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Pembrolizumab bests ipilimumab in advanced melanoma
Pembrolizumab was superior to ipilimumab, the standard of care, as first-line therapy for advanced melanoma in the phase III KEYNOTE-006 trial.
Pembrolizumab (Keytruda) hit all of its primary survival end points and nearly tripled response rates from 12% with ipilimumab (Yervoy) to 33% in the first frontline head-to-head comparison of the two immune checkpoint inhibitors.
Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37%, compared with ipilimumab, study author Dr. Antoni Ribas reported at the annual meeting of the American Association for Cancer Research.
“We think that this data should change the paradigm of treatment for these patients, and the standard of care should quickly shift to giving PD-1 antibodies,” he said at a press briefing.
Pembrolizumab, a monoclonal antibody that inhibits programmed death receptor-1 (PD-1), is approved as second-line therapy for unresectable or metastatic melanoma after failing iplimumab or a BRAF inhibitor, if a BRAF V600 mutation is present.
Ipilimumab has been the gold standard against which everything else was measured, but “this is now expected to change the treatment landscape for melanoma. This is a very high impact trial,” Dr. Suzanne Topalian, director of the melanoma program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the briefing.
The 2011 approval of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as first-line therapy for advanced melanoma was a landmark moment, she said, not only for melanoma because it was the first drug ever to show a survival advantage in a randomized trial, but also for immunotherapy because it was the first checkpoint blocker to show such a benefit.
Results of the KEYSTONE-006 trial, simultaneously published on line (N. Engl. J. Med. 2015. DOI: 10.1056/NEJMoa1503093), prompted the safety monitoring committee to recommend stopping the trial early and allowing ipilimumab patients to receive pembrolizumab.
Lead investigator Dr. Caroline Robert, head of dermatology at Institut Gustave-Roussy in Paris, said in a statement that she hoped the results would accelerate regulatory approval of pembrolizumab in Europe, where the drug is still not on the market.
KEYNOTE-006 included 834 patients with unresectable, ipilimumab-naive, stage III or IV melanoma treated with no more than one previous systemic therapy who were randomly assigned to 10 mg/kg pembrolizumab either every 2 weeks or every 3 weeks or four cycles of 3 mg/kg ipilimumab every 3 weeks, until disease progression or unacceptable toxicity. Treatment response was assessed 12 weeks after randomization and every 6 weeks thereafter per RECIST guideline v1.1 by central review and per immune-related response criteria by investigator review.
Two-thirds of patients were treatment naive, 79% had PD-ligand 1(PD-L1)-positive tumors, and 36% had BRAF V600-mutant tumors.
At the first interim analysis after a median follow-up of 8 months, 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (Hazard ratio, 0.58; P < .001), Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, reported.
The benefit was seen across all prespecified subgroups, including PD-L1-positive and PD-L1-negative tumors.
At the time of the analysis, responses by RECIST were ongoing in 89.4% of patients treated with pembrolizumab every 2 weeks, 96.7% on pembrolizumab every 3 weeks, and 88% given ipilumumab.
The median duration of response was 251 days in the pembrolizumab every 2 weeks-arm, but had not been reached in the other two arms.
There has been no evidence of resistance, and only a small minority, perhaps 5-10% of patients, have escape lesions or progress after response, he said.
At the second interim analysis after a median follow-up of 13.8 months, 1-year overall survival rates were 74% for pembrolizumab every 2 weeks (HR, 0.63; P = .0005), 68.4% for pembrolizumab every 3 weeks (HR, 0.69; P = .0036), and 58.2% for ipilimumab. The survival benefit extended to all subgroups, except the 18% of patients with PD-L1-negative tumors, although sample sizes were small and confidence intervals wide.
Efficacy and tolerability was similar for both pembrolizumab dosing schedules, Dr. Ribas said. Treatment-related grade 3-4 adverse events were lower in the pembrolizumab every 2 and 3 weeks arms than with ipilimumab (13.3% vs. 10.1% vs. 20%), despite exposure to pembrolizumab being nearly 3 times as long (164 days vs. 151.5 days vs. 50 days).
When asked how the findings would change his practice tomorrow, Dr. Ribas said pembrolizumab should be used first line but that he will continue to use ipilimumab, either alone or in combination with a PD-1 inhibitor, because it can give durable responses. The critical unanswered question of what the most effective sequence or combination of checkpoint inhibitors is will take years to answer.
“This is just the start,” he said. “This is amazing that single-agent checkpoint blockade gives these responses in melanoma and as you will see in lung cancer, but the reality is that there’s two-thirds of patients who do not respond and we have to do something about that.”
The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.
Pembrolizumab was superior to ipilimumab, the standard of care, as first-line therapy for advanced melanoma in the phase III KEYNOTE-006 trial.
Pembrolizumab (Keytruda) hit all of its primary survival end points and nearly tripled response rates from 12% with ipilimumab (Yervoy) to 33% in the first frontline head-to-head comparison of the two immune checkpoint inhibitors.
Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37%, compared with ipilimumab, study author Dr. Antoni Ribas reported at the annual meeting of the American Association for Cancer Research.
“We think that this data should change the paradigm of treatment for these patients, and the standard of care should quickly shift to giving PD-1 antibodies,” he said at a press briefing.
Pembrolizumab, a monoclonal antibody that inhibits programmed death receptor-1 (PD-1), is approved as second-line therapy for unresectable or metastatic melanoma after failing iplimumab or a BRAF inhibitor, if a BRAF V600 mutation is present.
Ipilimumab has been the gold standard against which everything else was measured, but “this is now expected to change the treatment landscape for melanoma. This is a very high impact trial,” Dr. Suzanne Topalian, director of the melanoma program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the briefing.
The 2011 approval of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as first-line therapy for advanced melanoma was a landmark moment, she said, not only for melanoma because it was the first drug ever to show a survival advantage in a randomized trial, but also for immunotherapy because it was the first checkpoint blocker to show such a benefit.
Results of the KEYSTONE-006 trial, simultaneously published on line (N. Engl. J. Med. 2015. DOI: 10.1056/NEJMoa1503093), prompted the safety monitoring committee to recommend stopping the trial early and allowing ipilimumab patients to receive pembrolizumab.
Lead investigator Dr. Caroline Robert, head of dermatology at Institut Gustave-Roussy in Paris, said in a statement that she hoped the results would accelerate regulatory approval of pembrolizumab in Europe, where the drug is still not on the market.
KEYNOTE-006 included 834 patients with unresectable, ipilimumab-naive, stage III or IV melanoma treated with no more than one previous systemic therapy who were randomly assigned to 10 mg/kg pembrolizumab either every 2 weeks or every 3 weeks or four cycles of 3 mg/kg ipilimumab every 3 weeks, until disease progression or unacceptable toxicity. Treatment response was assessed 12 weeks after randomization and every 6 weeks thereafter per RECIST guideline v1.1 by central review and per immune-related response criteria by investigator review.
Two-thirds of patients were treatment naive, 79% had PD-ligand 1(PD-L1)-positive tumors, and 36% had BRAF V600-mutant tumors.
At the first interim analysis after a median follow-up of 8 months, 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (Hazard ratio, 0.58; P < .001), Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, reported.
The benefit was seen across all prespecified subgroups, including PD-L1-positive and PD-L1-negative tumors.
At the time of the analysis, responses by RECIST were ongoing in 89.4% of patients treated with pembrolizumab every 2 weeks, 96.7% on pembrolizumab every 3 weeks, and 88% given ipilumumab.
The median duration of response was 251 days in the pembrolizumab every 2 weeks-arm, but had not been reached in the other two arms.
There has been no evidence of resistance, and only a small minority, perhaps 5-10% of patients, have escape lesions or progress after response, he said.
At the second interim analysis after a median follow-up of 13.8 months, 1-year overall survival rates were 74% for pembrolizumab every 2 weeks (HR, 0.63; P = .0005), 68.4% for pembrolizumab every 3 weeks (HR, 0.69; P = .0036), and 58.2% for ipilimumab. The survival benefit extended to all subgroups, except the 18% of patients with PD-L1-negative tumors, although sample sizes were small and confidence intervals wide.
Efficacy and tolerability was similar for both pembrolizumab dosing schedules, Dr. Ribas said. Treatment-related grade 3-4 adverse events were lower in the pembrolizumab every 2 and 3 weeks arms than with ipilimumab (13.3% vs. 10.1% vs. 20%), despite exposure to pembrolizumab being nearly 3 times as long (164 days vs. 151.5 days vs. 50 days).
When asked how the findings would change his practice tomorrow, Dr. Ribas said pembrolizumab should be used first line but that he will continue to use ipilimumab, either alone or in combination with a PD-1 inhibitor, because it can give durable responses. The critical unanswered question of what the most effective sequence or combination of checkpoint inhibitors is will take years to answer.
“This is just the start,” he said. “This is amazing that single-agent checkpoint blockade gives these responses in melanoma and as you will see in lung cancer, but the reality is that there’s two-thirds of patients who do not respond and we have to do something about that.”
The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.
Pembrolizumab was superior to ipilimumab, the standard of care, as first-line therapy for advanced melanoma in the phase III KEYNOTE-006 trial.
Pembrolizumab (Keytruda) hit all of its primary survival end points and nearly tripled response rates from 12% with ipilimumab (Yervoy) to 33% in the first frontline head-to-head comparison of the two immune checkpoint inhibitors.
Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37%, compared with ipilimumab, study author Dr. Antoni Ribas reported at the annual meeting of the American Association for Cancer Research.
“We think that this data should change the paradigm of treatment for these patients, and the standard of care should quickly shift to giving PD-1 antibodies,” he said at a press briefing.
Pembrolizumab, a monoclonal antibody that inhibits programmed death receptor-1 (PD-1), is approved as second-line therapy for unresectable or metastatic melanoma after failing iplimumab or a BRAF inhibitor, if a BRAF V600 mutation is present.
Ipilimumab has been the gold standard against which everything else was measured, but “this is now expected to change the treatment landscape for melanoma. This is a very high impact trial,” Dr. Suzanne Topalian, director of the melanoma program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the briefing.
The 2011 approval of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as first-line therapy for advanced melanoma was a landmark moment, she said, not only for melanoma because it was the first drug ever to show a survival advantage in a randomized trial, but also for immunotherapy because it was the first checkpoint blocker to show such a benefit.
Results of the KEYSTONE-006 trial, simultaneously published on line (N. Engl. J. Med. 2015. DOI: 10.1056/NEJMoa1503093), prompted the safety monitoring committee to recommend stopping the trial early and allowing ipilimumab patients to receive pembrolizumab.
Lead investigator Dr. Caroline Robert, head of dermatology at Institut Gustave-Roussy in Paris, said in a statement that she hoped the results would accelerate regulatory approval of pembrolizumab in Europe, where the drug is still not on the market.
KEYNOTE-006 included 834 patients with unresectable, ipilimumab-naive, stage III or IV melanoma treated with no more than one previous systemic therapy who were randomly assigned to 10 mg/kg pembrolizumab either every 2 weeks or every 3 weeks or four cycles of 3 mg/kg ipilimumab every 3 weeks, until disease progression or unacceptable toxicity. Treatment response was assessed 12 weeks after randomization and every 6 weeks thereafter per RECIST guideline v1.1 by central review and per immune-related response criteria by investigator review.
Two-thirds of patients were treatment naive, 79% had PD-ligand 1(PD-L1)-positive tumors, and 36% had BRAF V600-mutant tumors.
At the first interim analysis after a median follow-up of 8 months, 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (Hazard ratio, 0.58; P < .001), Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, reported.
The benefit was seen across all prespecified subgroups, including PD-L1-positive and PD-L1-negative tumors.
At the time of the analysis, responses by RECIST were ongoing in 89.4% of patients treated with pembrolizumab every 2 weeks, 96.7% on pembrolizumab every 3 weeks, and 88% given ipilumumab.
The median duration of response was 251 days in the pembrolizumab every 2 weeks-arm, but had not been reached in the other two arms.
There has been no evidence of resistance, and only a small minority, perhaps 5-10% of patients, have escape lesions or progress after response, he said.
At the second interim analysis after a median follow-up of 13.8 months, 1-year overall survival rates were 74% for pembrolizumab every 2 weeks (HR, 0.63; P = .0005), 68.4% for pembrolizumab every 3 weeks (HR, 0.69; P = .0036), and 58.2% for ipilimumab. The survival benefit extended to all subgroups, except the 18% of patients with PD-L1-negative tumors, although sample sizes were small and confidence intervals wide.
Efficacy and tolerability was similar for both pembrolizumab dosing schedules, Dr. Ribas said. Treatment-related grade 3-4 adverse events were lower in the pembrolizumab every 2 and 3 weeks arms than with ipilimumab (13.3% vs. 10.1% vs. 20%), despite exposure to pembrolizumab being nearly 3 times as long (164 days vs. 151.5 days vs. 50 days).
When asked how the findings would change his practice tomorrow, Dr. Ribas said pembrolizumab should be used first line but that he will continue to use ipilimumab, either alone or in combination with a PD-1 inhibitor, because it can give durable responses. The critical unanswered question of what the most effective sequence or combination of checkpoint inhibitors is will take years to answer.
“This is just the start,” he said. “This is amazing that single-agent checkpoint blockade gives these responses in melanoma and as you will see in lung cancer, but the reality is that there’s two-thirds of patients who do not respond and we have to do something about that.”
The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.
FROM THE AACR ANNUAL MEETING
Key clinical point: Pembrolizumab was superior to ipilimumab, the standard of care, for first-line treatment of advanced melanoma.
Major finding: Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37% compared with ipilimumab.
Data source: Phase III, randomized, open-label trial in 834 patients with advanced melanoma with no more than one prior systemic therapy.
Disclosures: The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol-Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.
Sleep disorders in patients with cancer
Sleep disturbances are common among patients with cancer for many reasons. Sleep problems can be present at any stage during treatment for cancer and in some patients, sleep disturbance may be the presenting symptoms that lead to the diagnosis of some types of cancer. Poor sleep impairs quality of life In people with cancer, but most do not specifically complain of sleep problems unless they are explicitly asked. Insomnia and fatigue are most common sleep disorders in this cohort, although primary sleep disorders, including obstructive sleep apnea and restless legs syndrome, which are common in the general population, have not been carefully studied in the oncology setting despite significant their impairment of quality of life.
Click on the PDF icon at the top of this introduction to read the full article.
disorder
Sleep disturbances are common among patients with cancer for many reasons. Sleep problems can be present at any stage during treatment for cancer and in some patients, sleep disturbance may be the presenting symptoms that lead to the diagnosis of some types of cancer. Poor sleep impairs quality of life In people with cancer, but most do not specifically complain of sleep problems unless they are explicitly asked. Insomnia and fatigue are most common sleep disorders in this cohort, although primary sleep disorders, including obstructive sleep apnea and restless legs syndrome, which are common in the general population, have not been carefully studied in the oncology setting despite significant their impairment of quality of life.
Click on the PDF icon at the top of this introduction to read the full article.
Sleep disturbances are common among patients with cancer for many reasons. Sleep problems can be present at any stage during treatment for cancer and in some patients, sleep disturbance may be the presenting symptoms that lead to the diagnosis of some types of cancer. Poor sleep impairs quality of life In people with cancer, but most do not specifically complain of sleep problems unless they are explicitly asked. Insomnia and fatigue are most common sleep disorders in this cohort, although primary sleep disorders, including obstructive sleep apnea and restless legs syndrome, which are common in the general population, have not been carefully studied in the oncology setting despite significant their impairment of quality of life.
Click on the PDF icon at the top of this introduction to read the full article.
disorder
disorder
Update on Melanoma Guidelines: Report From the AAD Meeting
Melanoma was an important topic at multiple sessions of the 73rd Annual Meeting of the American Academy of Dermatology (AAD) in San Francisco, California. Dr. Susan M. Swetter reviews the AAD and National Comprehensive Cancer Network recommendations for biopsy of pigmented suspicious lesions. She also discusses when sentinel lymph node biopsies are recommended and factors that would indicate a patient needs a sentinel lymph node biopsy. Dr. Swetter also outlines surgical margins for melanoma and emphasizes that these are clinical margins taken at the time of surgery, not histologic margins. She concludes with a review of the melanoma subtype lentigo maligna.
Melanoma was an important topic at multiple sessions of the 73rd Annual Meeting of the American Academy of Dermatology (AAD) in San Francisco, California. Dr. Susan M. Swetter reviews the AAD and National Comprehensive Cancer Network recommendations for biopsy of pigmented suspicious lesions. She also discusses when sentinel lymph node biopsies are recommended and factors that would indicate a patient needs a sentinel lymph node biopsy. Dr. Swetter also outlines surgical margins for melanoma and emphasizes that these are clinical margins taken at the time of surgery, not histologic margins. She concludes with a review of the melanoma subtype lentigo maligna.
Melanoma was an important topic at multiple sessions of the 73rd Annual Meeting of the American Academy of Dermatology (AAD) in San Francisco, California. Dr. Susan M. Swetter reviews the AAD and National Comprehensive Cancer Network recommendations for biopsy of pigmented suspicious lesions. She also discusses when sentinel lymph node biopsies are recommended and factors that would indicate a patient needs a sentinel lymph node biopsy. Dr. Swetter also outlines surgical margins for melanoma and emphasizes that these are clinical margins taken at the time of surgery, not histologic margins. She concludes with a review of the melanoma subtype lentigo maligna.
New melanoma therapies may break the bank
HOUSTON – Newer systemic therapies for metastatic malignant melanoma have resulted in significant gains in survival, but at a cost that may be unsustainable in the near future, according to Dr. Jeffrey E. Gershenwald.
Up to one-half of all expenses related to the treatment of malignant melanoma are accounted for by the care of patients with advanced disease, yet patients with distant metastases (stage IV disease) account for only about 2% of all patients, said Dr. Gershenwald, professor of surgical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.
“How best can we achieve the right therapy for the right patient at the right time, and as we learn more and more about some of the therapies, particularly in melanoma, for the right length of time? We can’t really afford to give treatments in perpetuity, so we need to know how long they actually need to be delivered in order to have optimal value for the patient,” he said at the annual Society of Surgical Oncology Cancer Symposium.
Over the last 3 decades, and particularly over the last 5 years, there have been tremendous forward strides in therapy. In 1975, when dacarbazine became the standard of care for metastatic melanoma, it was associated with response rates of only about 6%-15%, durable responses in only 5%-15% of patients, and a median overall survival of about 6-9 months, Dr. Gershenwald reported.
Treatment toxicities, but not response rates, increased with the introduction of interleukin-2 in 1998, which for want of a better drug became the new preferred treatment.
But with the introduction of new systemic therapies, such as immune checkpoint inhibitors (ipilimumab [Yervoy], nivolumab [Opdivo], and pembrolizumab [Keytruda]) and targeted agents (vemurafenib [Zelboraf], dabrafenib [Tafinlar], and trametinib [Mekinist]), response rates have soared, resulting in an improvement in 1-year survival rates from about 30% to 35% in 1970 to as high as 80% in clinical trials in 2014.
Increased survival, higher costs
Dr. Gershenwald pointed to a recently published cost-effectiveness analysis of treatment strategies for BRAF-mutated metastatic melanoma. In it, the authors noted that vemurafenib costs $13,000 per month, translating into $207,000 for a patient with median survival. Patients for whom vemurafenib fails are often put on ipilimumab, at $150,000 per course.
The authors calculated that the incremental cost-effectiveness ratio (ICER) for vemurafenib compared with dacarbazine was nearly $354,993 per quality-adjusted life-year (QALY) gained, a figure that is more than threefold higher than widely accepted thresholds for cost-effective treatment ($50,000-$100,000 per QALY gained).
The ICER for firstline vemurafenib followed by ipilimumab was $158,139, still well above the accepted limits.
The authors of the cost analysis noted that the treatments could become cost effective if drug prices were to drop significantly, or if clinical trials could establish whether it was possible to achieve a durable response without continued therapy.
Going forward, clinicians will need to consider disease burden, including both the extent and growth rate of the disease, as well as the risk of recurrence, in deciding whether to use adjuvant therapies, Dr. Gershenwald said.
In addition, clinical choices will be based on disease biology, predictors of response (although few such predictors currently exist), the likelihood of resistance, and drug toxicities, quality of life, and ease of administration, he said.
Dr. Gershenwald disclosed serving on a Merck advisory board.
HOUSTON – Newer systemic therapies for metastatic malignant melanoma have resulted in significant gains in survival, but at a cost that may be unsustainable in the near future, according to Dr. Jeffrey E. Gershenwald.
Up to one-half of all expenses related to the treatment of malignant melanoma are accounted for by the care of patients with advanced disease, yet patients with distant metastases (stage IV disease) account for only about 2% of all patients, said Dr. Gershenwald, professor of surgical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.
“How best can we achieve the right therapy for the right patient at the right time, and as we learn more and more about some of the therapies, particularly in melanoma, for the right length of time? We can’t really afford to give treatments in perpetuity, so we need to know how long they actually need to be delivered in order to have optimal value for the patient,” he said at the annual Society of Surgical Oncology Cancer Symposium.
Over the last 3 decades, and particularly over the last 5 years, there have been tremendous forward strides in therapy. In 1975, when dacarbazine became the standard of care for metastatic melanoma, it was associated with response rates of only about 6%-15%, durable responses in only 5%-15% of patients, and a median overall survival of about 6-9 months, Dr. Gershenwald reported.
Treatment toxicities, but not response rates, increased with the introduction of interleukin-2 in 1998, which for want of a better drug became the new preferred treatment.
But with the introduction of new systemic therapies, such as immune checkpoint inhibitors (ipilimumab [Yervoy], nivolumab [Opdivo], and pembrolizumab [Keytruda]) and targeted agents (vemurafenib [Zelboraf], dabrafenib [Tafinlar], and trametinib [Mekinist]), response rates have soared, resulting in an improvement in 1-year survival rates from about 30% to 35% in 1970 to as high as 80% in clinical trials in 2014.
Increased survival, higher costs
Dr. Gershenwald pointed to a recently published cost-effectiveness analysis of treatment strategies for BRAF-mutated metastatic melanoma. In it, the authors noted that vemurafenib costs $13,000 per month, translating into $207,000 for a patient with median survival. Patients for whom vemurafenib fails are often put on ipilimumab, at $150,000 per course.
The authors calculated that the incremental cost-effectiveness ratio (ICER) for vemurafenib compared with dacarbazine was nearly $354,993 per quality-adjusted life-year (QALY) gained, a figure that is more than threefold higher than widely accepted thresholds for cost-effective treatment ($50,000-$100,000 per QALY gained).
The ICER for firstline vemurafenib followed by ipilimumab was $158,139, still well above the accepted limits.
The authors of the cost analysis noted that the treatments could become cost effective if drug prices were to drop significantly, or if clinical trials could establish whether it was possible to achieve a durable response without continued therapy.
Going forward, clinicians will need to consider disease burden, including both the extent and growth rate of the disease, as well as the risk of recurrence, in deciding whether to use adjuvant therapies, Dr. Gershenwald said.
In addition, clinical choices will be based on disease biology, predictors of response (although few such predictors currently exist), the likelihood of resistance, and drug toxicities, quality of life, and ease of administration, he said.
Dr. Gershenwald disclosed serving on a Merck advisory board.
HOUSTON – Newer systemic therapies for metastatic malignant melanoma have resulted in significant gains in survival, but at a cost that may be unsustainable in the near future, according to Dr. Jeffrey E. Gershenwald.
Up to one-half of all expenses related to the treatment of malignant melanoma are accounted for by the care of patients with advanced disease, yet patients with distant metastases (stage IV disease) account for only about 2% of all patients, said Dr. Gershenwald, professor of surgical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.
“How best can we achieve the right therapy for the right patient at the right time, and as we learn more and more about some of the therapies, particularly in melanoma, for the right length of time? We can’t really afford to give treatments in perpetuity, so we need to know how long they actually need to be delivered in order to have optimal value for the patient,” he said at the annual Society of Surgical Oncology Cancer Symposium.
Over the last 3 decades, and particularly over the last 5 years, there have been tremendous forward strides in therapy. In 1975, when dacarbazine became the standard of care for metastatic melanoma, it was associated with response rates of only about 6%-15%, durable responses in only 5%-15% of patients, and a median overall survival of about 6-9 months, Dr. Gershenwald reported.
Treatment toxicities, but not response rates, increased with the introduction of interleukin-2 in 1998, which for want of a better drug became the new preferred treatment.
But with the introduction of new systemic therapies, such as immune checkpoint inhibitors (ipilimumab [Yervoy], nivolumab [Opdivo], and pembrolizumab [Keytruda]) and targeted agents (vemurafenib [Zelboraf], dabrafenib [Tafinlar], and trametinib [Mekinist]), response rates have soared, resulting in an improvement in 1-year survival rates from about 30% to 35% in 1970 to as high as 80% in clinical trials in 2014.
Increased survival, higher costs
Dr. Gershenwald pointed to a recently published cost-effectiveness analysis of treatment strategies for BRAF-mutated metastatic melanoma. In it, the authors noted that vemurafenib costs $13,000 per month, translating into $207,000 for a patient with median survival. Patients for whom vemurafenib fails are often put on ipilimumab, at $150,000 per course.
The authors calculated that the incremental cost-effectiveness ratio (ICER) for vemurafenib compared with dacarbazine was nearly $354,993 per quality-adjusted life-year (QALY) gained, a figure that is more than threefold higher than widely accepted thresholds for cost-effective treatment ($50,000-$100,000 per QALY gained).
The ICER for firstline vemurafenib followed by ipilimumab was $158,139, still well above the accepted limits.
The authors of the cost analysis noted that the treatments could become cost effective if drug prices were to drop significantly, or if clinical trials could establish whether it was possible to achieve a durable response without continued therapy.
Going forward, clinicians will need to consider disease burden, including both the extent and growth rate of the disease, as well as the risk of recurrence, in deciding whether to use adjuvant therapies, Dr. Gershenwald said.
In addition, clinical choices will be based on disease biology, predictors of response (although few such predictors currently exist), the likelihood of resistance, and drug toxicities, quality of life, and ease of administration, he said.
Dr. Gershenwald disclosed serving on a Merck advisory board.
AT SSO 2015
Key clinical point: Immunotherapies and targeted agents for metastatic melanoma are effective but very costly.
Major finding: The incremental cost-effectiveness ratio for vemurafenib, compared with dacarbazine, was nearly $354,993 per quality-adjusted life-year gained.
Data source: A review of data on the efficacy and costs of therapy for metastatic malignant melanoma.
Disclosures: Dr. Gershenwald disclosed serving on a Merck advisory board.
Melanoma incidence drops for U.S. children and teens
The incidence of melanoma among American children and teens decreased by approximately 12% from 2004 to 2010, with the decline most notable for adolescents. The findings were published online in the Journal of Pediatrics.
In a review of data from the period of 2000-2010, Dr. Laura Campbell of Stanford (Calif.) University and her colleagues at Case Western Reserve University in Cleveland found an overall reduction in melanoma diagnoses of 11.58% per year for the period of 2004-2010 (J. Pediatr. 2015 [doi: 10.1016/j.jpeds. 2015.02.050]).
The study was conducted at Case Western Reserve University, and the researchers used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER-18) registry to examine trends in the incidence of pediatric melanoma.
Of note, the number of new melanoma cases decreased significantly (approximately 11%) among 15- to19-year-olds between 2003 and 2010. In addition, the overall incidence of melanoma decreased significantly (7%) among boys between 2000 and 2010.
The data revealed significant decreases for the number of new cases of melanoma on the trunk (15% per year from 2004 to 2010) and upper extremities (5% from 2000 to 2010).
Dr. Campbell and her colleagues determined that a melanoma diagnosis was equally likely for male and female patients, and was more common in older than in younger patients. White patients had by far the greatest incidence of melanoma, with 97% of the overall diagnoses; 90% of the cases were in non-Hispanic whites. Superficial spreading melanoma was the most common type of melanoma, at 31%, though nodular histology was seen almost as frequently in the 0- to 9-year-olds. This younger group was more likely to have thicker tumors, ulceration, lymph node involvement, and distant metastases.
Drawing on this large registry allowed researchers more confidence that they were identifying true trends in melanoma incidence, Dr. Campbell noted.
The reasons for this decrease, which stands in contrast to earlier data showing increased incidence rates of pediatric melanoma, were not examined in this study. However, Dr. Campbell drew on these earlier studies, as well as some international studies, to identify the potential contribution of public health campaigns advocating sun protection. These campaigns began in the 1990s in the United States, and would have benefited the 15- to 19-year olds in the SEER-18 data, in whom melanoma incidence decreased beginning in 2003. Some Swedish and Australian studies showing decreased melanoma cases were confounded by an immigration-driven decrease in the highest risk light-skinned population, noted Dr. Campbell; however, the quality of the SEER-18 data allowed researchers to account for this variable, she said.
Although the widespread adoption of sun-protective behaviors (wearing hats and protective clothing, using sunscreen appropriately, and avoiding midday sun exposure) may have accounted for some of the reduction in pediatric melanomas, other societal changes may have been at play.
“We hypothesize that there has been a shift in youth participating increasingly in indoor activities, such as television/electronic devices, which may be decreasing their UVR exposure,” Dr. Campbell said.
The incidence of melanoma among American children and teens decreased by approximately 12% from 2004 to 2010, with the decline most notable for adolescents. The findings were published online in the Journal of Pediatrics.
In a review of data from the period of 2000-2010, Dr. Laura Campbell of Stanford (Calif.) University and her colleagues at Case Western Reserve University in Cleveland found an overall reduction in melanoma diagnoses of 11.58% per year for the period of 2004-2010 (J. Pediatr. 2015 [doi: 10.1016/j.jpeds. 2015.02.050]).
The study was conducted at Case Western Reserve University, and the researchers used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER-18) registry to examine trends in the incidence of pediatric melanoma.
Of note, the number of new melanoma cases decreased significantly (approximately 11%) among 15- to19-year-olds between 2003 and 2010. In addition, the overall incidence of melanoma decreased significantly (7%) among boys between 2000 and 2010.
The data revealed significant decreases for the number of new cases of melanoma on the trunk (15% per year from 2004 to 2010) and upper extremities (5% from 2000 to 2010).
Dr. Campbell and her colleagues determined that a melanoma diagnosis was equally likely for male and female patients, and was more common in older than in younger patients. White patients had by far the greatest incidence of melanoma, with 97% of the overall diagnoses; 90% of the cases were in non-Hispanic whites. Superficial spreading melanoma was the most common type of melanoma, at 31%, though nodular histology was seen almost as frequently in the 0- to 9-year-olds. This younger group was more likely to have thicker tumors, ulceration, lymph node involvement, and distant metastases.
Drawing on this large registry allowed researchers more confidence that they were identifying true trends in melanoma incidence, Dr. Campbell noted.
The reasons for this decrease, which stands in contrast to earlier data showing increased incidence rates of pediatric melanoma, were not examined in this study. However, Dr. Campbell drew on these earlier studies, as well as some international studies, to identify the potential contribution of public health campaigns advocating sun protection. These campaigns began in the 1990s in the United States, and would have benefited the 15- to 19-year olds in the SEER-18 data, in whom melanoma incidence decreased beginning in 2003. Some Swedish and Australian studies showing decreased melanoma cases were confounded by an immigration-driven decrease in the highest risk light-skinned population, noted Dr. Campbell; however, the quality of the SEER-18 data allowed researchers to account for this variable, she said.
Although the widespread adoption of sun-protective behaviors (wearing hats and protective clothing, using sunscreen appropriately, and avoiding midday sun exposure) may have accounted for some of the reduction in pediatric melanomas, other societal changes may have been at play.
“We hypothesize that there has been a shift in youth participating increasingly in indoor activities, such as television/electronic devices, which may be decreasing their UVR exposure,” Dr. Campbell said.
The incidence of melanoma among American children and teens decreased by approximately 12% from 2004 to 2010, with the decline most notable for adolescents. The findings were published online in the Journal of Pediatrics.
In a review of data from the period of 2000-2010, Dr. Laura Campbell of Stanford (Calif.) University and her colleagues at Case Western Reserve University in Cleveland found an overall reduction in melanoma diagnoses of 11.58% per year for the period of 2004-2010 (J. Pediatr. 2015 [doi: 10.1016/j.jpeds. 2015.02.050]).
The study was conducted at Case Western Reserve University, and the researchers used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER-18) registry to examine trends in the incidence of pediatric melanoma.
Of note, the number of new melanoma cases decreased significantly (approximately 11%) among 15- to19-year-olds between 2003 and 2010. In addition, the overall incidence of melanoma decreased significantly (7%) among boys between 2000 and 2010.
The data revealed significant decreases for the number of new cases of melanoma on the trunk (15% per year from 2004 to 2010) and upper extremities (5% from 2000 to 2010).
Dr. Campbell and her colleagues determined that a melanoma diagnosis was equally likely for male and female patients, and was more common in older than in younger patients. White patients had by far the greatest incidence of melanoma, with 97% of the overall diagnoses; 90% of the cases were in non-Hispanic whites. Superficial spreading melanoma was the most common type of melanoma, at 31%, though nodular histology was seen almost as frequently in the 0- to 9-year-olds. This younger group was more likely to have thicker tumors, ulceration, lymph node involvement, and distant metastases.
Drawing on this large registry allowed researchers more confidence that they were identifying true trends in melanoma incidence, Dr. Campbell noted.
The reasons for this decrease, which stands in contrast to earlier data showing increased incidence rates of pediatric melanoma, were not examined in this study. However, Dr. Campbell drew on these earlier studies, as well as some international studies, to identify the potential contribution of public health campaigns advocating sun protection. These campaigns began in the 1990s in the United States, and would have benefited the 15- to 19-year olds in the SEER-18 data, in whom melanoma incidence decreased beginning in 2003. Some Swedish and Australian studies showing decreased melanoma cases were confounded by an immigration-driven decrease in the highest risk light-skinned population, noted Dr. Campbell; however, the quality of the SEER-18 data allowed researchers to account for this variable, she said.
Although the widespread adoption of sun-protective behaviors (wearing hats and protective clothing, using sunscreen appropriately, and avoiding midday sun exposure) may have accounted for some of the reduction in pediatric melanomas, other societal changes may have been at play.
“We hypothesize that there has been a shift in youth participating increasingly in indoor activities, such as television/electronic devices, which may be decreasing their UVR exposure,” Dr. Campbell said.
FROM THE JOURNAL OF PEDIATRICS
Key clinical point: The overall incidence of melanoma in American children and teens decreased from 2004 to 2010.
Major finding: Researchers identified 1,185 patients younger than 20 years of age with melanoma diagnoses during the period of 2000-2010, and noted a significant decrease of 11.58% per year in melanoma diagnoses from 2004 to 2010.
Data source: The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER-18) registry for 2000-2010.
Disclosures: The authors reported no conflicts of interest.
Medicare beneficiaries often experience delays before melanoma surgery
About 22% of Medicare beneficiaries experience a delay of longer than 1.5 months between melanoma diagnosis and surgery, according to findings from a retrospective cohort study.
Of 32,501 melanoma cases from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, about 77.7% underwent excision within 1.5 months of biopsy, and of those who underwent excision after 1.5 months, 8.1% experienced a delay of more than 3 months. The risk-adjusted incidence of surgical delay longer than 1.5 months was significantly increased for those aged 85 years and older, compared with those aged 65 years and younger (odds ratio, 1.28), for those with a prior melanoma (OR, 1.20), and for those with three or more Elixhauser comorbidities (OR, 1.18), Dr. Jason P. Lott of Yale University, New Haven, Conn. and his colleagues reported online April 8 in JAMA Dermatology.
The lowest risk of delay was among those who underwent biopsy and excision by dermatologists (probability, 16.5%), and the highest was among those with a biopsy performed by a nondermatologist and excised by a primary care physician (probability, 30.7%), the investigators said (JAMA Dermatol. 2015 April 8 [doi:10.1001/jamadermatol.2015.119]).
The study, which provides the first population-based estimates of melanoma surgery delay among Medicare beneficiaries, and which shows that delays are relatively common, highlights “opportunities for quality improvement in dermatologic care and suggests that efforts to minimize the delay of surgery for melanoma might focus on increased access to dermatologic expertise and enhanced coordination of care among different specialists,” the investigators concluded.
This study was supported by the Robert Wood Johnson Foundation and the P30 Cancer Center Support Grant at the Yale Comprehensive Cancer Center.
Dr. Lott reported having no disclosures. Coauthor Dr. Cary P. Gross received research grant support from Johnson & Johnson, Merck, and 21st Century Oncology.
About 22% of Medicare beneficiaries experience a delay of longer than 1.5 months between melanoma diagnosis and surgery, according to findings from a retrospective cohort study.
Of 32,501 melanoma cases from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, about 77.7% underwent excision within 1.5 months of biopsy, and of those who underwent excision after 1.5 months, 8.1% experienced a delay of more than 3 months. The risk-adjusted incidence of surgical delay longer than 1.5 months was significantly increased for those aged 85 years and older, compared with those aged 65 years and younger (odds ratio, 1.28), for those with a prior melanoma (OR, 1.20), and for those with three or more Elixhauser comorbidities (OR, 1.18), Dr. Jason P. Lott of Yale University, New Haven, Conn. and his colleagues reported online April 8 in JAMA Dermatology.
The lowest risk of delay was among those who underwent biopsy and excision by dermatologists (probability, 16.5%), and the highest was among those with a biopsy performed by a nondermatologist and excised by a primary care physician (probability, 30.7%), the investigators said (JAMA Dermatol. 2015 April 8 [doi:10.1001/jamadermatol.2015.119]).
The study, which provides the first population-based estimates of melanoma surgery delay among Medicare beneficiaries, and which shows that delays are relatively common, highlights “opportunities for quality improvement in dermatologic care and suggests that efforts to minimize the delay of surgery for melanoma might focus on increased access to dermatologic expertise and enhanced coordination of care among different specialists,” the investigators concluded.
This study was supported by the Robert Wood Johnson Foundation and the P30 Cancer Center Support Grant at the Yale Comprehensive Cancer Center.
Dr. Lott reported having no disclosures. Coauthor Dr. Cary P. Gross received research grant support from Johnson & Johnson, Merck, and 21st Century Oncology.
About 22% of Medicare beneficiaries experience a delay of longer than 1.5 months between melanoma diagnosis and surgery, according to findings from a retrospective cohort study.
Of 32,501 melanoma cases from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, about 77.7% underwent excision within 1.5 months of biopsy, and of those who underwent excision after 1.5 months, 8.1% experienced a delay of more than 3 months. The risk-adjusted incidence of surgical delay longer than 1.5 months was significantly increased for those aged 85 years and older, compared with those aged 65 years and younger (odds ratio, 1.28), for those with a prior melanoma (OR, 1.20), and for those with three or more Elixhauser comorbidities (OR, 1.18), Dr. Jason P. Lott of Yale University, New Haven, Conn. and his colleagues reported online April 8 in JAMA Dermatology.
The lowest risk of delay was among those who underwent biopsy and excision by dermatologists (probability, 16.5%), and the highest was among those with a biopsy performed by a nondermatologist and excised by a primary care physician (probability, 30.7%), the investigators said (JAMA Dermatol. 2015 April 8 [doi:10.1001/jamadermatol.2015.119]).
The study, which provides the first population-based estimates of melanoma surgery delay among Medicare beneficiaries, and which shows that delays are relatively common, highlights “opportunities for quality improvement in dermatologic care and suggests that efforts to minimize the delay of surgery for melanoma might focus on increased access to dermatologic expertise and enhanced coordination of care among different specialists,” the investigators concluded.
This study was supported by the Robert Wood Johnson Foundation and the P30 Cancer Center Support Grant at the Yale Comprehensive Cancer Center.
Dr. Lott reported having no disclosures. Coauthor Dr. Cary P. Gross received research grant support from Johnson & Johnson, Merck, and 21st Century Oncology.
FROM JAMA DERMATOLOGY
Key clinical point: Opportunities exist for improving the timely delivery of melanoma surgery for Medicare beneficiaries.
Major finding: A total of 22% of Medicare beneficiaries had a delay of more than 1.5 months between melanoma diagnosis and surgery.
Data source: A retrospective cohort study involving 32,501 melanoma cases.
Disclosures:This study was supported by the Robert Wood Johnson Foundation and the P30 Cancer Center Support Grant at the Yale Comprehensive Cancer Center. Dr. Lott reported having no disclosures. Coauthor Dr. Cary P. Gross received research grant support from Johnson & Johnson, Merck, and 21st Century Oncology.
Worse melanoma outcomes found in pregnant women
SAN FRANCISCO – Pregnancy increases the risk of poor outcomes in melanoma, according to a review of melanoma cases at the Cleveland Clinic.
The effect of pregnancy on melanoma has been debated for more than a decade. Some studies have found evidence of worse outcomes, but others have not. That prompted Dr. Natasha Mesinkovska, a dermatologist at the clinic, and her colleagues to review their own melanoma outcomes over the past 20 years. They compared 49 women who were pregnant or within a year of pregnancy at diagnosis, with 418 women of childbearing age who were not pregnant. All the patients had at least 2 years follow-up.
Mortality (20% vs. 10.3%; P = .06); recurrence (12.5% vs. 1.4%; P < .001); metastasis (25% vs. 12.7%; P = .03); and the use of radiation and chemotherapy were all more common in the pregnancy group. On logistic regression, women who were pregnant or recently pregnant at the time of melanoma diagnosis were 5.1 times more likely to die of the disease than those who weren’t (P = .03), Dr. Mesinkovska reported at the annual meeting of the American Academy of Dermatology.
The findings prompted the investigators to compare histologic specimens from 17 pregnant and 14 nonpregnant women to find an explanation.
Pregnancy melanomas had reduced PD-1 [programmed cell death] expression (18.3 vs. 45 cells per high-power field [hpf]); decreased CD-3 [cluster of differentiation 3] (191.7 vs. 265.7 cells/hpf); and increased CD-3/PD-1 ratios (57.4 vs. 8.3).
The findings were statistically significant and may have treatment implications for the use in recently pregnant women of antibodies against PD-1 cell-surface receptors, a class of biologics that include nivolumab and pembrolizumab, both approved in 2014 for advanced melanoma. With reduced expression of PD-1, tumors arising around pregnancy might not be as sensitive to such agents.
Labeling for both biologics, however, note the risk of fetal harm, and advise the use of effective contraception while on the agents and for several months after their discontinuation. Both agents should also be discontinued during breastfeeding.
“Immune ignorance may predominate in melanoma specimens in pregnancy. Most novel melanoma therapies target immune modulation. There’s a need in some pregnant women for neoadjuvant treatment prior to immunotherapy to convert them to an inflamed phenotype,” Dr. Mesinkovska said.
Dr. Mesinkovska said she has no relevant financial disclosures.
SAN FRANCISCO – Pregnancy increases the risk of poor outcomes in melanoma, according to a review of melanoma cases at the Cleveland Clinic.
The effect of pregnancy on melanoma has been debated for more than a decade. Some studies have found evidence of worse outcomes, but others have not. That prompted Dr. Natasha Mesinkovska, a dermatologist at the clinic, and her colleagues to review their own melanoma outcomes over the past 20 years. They compared 49 women who were pregnant or within a year of pregnancy at diagnosis, with 418 women of childbearing age who were not pregnant. All the patients had at least 2 years follow-up.
Mortality (20% vs. 10.3%; P = .06); recurrence (12.5% vs. 1.4%; P < .001); metastasis (25% vs. 12.7%; P = .03); and the use of radiation and chemotherapy were all more common in the pregnancy group. On logistic regression, women who were pregnant or recently pregnant at the time of melanoma diagnosis were 5.1 times more likely to die of the disease than those who weren’t (P = .03), Dr. Mesinkovska reported at the annual meeting of the American Academy of Dermatology.
The findings prompted the investigators to compare histologic specimens from 17 pregnant and 14 nonpregnant women to find an explanation.
Pregnancy melanomas had reduced PD-1 [programmed cell death] expression (18.3 vs. 45 cells per high-power field [hpf]); decreased CD-3 [cluster of differentiation 3] (191.7 vs. 265.7 cells/hpf); and increased CD-3/PD-1 ratios (57.4 vs. 8.3).
The findings were statistically significant and may have treatment implications for the use in recently pregnant women of antibodies against PD-1 cell-surface receptors, a class of biologics that include nivolumab and pembrolizumab, both approved in 2014 for advanced melanoma. With reduced expression of PD-1, tumors arising around pregnancy might not be as sensitive to such agents.
Labeling for both biologics, however, note the risk of fetal harm, and advise the use of effective contraception while on the agents and for several months after their discontinuation. Both agents should also be discontinued during breastfeeding.
“Immune ignorance may predominate in melanoma specimens in pregnancy. Most novel melanoma therapies target immune modulation. There’s a need in some pregnant women for neoadjuvant treatment prior to immunotherapy to convert them to an inflamed phenotype,” Dr. Mesinkovska said.
Dr. Mesinkovska said she has no relevant financial disclosures.
SAN FRANCISCO – Pregnancy increases the risk of poor outcomes in melanoma, according to a review of melanoma cases at the Cleveland Clinic.
The effect of pregnancy on melanoma has been debated for more than a decade. Some studies have found evidence of worse outcomes, but others have not. That prompted Dr. Natasha Mesinkovska, a dermatologist at the clinic, and her colleagues to review their own melanoma outcomes over the past 20 years. They compared 49 women who were pregnant or within a year of pregnancy at diagnosis, with 418 women of childbearing age who were not pregnant. All the patients had at least 2 years follow-up.
Mortality (20% vs. 10.3%; P = .06); recurrence (12.5% vs. 1.4%; P < .001); metastasis (25% vs. 12.7%; P = .03); and the use of radiation and chemotherapy were all more common in the pregnancy group. On logistic regression, women who were pregnant or recently pregnant at the time of melanoma diagnosis were 5.1 times more likely to die of the disease than those who weren’t (P = .03), Dr. Mesinkovska reported at the annual meeting of the American Academy of Dermatology.
The findings prompted the investigators to compare histologic specimens from 17 pregnant and 14 nonpregnant women to find an explanation.
Pregnancy melanomas had reduced PD-1 [programmed cell death] expression (18.3 vs. 45 cells per high-power field [hpf]); decreased CD-3 [cluster of differentiation 3] (191.7 vs. 265.7 cells/hpf); and increased CD-3/PD-1 ratios (57.4 vs. 8.3).
The findings were statistically significant and may have treatment implications for the use in recently pregnant women of antibodies against PD-1 cell-surface receptors, a class of biologics that include nivolumab and pembrolizumab, both approved in 2014 for advanced melanoma. With reduced expression of PD-1, tumors arising around pregnancy might not be as sensitive to such agents.
Labeling for both biologics, however, note the risk of fetal harm, and advise the use of effective contraception while on the agents and for several months after their discontinuation. Both agents should also be discontinued during breastfeeding.
“Immune ignorance may predominate in melanoma specimens in pregnancy. Most novel melanoma therapies target immune modulation. There’s a need in some pregnant women for neoadjuvant treatment prior to immunotherapy to convert them to an inflamed phenotype,” Dr. Mesinkovska said.
Dr. Mesinkovska said she has no relevant financial disclosures.
AT AAD 2015
Key clinical point: Heighten melanoma surveillance in and around pregnancy, and treat lesions aggressively.
Major finding: Melanoma mortality (20% vs. 10.3%; P = .06); recurrence (12.5% vs. 1.4%; P < .001); and metastasis (25% vs. 12.7%; P = .03) were higher in 49 women diagnosed with melanoma while pregnant or within a year of pregnancy, compared with 418 women of childbearing age who were not pregnant.
Data source: Review of 467 melanoma cases at the Cleveland Clinic.
Disclosures: The lead investigator has no relevant financial disclosures.
Metastatic melanoma masquerading as disseminated sporotrichosis
Click on the PDF icon at the top of this introduction to read the full article.
Click on the PDF icon at the top of this introduction to read the full article.
Click on the PDF icon at the top of this introduction to read the full article.
Avoid voriconazole in transplant patients at risk for skin cancer
SAN FRANCISCO – Voriconazole increased the risk of squamous cell carcinoma by 73% in a review of 455 lung transplant patients at the University of California, San Francisco.
The increase was for any exposure to the drug after transplant (adjusted hazard ratio, 1.73; P = .03). The investigators also found that each additional 30-day exposure at 200 mg of voriconazole twice daily increased the risk of squamous cell carcinoma (SCC) by 3.0% (HR, 1.03; P < .001). The results were adjusted for age at transplant, sex, and race. Overall, SCC risk was highest among white men aged 50 years or older at the time of transplant.
Although voriconazole did protect against posttransplant Aspergillus colonization (aHR, 0.50; P < .001), it did not reduce the risk of invasive aspergillosis. The drug reduced all-cause mortality only among colonized subjects (aHR, 0.34; P = .03), and offered no mortality benefit among those who were not colonized.
There was no difference in all-cause mortality between patients who had any exposure to voriconazole and those who did not, “but we actually found a 2% increased risk of death for each 1 month on the medication. Patients who weren’t colonized were the ones contributing to this increased risk of death,” said lead investigator Matthew Mansh, now a medical student at Stanford (Calif.) University.
There was no increased risk of SCC with alternative antifungals, including inhaled amphotericin and posaconazole. These alternatives should be considered instead of voriconazole in people at higher risk for skin cancer after lung transplants, according to the study, Mr. Mansh noted.
Voriconazole, which is widely used for antifungal prophylaxis after solid organ transplants, has been linked to skin cancer. The reason for the carcinogenic effect is not known; researchers are working to unravel the molecular mechanisms.
“Physicians should be cautious when using voriconazole in the care of transplant recipients. If you see a patient who is developing phototoxicity” with voriconazole, “and if they don’t have evidence of Aspergillus colonization, you may want to limit exposure to high doses of this drug or suggest an alternative,” Mr. Mansh said.
“We have now demonstrated that the alternatives “don’t carry this increased risk of cutaneous SCC,” Mr. Mansh said at the American Academy of Dermatology annual meeting.
The mean age of the study patients at transplant was 52 years, and the majority of patients were white; slightly more than half were men. Most had bilateral lung transplants, with pulmonary fibrosis at the leading indication.
Voriconazole was used in 85% of the patients for an average of 10 months. A quarter of voriconazole patients developed SCC within 5 years of transplant, and 43% within 10 years. Among patients who did not receive the drug, 15% developed SCC within 5 years of transplant, and 28% developed SCC within 10 years of transplant.
“The benefit of voriconazole in terms of death was limited to patients with evidence of Aspergillus colonization, and it wasn’t dose dependent. Patients who had a higher cumulative exposure did not get more benefit,” Mr. Mansh said.
Mr. Mansh had no relevant disclosures.
 |
Dr. Paul T. Nghiem |
This is a carefully done study with a practical message: voriconazole patients are at a prolonged increased risk for squamous cell carcinoma. If patients develop phototoxicity or are fair-skinned, have sun damage, a history of squamous cell carcinoma or other risk factors, I think it’s highly appropriate to suggest an alternative. The alternatives are not at all associated with phototoxicity or squamous cell carcinoma.
Dr. Paul T. Nghiem moderated the late-breaker presentation in which the study was presented and is a professor of dermatology at the University of Washington, Seattle. Dr. Nghiem had no disclosures related to the study.
|
Dr. Paul T. Nghiem |
This is a carefully done study with a practical message: voriconazole patients are at a prolonged increased risk for squamous cell carcinoma. If patients develop phototoxicity or are fair-skinned, have sun damage, a history of squamous cell carcinoma or other risk factors, I think it’s highly appropriate to suggest an alternative. The alternatives are not at all associated with phototoxicity or squamous cell carcinoma.
Dr. Paul T. Nghiem moderated the late-breaker presentation in which the study was presented and is a professor of dermatology at the University of Washington, Seattle. Dr. Nghiem had no disclosures related to the study.
|
Dr. Paul T. Nghiem |
This is a carefully done study with a practical message: voriconazole patients are at a prolonged increased risk for squamous cell carcinoma. If patients develop phototoxicity or are fair-skinned, have sun damage, a history of squamous cell carcinoma or other risk factors, I think it’s highly appropriate to suggest an alternative. The alternatives are not at all associated with phototoxicity or squamous cell carcinoma.
Dr. Paul T. Nghiem moderated the late-breaker presentation in which the study was presented and is a professor of dermatology at the University of Washington, Seattle. Dr. Nghiem had no disclosures related to the study.
SAN FRANCISCO – Voriconazole increased the risk of squamous cell carcinoma by 73% in a review of 455 lung transplant patients at the University of California, San Francisco.
The increase was for any exposure to the drug after transplant (adjusted hazard ratio, 1.73; P = .03). The investigators also found that each additional 30-day exposure at 200 mg of voriconazole twice daily increased the risk of squamous cell carcinoma (SCC) by 3.0% (HR, 1.03; P < .001). The results were adjusted for age at transplant, sex, and race. Overall, SCC risk was highest among white men aged 50 years or older at the time of transplant.
Although voriconazole did protect against posttransplant Aspergillus colonization (aHR, 0.50; P < .001), it did not reduce the risk of invasive aspergillosis. The drug reduced all-cause mortality only among colonized subjects (aHR, 0.34; P = .03), and offered no mortality benefit among those who were not colonized.
There was no difference in all-cause mortality between patients who had any exposure to voriconazole and those who did not, “but we actually found a 2% increased risk of death for each 1 month on the medication. Patients who weren’t colonized were the ones contributing to this increased risk of death,” said lead investigator Matthew Mansh, now a medical student at Stanford (Calif.) University.
There was no increased risk of SCC with alternative antifungals, including inhaled amphotericin and posaconazole. These alternatives should be considered instead of voriconazole in people at higher risk for skin cancer after lung transplants, according to the study, Mr. Mansh noted.
Voriconazole, which is widely used for antifungal prophylaxis after solid organ transplants, has been linked to skin cancer. The reason for the carcinogenic effect is not known; researchers are working to unravel the molecular mechanisms.
“Physicians should be cautious when using voriconazole in the care of transplant recipients. If you see a patient who is developing phototoxicity” with voriconazole, “and if they don’t have evidence of Aspergillus colonization, you may want to limit exposure to high doses of this drug or suggest an alternative,” Mr. Mansh said.
“We have now demonstrated that the alternatives “don’t carry this increased risk of cutaneous SCC,” Mr. Mansh said at the American Academy of Dermatology annual meeting.
The mean age of the study patients at transplant was 52 years, and the majority of patients were white; slightly more than half were men. Most had bilateral lung transplants, with pulmonary fibrosis at the leading indication.
Voriconazole was used in 85% of the patients for an average of 10 months. A quarter of voriconazole patients developed SCC within 5 years of transplant, and 43% within 10 years. Among patients who did not receive the drug, 15% developed SCC within 5 years of transplant, and 28% developed SCC within 10 years of transplant.
“The benefit of voriconazole in terms of death was limited to patients with evidence of Aspergillus colonization, and it wasn’t dose dependent. Patients who had a higher cumulative exposure did not get more benefit,” Mr. Mansh said.
Mr. Mansh had no relevant disclosures.
SAN FRANCISCO – Voriconazole increased the risk of squamous cell carcinoma by 73% in a review of 455 lung transplant patients at the University of California, San Francisco.
The increase was for any exposure to the drug after transplant (adjusted hazard ratio, 1.73; P = .03). The investigators also found that each additional 30-day exposure at 200 mg of voriconazole twice daily increased the risk of squamous cell carcinoma (SCC) by 3.0% (HR, 1.03; P < .001). The results were adjusted for age at transplant, sex, and race. Overall, SCC risk was highest among white men aged 50 years or older at the time of transplant.
Although voriconazole did protect against posttransplant Aspergillus colonization (aHR, 0.50; P < .001), it did not reduce the risk of invasive aspergillosis. The drug reduced all-cause mortality only among colonized subjects (aHR, 0.34; P = .03), and offered no mortality benefit among those who were not colonized.
There was no difference in all-cause mortality between patients who had any exposure to voriconazole and those who did not, “but we actually found a 2% increased risk of death for each 1 month on the medication. Patients who weren’t colonized were the ones contributing to this increased risk of death,” said lead investigator Matthew Mansh, now a medical student at Stanford (Calif.) University.
There was no increased risk of SCC with alternative antifungals, including inhaled amphotericin and posaconazole. These alternatives should be considered instead of voriconazole in people at higher risk for skin cancer after lung transplants, according to the study, Mr. Mansh noted.
Voriconazole, which is widely used for antifungal prophylaxis after solid organ transplants, has been linked to skin cancer. The reason for the carcinogenic effect is not known; researchers are working to unravel the molecular mechanisms.
“Physicians should be cautious when using voriconazole in the care of transplant recipients. If you see a patient who is developing phototoxicity” with voriconazole, “and if they don’t have evidence of Aspergillus colonization, you may want to limit exposure to high doses of this drug or suggest an alternative,” Mr. Mansh said.
“We have now demonstrated that the alternatives “don’t carry this increased risk of cutaneous SCC,” Mr. Mansh said at the American Academy of Dermatology annual meeting.
The mean age of the study patients at transplant was 52 years, and the majority of patients were white; slightly more than half were men. Most had bilateral lung transplants, with pulmonary fibrosis at the leading indication.
Voriconazole was used in 85% of the patients for an average of 10 months. A quarter of voriconazole patients developed SCC within 5 years of transplant, and 43% within 10 years. Among patients who did not receive the drug, 15% developed SCC within 5 years of transplant, and 28% developed SCC within 10 years of transplant.
“The benefit of voriconazole in terms of death was limited to patients with evidence of Aspergillus colonization, and it wasn’t dose dependent. Patients who had a higher cumulative exposure did not get more benefit,” Mr. Mansh said.
Mr. Mansh had no relevant disclosures.
AT AAD 2015
Key clinical point: Use an alternative antifungal after lung transplant in white men aged 50 years and older.
Major finding: Exposure to voriconazole increased the risk of squamous cell carcinoma by 73% after lung transplant (aHR, 1.73; P = .03); each additional 30‐day exposure at 200 mg twice daily increased the risk by 3.0% (HR 1.03; P < .001).
Data source: Retrospective cohort study of 455 lung transplant patients
Disclosures: The lead investigator had no relevant disclosures.
Personalized melanoma vaccine evokes immune response
A customized vaccine targeting patient-specific, tumor neoantigens evoked an immune response in three adults with advanced cutaneous melanoma in a proof-of-principle study that paves the way for a phase I trial.
The data are “too premature to conclude that the treatment had any therapeutic benefit to the patients,” Dr. Gerald P. Linette of Washington University in St. Louis, Mo., said in a teleconference. However, he noted that a phase I trial would likely begin within the next 9-12 months.
“Our primary goal was to see if this was safe, and if we could elicit an immune response,” Dr. Linette said.
Vaccination not only augmented T-cell immunity directed against naturally occurring, dominant tumor neoantigens, but also expanded the breadth of the immune response by revealing additional subdominant neoantigens, lead author Beatriz M. Carreno, Ph.D., of Washington University in St. Louis and her associates reported online April 2 in Science (doi:10.1126/science.aaa3828).
All three patients had stage IIIC, resected, cutaneous melanoma and had failed prior therapy with ipilimumab (Yervoy).
Some melanoma patients harbor tumor missense mutations, translated into amino acid substitutions (AAS). These mutations are thought to produce antigens that the immune system perceives as foreign, prompting a tumor-specific T-cell response. Heretofore, there has been no systematic evaluation of these neoantigens or whether vaccination can enhance these responses.
The aim of the current study was to determine the safety, tolerability, and immunologic responses to AAS peptides inside a modified dendritic cell vaccine. Seven AAS peptide candidates were selected among validated HLA-A*02:01 binders, along with the melanoma peptides G209-2M and G280-9V as positive controls for vaccination.
In each patient, T cell immunity to one AAS peptide was detected in prevaccine peripheral blood mononuclear cell samples.
The treatment differs from other personalized cancer vaccines in two key ways, Dr. Carreno said in the teleconference.
“We mature the [dendritic] cells before we give them back to the patients; the cells make growth factors that we have previously shown are important to the generation of the immune response,” she said. In addition, the vaccine was given as an infusion, rather than an injection, she noted.
Vaccination augmented the T-cell response to the three neoantigens – TMEM48 F169L, SEC24A P469, EXOC8 Q656P – with observed frequencies of 23%, 64%, and 89%, respectively.
Immune monitoring also detected T-cell immunity to two additional neoantigens per patient, Dr. Carreno and her associates reported.
Robust immune responses were detected as early as week 2 and peaked at weeks 8-9 after the initial dose. Each patient received three vaccine doses, without side effects or toxicity.
“Vaccination against tumor antigens appears safe as all three patients are alive and well, with no autoimmune adverse events,” the researchers wrote. Post vaccine restaging CT revealed stable disease in a 54-year-old man with BRAF V6003 mutation-positive melanoma. A second man, who had achieved a complete response to ipilimumab for BRAF V6003-positive disease, remains in complete remission after receiving the vaccine in the adjuvant setting.
The vaccine induced 30% tumor reduction in a woman with extensive skin metastases and 5-12 mm lung nodules after ipilimumab and vemurafenib (Zelboraf), but tumor size returned back to baseline dimensions 12 weeks later with no new disease sites. Her disease has remained stable for the past 8 months, the researchers said.
However, it is too soon to attribute a clinical benefit to the observed immune response to the vaccine, Dr. Linette emphasized. “I would be speculating if I said the vaccine had any benefit to the patients,” he said.
Vaccination increased the frequency of most existing prevaccine T-cell receptor-beta (TCR-beta) clonotypes and revealed new clonotypes for 6 neoantigens.
For both dominant and subdominant neoantigens, the TCR-beta repertoire was increased significantly after vaccination. For example, 84 clonotypes representing 19 TCR-beta families were detected for TKT R438W, 61 clonotypes representing 12 TCR-beta families were detected for SEC24A P469L, and 12 clonotypes representing 8 TCR-beta families were detected for EXOC8 Q656P.
“The revelation of a highly diverse TCR-beta repertoire specific for dominant and subdominant neoantigens was surprising and points to a potentially rich pool of naive tumor-specific T cells that remain ignorant unless activated by vaccination,” the researchers wrote.
Recent data indicate that CTLA-4 monoclonal antibody use can alter TCR repertoire diversity in patients, suggesting a potential strategy of combination checkpoint inhibitors, including ipilimumab, and neoantigen vaccines. The novel vaccine strategy also could be used to treat other malignancies with high mutational burdens such as lung, bladder, and colorectal cancers, while other genomic alterations may generate potential neoantigens relevant in low–mutational burden cancers such as leukemia, the authors suggest.
Although the cells in this study were grown in a specialized laboratory, “as the technology improves, I think this [strategy] will become reproducible and available at other medical centers,” Dr. Linette said.
This work was supported by Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Our Mark on Melanoma (MOM) Foundation, Come Out Swinging (COS) Foundation, Blackout Melanoma Foundation and the National Cancer Institute.
Heidi Splete contributed to this story.
A customized vaccine targeting patient-specific, tumor neoantigens evoked an immune response in three adults with advanced cutaneous melanoma in a proof-of-principle study that paves the way for a phase I trial.
The data are “too premature to conclude that the treatment had any therapeutic benefit to the patients,” Dr. Gerald P. Linette of Washington University in St. Louis, Mo., said in a teleconference. However, he noted that a phase I trial would likely begin within the next 9-12 months.
“Our primary goal was to see if this was safe, and if we could elicit an immune response,” Dr. Linette said.
Vaccination not only augmented T-cell immunity directed against naturally occurring, dominant tumor neoantigens, but also expanded the breadth of the immune response by revealing additional subdominant neoantigens, lead author Beatriz M. Carreno, Ph.D., of Washington University in St. Louis and her associates reported online April 2 in Science (doi:10.1126/science.aaa3828).
All three patients had stage IIIC, resected, cutaneous melanoma and had failed prior therapy with ipilimumab (Yervoy).
Some melanoma patients harbor tumor missense mutations, translated into amino acid substitutions (AAS). These mutations are thought to produce antigens that the immune system perceives as foreign, prompting a tumor-specific T-cell response. Heretofore, there has been no systematic evaluation of these neoantigens or whether vaccination can enhance these responses.
The aim of the current study was to determine the safety, tolerability, and immunologic responses to AAS peptides inside a modified dendritic cell vaccine. Seven AAS peptide candidates were selected among validated HLA-A*02:01 binders, along with the melanoma peptides G209-2M and G280-9V as positive controls for vaccination.
In each patient, T cell immunity to one AAS peptide was detected in prevaccine peripheral blood mononuclear cell samples.
The treatment differs from other personalized cancer vaccines in two key ways, Dr. Carreno said in the teleconference.
“We mature the [dendritic] cells before we give them back to the patients; the cells make growth factors that we have previously shown are important to the generation of the immune response,” she said. In addition, the vaccine was given as an infusion, rather than an injection, she noted.
Vaccination augmented the T-cell response to the three neoantigens – TMEM48 F169L, SEC24A P469, EXOC8 Q656P – with observed frequencies of 23%, 64%, and 89%, respectively.
Immune monitoring also detected T-cell immunity to two additional neoantigens per patient, Dr. Carreno and her associates reported.
Robust immune responses were detected as early as week 2 and peaked at weeks 8-9 after the initial dose. Each patient received three vaccine doses, without side effects or toxicity.
“Vaccination against tumor antigens appears safe as all three patients are alive and well, with no autoimmune adverse events,” the researchers wrote. Post vaccine restaging CT revealed stable disease in a 54-year-old man with BRAF V6003 mutation-positive melanoma. A second man, who had achieved a complete response to ipilimumab for BRAF V6003-positive disease, remains in complete remission after receiving the vaccine in the adjuvant setting.
The vaccine induced 30% tumor reduction in a woman with extensive skin metastases and 5-12 mm lung nodules after ipilimumab and vemurafenib (Zelboraf), but tumor size returned back to baseline dimensions 12 weeks later with no new disease sites. Her disease has remained stable for the past 8 months, the researchers said.
However, it is too soon to attribute a clinical benefit to the observed immune response to the vaccine, Dr. Linette emphasized. “I would be speculating if I said the vaccine had any benefit to the patients,” he said.
Vaccination increased the frequency of most existing prevaccine T-cell receptor-beta (TCR-beta) clonotypes and revealed new clonotypes for 6 neoantigens.
For both dominant and subdominant neoantigens, the TCR-beta repertoire was increased significantly after vaccination. For example, 84 clonotypes representing 19 TCR-beta families were detected for TKT R438W, 61 clonotypes representing 12 TCR-beta families were detected for SEC24A P469L, and 12 clonotypes representing 8 TCR-beta families were detected for EXOC8 Q656P.
“The revelation of a highly diverse TCR-beta repertoire specific for dominant and subdominant neoantigens was surprising and points to a potentially rich pool of naive tumor-specific T cells that remain ignorant unless activated by vaccination,” the researchers wrote.
Recent data indicate that CTLA-4 monoclonal antibody use can alter TCR repertoire diversity in patients, suggesting a potential strategy of combination checkpoint inhibitors, including ipilimumab, and neoantigen vaccines. The novel vaccine strategy also could be used to treat other malignancies with high mutational burdens such as lung, bladder, and colorectal cancers, while other genomic alterations may generate potential neoantigens relevant in low–mutational burden cancers such as leukemia, the authors suggest.
Although the cells in this study were grown in a specialized laboratory, “as the technology improves, I think this [strategy] will become reproducible and available at other medical centers,” Dr. Linette said.
This work was supported by Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Our Mark on Melanoma (MOM) Foundation, Come Out Swinging (COS) Foundation, Blackout Melanoma Foundation and the National Cancer Institute.
Heidi Splete contributed to this story.
A customized vaccine targeting patient-specific, tumor neoantigens evoked an immune response in three adults with advanced cutaneous melanoma in a proof-of-principle study that paves the way for a phase I trial.
The data are “too premature to conclude that the treatment had any therapeutic benefit to the patients,” Dr. Gerald P. Linette of Washington University in St. Louis, Mo., said in a teleconference. However, he noted that a phase I trial would likely begin within the next 9-12 months.
“Our primary goal was to see if this was safe, and if we could elicit an immune response,” Dr. Linette said.
Vaccination not only augmented T-cell immunity directed against naturally occurring, dominant tumor neoantigens, but also expanded the breadth of the immune response by revealing additional subdominant neoantigens, lead author Beatriz M. Carreno, Ph.D., of Washington University in St. Louis and her associates reported online April 2 in Science (doi:10.1126/science.aaa3828).
All three patients had stage IIIC, resected, cutaneous melanoma and had failed prior therapy with ipilimumab (Yervoy).
Some melanoma patients harbor tumor missense mutations, translated into amino acid substitutions (AAS). These mutations are thought to produce antigens that the immune system perceives as foreign, prompting a tumor-specific T-cell response. Heretofore, there has been no systematic evaluation of these neoantigens or whether vaccination can enhance these responses.
The aim of the current study was to determine the safety, tolerability, and immunologic responses to AAS peptides inside a modified dendritic cell vaccine. Seven AAS peptide candidates were selected among validated HLA-A*02:01 binders, along with the melanoma peptides G209-2M and G280-9V as positive controls for vaccination.
In each patient, T cell immunity to one AAS peptide was detected in prevaccine peripheral blood mononuclear cell samples.
The treatment differs from other personalized cancer vaccines in two key ways, Dr. Carreno said in the teleconference.
“We mature the [dendritic] cells before we give them back to the patients; the cells make growth factors that we have previously shown are important to the generation of the immune response,” she said. In addition, the vaccine was given as an infusion, rather than an injection, she noted.
Vaccination augmented the T-cell response to the three neoantigens – TMEM48 F169L, SEC24A P469, EXOC8 Q656P – with observed frequencies of 23%, 64%, and 89%, respectively.
Immune monitoring also detected T-cell immunity to two additional neoantigens per patient, Dr. Carreno and her associates reported.
Robust immune responses were detected as early as week 2 and peaked at weeks 8-9 after the initial dose. Each patient received three vaccine doses, without side effects or toxicity.
“Vaccination against tumor antigens appears safe as all three patients are alive and well, with no autoimmune adverse events,” the researchers wrote. Post vaccine restaging CT revealed stable disease in a 54-year-old man with BRAF V6003 mutation-positive melanoma. A second man, who had achieved a complete response to ipilimumab for BRAF V6003-positive disease, remains in complete remission after receiving the vaccine in the adjuvant setting.
The vaccine induced 30% tumor reduction in a woman with extensive skin metastases and 5-12 mm lung nodules after ipilimumab and vemurafenib (Zelboraf), but tumor size returned back to baseline dimensions 12 weeks later with no new disease sites. Her disease has remained stable for the past 8 months, the researchers said.
However, it is too soon to attribute a clinical benefit to the observed immune response to the vaccine, Dr. Linette emphasized. “I would be speculating if I said the vaccine had any benefit to the patients,” he said.
Vaccination increased the frequency of most existing prevaccine T-cell receptor-beta (TCR-beta) clonotypes and revealed new clonotypes for 6 neoantigens.
For both dominant and subdominant neoantigens, the TCR-beta repertoire was increased significantly after vaccination. For example, 84 clonotypes representing 19 TCR-beta families were detected for TKT R438W, 61 clonotypes representing 12 TCR-beta families were detected for SEC24A P469L, and 12 clonotypes representing 8 TCR-beta families were detected for EXOC8 Q656P.
“The revelation of a highly diverse TCR-beta repertoire specific for dominant and subdominant neoantigens was surprising and points to a potentially rich pool of naive tumor-specific T cells that remain ignorant unless activated by vaccination,” the researchers wrote.
Recent data indicate that CTLA-4 monoclonal antibody use can alter TCR repertoire diversity in patients, suggesting a potential strategy of combination checkpoint inhibitors, including ipilimumab, and neoantigen vaccines. The novel vaccine strategy also could be used to treat other malignancies with high mutational burdens such as lung, bladder, and colorectal cancers, while other genomic alterations may generate potential neoantigens relevant in low–mutational burden cancers such as leukemia, the authors suggest.
Although the cells in this study were grown in a specialized laboratory, “as the technology improves, I think this [strategy] will become reproducible and available at other medical centers,” Dr. Linette said.
This work was supported by Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Our Mark on Melanoma (MOM) Foundation, Come Out Swinging (COS) Foundation, Blackout Melanoma Foundation and the National Cancer Institute.
Heidi Splete contributed to this story.
FROM SCIENCE
Key clinical point: Vaccination against patient-specific tumor neoantigens may represent a novel therapeutic strategy in melanoma and other malignancies.
Major finding: The vaccine enhanced T-cell immunity to naturally occurring neoantigens and revealed two additional neoantigens per patient.
Data source: Proof-of-principle study of three patients with resected, cutaneous melanoma.
Disclosures: This work was supported by Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Our Mark on Melanoma (MOM) Foundation, Come Out Swinging (COS) Foundation, Blackout Melanoma Foundation and the National Cancer Institute.
