Melanoma

Immunotherapy with checkpoint inhibitors has ushered in a new era of cancer therapy, with some patients showing dramatic responses and significantly better outcomes than with other therapies across many cancer types. But some patients do worse, sometimes much worse.

A subset of patients who undergo immunotherapy experience unexpected, rapid disease progression, with a dramatic acceleration of disease trajectory. They also have a shorter progression-free survival and overall survival than would have been expected.

This has been described as hyperprogression and has been termed “hyperprogressive disease” (HPD). It has been seen in a variety of cancers; the incidence ranges from 4% to 29% in the studies reported to date.

There has been some debate over whether this is a real phenomenon or whether it is part of the natural course of disease.

HPD is a “provocative phenomenon,” wrote the authors of a recent commentary entitled “Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?”

“This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease,” said the author of another commentary.

But the tide is now turning toward acceptance of HPD, said Kartik Sehgal, MD, an oncologist at Dana-Farber Cancer Institute and Harvard University, both in Boston.

“With publication of multiple clinical reports of different cancer types worldwide, hyperprogression is now accepted by most oncologists to be a true phenomenon rather than natural progression of disease,” Dr. Sehgal said.

He authored an invited commentary in JAMA Network Openabout one of the latest meta-analyses (JAMA Netw Open. 2021;4[3]:e211136) to investigate HPD during immunotherapy. One of the biggest issues is that the studies that have reported on HPD have been retrospective, with a lack of comparator groups and a lack of a standardized definition of hyperprogression. Dr. Sehgal emphasized the need to study hyperprogression in well-designed prospective studies.
 

Existing data on HPD

HPD was described as “a new pattern of progression” seen in patients undergoing immune checkpoint inhibitor therapy in a 2017 article published in Clinical Cancer Research. Authors Stephane Champiat, MD, PhD, of Institut Gustave Roussy, Universite Paris Saclay, Villejuif, France, and colleagues cited “anecdotal occurrences” of HPD among patients in phase 1 trials of anti–PD-1/PD-L1 agents.

In that study, HPD was defined by tumor growth rate ratio. The incidence was 9% among 213 patients.

The findings raised concerns about treating elderly patients with anti–PD-1/PD-L1 monotherapy, according to the authors, who called for further study.

That same year, Roberto Ferrara, MD, and colleagues from the Insitut Gustave Roussy reported additional data indicating an incidence of HPD of 16% among 333 patients with non–small cell lung cancer who underwent immunotherapy at eight centers from 2012 to 2017. The findings, which were presented at the 2017 World Conference on Lung Cancer and reported at the time by this news organization, also showed that the incidence of HPD was higher with immunotherapy than with single-agent chemotherapy (5%).

Median overall survival (OS) was just 3.4 months among those with HPD, compared with 13 months in the overall study population – worse, even, than the median 5.4-month OS observed among patients with progressive disease who received immunotherapy.

In the wake of these findings, numerous researchers have attempted to better define HPD, its incidence, and patient factors associated with developing HPD while undergoing immunotherapy.

However, there is little so far to show for those efforts, Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

“Many questions remain to be answered,” said Dr. Subbiah, clinical medical director of the Clinical Center for Targeted Therapy in the division of cancer medicine at MD Anderson. He was the senior author of the “Fact, Fiction, or Alternative Fact?” commentary.

Work is underway to elucidate biological mechanisms. Some groups have implicated the Fc region of antibodies. Another group has reported EGFR and MDM2/MDM4 amplifications in patients with HPD, Dr. Subbiah and colleagues noted.

Other “proposed contributing pathological mechanisms include modulation of tumor immune microenvironment through macrophages and regulatory T cells as well as activation of oncogenic signaling pathways,” noted Dr. Sehgal.

Both groups of authors emphasize the urgent need for prospective studies.

It is imperative to confirm underlying biology, predict which patients are at risk, and identify therapeutic directions for patients who experience HPD, Dr. Subbiah said.

The main challenge is defining HPD, he added. Definitions that have been proposed include tumor growth at least two times greater than in control persons, a 15% increase in tumor burden in a set period, and disease progression of 50% from the first evaluation before treatment, he said.

The recent meta-analysis by Hyo Jung Park, MD, PhD, and colleagues, which Dr. Sehgal addressed in his invited commentary, highlights the many approaches used for defining HPD.

Depending on the definition used, the incidence of HPD across 24 studies involving more than 3,100 patients ranged from 5.9% to 43.1%.

“Hyperprogressive disease could be overestimated or underestimated based on current assessment,” Dr. Park and colleagues concluded. They highlighted the importance of “establishing uniform and clinically relevant criteria based on currently available evidence.”
 

Steps for solving the HPD mystery

“I think we need to come up with consensus criteria for an HPD definition. We need a unified definition,” Dr. Subbiah said. “We also need to design prospective studies to prove or disprove the immunotherapy-HPD association.”

Prospective registries with independent review of patients with suspected immunotherapy-related HPD would be useful for assessing the true incidence and the biology of HPD among patients undergoing immunotherapy, he suggested.

“We need to know the immunologic signals of HPD. This can give us an idea if patients can be prospectively identified for being at risk,” he said. “We also need to know what to do if they are at risk.”

Dr. Sehgal also called for consensus on an HPD definition, with input from a multidisciplinary group that includes “colleagues from radiology, medical oncology, radiation oncology. Getting expertise from different disciplines would be helpful,” he said.

Dr. Park and colleagues suggested several key requirements for an optimal HP definition, such as the inclusion of multiple variables for measuring tumor growth acceleration, “sufficiently quantitative” criteria for determining time to failure, and establishment of a standardized measure of tumor growth acceleration.

The agreed-upon definition of HPD could be applied to patients in a prospective registry and to existing trial data, Dr. Sehgal said.

“Eventually, the goal of this exercise is to [determine] how we can help our patients the best, having a biomarker that can at least inform us in terms of being aware and being proactive in terms of looking for this ... so that interventions can be brought on earlier,” he said.

“If we know what may be a biological mechanism, we can design trials that are designed to look at how to overcome that HPD,” he said.

Dr. Sehgal said he believes HPD is triggered in some way by treatment, including immunotherapy, chemotherapy, and targeted therapy, but perhaps in different ways for each.

He estimated the true incidence of immunotherapy-related HPD will be in the 9%-10% range.

“This is a substantial number of patients, so it’s important that we try to understand this phenomenon, using, again, uniform criteria,” he said.
 

Current treatment decision-making

Until more is known, Dr. Sehgal said he considers the potential risk factors when treating patients with immunotherapy.

For example, the presence of MDM2 or MDM4 amplification on a genomic profile may factor into his treatment decision-making when it comes to using immunotherapy or immunotherapy in combination with chemotherapy, he said.

“Is that the only factor that is going to make me choose one thing or another? No,” Dr. Sehgal said. However, he said it would make him more “proactive in making sure the patient is doing clinically okay” and in determining when to obtain on-treatment imaging studies.

Dr. Subbiah emphasized the relative benefit of immunotherapy, noting that survival with chemotherapy for many difficult-to-treat cancers in the relapsed/refractory metastatic setting is less than 2 years.

Immunotherapy with checkpoint inhibitors has allowed some of these patients to live longer (with survival reported to be more than 10 years for patients with metastatic melanoma).

“Immunotherapy has been a game changer; it has been transformative in the lives of these patients,” Dr. Subbiah said. “So unless there is any other contraindication, the benefit of receiving immunotherapy for an approved indication far outweighs the risk of HPD.”

A version of this article first appeared on Medscape.com.

Immunotherapy with checkpoint inhibitors has ushered in a new era of cancer therapy, with some patients showing dramatic responses and significantly better outcomes than with other therapies across many cancer types. But some patients do worse, sometimes much worse.

A subset of patients who undergo immunotherapy experience unexpected, rapid disease progression, with a dramatic acceleration of disease trajectory. They also have a shorter progression-free survival and overall survival than would have been expected.

This has been described as hyperprogression and has been termed “hyperprogressive disease” (HPD). It has been seen in a variety of cancers; the incidence ranges from 4% to 29% in the studies reported to date.

There has been some debate over whether this is a real phenomenon or whether it is part of the natural course of disease.

HPD is a “provocative phenomenon,” wrote the authors of a recent commentary entitled “Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?”

“This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease,” said the author of another commentary.

But the tide is now turning toward acceptance of HPD, said Kartik Sehgal, MD, an oncologist at Dana-Farber Cancer Institute and Harvard University, both in Boston.

“With publication of multiple clinical reports of different cancer types worldwide, hyperprogression is now accepted by most oncologists to be a true phenomenon rather than natural progression of disease,” Dr. Sehgal said.

He authored an invited commentary in JAMA Network Openabout one of the latest meta-analyses (JAMA Netw Open. 2021;4[3]:e211136) to investigate HPD during immunotherapy. One of the biggest issues is that the studies that have reported on HPD have been retrospective, with a lack of comparator groups and a lack of a standardized definition of hyperprogression. Dr. Sehgal emphasized the need to study hyperprogression in well-designed prospective studies.
 

Existing data on HPD

HPD was described as “a new pattern of progression” seen in patients undergoing immune checkpoint inhibitor therapy in a 2017 article published in Clinical Cancer Research. Authors Stephane Champiat, MD, PhD, of Institut Gustave Roussy, Universite Paris Saclay, Villejuif, France, and colleagues cited “anecdotal occurrences” of HPD among patients in phase 1 trials of anti–PD-1/PD-L1 agents.

In that study, HPD was defined by tumor growth rate ratio. The incidence was 9% among 213 patients.

The findings raised concerns about treating elderly patients with anti–PD-1/PD-L1 monotherapy, according to the authors, who called for further study.

That same year, Roberto Ferrara, MD, and colleagues from the Insitut Gustave Roussy reported additional data indicating an incidence of HPD of 16% among 333 patients with non–small cell lung cancer who underwent immunotherapy at eight centers from 2012 to 2017. The findings, which were presented at the 2017 World Conference on Lung Cancer and reported at the time by this news organization, also showed that the incidence of HPD was higher with immunotherapy than with single-agent chemotherapy (5%).

Median overall survival (OS) was just 3.4 months among those with HPD, compared with 13 months in the overall study population – worse, even, than the median 5.4-month OS observed among patients with progressive disease who received immunotherapy.

In the wake of these findings, numerous researchers have attempted to better define HPD, its incidence, and patient factors associated with developing HPD while undergoing immunotherapy.

However, there is little so far to show for those efforts, Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

“Many questions remain to be answered,” said Dr. Subbiah, clinical medical director of the Clinical Center for Targeted Therapy in the division of cancer medicine at MD Anderson. He was the senior author of the “Fact, Fiction, or Alternative Fact?” commentary.

Work is underway to elucidate biological mechanisms. Some groups have implicated the Fc region of antibodies. Another group has reported EGFR and MDM2/MDM4 amplifications in patients with HPD, Dr. Subbiah and colleagues noted.

Other “proposed contributing pathological mechanisms include modulation of tumor immune microenvironment through macrophages and regulatory T cells as well as activation of oncogenic signaling pathways,” noted Dr. Sehgal.

Both groups of authors emphasize the urgent need for prospective studies.

It is imperative to confirm underlying biology, predict which patients are at risk, and identify therapeutic directions for patients who experience HPD, Dr. Subbiah said.

The main challenge is defining HPD, he added. Definitions that have been proposed include tumor growth at least two times greater than in control persons, a 15% increase in tumor burden in a set period, and disease progression of 50% from the first evaluation before treatment, he said.

The recent meta-analysis by Hyo Jung Park, MD, PhD, and colleagues, which Dr. Sehgal addressed in his invited commentary, highlights the many approaches used for defining HPD.

Depending on the definition used, the incidence of HPD across 24 studies involving more than 3,100 patients ranged from 5.9% to 43.1%.

“Hyperprogressive disease could be overestimated or underestimated based on current assessment,” Dr. Park and colleagues concluded. They highlighted the importance of “establishing uniform and clinically relevant criteria based on currently available evidence.”
 

Steps for solving the HPD mystery

“I think we need to come up with consensus criteria for an HPD definition. We need a unified definition,” Dr. Subbiah said. “We also need to design prospective studies to prove or disprove the immunotherapy-HPD association.”

Prospective registries with independent review of patients with suspected immunotherapy-related HPD would be useful for assessing the true incidence and the biology of HPD among patients undergoing immunotherapy, he suggested.

“We need to know the immunologic signals of HPD. This can give us an idea if patients can be prospectively identified for being at risk,” he said. “We also need to know what to do if they are at risk.”

Dr. Sehgal also called for consensus on an HPD definition, with input from a multidisciplinary group that includes “colleagues from radiology, medical oncology, radiation oncology. Getting expertise from different disciplines would be helpful,” he said.

Dr. Park and colleagues suggested several key requirements for an optimal HP definition, such as the inclusion of multiple variables for measuring tumor growth acceleration, “sufficiently quantitative” criteria for determining time to failure, and establishment of a standardized measure of tumor growth acceleration.

The agreed-upon definition of HPD could be applied to patients in a prospective registry and to existing trial data, Dr. Sehgal said.

“Eventually, the goal of this exercise is to [determine] how we can help our patients the best, having a biomarker that can at least inform us in terms of being aware and being proactive in terms of looking for this ... so that interventions can be brought on earlier,” he said.

“If we know what may be a biological mechanism, we can design trials that are designed to look at how to overcome that HPD,” he said.

Dr. Sehgal said he believes HPD is triggered in some way by treatment, including immunotherapy, chemotherapy, and targeted therapy, but perhaps in different ways for each.

He estimated the true incidence of immunotherapy-related HPD will be in the 9%-10% range.

“This is a substantial number of patients, so it’s important that we try to understand this phenomenon, using, again, uniform criteria,” he said.
 

Current treatment decision-making

Until more is known, Dr. Sehgal said he considers the potential risk factors when treating patients with immunotherapy.

For example, the presence of MDM2 or MDM4 amplification on a genomic profile may factor into his treatment decision-making when it comes to using immunotherapy or immunotherapy in combination with chemotherapy, he said.

“Is that the only factor that is going to make me choose one thing or another? No,” Dr. Sehgal said. However, he said it would make him more “proactive in making sure the patient is doing clinically okay” and in determining when to obtain on-treatment imaging studies.

Dr. Subbiah emphasized the relative benefit of immunotherapy, noting that survival with chemotherapy for many difficult-to-treat cancers in the relapsed/refractory metastatic setting is less than 2 years.

Immunotherapy with checkpoint inhibitors has allowed some of these patients to live longer (with survival reported to be more than 10 years for patients with metastatic melanoma).

“Immunotherapy has been a game changer; it has been transformative in the lives of these patients,” Dr. Subbiah said. “So unless there is any other contraindication, the benefit of receiving immunotherapy for an approved indication far outweighs the risk of HPD.”

A version of this article first appeared on Medscape.com.

Immunotherapy with checkpoint inhibitors has ushered in a new era of cancer therapy, with some patients showing dramatic responses and significantly better outcomes than with other therapies across many cancer types. But some patients do worse, sometimes much worse.

A subset of patients who undergo immunotherapy experience unexpected, rapid disease progression, with a dramatic acceleration of disease trajectory. They also have a shorter progression-free survival and overall survival than would have been expected.

This has been described as hyperprogression and has been termed “hyperprogressive disease” (HPD). It has been seen in a variety of cancers; the incidence ranges from 4% to 29% in the studies reported to date.

There has been some debate over whether this is a real phenomenon or whether it is part of the natural course of disease.

HPD is a “provocative phenomenon,” wrote the authors of a recent commentary entitled “Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?”

“This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease,” said the author of another commentary.

But the tide is now turning toward acceptance of HPD, said Kartik Sehgal, MD, an oncologist at Dana-Farber Cancer Institute and Harvard University, both in Boston.

“With publication of multiple clinical reports of different cancer types worldwide, hyperprogression is now accepted by most oncologists to be a true phenomenon rather than natural progression of disease,” Dr. Sehgal said.

He authored an invited commentary in JAMA Network Openabout one of the latest meta-analyses (JAMA Netw Open. 2021;4[3]:e211136) to investigate HPD during immunotherapy. One of the biggest issues is that the studies that have reported on HPD have been retrospective, with a lack of comparator groups and a lack of a standardized definition of hyperprogression. Dr. Sehgal emphasized the need to study hyperprogression in well-designed prospective studies.
 

Existing data on HPD

HPD was described as “a new pattern of progression” seen in patients undergoing immune checkpoint inhibitor therapy in a 2017 article published in Clinical Cancer Research. Authors Stephane Champiat, MD, PhD, of Institut Gustave Roussy, Universite Paris Saclay, Villejuif, France, and colleagues cited “anecdotal occurrences” of HPD among patients in phase 1 trials of anti–PD-1/PD-L1 agents.

In that study, HPD was defined by tumor growth rate ratio. The incidence was 9% among 213 patients.

The findings raised concerns about treating elderly patients with anti–PD-1/PD-L1 monotherapy, according to the authors, who called for further study.

That same year, Roberto Ferrara, MD, and colleagues from the Insitut Gustave Roussy reported additional data indicating an incidence of HPD of 16% among 333 patients with non–small cell lung cancer who underwent immunotherapy at eight centers from 2012 to 2017. The findings, which were presented at the 2017 World Conference on Lung Cancer and reported at the time by this news organization, also showed that the incidence of HPD was higher with immunotherapy than with single-agent chemotherapy (5%).

Median overall survival (OS) was just 3.4 months among those with HPD, compared with 13 months in the overall study population – worse, even, than the median 5.4-month OS observed among patients with progressive disease who received immunotherapy.

In the wake of these findings, numerous researchers have attempted to better define HPD, its incidence, and patient factors associated with developing HPD while undergoing immunotherapy.

However, there is little so far to show for those efforts, Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

“Many questions remain to be answered,” said Dr. Subbiah, clinical medical director of the Clinical Center for Targeted Therapy in the division of cancer medicine at MD Anderson. He was the senior author of the “Fact, Fiction, or Alternative Fact?” commentary.

Work is underway to elucidate biological mechanisms. Some groups have implicated the Fc region of antibodies. Another group has reported EGFR and MDM2/MDM4 amplifications in patients with HPD, Dr. Subbiah and colleagues noted.

Other “proposed contributing pathological mechanisms include modulation of tumor immune microenvironment through macrophages and regulatory T cells as well as activation of oncogenic signaling pathways,” noted Dr. Sehgal.

Both groups of authors emphasize the urgent need for prospective studies.

It is imperative to confirm underlying biology, predict which patients are at risk, and identify therapeutic directions for patients who experience HPD, Dr. Subbiah said.

The main challenge is defining HPD, he added. Definitions that have been proposed include tumor growth at least two times greater than in control persons, a 15% increase in tumor burden in a set period, and disease progression of 50% from the first evaluation before treatment, he said.

The recent meta-analysis by Hyo Jung Park, MD, PhD, and colleagues, which Dr. Sehgal addressed in his invited commentary, highlights the many approaches used for defining HPD.

Depending on the definition used, the incidence of HPD across 24 studies involving more than 3,100 patients ranged from 5.9% to 43.1%.

“Hyperprogressive disease could be overestimated or underestimated based on current assessment,” Dr. Park and colleagues concluded. They highlighted the importance of “establishing uniform and clinically relevant criteria based on currently available evidence.”
 

Steps for solving the HPD mystery

“I think we need to come up with consensus criteria for an HPD definition. We need a unified definition,” Dr. Subbiah said. “We also need to design prospective studies to prove or disprove the immunotherapy-HPD association.”

Prospective registries with independent review of patients with suspected immunotherapy-related HPD would be useful for assessing the true incidence and the biology of HPD among patients undergoing immunotherapy, he suggested.

“We need to know the immunologic signals of HPD. This can give us an idea if patients can be prospectively identified for being at risk,” he said. “We also need to know what to do if they are at risk.”

Dr. Sehgal also called for consensus on an HPD definition, with input from a multidisciplinary group that includes “colleagues from radiology, medical oncology, radiation oncology. Getting expertise from different disciplines would be helpful,” he said.

Dr. Park and colleagues suggested several key requirements for an optimal HP definition, such as the inclusion of multiple variables for measuring tumor growth acceleration, “sufficiently quantitative” criteria for determining time to failure, and establishment of a standardized measure of tumor growth acceleration.

The agreed-upon definition of HPD could be applied to patients in a prospective registry and to existing trial data, Dr. Sehgal said.

“Eventually, the goal of this exercise is to [determine] how we can help our patients the best, having a biomarker that can at least inform us in terms of being aware and being proactive in terms of looking for this ... so that interventions can be brought on earlier,” he said.

“If we know what may be a biological mechanism, we can design trials that are designed to look at how to overcome that HPD,” he said.

Dr. Sehgal said he believes HPD is triggered in some way by treatment, including immunotherapy, chemotherapy, and targeted therapy, but perhaps in different ways for each.

He estimated the true incidence of immunotherapy-related HPD will be in the 9%-10% range.

“This is a substantial number of patients, so it’s important that we try to understand this phenomenon, using, again, uniform criteria,” he said.
 

Current treatment decision-making

Until more is known, Dr. Sehgal said he considers the potential risk factors when treating patients with immunotherapy.

For example, the presence of MDM2 or MDM4 amplification on a genomic profile may factor into his treatment decision-making when it comes to using immunotherapy or immunotherapy in combination with chemotherapy, he said.

“Is that the only factor that is going to make me choose one thing or another? No,” Dr. Sehgal said. However, he said it would make him more “proactive in making sure the patient is doing clinically okay” and in determining when to obtain on-treatment imaging studies.

Dr. Subbiah emphasized the relative benefit of immunotherapy, noting that survival with chemotherapy for many difficult-to-treat cancers in the relapsed/refractory metastatic setting is less than 2 years.

Immunotherapy with checkpoint inhibitors has allowed some of these patients to live longer (with survival reported to be more than 10 years for patients with metastatic melanoma).

“Immunotherapy has been a game changer; it has been transformative in the lives of these patients,” Dr. Subbiah said. “So unless there is any other contraindication, the benefit of receiving immunotherapy for an approved indication far outweighs the risk of HPD.”

A version of this article first appeared on Medscape.com.

A ban on the use of tanning beds by minors aged 14-17 years in the United States would prevent over 15,000 cases of melanoma and cost less than other, well-established public health interventions, according to a microsimulation of that age group’s virtual life course.

“Even with extensive sensitivity analyses on the costs of inspections, noncompliance with a ban, and the risk of developing melanoma in those who have used tanning beds, a ban can be considered highly cost effective,” Antoine Eskander, MD, ScM, of the University of Toronto, and associates said in Cancer.

Compared with no ban, such an intervention could save over $205 million in lifetime health care costs among the 17.1 million young people (based on the 2010 Census population) who would be affected, they said.

The more than 15,000 melanoma cases and 3,300 recurrences prevented would save $12 per average minor after adjusting for societal costs, such as lost productivity, formal and informal health care, economic losses to the tanning bed industry, and the need for monitoring, the investigators reported.

Switching to quality-adjusted life-years shows an improvement of 0.0002 QALYs per child for a ban, based on an overall cost of almost $24.9 per QALY, compared with no ban, they said, which makes it “more cost effective than many well-established public health interventions”:

• Processed meats taxation ($270/QALY).
• Smoking education campaign ($1,337/QALY).
• Cervical cancer screening ($2,166/QALY).
• Breast cancer screening ($29,284/QALY).
• Lung cancer screening ($49,200-$96,700/QALY).

Among the many parameters included in the microsimulation were the odds ratio of developing melanoma from exposure to tanning beds before age 25 (1.35), melanoma stage at presentation, risk of recurrence, and the cost of four annual inspections for each of the nation’s more than 13,000 tanning salons, Dr. Eskander and associates explained.

rfranki@mdedge.com

A ban on the use of tanning beds by minors aged 14-17 years in the United States would prevent over 15,000 cases of melanoma and cost less than other, well-established public health interventions, according to a microsimulation of that age group’s virtual life course.

“Even with extensive sensitivity analyses on the costs of inspections, noncompliance with a ban, and the risk of developing melanoma in those who have used tanning beds, a ban can be considered highly cost effective,” Antoine Eskander, MD, ScM, of the University of Toronto, and associates said in Cancer.

Compared with no ban, such an intervention could save over $205 million in lifetime health care costs among the 17.1 million young people (based on the 2010 Census population) who would be affected, they said.

The more than 15,000 melanoma cases and 3,300 recurrences prevented would save $12 per average minor after adjusting for societal costs, such as lost productivity, formal and informal health care, economic losses to the tanning bed industry, and the need for monitoring, the investigators reported.

Switching to quality-adjusted life-years shows an improvement of 0.0002 QALYs per child for a ban, based on an overall cost of almost $24.9 per QALY, compared with no ban, they said, which makes it “more cost effective than many well-established public health interventions”:

• Processed meats taxation ($270/QALY).
• Smoking education campaign ($1,337/QALY).
• Cervical cancer screening ($2,166/QALY).
• Breast cancer screening ($29,284/QALY).
• Lung cancer screening ($49,200-$96,700/QALY).

Among the many parameters included in the microsimulation were the odds ratio of developing melanoma from exposure to tanning beds before age 25 (1.35), melanoma stage at presentation, risk of recurrence, and the cost of four annual inspections for each of the nation’s more than 13,000 tanning salons, Dr. Eskander and associates explained.

rfranki@mdedge.com

A ban on the use of tanning beds by minors aged 14-17 years in the United States would prevent over 15,000 cases of melanoma and cost less than other, well-established public health interventions, according to a microsimulation of that age group’s virtual life course.

“Even with extensive sensitivity analyses on the costs of inspections, noncompliance with a ban, and the risk of developing melanoma in those who have used tanning beds, a ban can be considered highly cost effective,” Antoine Eskander, MD, ScM, of the University of Toronto, and associates said in Cancer.

Compared with no ban, such an intervention could save over $205 million in lifetime health care costs among the 17.1 million young people (based on the 2010 Census population) who would be affected, they said.

The more than 15,000 melanoma cases and 3,300 recurrences prevented would save $12 per average minor after adjusting for societal costs, such as lost productivity, formal and informal health care, economic losses to the tanning bed industry, and the need for monitoring, the investigators reported.

Switching to quality-adjusted life-years shows an improvement of 0.0002 QALYs per child for a ban, based on an overall cost of almost $24.9 per QALY, compared with no ban, they said, which makes it “more cost effective than many well-established public health interventions”:

• Processed meats taxation ($270/QALY).
• Smoking education campaign ($1,337/QALY).
• Cervical cancer screening ($2,166/QALY).
• Breast cancer screening ($29,284/QALY).
• Lung cancer screening ($49,200-$96,700/QALY).

Among the many parameters included in the microsimulation were the odds ratio of developing melanoma from exposure to tanning beds before age 25 (1.35), melanoma stage at presentation, risk of recurrence, and the cost of four annual inspections for each of the nation’s more than 13,000 tanning salons, Dr. Eskander and associates explained.

rfranki@mdedge.com

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

First-line tebentafusp significantly improved overall survival (OS) when compared with immunotherapy or chemotherapy in patients with metastatic uveal melanoma in a phase 3 trial.

Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).

Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.

In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.

Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
 

Prolonged OS despite low response rate

At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.

At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).

The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.

The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.

Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.

“So this drug is slowing down developing disease,” she said.
 

‘Manageable’ adverse events

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.

While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.

The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
 

‘Practice-changing’ results

“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.

She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.

The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.

The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.

First-line tebentafusp significantly improved overall survival (OS) when compared with immunotherapy or chemotherapy in patients with metastatic uveal melanoma in a phase 3 trial.

Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).

Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.

In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.

Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
 

Prolonged OS despite low response rate

At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.

At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).

The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.

The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.

Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.

“So this drug is slowing down developing disease,” she said.
 

‘Manageable’ adverse events

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.

While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.

The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
 

‘Practice-changing’ results

“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.

She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.

The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.

The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.

First-line tebentafusp significantly improved overall survival (OS) when compared with immunotherapy or chemotherapy in patients with metastatic uveal melanoma in a phase 3 trial.

Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).

Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.

In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.

Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
 

Prolonged OS despite low response rate

At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.

At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).

The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.

The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.

Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.

“So this drug is slowing down developing disease,” she said.
 

‘Manageable’ adverse events

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.

While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.

The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
 

‘Practice-changing’ results

“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.

She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.

The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.

The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.

Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.

They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.

In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”

Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.

The findings were published online in Annals of Oncology.

“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.

“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.

Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
 

Largest series to document delayed reactions

Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.

Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.

An expert not involved in the study agrees.

“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.

“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.

Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
 

Median onset was 16 months

The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.

The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.

In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.

Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.

Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
 

An early warning system

The most common reactions were colitis, pneumonitis, and rash.

The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.

“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.

Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.

On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.

Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
 

Question on treatment duration

No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.

The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.

The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.

However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.

“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.

Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.

No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.

They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.

In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”

Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.

The findings were published online in Annals of Oncology.

“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.

“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.

Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
 

Largest series to document delayed reactions

Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.

Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.

An expert not involved in the study agrees.

“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.

“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.

Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
 

Median onset was 16 months

The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.

The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.

In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.

Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.

Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
 

An early warning system

The most common reactions were colitis, pneumonitis, and rash.

The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.

“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.

Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.

On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.

Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
 

Question on treatment duration

No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.

The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.

The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.

However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.

“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.

Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.

No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.

They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.

In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”

Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.

The findings were published online in Annals of Oncology.

“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.

“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.

Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
 

Largest series to document delayed reactions

Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.

Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.

An expert not involved in the study agrees.

“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.

“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.

Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
 

Median onset was 16 months

The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.

The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.

In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.

Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.

Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
 

An early warning system

The most common reactions were colitis, pneumonitis, and rash.

The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.

“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.

Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.

On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.

Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
 

Question on treatment duration

No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.

The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.

The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.

However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.

“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.

Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.

No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The next 20 years will see a big shift in cancer type rankings, researchers predict.

At the moment, the most common cancers in the United States are breast, lung, prostate, colorectal, and melanoma.

By 2040, melanoma will have become the second most common cancer type, while prostate cancer will drop in incidence all the way to 14, the study authors predicted. Breast cancer will remain the top cancer to be diagnosed, lung cancer will drop from second to third, and colorectal cancer will remain at fourth.

These predicted rankings of cancer types by their total number of annual cases were published online April 7, 2021, in JAMA Network Open.

The authors also rank cancer type by mortality. Currently, most cancer deaths are caused by lung cancer, followed by colorectal, pancreatic, and breast. By 2040, the most notable change in cancer deaths is that liver and intrahepatic bile duct cancer, currently at sixth, will jump up to third.

Two decades from now, the ranking in terms of cancer deaths will be lung, pancreatic, liver and intrahepatic bile duct, and colorectal.

“Our findings reflect the shifting dynamics of cancer screening and treatment,” lead author Lola Rahib, PhD, a pancreatic cancer scientist at Cancer Commons, the advocacy nonprofit, commented in a press statement.

The new analysis used population-growth projections (based on 2010 U.S. Census data) and current population-based cancer incidence and death rates (from Surveillance, Epidemiology, and End Results 2014-2016) to calculate the changes in incidences and deaths to the year 2040.

The projected, estimated numbers are not ironclad, the researchers acknowledged.

“Our projections assume that the observed rates and trends [from recent years] don’t change over time,” Dr. Rahib said in an interview, but she pointed out that change may indeed happen.

“Any long-term projections should be considered with a grain of salt,” said Kim Miller, MPH, a surveillance research scientist at the American Cancer Society, who was approached for comment.

Dr. Miller explained that “cancer trends can sometimes rapidly change within a few years.” Projections just 2-4 years ahead are “extremely difficult” and those 20 years ahead are even more so, she added in an interview.

“We’re encouraged to see the projected decreases in deaths from lung, colorectal, and breast cancer in the coming years,” said coauthor Lynn Matrisian, PhD, MBA, chief science officer at the Pancreatic Cancer Action Network. “It’s time to shift focus to some of the less commonly diagnosed cancers with the lowest survival rates, like pancreatic and liver cancer.”
 

Difference in opinion on prostate cancer

The huge fall in the incidence of prostate cancer that the authors predict will come about as a result of changes in prostate-specific antigen (PSA)–screening recommendations over the last 15 years, they suggested.

“The most recent change in 2018 recommends that men aged 55-69 can make their own decisions regarding screening, but previous changes recommended against PSA screening,” said Dr. Rahib.

“These changes in screening guidelines have influenced the number of diagnoses of prostate cancer in recent years and will continue to do so to 2040,” Dr. Rahib commented.

Dr. Miller casts doubt on this prediction.

Using data through 2017, “we have seen that the patterns in prostate cancer incidence are already shifting from the steep declines we saw in the early 2010s,” she said. “I would use caution when interpreting the overall trends for prostate, because this cancer in particular is dramatically affected by changes in recommendations for screening with the PSA test.”

Screening has also influenced colorectal cancer incidence, the authors pointed out, saying that the uptake of colorectal cancer screening is associated with a decrease in the number of colorectal cancers and deaths out to 2040, as a result of effectiveness of screening.

For breast cancer, the authors highlighted the fact that, although the number of breast cancers will continue to increase, the number of breast cancer deaths will decrease. That ongoing trend is most likely attributable to increased screening and advancements in treatment.

The study was supported by the National Institutes of Health, National Cancer Institute, the Cancer Prevention and Research Institute of Texas, Cancer Commons and the Pancreatic Cancer Action Network. The study authors and Dr. Miller disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The next 20 years will see a big shift in cancer type rankings, researchers predict.

At the moment, the most common cancers in the United States are breast, lung, prostate, colorectal, and melanoma.

By 2040, melanoma will have become the second most common cancer type, while prostate cancer will drop in incidence all the way to 14, the study authors predicted. Breast cancer will remain the top cancer to be diagnosed, lung cancer will drop from second to third, and colorectal cancer will remain at fourth.

These predicted rankings of cancer types by their total number of annual cases were published online April 7, 2021, in JAMA Network Open.

The authors also rank cancer type by mortality. Currently, most cancer deaths are caused by lung cancer, followed by colorectal, pancreatic, and breast. By 2040, the most notable change in cancer deaths is that liver and intrahepatic bile duct cancer, currently at sixth, will jump up to third.

Two decades from now, the ranking in terms of cancer deaths will be lung, pancreatic, liver and intrahepatic bile duct, and colorectal.

“Our findings reflect the shifting dynamics of cancer screening and treatment,” lead author Lola Rahib, PhD, a pancreatic cancer scientist at Cancer Commons, the advocacy nonprofit, commented in a press statement.

The new analysis used population-growth projections (based on 2010 U.S. Census data) and current population-based cancer incidence and death rates (from Surveillance, Epidemiology, and End Results 2014-2016) to calculate the changes in incidences and deaths to the year 2040.

The projected, estimated numbers are not ironclad, the researchers acknowledged.

“Our projections assume that the observed rates and trends [from recent years] don’t change over time,” Dr. Rahib said in an interview, but she pointed out that change may indeed happen.

“Any long-term projections should be considered with a grain of salt,” said Kim Miller, MPH, a surveillance research scientist at the American Cancer Society, who was approached for comment.

Dr. Miller explained that “cancer trends can sometimes rapidly change within a few years.” Projections just 2-4 years ahead are “extremely difficult” and those 20 years ahead are even more so, she added in an interview.

“We’re encouraged to see the projected decreases in deaths from lung, colorectal, and breast cancer in the coming years,” said coauthor Lynn Matrisian, PhD, MBA, chief science officer at the Pancreatic Cancer Action Network. “It’s time to shift focus to some of the less commonly diagnosed cancers with the lowest survival rates, like pancreatic and liver cancer.”
 

Difference in opinion on prostate cancer

The huge fall in the incidence of prostate cancer that the authors predict will come about as a result of changes in prostate-specific antigen (PSA)–screening recommendations over the last 15 years, they suggested.

“The most recent change in 2018 recommends that men aged 55-69 can make their own decisions regarding screening, but previous changes recommended against PSA screening,” said Dr. Rahib.

“These changes in screening guidelines have influenced the number of diagnoses of prostate cancer in recent years and will continue to do so to 2040,” Dr. Rahib commented.

Dr. Miller casts doubt on this prediction.

Using data through 2017, “we have seen that the patterns in prostate cancer incidence are already shifting from the steep declines we saw in the early 2010s,” she said. “I would use caution when interpreting the overall trends for prostate, because this cancer in particular is dramatically affected by changes in recommendations for screening with the PSA test.”

Screening has also influenced colorectal cancer incidence, the authors pointed out, saying that the uptake of colorectal cancer screening is associated with a decrease in the number of colorectal cancers and deaths out to 2040, as a result of effectiveness of screening.

For breast cancer, the authors highlighted the fact that, although the number of breast cancers will continue to increase, the number of breast cancer deaths will decrease. That ongoing trend is most likely attributable to increased screening and advancements in treatment.

The study was supported by the National Institutes of Health, National Cancer Institute, the Cancer Prevention and Research Institute of Texas, Cancer Commons and the Pancreatic Cancer Action Network. The study authors and Dr. Miller disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The next 20 years will see a big shift in cancer type rankings, researchers predict.

At the moment, the most common cancers in the United States are breast, lung, prostate, colorectal, and melanoma.

By 2040, melanoma will have become the second most common cancer type, while prostate cancer will drop in incidence all the way to 14, the study authors predicted. Breast cancer will remain the top cancer to be diagnosed, lung cancer will drop from second to third, and colorectal cancer will remain at fourth.

These predicted rankings of cancer types by their total number of annual cases were published online April 7, 2021, in JAMA Network Open.

The authors also rank cancer type by mortality. Currently, most cancer deaths are caused by lung cancer, followed by colorectal, pancreatic, and breast. By 2040, the most notable change in cancer deaths is that liver and intrahepatic bile duct cancer, currently at sixth, will jump up to third.

Two decades from now, the ranking in terms of cancer deaths will be lung, pancreatic, liver and intrahepatic bile duct, and colorectal.

“Our findings reflect the shifting dynamics of cancer screening and treatment,” lead author Lola Rahib, PhD, a pancreatic cancer scientist at Cancer Commons, the advocacy nonprofit, commented in a press statement.

The new analysis used population-growth projections (based on 2010 U.S. Census data) and current population-based cancer incidence and death rates (from Surveillance, Epidemiology, and End Results 2014-2016) to calculate the changes in incidences and deaths to the year 2040.

The projected, estimated numbers are not ironclad, the researchers acknowledged.

“Our projections assume that the observed rates and trends [from recent years] don’t change over time,” Dr. Rahib said in an interview, but she pointed out that change may indeed happen.

“Any long-term projections should be considered with a grain of salt,” said Kim Miller, MPH, a surveillance research scientist at the American Cancer Society, who was approached for comment.

Dr. Miller explained that “cancer trends can sometimes rapidly change within a few years.” Projections just 2-4 years ahead are “extremely difficult” and those 20 years ahead are even more so, she added in an interview.

“We’re encouraged to see the projected decreases in deaths from lung, colorectal, and breast cancer in the coming years,” said coauthor Lynn Matrisian, PhD, MBA, chief science officer at the Pancreatic Cancer Action Network. “It’s time to shift focus to some of the less commonly diagnosed cancers with the lowest survival rates, like pancreatic and liver cancer.”
 

Difference in opinion on prostate cancer

The huge fall in the incidence of prostate cancer that the authors predict will come about as a result of changes in prostate-specific antigen (PSA)–screening recommendations over the last 15 years, they suggested.

“The most recent change in 2018 recommends that men aged 55-69 can make their own decisions regarding screening, but previous changes recommended against PSA screening,” said Dr. Rahib.

“These changes in screening guidelines have influenced the number of diagnoses of prostate cancer in recent years and will continue to do so to 2040,” Dr. Rahib commented.

Dr. Miller casts doubt on this prediction.

Using data through 2017, “we have seen that the patterns in prostate cancer incidence are already shifting from the steep declines we saw in the early 2010s,” she said. “I would use caution when interpreting the overall trends for prostate, because this cancer in particular is dramatically affected by changes in recommendations for screening with the PSA test.”

Screening has also influenced colorectal cancer incidence, the authors pointed out, saying that the uptake of colorectal cancer screening is associated with a decrease in the number of colorectal cancers and deaths out to 2040, as a result of effectiveness of screening.

For breast cancer, the authors highlighted the fact that, although the number of breast cancers will continue to increase, the number of breast cancer deaths will decrease. That ongoing trend is most likely attributable to increased screening and advancements in treatment.

The study was supported by the National Institutes of Health, National Cancer Institute, the Cancer Prevention and Research Institute of Texas, Cancer Commons and the Pancreatic Cancer Action Network. The study authors and Dr. Miller disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Asian Americans with melanoma presented at a younger age but with higher rates of invasive disease and at later stages of disease, compared with non-Hispanic Whites, according to a secondary analysis of data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

The findings are consistent with previous studies indicating delayed detection of melanoma in Asians, compared with non-Hispanic Whites, and provide a window into Asian American communities specifically, Erica M. Lin, a medical student at Brown University, Providence, R.I., said at the annual Skin of Color Society Symposium. The majority of studies on melanoma in Asians have originated in Asia, noted Ms. Lin, whose coauthor was Eunyoung Cho, ScD, an associate professor in the department of dermatology and director of the clinical and translational research program at Brown University. Their analysis covered registries from 10 geographic areas representing 54% of the U.S. Asian American population over a 25-year period, from 1990 to 2014.

Asian Americans with melanoma were more likely to present at an invasive stage than non-Hispanic Whites (82.9% vs. 72.2%, P < .001), and they were significantly more likely to present when the disease had progressed to a distant stage (9.39% vs. 2.51%, P < .001), even though they were of younger ages at the time of those diagnoses, Ms. Lin reported at the meeting. (The numbers do not account for unknown or unstaged melanoma cases.)

Significantly fewer Asian Americans presented at the “in situ” stage, compared with non-Hispanic Whites (17.11% vs. 27.78%). The lower extremities were the most common site in Asian Americans, compared with the trunk in Non-Hispanic Whites.

The SEER registries covered the eight largest Asian American groups: Asian Indians/Pakistanis, Chinese, Filipinos, Japanese, Kampucheans (Cambodians), Koreans, Laotians, and Vietnamese. Melanoma was more common in females across the groups (53% of females vs. 47% of males), with the exception of Asian Indians/Pakistanis.

While melanoma increased significantly over time among non-Hispanic Whites – a mean 24% increase per 5-year period – there was “no significant change in melanoma rates in Asians,” Ms. Lin said.

The lack of increase in Asian American communities combined with the other findings is “potentially concerning” and suggests “that there may be cases that are not being identified,” she said in an interview after the meeting. In their abstract, she and Dr. Cho noted that their findings underscore the need for further prevention, screening, and surveillance measures.

The NCI’s SEER program is a coordinated system of cancer registries across the United States that collects data on every case of cancer reported in 19 geographic areas.

Asian Americans with melanoma presented at a younger age but with higher rates of invasive disease and at later stages of disease, compared with non-Hispanic Whites, according to a secondary analysis of data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

The findings are consistent with previous studies indicating delayed detection of melanoma in Asians, compared with non-Hispanic Whites, and provide a window into Asian American communities specifically, Erica M. Lin, a medical student at Brown University, Providence, R.I., said at the annual Skin of Color Society Symposium. The majority of studies on melanoma in Asians have originated in Asia, noted Ms. Lin, whose coauthor was Eunyoung Cho, ScD, an associate professor in the department of dermatology and director of the clinical and translational research program at Brown University. Their analysis covered registries from 10 geographic areas representing 54% of the U.S. Asian American population over a 25-year period, from 1990 to 2014.

Asian Americans with melanoma were more likely to present at an invasive stage than non-Hispanic Whites (82.9% vs. 72.2%, P < .001), and they were significantly more likely to present when the disease had progressed to a distant stage (9.39% vs. 2.51%, P < .001), even though they were of younger ages at the time of those diagnoses, Ms. Lin reported at the meeting. (The numbers do not account for unknown or unstaged melanoma cases.)

Significantly fewer Asian Americans presented at the “in situ” stage, compared with non-Hispanic Whites (17.11% vs. 27.78%). The lower extremities were the most common site in Asian Americans, compared with the trunk in Non-Hispanic Whites.

The SEER registries covered the eight largest Asian American groups: Asian Indians/Pakistanis, Chinese, Filipinos, Japanese, Kampucheans (Cambodians), Koreans, Laotians, and Vietnamese. Melanoma was more common in females across the groups (53% of females vs. 47% of males), with the exception of Asian Indians/Pakistanis.

While melanoma increased significantly over time among non-Hispanic Whites – a mean 24% increase per 5-year period – there was “no significant change in melanoma rates in Asians,” Ms. Lin said.

The lack of increase in Asian American communities combined with the other findings is “potentially concerning” and suggests “that there may be cases that are not being identified,” she said in an interview after the meeting. In their abstract, she and Dr. Cho noted that their findings underscore the need for further prevention, screening, and surveillance measures.

The NCI’s SEER program is a coordinated system of cancer registries across the United States that collects data on every case of cancer reported in 19 geographic areas.

Asian Americans with melanoma presented at a younger age but with higher rates of invasive disease and at later stages of disease, compared with non-Hispanic Whites, according to a secondary analysis of data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

The findings are consistent with previous studies indicating delayed detection of melanoma in Asians, compared with non-Hispanic Whites, and provide a window into Asian American communities specifically, Erica M. Lin, a medical student at Brown University, Providence, R.I., said at the annual Skin of Color Society Symposium. The majority of studies on melanoma in Asians have originated in Asia, noted Ms. Lin, whose coauthor was Eunyoung Cho, ScD, an associate professor in the department of dermatology and director of the clinical and translational research program at Brown University. Their analysis covered registries from 10 geographic areas representing 54% of the U.S. Asian American population over a 25-year period, from 1990 to 2014.

Asian Americans with melanoma were more likely to present at an invasive stage than non-Hispanic Whites (82.9% vs. 72.2%, P < .001), and they were significantly more likely to present when the disease had progressed to a distant stage (9.39% vs. 2.51%, P < .001), even though they were of younger ages at the time of those diagnoses, Ms. Lin reported at the meeting. (The numbers do not account for unknown or unstaged melanoma cases.)

Significantly fewer Asian Americans presented at the “in situ” stage, compared with non-Hispanic Whites (17.11% vs. 27.78%). The lower extremities were the most common site in Asian Americans, compared with the trunk in Non-Hispanic Whites.

The SEER registries covered the eight largest Asian American groups: Asian Indians/Pakistanis, Chinese, Filipinos, Japanese, Kampucheans (Cambodians), Koreans, Laotians, and Vietnamese. Melanoma was more common in females across the groups (53% of females vs. 47% of males), with the exception of Asian Indians/Pakistanis.

While melanoma increased significantly over time among non-Hispanic Whites – a mean 24% increase per 5-year period – there was “no significant change in melanoma rates in Asians,” Ms. Lin said.

The lack of increase in Asian American communities combined with the other findings is “potentially concerning” and suggests “that there may be cases that are not being identified,” she said in an interview after the meeting. In their abstract, she and Dr. Cho noted that their findings underscore the need for further prevention, screening, and surveillance measures.

The NCI’s SEER program is a coordinated system of cancer registries across the United States that collects data on every case of cancer reported in 19 geographic areas.

Pneumonitis is an uncommon and potentially life-threatening complication of immune checkpoint inhibitor (ICI) therapy. A fraction of patients with ICI-related pneumonitis fail to respond to initial therapy with high-dose systemic steroids.

The recently published experiences at two major cancer centers shed light on the outcomes from treatment and can provide some advice to clinicians for dealing with affected patients.
 

The Johns Hopkins experience

Because ICI-related pneumonitis typically improves within 48-72 hours of steroid therapy, at Johns Hopkins University, Baltimore, steroid-refractory pneumonitis is defined as pneumonitis that demonstrates no clinical improvement after high-dose corticosteroids for 2-14 days. If the immune toxicity–specialized, multidisciplinary management team implements additional immunosuppressive therapy, that is regarded as confirmatory evidence.

Aanika Balaji, a medical student at Johns Hopkins University, and colleagues retrospectively summarized the clinical course of 12 patients with ICI-related pneumonitis between 2011 and 2020. Clinical improvement with subsequent treatment was evidenced by reduction in either level of care or oxygen requirements.

Three-quarters of the patients were current or former smokers, and the same proportion had lung cancer. Most patients (91.6%) had received chemotherapy, 58.3% had prior chest radiotherapy, and 58.3% had achieved partial response or stable disease with an ICI.

Steroid-refractory ICI-related pneumonitis developed between 40 and 127 days (median, 85 days) after the first dose of ICI therapy. Subsequent immunosuppressive management included IVIg, infliximab, or the combination, in addition to ICU-level supportive care.

Among the seven patients who received IVIg alone, two patients (29%) achieved clinical improvement and hospital discharge. The remainder died.

The two patients treated with infliximab and the three patients treated with sequential IVIg and infliximab died. All deaths were attributed to ICI-related pneumonitis or infectious complications.

Overall, clinically relevant findings were:

• Steroid-refractory ICI-related pneumonitis was seen in 18.5% of patients referred for multidisciplinary care.
• Steroid-refractory ICI-related pneumonitis occurred at a median of 85 days into a patient’s ICI treatment.
• Some patients improved clinically after IVIg therapy, but mortality was high overall.
• Infliximab therapy, alone or in combination with IVIg, was ineffective.

The Memorial Sloan Kettering experience

Jason Beattie, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues performed a retrospective study of patients who had pneumonitis after ICI therapy and/or received immune modulator therapy after corticosteroids in the setting of ICI cancer treatment.

Manual record review was performed to exclude cases of pneumonitis from other causes. The period reviewed was roughly contemporaneous with the Johns Hopkins series.

Patients with ICI-related pneumonitis were divided into “steroid refractory” (i.e., no response to high-dose corticosteroids) or “steroid resistant” (i.e., initial response, followed by worsening) categories.

The researchers identified 26 patients with ICI-related pneumonitis, all of whom had advanced malignancy (8 lung cancer, 4 malignant melanoma, 4 renal cell cancer, and 10 “other” cancers).

A majority of patients (85%) were current or former smokers, 73% had received ICI monotherapy, 35% had received prior chest radiation at a median interval of 4.9 months prior to pneumonitis onset, and 27% had preexisting pulmonary disease.

Twelve patients (46%) had steroid-refractory ICI-related pneumonitis, and 14 (54%) had steroid-resistant ICI-related pneumonitis.

The two groups differed in time to pneumonitis onset (a median of 68 days in the refractory group and 182 days in the resistant group) and time to immune modulator therapy after beginning steroids (median 7 days and 2.9 months, respectively). In the steroid-refractory cases, pneumonitis was more severe.

In addition to corticosteroids, most patients received infliximab monotherapy or infliximab with mycophenolate mofetil. In contrast to the Johns Hopkins series, IVIg was not used in the Memorial Sloan Kettering cases.

Outcomes from immune modulators were graded based on clinical evidence (progress notes, oxygen requirements, level of care, radiologic information, etc.) of resolution of pneumonitis on imaging at least 8 weeks after cessation of steroids and immune modulator therapy, durable improvement for at least 8 weeks after immune modulator therapy, transient improvement followed by pneumonitis relapse or inadequate follow-up because of death or hospice referral, or no improvement.

Ten patients (38%) had durable improvement of ICI-related pneumonitis, of whom three (12%) had complete resolution. Two of the patients with complete resolution had steroid-refractory pneumonitis, both of whom had received infliximab followed by mycophenolate mofetil.

Among the seven patients with durable improvement, four remained alive on immune modulators. Time to resolution of pneumonitis was protracted, ranging from 2.3 months to 8.4 months in the steroid-refractory patients.

Durable response was less common with steroid-refractory (25%) than steroid-resistant (50%) disease, with a significant difference in 90-day survival of 25% and 71%, respectively.

Among the 13 (50%) patients with transient improvement in ICI-related pneumonitis, 8 ultimately died, either because of recurrent ICI-related pneumonitis or infection. All three patients with no improvement from immune modulators died.

The 90-day all-cause mortality was 50%, with durable pneumonitis improvement and freedom from severe infectious complications occurring in only about a third of patients.
 

Lessons for clinicians

The National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society of Medical Oncology have all published guidelines and recommendations for immunosuppression for steroid-refractory adverse events from ICIs.

Unfortunately, there is little experience with steroid-unresponsive ICI-related pneumonitis. The ideal sequence, dose, and duration of additional immune modulator therapy for ICI-related pneumonitis are unclear and may differ from the approaches to other immune-related toxicities.

This is important because, as suggested in an editorial by Margaret Gatti-Mays, MD, and James L. Gulley, MD, PhD, it is likely that ICI-related pneumonitis will be seen more in routine practice than in clinical trial populations. In addition, across all tumor types, ICI-related pneumonitis is the most common cause of ICI-associated death from toxicity.

The retrospective studies from Johns Hopkins and Memorial Sloan Kettering constitute the largest published experience with ICI-related pneumonitis and yield important clinical insights.

Uniform definitions of potentially important patient subgroups (e.g., steroid refractory vs. steroid resistant) are needed. The steroid-refractory and steroid-resistant subgroups have distinctly different clinical features and outcomes. Uniformity in the subgroup definitions would be a useful starting point from both clinical and research perspectives.

Preferred treatment choices need to be tested systematically in multi-institutional studies. Any potential impact of treatment for ICI-related pneumonitis on antitumor immune control should be identified.

Endpoints of interest need to be defined and measured prospectively. All-cause mortality after 90 days is important, but, as the authors of both reviews noted, there are vitally important narratives and differences in functionality that are completely concealed by restricting the focus to mortality.

Potential causal relationships with antecedent exposure to tobacco, radiation, intrathoracic tumor burden, or other factors need to be defined.

Clinicians need predictive biomarkers for ICI-related pneumonitis (e.g., in peripheral blood, pulmonary function testing, or bronchoscopy specimens). At-risk patients may benefit from early intervention.

The limitations of single-institution record reviews in guiding real-world patient management notwithstanding, these reviews illustrate the value of registries and prospective studies to guide the path forward. Taking these next steps will ensure for our patients that the success of immune-targeted therapy against their cancer never becomes a Pyrrhic victory.

The Johns Hopkins investigators and the editorialists reported having no disclosures. The Memorial Sloan Kettering investigators disclosed relationships with Targeted Oncology, Merck, Array BioPharma, Novartis, and many other companies.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Pneumonitis is an uncommon and potentially life-threatening complication of immune checkpoint inhibitor (ICI) therapy. A fraction of patients with ICI-related pneumonitis fail to respond to initial therapy with high-dose systemic steroids.

The recently published experiences at two major cancer centers shed light on the outcomes from treatment and can provide some advice to clinicians for dealing with affected patients.
 

The Johns Hopkins experience

Because ICI-related pneumonitis typically improves within 48-72 hours of steroid therapy, at Johns Hopkins University, Baltimore, steroid-refractory pneumonitis is defined as pneumonitis that demonstrates no clinical improvement after high-dose corticosteroids for 2-14 days. If the immune toxicity–specialized, multidisciplinary management team implements additional immunosuppressive therapy, that is regarded as confirmatory evidence.

Aanika Balaji, a medical student at Johns Hopkins University, and colleagues retrospectively summarized the clinical course of 12 patients with ICI-related pneumonitis between 2011 and 2020. Clinical improvement with subsequent treatment was evidenced by reduction in either level of care or oxygen requirements.

Three-quarters of the patients were current or former smokers, and the same proportion had lung cancer. Most patients (91.6%) had received chemotherapy, 58.3% had prior chest radiotherapy, and 58.3% had achieved partial response or stable disease with an ICI.

Steroid-refractory ICI-related pneumonitis developed between 40 and 127 days (median, 85 days) after the first dose of ICI therapy. Subsequent immunosuppressive management included IVIg, infliximab, or the combination, in addition to ICU-level supportive care.

Among the seven patients who received IVIg alone, two patients (29%) achieved clinical improvement and hospital discharge. The remainder died.

The two patients treated with infliximab and the three patients treated with sequential IVIg and infliximab died. All deaths were attributed to ICI-related pneumonitis or infectious complications.

Overall, clinically relevant findings were:

• Steroid-refractory ICI-related pneumonitis was seen in 18.5% of patients referred for multidisciplinary care.
• Steroid-refractory ICI-related pneumonitis occurred at a median of 85 days into a patient’s ICI treatment.
• Some patients improved clinically after IVIg therapy, but mortality was high overall.
• Infliximab therapy, alone or in combination with IVIg, was ineffective.

The Memorial Sloan Kettering experience

Jason Beattie, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues performed a retrospective study of patients who had pneumonitis after ICI therapy and/or received immune modulator therapy after corticosteroids in the setting of ICI cancer treatment.

Manual record review was performed to exclude cases of pneumonitis from other causes. The period reviewed was roughly contemporaneous with the Johns Hopkins series.

Patients with ICI-related pneumonitis were divided into “steroid refractory” (i.e., no response to high-dose corticosteroids) or “steroid resistant” (i.e., initial response, followed by worsening) categories.

The researchers identified 26 patients with ICI-related pneumonitis, all of whom had advanced malignancy (8 lung cancer, 4 malignant melanoma, 4 renal cell cancer, and 10 “other” cancers).

A majority of patients (85%) were current or former smokers, 73% had received ICI monotherapy, 35% had received prior chest radiation at a median interval of 4.9 months prior to pneumonitis onset, and 27% had preexisting pulmonary disease.

Twelve patients (46%) had steroid-refractory ICI-related pneumonitis, and 14 (54%) had steroid-resistant ICI-related pneumonitis.

The two groups differed in time to pneumonitis onset (a median of 68 days in the refractory group and 182 days in the resistant group) and time to immune modulator therapy after beginning steroids (median 7 days and 2.9 months, respectively). In the steroid-refractory cases, pneumonitis was more severe.

In addition to corticosteroids, most patients received infliximab monotherapy or infliximab with mycophenolate mofetil. In contrast to the Johns Hopkins series, IVIg was not used in the Memorial Sloan Kettering cases.

Outcomes from immune modulators were graded based on clinical evidence (progress notes, oxygen requirements, level of care, radiologic information, etc.) of resolution of pneumonitis on imaging at least 8 weeks after cessation of steroids and immune modulator therapy, durable improvement for at least 8 weeks after immune modulator therapy, transient improvement followed by pneumonitis relapse or inadequate follow-up because of death or hospice referral, or no improvement.

Ten patients (38%) had durable improvement of ICI-related pneumonitis, of whom three (12%) had complete resolution. Two of the patients with complete resolution had steroid-refractory pneumonitis, both of whom had received infliximab followed by mycophenolate mofetil.

Among the seven patients with durable improvement, four remained alive on immune modulators. Time to resolution of pneumonitis was protracted, ranging from 2.3 months to 8.4 months in the steroid-refractory patients.

Durable response was less common with steroid-refractory (25%) than steroid-resistant (50%) disease, with a significant difference in 90-day survival of 25% and 71%, respectively.

Among the 13 (50%) patients with transient improvement in ICI-related pneumonitis, 8 ultimately died, either because of recurrent ICI-related pneumonitis or infection. All three patients with no improvement from immune modulators died.

The 90-day all-cause mortality was 50%, with durable pneumonitis improvement and freedom from severe infectious complications occurring in only about a third of patients.
 

Lessons for clinicians

The National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society of Medical Oncology have all published guidelines and recommendations for immunosuppression for steroid-refractory adverse events from ICIs.

Unfortunately, there is little experience with steroid-unresponsive ICI-related pneumonitis. The ideal sequence, dose, and duration of additional immune modulator therapy for ICI-related pneumonitis are unclear and may differ from the approaches to other immune-related toxicities.

This is important because, as suggested in an editorial by Margaret Gatti-Mays, MD, and James L. Gulley, MD, PhD, it is likely that ICI-related pneumonitis will be seen more in routine practice than in clinical trial populations. In addition, across all tumor types, ICI-related pneumonitis is the most common cause of ICI-associated death from toxicity.

The retrospective studies from Johns Hopkins and Memorial Sloan Kettering constitute the largest published experience with ICI-related pneumonitis and yield important clinical insights.

Uniform definitions of potentially important patient subgroups (e.g., steroid refractory vs. steroid resistant) are needed. The steroid-refractory and steroid-resistant subgroups have distinctly different clinical features and outcomes. Uniformity in the subgroup definitions would be a useful starting point from both clinical and research perspectives.

Preferred treatment choices need to be tested systematically in multi-institutional studies. Any potential impact of treatment for ICI-related pneumonitis on antitumor immune control should be identified.

Endpoints of interest need to be defined and measured prospectively. All-cause mortality after 90 days is important, but, as the authors of both reviews noted, there are vitally important narratives and differences in functionality that are completely concealed by restricting the focus to mortality.

Potential causal relationships with antecedent exposure to tobacco, radiation, intrathoracic tumor burden, or other factors need to be defined.

Clinicians need predictive biomarkers for ICI-related pneumonitis (e.g., in peripheral blood, pulmonary function testing, or bronchoscopy specimens). At-risk patients may benefit from early intervention.

The limitations of single-institution record reviews in guiding real-world patient management notwithstanding, these reviews illustrate the value of registries and prospective studies to guide the path forward. Taking these next steps will ensure for our patients that the success of immune-targeted therapy against their cancer never becomes a Pyrrhic victory.

The Johns Hopkins investigators and the editorialists reported having no disclosures. The Memorial Sloan Kettering investigators disclosed relationships with Targeted Oncology, Merck, Array BioPharma, Novartis, and many other companies.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Pneumonitis is an uncommon and potentially life-threatening complication of immune checkpoint inhibitor (ICI) therapy. A fraction of patients with ICI-related pneumonitis fail to respond to initial therapy with high-dose systemic steroids.

The recently published experiences at two major cancer centers shed light on the outcomes from treatment and can provide some advice to clinicians for dealing with affected patients.
 

The Johns Hopkins experience

Because ICI-related pneumonitis typically improves within 48-72 hours of steroid therapy, at Johns Hopkins University, Baltimore, steroid-refractory pneumonitis is defined as pneumonitis that demonstrates no clinical improvement after high-dose corticosteroids for 2-14 days. If the immune toxicity–specialized, multidisciplinary management team implements additional immunosuppressive therapy, that is regarded as confirmatory evidence.

Aanika Balaji, a medical student at Johns Hopkins University, and colleagues retrospectively summarized the clinical course of 12 patients with ICI-related pneumonitis between 2011 and 2020. Clinical improvement with subsequent treatment was evidenced by reduction in either level of care or oxygen requirements.

Three-quarters of the patients were current or former smokers, and the same proportion had lung cancer. Most patients (91.6%) had received chemotherapy, 58.3% had prior chest radiotherapy, and 58.3% had achieved partial response or stable disease with an ICI.

Steroid-refractory ICI-related pneumonitis developed between 40 and 127 days (median, 85 days) after the first dose of ICI therapy. Subsequent immunosuppressive management included IVIg, infliximab, or the combination, in addition to ICU-level supportive care.

Among the seven patients who received IVIg alone, two patients (29%) achieved clinical improvement and hospital discharge. The remainder died.

The two patients treated with infliximab and the three patients treated with sequential IVIg and infliximab died. All deaths were attributed to ICI-related pneumonitis or infectious complications.

Overall, clinically relevant findings were:

• Steroid-refractory ICI-related pneumonitis was seen in 18.5% of patients referred for multidisciplinary care.
• Steroid-refractory ICI-related pneumonitis occurred at a median of 85 days into a patient’s ICI treatment.
• Some patients improved clinically after IVIg therapy, but mortality was high overall.
• Infliximab therapy, alone or in combination with IVIg, was ineffective.

The Memorial Sloan Kettering experience

Jason Beattie, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues performed a retrospective study of patients who had pneumonitis after ICI therapy and/or received immune modulator therapy after corticosteroids in the setting of ICI cancer treatment.

Manual record review was performed to exclude cases of pneumonitis from other causes. The period reviewed was roughly contemporaneous with the Johns Hopkins series.

Patients with ICI-related pneumonitis were divided into “steroid refractory” (i.e., no response to high-dose corticosteroids) or “steroid resistant” (i.e., initial response, followed by worsening) categories.

The researchers identified 26 patients with ICI-related pneumonitis, all of whom had advanced malignancy (8 lung cancer, 4 malignant melanoma, 4 renal cell cancer, and 10 “other” cancers).

A majority of patients (85%) were current or former smokers, 73% had received ICI monotherapy, 35% had received prior chest radiation at a median interval of 4.9 months prior to pneumonitis onset, and 27% had preexisting pulmonary disease.

Twelve patients (46%) had steroid-refractory ICI-related pneumonitis, and 14 (54%) had steroid-resistant ICI-related pneumonitis.

The two groups differed in time to pneumonitis onset (a median of 68 days in the refractory group and 182 days in the resistant group) and time to immune modulator therapy after beginning steroids (median 7 days and 2.9 months, respectively). In the steroid-refractory cases, pneumonitis was more severe.

In addition to corticosteroids, most patients received infliximab monotherapy or infliximab with mycophenolate mofetil. In contrast to the Johns Hopkins series, IVIg was not used in the Memorial Sloan Kettering cases.

Outcomes from immune modulators were graded based on clinical evidence (progress notes, oxygen requirements, level of care, radiologic information, etc.) of resolution of pneumonitis on imaging at least 8 weeks after cessation of steroids and immune modulator therapy, durable improvement for at least 8 weeks after immune modulator therapy, transient improvement followed by pneumonitis relapse or inadequate follow-up because of death or hospice referral, or no improvement.

Ten patients (38%) had durable improvement of ICI-related pneumonitis, of whom three (12%) had complete resolution. Two of the patients with complete resolution had steroid-refractory pneumonitis, both of whom had received infliximab followed by mycophenolate mofetil.

Among the seven patients with durable improvement, four remained alive on immune modulators. Time to resolution of pneumonitis was protracted, ranging from 2.3 months to 8.4 months in the steroid-refractory patients.

Durable response was less common with steroid-refractory (25%) than steroid-resistant (50%) disease, with a significant difference in 90-day survival of 25% and 71%, respectively.

Among the 13 (50%) patients with transient improvement in ICI-related pneumonitis, 8 ultimately died, either because of recurrent ICI-related pneumonitis or infection. All three patients with no improvement from immune modulators died.

The 90-day all-cause mortality was 50%, with durable pneumonitis improvement and freedom from severe infectious complications occurring in only about a third of patients.
 

Lessons for clinicians

The National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society of Medical Oncology have all published guidelines and recommendations for immunosuppression for steroid-refractory adverse events from ICIs.

Unfortunately, there is little experience with steroid-unresponsive ICI-related pneumonitis. The ideal sequence, dose, and duration of additional immune modulator therapy for ICI-related pneumonitis are unclear and may differ from the approaches to other immune-related toxicities.

This is important because, as suggested in an editorial by Margaret Gatti-Mays, MD, and James L. Gulley, MD, PhD, it is likely that ICI-related pneumonitis will be seen more in routine practice than in clinical trial populations. In addition, across all tumor types, ICI-related pneumonitis is the most common cause of ICI-associated death from toxicity.

The retrospective studies from Johns Hopkins and Memorial Sloan Kettering constitute the largest published experience with ICI-related pneumonitis and yield important clinical insights.

Uniform definitions of potentially important patient subgroups (e.g., steroid refractory vs. steroid resistant) are needed. The steroid-refractory and steroid-resistant subgroups have distinctly different clinical features and outcomes. Uniformity in the subgroup definitions would be a useful starting point from both clinical and research perspectives.

Preferred treatment choices need to be tested systematically in multi-institutional studies. Any potential impact of treatment for ICI-related pneumonitis on antitumor immune control should be identified.

Endpoints of interest need to be defined and measured prospectively. All-cause mortality after 90 days is important, but, as the authors of both reviews noted, there are vitally important narratives and differences in functionality that are completely concealed by restricting the focus to mortality.

Potential causal relationships with antecedent exposure to tobacco, radiation, intrathoracic tumor burden, or other factors need to be defined.

Clinicians need predictive biomarkers for ICI-related pneumonitis (e.g., in peripheral blood, pulmonary function testing, or bronchoscopy specimens). At-risk patients may benefit from early intervention.

The limitations of single-institution record reviews in guiding real-world patient management notwithstanding, these reviews illustrate the value of registries and prospective studies to guide the path forward. Taking these next steps will ensure for our patients that the success of immune-targeted therapy against their cancer never becomes a Pyrrhic victory.

The Johns Hopkins investigators and the editorialists reported having no disclosures. The Memorial Sloan Kettering investigators disclosed relationships with Targeted Oncology, Merck, Array BioPharma, Novartis, and many other companies.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Patients at very high risk for melanoma, including those with a family history or with inherited pathogenic variants of genes that increase the risk, likely benefit from routine whole-body screening for melanoma and education about UV protection.

Those are key findings from the first prospective cohort study to quantify the benefit of screening in melanoma-prone families, which was published online April 2 in Cancer Epidemiology, Biomarkers & Prevention.

“Whole-body screening for melanoma is currently routine for individuals at high risk for melanoma, which includes people from melanoma-prone families (at least two relatives who have had melanoma) and those with inherited pathogenic gene variants of the CDKN2A or CDK4 genes, which increase risk for melanoma,” lead author Michael R. Sargen, MD, said in an interview. “In our study, we investigated whether screening and educational interventions, including education about the appearance of melanoma and strategies for protecting skin from ultraviolet damage, contributed to early diagnosis of melanoma in individuals from melanoma-prone families.”

Of the 293 individuals who enrolled in the study between 1976 and 2014, 246 were diagnosed with melanoma before enrollment (the prestudy cohort) and 47 were diagnosed after enrollment (the prospective cohort). The researchers compared differences in melanoma thickness and tumor stage between participants in the prestudy and prospective cohorts, and compared tumor-thickness trends between participants in their study and cases in the general population using data from Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 2016. Because information on melanoma thickness was missing for 24% of melanoma cases in the NCI Familial Melanoma Study and 8.7% of melanoma cases found in the SEER registry, the researchers imputed the missing data.

After adjusting for gender and age, Dr. Sargen and his colleagues found that participants in the prospective cohort had significantly thinner melanomas, compared with those in the prestudy cohort (0.6 mm vs. 1.1 mm, respectively; P < .001). In addition, 83% of those in the prospective cohort were significantly more likely to be diagnosed at the early T1 stage, compared with 40% of those in the prestudy cohort (P < .001).

In their analysis, they also determined that after adjusting for gender and age, “all NCI family cases had systematically lower thickness than SEER cases during the study period.” The reductions in melanoma thickness and tumor stage, they concluded, “were not fully explained by calendar period effects of decreasing thickness in the general population and point to the potential benefit of skin cancer screening for patients with a family history of melanoma and those with pathogenic germline variants of melanoma-susceptibility genes.”

“Our data provide reassuring evidence that screening, alongside education about proper UV protection and the appearance of melanoma, is likely benefiting patients with a significantly elevated risk for melanoma,” Dr. Sargen said in the interview “Further studies are needed to determine whether individuals without a family history of melanoma may benefit from whole-body screening, and whether the benefits vary by ethnicity.”

He acknowledged certain limitations of the study, including the relatively small sample size of melanoma cases in the NCI Familial Melanoma Study and the imputation of missing melanoma-thickness data. “Additionally, since this was a prospective cohort study, we were not able to distinguish the independent effect of each intervention,” he said. “Randomized controlled studies are needed to understand the impact of each aspect of the intervention, such as whole-body screening, melanoma education, or strategies for skin protection.”

In an interview, Maryam M. Asgari, MD, professor of dermatology at Harvard University, Boston, called the analysis “well done,” but commented on the potential role of selection bias impacting the findings. “People who have a strong family history of melanoma and who are opting to engage in an NCI study and come in for full-body skin checks and go through that education process may have very different health-seeking behaviors than individuals in the general population that would be reported to SEER,” she said.

She also raised the question of whether the results were driven by the early detection through the NCI’s program of provider screening or through the educational component that enables earlier self-detection. “If you’re an individual involved in a study and that brings attention to your moles and you have a strong family history of melanoma to begin with, it is not surprising that you are going to have heightened awareness of any changing mole and therefore are more likely to have melanoma detected at an earlier stage,” Dr. Asgari said.

The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. Dr. Sargen reported having no financial disclosures.
Dr. Asgari disclosed that she has received research support from the Melanoma Research Alliance.
 

dbrunk@mdedge.com

Patients at very high risk for melanoma, including those with a family history or with inherited pathogenic variants of genes that increase the risk, likely benefit from routine whole-body screening for melanoma and education about UV protection.

Those are key findings from the first prospective cohort study to quantify the benefit of screening in melanoma-prone families, which was published online April 2 in Cancer Epidemiology, Biomarkers & Prevention.

“Whole-body screening for melanoma is currently routine for individuals at high risk for melanoma, which includes people from melanoma-prone families (at least two relatives who have had melanoma) and those with inherited pathogenic gene variants of the CDKN2A or CDK4 genes, which increase risk for melanoma,” lead author Michael R. Sargen, MD, said in an interview. “In our study, we investigated whether screening and educational interventions, including education about the appearance of melanoma and strategies for protecting skin from ultraviolet damage, contributed to early diagnosis of melanoma in individuals from melanoma-prone families.”

Of the 293 individuals who enrolled in the study between 1976 and 2014, 246 were diagnosed with melanoma before enrollment (the prestudy cohort) and 47 were diagnosed after enrollment (the prospective cohort). The researchers compared differences in melanoma thickness and tumor stage between participants in the prestudy and prospective cohorts, and compared tumor-thickness trends between participants in their study and cases in the general population using data from Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 2016. Because information on melanoma thickness was missing for 24% of melanoma cases in the NCI Familial Melanoma Study and 8.7% of melanoma cases found in the SEER registry, the researchers imputed the missing data.

After adjusting for gender and age, Dr. Sargen and his colleagues found that participants in the prospective cohort had significantly thinner melanomas, compared with those in the prestudy cohort (0.6 mm vs. 1.1 mm, respectively; P < .001). In addition, 83% of those in the prospective cohort were significantly more likely to be diagnosed at the early T1 stage, compared with 40% of those in the prestudy cohort (P < .001).

In their analysis, they also determined that after adjusting for gender and age, “all NCI family cases had systematically lower thickness than SEER cases during the study period.” The reductions in melanoma thickness and tumor stage, they concluded, “were not fully explained by calendar period effects of decreasing thickness in the general population and point to the potential benefit of skin cancer screening for patients with a family history of melanoma and those with pathogenic germline variants of melanoma-susceptibility genes.”

“Our data provide reassuring evidence that screening, alongside education about proper UV protection and the appearance of melanoma, is likely benefiting patients with a significantly elevated risk for melanoma,” Dr. Sargen said in the interview “Further studies are needed to determine whether individuals without a family history of melanoma may benefit from whole-body screening, and whether the benefits vary by ethnicity.”

He acknowledged certain limitations of the study, including the relatively small sample size of melanoma cases in the NCI Familial Melanoma Study and the imputation of missing melanoma-thickness data. “Additionally, since this was a prospective cohort study, we were not able to distinguish the independent effect of each intervention,” he said. “Randomized controlled studies are needed to understand the impact of each aspect of the intervention, such as whole-body screening, melanoma education, or strategies for skin protection.”

In an interview, Maryam M. Asgari, MD, professor of dermatology at Harvard University, Boston, called the analysis “well done,” but commented on the potential role of selection bias impacting the findings. “People who have a strong family history of melanoma and who are opting to engage in an NCI study and come in for full-body skin checks and go through that education process may have very different health-seeking behaviors than individuals in the general population that would be reported to SEER,” she said.

She also raised the question of whether the results were driven by the early detection through the NCI’s program of provider screening or through the educational component that enables earlier self-detection. “If you’re an individual involved in a study and that brings attention to your moles and you have a strong family history of melanoma to begin with, it is not surprising that you are going to have heightened awareness of any changing mole and therefore are more likely to have melanoma detected at an earlier stage,” Dr. Asgari said.

The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. Dr. Sargen reported having no financial disclosures.
Dr. Asgari disclosed that she has received research support from the Melanoma Research Alliance.
 

dbrunk@mdedge.com

Patients at very high risk for melanoma, including those with a family history or with inherited pathogenic variants of genes that increase the risk, likely benefit from routine whole-body screening for melanoma and education about UV protection.

Those are key findings from the first prospective cohort study to quantify the benefit of screening in melanoma-prone families, which was published online April 2 in Cancer Epidemiology, Biomarkers & Prevention.

“Whole-body screening for melanoma is currently routine for individuals at high risk for melanoma, which includes people from melanoma-prone families (at least two relatives who have had melanoma) and those with inherited pathogenic gene variants of the CDKN2A or CDK4 genes, which increase risk for melanoma,” lead author Michael R. Sargen, MD, said in an interview. “In our study, we investigated whether screening and educational interventions, including education about the appearance of melanoma and strategies for protecting skin from ultraviolet damage, contributed to early diagnosis of melanoma in individuals from melanoma-prone families.”

Of the 293 individuals who enrolled in the study between 1976 and 2014, 246 were diagnosed with melanoma before enrollment (the prestudy cohort) and 47 were diagnosed after enrollment (the prospective cohort). The researchers compared differences in melanoma thickness and tumor stage between participants in the prestudy and prospective cohorts, and compared tumor-thickness trends between participants in their study and cases in the general population using data from Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 2016. Because information on melanoma thickness was missing for 24% of melanoma cases in the NCI Familial Melanoma Study and 8.7% of melanoma cases found in the SEER registry, the researchers imputed the missing data.

After adjusting for gender and age, Dr. Sargen and his colleagues found that participants in the prospective cohort had significantly thinner melanomas, compared with those in the prestudy cohort (0.6 mm vs. 1.1 mm, respectively; P < .001). In addition, 83% of those in the prospective cohort were significantly more likely to be diagnosed at the early T1 stage, compared with 40% of those in the prestudy cohort (P < .001).

In their analysis, they also determined that after adjusting for gender and age, “all NCI family cases had systematically lower thickness than SEER cases during the study period.” The reductions in melanoma thickness and tumor stage, they concluded, “were not fully explained by calendar period effects of decreasing thickness in the general population and point to the potential benefit of skin cancer screening for patients with a family history of melanoma and those with pathogenic germline variants of melanoma-susceptibility genes.”

“Our data provide reassuring evidence that screening, alongside education about proper UV protection and the appearance of melanoma, is likely benefiting patients with a significantly elevated risk for melanoma,” Dr. Sargen said in the interview “Further studies are needed to determine whether individuals without a family history of melanoma may benefit from whole-body screening, and whether the benefits vary by ethnicity.”

He acknowledged certain limitations of the study, including the relatively small sample size of melanoma cases in the NCI Familial Melanoma Study and the imputation of missing melanoma-thickness data. “Additionally, since this was a prospective cohort study, we were not able to distinguish the independent effect of each intervention,” he said. “Randomized controlled studies are needed to understand the impact of each aspect of the intervention, such as whole-body screening, melanoma education, or strategies for skin protection.”

In an interview, Maryam M. Asgari, MD, professor of dermatology at Harvard University, Boston, called the analysis “well done,” but commented on the potential role of selection bias impacting the findings. “People who have a strong family history of melanoma and who are opting to engage in an NCI study and come in for full-body skin checks and go through that education process may have very different health-seeking behaviors than individuals in the general population that would be reported to SEER,” she said.

She also raised the question of whether the results were driven by the early detection through the NCI’s program of provider screening or through the educational component that enables earlier self-detection. “If you’re an individual involved in a study and that brings attention to your moles and you have a strong family history of melanoma to begin with, it is not surprising that you are going to have heightened awareness of any changing mole and therefore are more likely to have melanoma detected at an earlier stage,” Dr. Asgari said.

The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. Dr. Sargen reported having no financial disclosures.
Dr. Asgari disclosed that she has received research support from the Melanoma Research Alliance.
 

dbrunk@mdedge.com