-L1 positive, although PD-L1 status was unknown in 7.3% of patients.

Patients received bempeg at 0.006 mg/kg and nivolumab at 360 mg every 3 weeks. They received a median of nine cycles (range, 1-34), and the median follow-up was 18.6 months.

Efficacy

In the 38 patients who were evaluable for efficacy, the overall response rate was 53% (n = 20), and the complete response rate was 34% (n = 13). The median time to response was 2.0 months, and the median time to complete response was 7.9 months.

Dr. Diab noted that responses were seen regardless of PD-L1 expression at baseline. The response rate was 39% among PD-L1-negative patients, 64% among PD-L1-positive patients, and 33% among patients whose PD-L1 status was unknown.

Dr. Diab also pointed out that responses were durable and deepened over time. The median duration of response was not reached, and 17 of the 20 responders had ongoing responses at last follow-up. The median progression-free survival has not been reached.

Safety

“This combination is safe and tolerable, there’s no overlapping immune-related adverse events, and the most common side effects are grade 1/2 flu-like symptoms,” Dr. Diab said.

The most common grade 1/2 treatment-related adverse events (AEs) were flu-like symptoms (80.5%), rash (70.7%), fatigue (65.9%), pruritus (48.8%), nausea (46.3%), arthralgia (43.9%), decreased appetite (36.6%), and myalgia (36.6%).

Dr. Diab noted that cytokine-related AEs (flu-like symptoms, rash, and pruritus) were easily managed with NSAIDs; decreased with subsequent cycles of treatment; and did not necessitate dose delays, reductions, or discontinuations.

Grade 3/4 treatment-related AEs included two cases of acute kidney injury, two cases of atrial fibrillation, one case of dizziness, one case of dyspnea, one case of hypoxia, one case of hyperglycemia, and one case of hypernatremia.

Five patients discontinued treatment because of related AEs, including cerebrovascular accident, peripheral edema, blood creatinine increase, malaise, and pharyngitis. There were no treatment-related deaths.

Dr. Diab said these results were used to support the recent breakthrough therapy designation granted to bempeg in combination with nivolumab. The results have also prompted a phase 3 trial in which researchers are comparing the combination with nivolumab alone (NCT03635983).

The phase 1/2 trial is sponsored by Nektar Therapeutics in collaboration with Bristol-Myers Squibb. Dr. Diab reported relationships with Nektar, Celgene, CureVac, Idera, and Pfizer.

SOURCE: Diab A et al. SITC 2019, Abstract O35.

The incidence of melanoma in the United States dropped significantly among adolescents and young adults aged 10 to 29 years between 2006 and 2015, according to results of a population-based registry study of 988,103 cases of invasive melanoma.

These data are observational, “and thus cannot conclusively determine the cause of this statistically and clinically significant decrease,” wrote Kelly G. Paulson, MD, PhD, of the Fred Hutchinson Cancer Research Center, Seattle, and colleagues. However, they added, “a likely explanation for the reduced melanoma incidence in adolescents and young adults is success at increased UV exposure protection. These data provide an impetus to further improve multimodal efforts aimed at reducing the burden of melanoma and encourage ongoing UV exposure protection efforts throughout the lifetime of individuals.”

Public health measures to promote sun-protective behaviors including sunscreen use, protective clothing, and seeking shade were initiated in the United States in the late 1990s and early 2000s, but the public health impact remains unknown, they noted in the study, published in JAMA Dermatology.

For the study, they reviewed data from the National Program of Cancer Registries – Surveillance Epidemiology and End Results combined database for the years 2001-2015. Overall, the incidence of invasive melanoma among people of all ages in the United States increased from 50,272 cases in 2001 to 83,362 in 2015. However, in 2015 only 67 cases were reported in children younger than 10 years, 251 in adolescents aged 10-19 years, and 1,973 in young adults (aged 20-29 years).

Between 2006 and 2015, the annual percentage change in melanoma incidence decreased by 4.4% for male adolescents, 5.4% for female adolescents, 3.7% for male young adults, and 3.6% for female young adults; these changes were statistically significant. The trends in incidence was similar when the population was limited to non-Hispanic whites, considered a high-risk group for melanoma.

By contrast, melanoma incidence increased by an annual percentage change of 1.8% for both men and women aged 40 years and older during the same period of time. Young adult women had a greater incidence of melanoma compared with young adult men (about twofold greater), but older men had a greater incidence of melanoma compared with older women, the researchers said.

The findings were limited by a lack of data about potential confounders, such as skin pigmentation, UV light exposure, sunburn history, sunscreen use, sun avoidance, protective clothing, and tanning bed use; and the absence of information kept the researchers from estimating an association between increased sun-protective behaviors and decreased incidence of melanoma.

“However, this change in behavior remains a plausible explanation for decreased melanoma rates in adolescent and young adult populations,” and the data support continued strategies to promote UV protection throughout life, they said.

The study was supported in part by the National Institutes of Health, the Fred Hutchinson Cancer Research Center Integrated Immunotherapy Research Core, and a Society for Immunotherapy of Cancer–Merck fellowship. Dr. Paulson disclosed grants from the Society for Immunotherapy of Cancer–Merck, bluebird biosciences, EMD Serono; she also disclosed an issued and licensed patent for a Merkel cell carcinoma T cell receptor.

SOURCE: Paulson KG et al. JAMA Dermatol. 2019. Nov 13. doi: 10.1001/jamadermatol.2019.3353.

The incidence of melanoma in the United States dropped significantly among adolescents and young adults aged 10 to 29 years between 2006 and 2015, according to results of a population-based registry study of 988,103 cases of invasive melanoma.

These data are observational, “and thus cannot conclusively determine the cause of this statistically and clinically significant decrease,” wrote Kelly G. Paulson, MD, PhD, of the Fred Hutchinson Cancer Research Center, Seattle, and colleagues. However, they added, “a likely explanation for the reduced melanoma incidence in adolescents and young adults is success at increased UV exposure protection. These data provide an impetus to further improve multimodal efforts aimed at reducing the burden of melanoma and encourage ongoing UV exposure protection efforts throughout the lifetime of individuals.”

Public health measures to promote sun-protective behaviors including sunscreen use, protective clothing, and seeking shade were initiated in the United States in the late 1990s and early 2000s, but the public health impact remains unknown, they noted in the study, published in JAMA Dermatology.

For the study, they reviewed data from the National Program of Cancer Registries – Surveillance Epidemiology and End Results combined database for the years 2001-2015. Overall, the incidence of invasive melanoma among people of all ages in the United States increased from 50,272 cases in 2001 to 83,362 in 2015. However, in 2015 only 67 cases were reported in children younger than 10 years, 251 in adolescents aged 10-19 years, and 1,973 in young adults (aged 20-29 years).

Between 2006 and 2015, the annual percentage change in melanoma incidence decreased by 4.4% for male adolescents, 5.4% for female adolescents, 3.7% for male young adults, and 3.6% for female young adults; these changes were statistically significant. The trends in incidence was similar when the population was limited to non-Hispanic whites, considered a high-risk group for melanoma.

By contrast, melanoma incidence increased by an annual percentage change of 1.8% for both men and women aged 40 years and older during the same period of time. Young adult women had a greater incidence of melanoma compared with young adult men (about twofold greater), but older men had a greater incidence of melanoma compared with older women, the researchers said.

The findings were limited by a lack of data about potential confounders, such as skin pigmentation, UV light exposure, sunburn history, sunscreen use, sun avoidance, protective clothing, and tanning bed use; and the absence of information kept the researchers from estimating an association between increased sun-protective behaviors and decreased incidence of melanoma.

“However, this change in behavior remains a plausible explanation for decreased melanoma rates in adolescent and young adult populations,” and the data support continued strategies to promote UV protection throughout life, they said.

The study was supported in part by the National Institutes of Health, the Fred Hutchinson Cancer Research Center Integrated Immunotherapy Research Core, and a Society for Immunotherapy of Cancer–Merck fellowship. Dr. Paulson disclosed grants from the Society for Immunotherapy of Cancer–Merck, bluebird biosciences, EMD Serono; she also disclosed an issued and licensed patent for a Merkel cell carcinoma T cell receptor.

SOURCE: Paulson KG et al. JAMA Dermatol. 2019. Nov 13. doi: 10.1001/jamadermatol.2019.3353.

The incidence of melanoma in the United States dropped significantly among adolescents and young adults aged 10 to 29 years between 2006 and 2015, according to results of a population-based registry study of 988,103 cases of invasive melanoma.

These data are observational, “and thus cannot conclusively determine the cause of this statistically and clinically significant decrease,” wrote Kelly G. Paulson, MD, PhD, of the Fred Hutchinson Cancer Research Center, Seattle, and colleagues. However, they added, “a likely explanation for the reduced melanoma incidence in adolescents and young adults is success at increased UV exposure protection. These data provide an impetus to further improve multimodal efforts aimed at reducing the burden of melanoma and encourage ongoing UV exposure protection efforts throughout the lifetime of individuals.”

Public health measures to promote sun-protective behaviors including sunscreen use, protective clothing, and seeking shade were initiated in the United States in the late 1990s and early 2000s, but the public health impact remains unknown, they noted in the study, published in JAMA Dermatology.

For the study, they reviewed data from the National Program of Cancer Registries – Surveillance Epidemiology and End Results combined database for the years 2001-2015. Overall, the incidence of invasive melanoma among people of all ages in the United States increased from 50,272 cases in 2001 to 83,362 in 2015. However, in 2015 only 67 cases were reported in children younger than 10 years, 251 in adolescents aged 10-19 years, and 1,973 in young adults (aged 20-29 years).

Between 2006 and 2015, the annual percentage change in melanoma incidence decreased by 4.4% for male adolescents, 5.4% for female adolescents, 3.7% for male young adults, and 3.6% for female young adults; these changes were statistically significant. The trends in incidence was similar when the population was limited to non-Hispanic whites, considered a high-risk group for melanoma.

By contrast, melanoma incidence increased by an annual percentage change of 1.8% for both men and women aged 40 years and older during the same period of time. Young adult women had a greater incidence of melanoma compared with young adult men (about twofold greater), but older men had a greater incidence of melanoma compared with older women, the researchers said.

The findings were limited by a lack of data about potential confounders, such as skin pigmentation, UV light exposure, sunburn history, sunscreen use, sun avoidance, protective clothing, and tanning bed use; and the absence of information kept the researchers from estimating an association between increased sun-protective behaviors and decreased incidence of melanoma.

“However, this change in behavior remains a plausible explanation for decreased melanoma rates in adolescent and young adult populations,” and the data support continued strategies to promote UV protection throughout life, they said.

The study was supported in part by the National Institutes of Health, the Fred Hutchinson Cancer Research Center Integrated Immunotherapy Research Core, and a Society for Immunotherapy of Cancer–Merck fellowship. Dr. Paulson disclosed grants from the Society for Immunotherapy of Cancer–Merck, bluebird biosciences, EMD Serono; she also disclosed an issued and licensed patent for a Merkel cell carcinoma T cell receptor.

SOURCE: Paulson KG et al. JAMA Dermatol. 2019. Nov 13. doi: 10.1001/jamadermatol.2019.3353.

NATIONAL HARBOR, MD. – A TLR9 agonist called CMP-001 can reverse resistance to anti–programmed death-1 (PD-1) therapy in patients with melanoma, a phase 1 trial suggests.

Jennifer Smith/MDedge News

Combination CMP-001 and pembrolizumab produced durable responses in patients who had progressed on prior anti–PD-1 therapy, and the combination was considered well tolerated.

CMP-001 is a CpG-A TLR9 agonist packaged in a viruslike particle, John Kirkwood, MD, of University of Pittsburgh Medical Center, explained in a late-breaking abstract at the annual meeting of the Society for Immunotherapy of Cancer. CMP-001 activates tumor-associated plasmacytoid dendritic cells and induces systemic tumor-specific CD8+ T-cell responses.

Dr. Kirkwood and associates are investigating CMP-001, given alone or in combination with pembrolizumab, in a phase 1 trial (NCT02680184) of patients with metastatic or unresectable melanoma who are refractory to anti–PD-1 therapy.

Data were presented on 144 patients who received CMP-001 in combination with pembrolizumab. About 40% of patients (39.6%) had elevated lactate dehydrogenase at baseline, and 32.6% had BRAF mutations.

All patients had received prior anti–PD-1 therapy alone (75%) and/or in combination (50%). For most patients (93.1%), their last response to anti–PD-1 therapy was progression.

For this study, the patients received intratumoral CMP-001 injections at a range of doses (1 mg, 3 mg, 5 mg, 7.5 mg, and 10 mg). CMP-001 was given weekly for either 2 weeks or 7 weeks, then every 3 weeks until discontinuation. There were two different formulations of CMP-001 given – 0.01% polysorbate 20 (PS20; n = 83) and 0.00167% PS20 (n = 61).
 

Safety

“CMP-001 in combination with pembrolizumab is very well tolerated, with no apparent increase in autoimmune toxicities associated with anti–PD-1,” Dr. Kirkwood said.

The most common treatment-related adverse events were flulike symptoms, including chills (72%), pyrexia (56%), fatigue (51%), nausea (45%), vomiting (29%), and headache (28%). Another common event was injection-site pain (28%).

The most common grade 3 adverse events were hypotension (n = 9) and hypertension (n = 7). Grade 4 events included hypotension, aspartate aminotransferase increase, and alanine aminotransferase increase (n = 1 for all). There were no grade 5 events.

Six patients discontinued treatment because of adverse events.
 

Response

The overall response rate was 25% (21/83) among patients who received the 0.01% PS20 formulation of CMP-001 and 11.5% (7/61) among patients who received the 0.00167% PS20 formulation.

Responses were similar in injected and noninjected target lesions. The median duration of response has not been reached at a median follow-up of 16.9 months.

“Intratumoral CMP-001 reverses resistance to anti–PD-1 in patients who have progressed on prior anti–PD-1 therapy,” Dr. Kirkwood said, adding that these data support further clinical development of CMP-001.

The research is sponsored by Checkmate Pharmaceuticals. Dr. Kirkwood disclosed relationships with Amgen, BMS, Immunocore, Iovance, Novartis, Elsevier, Castle, Merck, and Checkmate.

SOURCE: Kirkwood J et al. SITC 2019, Abstract O85.

NATIONAL HARBOR, MD. – A TLR9 agonist called CMP-001 can reverse resistance to anti–programmed death-1 (PD-1) therapy in patients with melanoma, a phase 1 trial suggests.

Jennifer Smith/MDedge News

Combination CMP-001 and pembrolizumab produced durable responses in patients who had progressed on prior anti–PD-1 therapy, and the combination was considered well tolerated.

CMP-001 is a CpG-A TLR9 agonist packaged in a viruslike particle, John Kirkwood, MD, of University of Pittsburgh Medical Center, explained in a late-breaking abstract at the annual meeting of the Society for Immunotherapy of Cancer. CMP-001 activates tumor-associated plasmacytoid dendritic cells and induces systemic tumor-specific CD8+ T-cell responses.

Dr. Kirkwood and associates are investigating CMP-001, given alone or in combination with pembrolizumab, in a phase 1 trial (NCT02680184) of patients with metastatic or unresectable melanoma who are refractory to anti–PD-1 therapy.

Data were presented on 144 patients who received CMP-001 in combination with pembrolizumab. About 40% of patients (39.6%) had elevated lactate dehydrogenase at baseline, and 32.6% had BRAF mutations.

All patients had received prior anti–PD-1 therapy alone (75%) and/or in combination (50%). For most patients (93.1%), their last response to anti–PD-1 therapy was progression.

For this study, the patients received intratumoral CMP-001 injections at a range of doses (1 mg, 3 mg, 5 mg, 7.5 mg, and 10 mg). CMP-001 was given weekly for either 2 weeks or 7 weeks, then every 3 weeks until discontinuation. There were two different formulations of CMP-001 given – 0.01% polysorbate 20 (PS20; n = 83) and 0.00167% PS20 (n = 61).
 

Safety

“CMP-001 in combination with pembrolizumab is very well tolerated, with no apparent increase in autoimmune toxicities associated with anti–PD-1,” Dr. Kirkwood said.

The most common treatment-related adverse events were flulike symptoms, including chills (72%), pyrexia (56%), fatigue (51%), nausea (45%), vomiting (29%), and headache (28%). Another common event was injection-site pain (28%).

The most common grade 3 adverse events were hypotension (n = 9) and hypertension (n = 7). Grade 4 events included hypotension, aspartate aminotransferase increase, and alanine aminotransferase increase (n = 1 for all). There were no grade 5 events.

Six patients discontinued treatment because of adverse events.
 

Response

The overall response rate was 25% (21/83) among patients who received the 0.01% PS20 formulation of CMP-001 and 11.5% (7/61) among patients who received the 0.00167% PS20 formulation.

Responses were similar in injected and noninjected target lesions. The median duration of response has not been reached at a median follow-up of 16.9 months.

“Intratumoral CMP-001 reverses resistance to anti–PD-1 in patients who have progressed on prior anti–PD-1 therapy,” Dr. Kirkwood said, adding that these data support further clinical development of CMP-001.

The research is sponsored by Checkmate Pharmaceuticals. Dr. Kirkwood disclosed relationships with Amgen, BMS, Immunocore, Iovance, Novartis, Elsevier, Castle, Merck, and Checkmate.

SOURCE: Kirkwood J et al. SITC 2019, Abstract O85.

NATIONAL HARBOR, MD. – A TLR9 agonist called CMP-001 can reverse resistance to anti–programmed death-1 (PD-1) therapy in patients with melanoma, a phase 1 trial suggests.

Jennifer Smith/MDedge News

Combination CMP-001 and pembrolizumab produced durable responses in patients who had progressed on prior anti–PD-1 therapy, and the combination was considered well tolerated.

CMP-001 is a CpG-A TLR9 agonist packaged in a viruslike particle, John Kirkwood, MD, of University of Pittsburgh Medical Center, explained in a late-breaking abstract at the annual meeting of the Society for Immunotherapy of Cancer. CMP-001 activates tumor-associated plasmacytoid dendritic cells and induces systemic tumor-specific CD8+ T-cell responses.

Dr. Kirkwood and associates are investigating CMP-001, given alone or in combination with pembrolizumab, in a phase 1 trial (NCT02680184) of patients with metastatic or unresectable melanoma who are refractory to anti–PD-1 therapy.

Data were presented on 144 patients who received CMP-001 in combination with pembrolizumab. About 40% of patients (39.6%) had elevated lactate dehydrogenase at baseline, and 32.6% had BRAF mutations.

All patients had received prior anti–PD-1 therapy alone (75%) and/or in combination (50%). For most patients (93.1%), their last response to anti–PD-1 therapy was progression.

For this study, the patients received intratumoral CMP-001 injections at a range of doses (1 mg, 3 mg, 5 mg, 7.5 mg, and 10 mg). CMP-001 was given weekly for either 2 weeks or 7 weeks, then every 3 weeks until discontinuation. There were two different formulations of CMP-001 given – 0.01% polysorbate 20 (PS20; n = 83) and 0.00167% PS20 (n = 61).
 

Safety

“CMP-001 in combination with pembrolizumab is very well tolerated, with no apparent increase in autoimmune toxicities associated with anti–PD-1,” Dr. Kirkwood said.

The most common treatment-related adverse events were flulike symptoms, including chills (72%), pyrexia (56%), fatigue (51%), nausea (45%), vomiting (29%), and headache (28%). Another common event was injection-site pain (28%).

The most common grade 3 adverse events were hypotension (n = 9) and hypertension (n = 7). Grade 4 events included hypotension, aspartate aminotransferase increase, and alanine aminotransferase increase (n = 1 for all). There were no grade 5 events.

Six patients discontinued treatment because of adverse events.
 

Response

The overall response rate was 25% (21/83) among patients who received the 0.01% PS20 formulation of CMP-001 and 11.5% (7/61) among patients who received the 0.00167% PS20 formulation.

Responses were similar in injected and noninjected target lesions. The median duration of response has not been reached at a median follow-up of 16.9 months.

“Intratumoral CMP-001 reverses resistance to anti–PD-1 in patients who have progressed on prior anti–PD-1 therapy,” Dr. Kirkwood said, adding that these data support further clinical development of CMP-001.

The research is sponsored by Checkmate Pharmaceuticals. Dr. Kirkwood disclosed relationships with Amgen, BMS, Immunocore, Iovance, Novartis, Elsevier, Castle, Merck, and Checkmate.

SOURCE: Kirkwood J et al. SITC 2019, Abstract O85.

LAS VEGAS – Dermatologists in Oregon have launched a project that targets melanoma by promoting education and early detection, with the goal of dramatically reducing melanoma deaths in the state of 4.2 million people.

Research shows that “early detection works in melanoma. And awareness seems to be important for the public in detecting melanoma early,” said Sancy Leachman, MD, PhD, professor and chair of the department of dermatology at Oregon Health & Science University, Portland, said at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.

Dr. Leachman, who is also the John D. Gray chair in melanoma research at OHSU, directs the “War on Melanoma” project, which was inspired by a project in the German state of Schleswig-Holstein that aimed to screen all residents aged over 21 years for melanoma. The project featured an education campaign and population-wide skin cancer screening, and mandated that certain patients – those at high risk and those who needed biopsies – would be referred to dermatologists (Br J Cancer. 2012 Feb 28;106[5]:970-4).

According to Dr. Leachman, the German project was initially a success, and was linked to a 50% decrease in melanoma mortality.

“In Oregon, we thought ‘that sounds very good, so we’re going to try that.’ ” But when it went national, the German project failed, she said, providing lessons for dermatologists in Oregon. “We’re going to try to improve upon the first [German] experiment by making ours controlled with a defined baseline. If it works, the plan is to extend it to select states nationwide.”

The War on Melanoma project was launched earlier this year. According to the university, the program is featuring or will feature the following elements:

• A media campaign called “Start Seeing Melanoma” that’s devoted to educating the public about the early detection of melanoma.
• The release of an iPhone app called MoleMapper that allows users to monitor moles over time.
• Education of medical professionals and partnerships with state-licensed skin care professionals such as massage therapists, cosmetologists, and tattoo artists.

In an interview at the meeting, Dr. Leachman said the project is expected to cost $1 million to $1.5 million over the first 18 months. At that time, she said, researchers will survey residents of Oregon and two control states – Washington and Utah– to see if their knowledge of melanoma has improved, compared with baseline survey results.

In 5 years, researchers plan to begin analyzing melanoma mortality in Oregon and the other states. “We hope to see a decline,” and to link it to increased awareness of melanoma, she said.

Dr. Leachman reported no relevant disclosures. She spoke during a forum on cutaneous malignancies at the meeting.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Dermatologists in Oregon have launched a project that targets melanoma by promoting education and early detection, with the goal of dramatically reducing melanoma deaths in the state of 4.2 million people.

Research shows that “early detection works in melanoma. And awareness seems to be important for the public in detecting melanoma early,” said Sancy Leachman, MD, PhD, professor and chair of the department of dermatology at Oregon Health & Science University, Portland, said at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.

Dr. Leachman, who is also the John D. Gray chair in melanoma research at OHSU, directs the “War on Melanoma” project, which was inspired by a project in the German state of Schleswig-Holstein that aimed to screen all residents aged over 21 years for melanoma. The project featured an education campaign and population-wide skin cancer screening, and mandated that certain patients – those at high risk and those who needed biopsies – would be referred to dermatologists (Br J Cancer. 2012 Feb 28;106[5]:970-4).

According to Dr. Leachman, the German project was initially a success, and was linked to a 50% decrease in melanoma mortality.

“In Oregon, we thought ‘that sounds very good, so we’re going to try that.’ ” But when it went national, the German project failed, she said, providing lessons for dermatologists in Oregon. “We’re going to try to improve upon the first [German] experiment by making ours controlled with a defined baseline. If it works, the plan is to extend it to select states nationwide.”

The War on Melanoma project was launched earlier this year. According to the university, the program is featuring or will feature the following elements:

• A media campaign called “Start Seeing Melanoma” that’s devoted to educating the public about the early detection of melanoma.
• The release of an iPhone app called MoleMapper that allows users to monitor moles over time.
• Education of medical professionals and partnerships with state-licensed skin care professionals such as massage therapists, cosmetologists, and tattoo artists.

In an interview at the meeting, Dr. Leachman said the project is expected to cost $1 million to $1.5 million over the first 18 months. At that time, she said, researchers will survey residents of Oregon and two control states – Washington and Utah– to see if their knowledge of melanoma has improved, compared with baseline survey results.

In 5 years, researchers plan to begin analyzing melanoma mortality in Oregon and the other states. “We hope to see a decline,” and to link it to increased awareness of melanoma, she said.

Dr. Leachman reported no relevant disclosures. She spoke during a forum on cutaneous malignancies at the meeting.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Dermatologists in Oregon have launched a project that targets melanoma by promoting education and early detection, with the goal of dramatically reducing melanoma deaths in the state of 4.2 million people.

Research shows that “early detection works in melanoma. And awareness seems to be important for the public in detecting melanoma early,” said Sancy Leachman, MD, PhD, professor and chair of the department of dermatology at Oregon Health & Science University, Portland, said at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.

Dr. Leachman, who is also the John D. Gray chair in melanoma research at OHSU, directs the “War on Melanoma” project, which was inspired by a project in the German state of Schleswig-Holstein that aimed to screen all residents aged over 21 years for melanoma. The project featured an education campaign and population-wide skin cancer screening, and mandated that certain patients – those at high risk and those who needed biopsies – would be referred to dermatologists (Br J Cancer. 2012 Feb 28;106[5]:970-4).

According to Dr. Leachman, the German project was initially a success, and was linked to a 50% decrease in melanoma mortality.

“In Oregon, we thought ‘that sounds very good, so we’re going to try that.’ ” But when it went national, the German project failed, she said, providing lessons for dermatologists in Oregon. “We’re going to try to improve upon the first [German] experiment by making ours controlled with a defined baseline. If it works, the plan is to extend it to select states nationwide.”

The War on Melanoma project was launched earlier this year. According to the university, the program is featuring or will feature the following elements:

• A media campaign called “Start Seeing Melanoma” that’s devoted to educating the public about the early detection of melanoma.
• The release of an iPhone app called MoleMapper that allows users to monitor moles over time.
• Education of medical professionals and partnerships with state-licensed skin care professionals such as massage therapists, cosmetologists, and tattoo artists.

In an interview at the meeting, Dr. Leachman said the project is expected to cost $1 million to $1.5 million over the first 18 months. At that time, she said, researchers will survey residents of Oregon and two control states – Washington and Utah– to see if their knowledge of melanoma has improved, compared with baseline survey results.

In 5 years, researchers plan to begin analyzing melanoma mortality in Oregon and the other states. “We hope to see a decline,” and to link it to increased awareness of melanoma, she said.

Dr. Leachman reported no relevant disclosures. She spoke during a forum on cutaneous malignancies at the meeting.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

dbrunk@mdedge.com

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

dbrunk@mdedge.com

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

dbrunk@mdedge.com

Certain myeloablative conditioning regimens are among several novel risk factors for melanoma after allogeneic hematopoietic stem cell transplantation (HCT), according to findings from a nested case-control study.

The study included 140 cases of melanoma and 557 controls matched by age at HCT, sex, primary disease, and survival time. The results showed a significantly increased melanoma risk in HCT survivors who received total body irradiation–based myeloablative conditioning, reduced-intensity conditioning with melphalan, or reduced-intensity conditioning with fludarabine, compared with those who received busulfan-based myeloablative conditioning (odds ratios, 1.77, 2.60, and 2.72, respectively), Megan M. Herr, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues reported in the Journal of the American Academy of Dermatology.

Melanoma risk also was increased in patients who experienced acute graft-versus-host disease (GVHD) with stage 2 or greater skin involvement (OR, 1.92 vs. those with no acute GVHD), chronic GVHD without skin involvement (OR, 1.91 vs. those with no chronic GVHD), or keratinocytic carcinoma (OR, 2.37), and in those who resided in areas with higher ambient ultraviolet radiation (OR for the highest vs. lowest tertile, 1.64).

The UV radiation finding was more pronounced for melanomas occurring 6 or more years after transplant (OR, 3.04 for highest vs. lowest tertile), whereas ambient UV radiation was not associated with melanomas occurring earlier (ORs, 1.37 for less than 3 years and 0.98 at 3-6 years), the investigators noted.

The findings, based on large-scale and detailed clinical data from the Center for International Blood and Marrow Transplant Research for HCT performed during 1985-2012, show that melanoma after HCT has a multifactorial etiology that includes patient-, transplant-, and posttransplant-related factors, they said, noting that the findings also underscore the importance of “prioritization of high-risk survivors for adherence to prevention and screening recommendations.”

Those recommendations call for routine skin examination and photoprotective precautions – particularly in HCT survivors at the highest risk – but studies of screening behaviors suggest that fewer than two-thirds of HCT survivors adhere to these recommendations, they said, concluding that further research on the cost-effectiveness of melanoma screening is warranted, as is investigation into whether current approaches are associated with melanoma risk.

This work was supported by the intramural research program of the National Cancer Institute, the National Institutes of Health, and the Department of Health & Human Services. The authors reported having no conflicts of interest.

sworcester@mdedge.com

SOURCE: Herr MM et al. J Am Acad Dermatol. 2019 Oct 22. doi: 10.1016/j.jaad.2019.10.034.




 

Certain myeloablative conditioning regimens are among several novel risk factors for melanoma after allogeneic hematopoietic stem cell transplantation (HCT), according to findings from a nested case-control study.

The study included 140 cases of melanoma and 557 controls matched by age at HCT, sex, primary disease, and survival time. The results showed a significantly increased melanoma risk in HCT survivors who received total body irradiation–based myeloablative conditioning, reduced-intensity conditioning with melphalan, or reduced-intensity conditioning with fludarabine, compared with those who received busulfan-based myeloablative conditioning (odds ratios, 1.77, 2.60, and 2.72, respectively), Megan M. Herr, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues reported in the Journal of the American Academy of Dermatology.

Melanoma risk also was increased in patients who experienced acute graft-versus-host disease (GVHD) with stage 2 or greater skin involvement (OR, 1.92 vs. those with no acute GVHD), chronic GVHD without skin involvement (OR, 1.91 vs. those with no chronic GVHD), or keratinocytic carcinoma (OR, 2.37), and in those who resided in areas with higher ambient ultraviolet radiation (OR for the highest vs. lowest tertile, 1.64).

The UV radiation finding was more pronounced for melanomas occurring 6 or more years after transplant (OR, 3.04 for highest vs. lowest tertile), whereas ambient UV radiation was not associated with melanomas occurring earlier (ORs, 1.37 for less than 3 years and 0.98 at 3-6 years), the investigators noted.

The findings, based on large-scale and detailed clinical data from the Center for International Blood and Marrow Transplant Research for HCT performed during 1985-2012, show that melanoma after HCT has a multifactorial etiology that includes patient-, transplant-, and posttransplant-related factors, they said, noting that the findings also underscore the importance of “prioritization of high-risk survivors for adherence to prevention and screening recommendations.”

Those recommendations call for routine skin examination and photoprotective precautions – particularly in HCT survivors at the highest risk – but studies of screening behaviors suggest that fewer than two-thirds of HCT survivors adhere to these recommendations, they said, concluding that further research on the cost-effectiveness of melanoma screening is warranted, as is investigation into whether current approaches are associated with melanoma risk.

This work was supported by the intramural research program of the National Cancer Institute, the National Institutes of Health, and the Department of Health & Human Services. The authors reported having no conflicts of interest.

sworcester@mdedge.com

SOURCE: Herr MM et al. J Am Acad Dermatol. 2019 Oct 22. doi: 10.1016/j.jaad.2019.10.034.




 

Certain myeloablative conditioning regimens are among several novel risk factors for melanoma after allogeneic hematopoietic stem cell transplantation (HCT), according to findings from a nested case-control study.

The study included 140 cases of melanoma and 557 controls matched by age at HCT, sex, primary disease, and survival time. The results showed a significantly increased melanoma risk in HCT survivors who received total body irradiation–based myeloablative conditioning, reduced-intensity conditioning with melphalan, or reduced-intensity conditioning with fludarabine, compared with those who received busulfan-based myeloablative conditioning (odds ratios, 1.77, 2.60, and 2.72, respectively), Megan M. Herr, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues reported in the Journal of the American Academy of Dermatology.

Melanoma risk also was increased in patients who experienced acute graft-versus-host disease (GVHD) with stage 2 or greater skin involvement (OR, 1.92 vs. those with no acute GVHD), chronic GVHD without skin involvement (OR, 1.91 vs. those with no chronic GVHD), or keratinocytic carcinoma (OR, 2.37), and in those who resided in areas with higher ambient ultraviolet radiation (OR for the highest vs. lowest tertile, 1.64).

The UV radiation finding was more pronounced for melanomas occurring 6 or more years after transplant (OR, 3.04 for highest vs. lowest tertile), whereas ambient UV radiation was not associated with melanomas occurring earlier (ORs, 1.37 for less than 3 years and 0.98 at 3-6 years), the investigators noted.

The findings, based on large-scale and detailed clinical data from the Center for International Blood and Marrow Transplant Research for HCT performed during 1985-2012, show that melanoma after HCT has a multifactorial etiology that includes patient-, transplant-, and posttransplant-related factors, they said, noting that the findings also underscore the importance of “prioritization of high-risk survivors for adherence to prevention and screening recommendations.”

Those recommendations call for routine skin examination and photoprotective precautions – particularly in HCT survivors at the highest risk – but studies of screening behaviors suggest that fewer than two-thirds of HCT survivors adhere to these recommendations, they said, concluding that further research on the cost-effectiveness of melanoma screening is warranted, as is investigation into whether current approaches are associated with melanoma risk.

This work was supported by the intramural research program of the National Cancer Institute, the National Institutes of Health, and the Department of Health & Human Services. The authors reported having no conflicts of interest.

sworcester@mdedge.com

SOURCE: Herr MM et al. J Am Acad Dermatol. 2019 Oct 22. doi: 10.1016/j.jaad.2019.10.034.




 

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

Mohs micrographic surgery (MMS) may be a viable alternative to wide margin excision (WME) in selected patients with early-stage invasive melanoma, according to a retrospective cohort study.

In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.

“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.

The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.

In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.

After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).

“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.

The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.

“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.

Mohs micrographic surgery (MMS) may be a viable alternative to wide margin excision (WME) in selected patients with early-stage invasive melanoma, according to a retrospective cohort study.

In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.

“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.

The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.

In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.

After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).

“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.

The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.

“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.

Mohs micrographic surgery (MMS) may be a viable alternative to wide margin excision (WME) in selected patients with early-stage invasive melanoma, according to a retrospective cohort study.

In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.

“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.

The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.

In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.

After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).

“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.

The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.

“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.