Immuno-oncology

A woman with two distinct primary tumors achieved complete regression of both after pembrolizumab therapy, investigators report.

This is the first documented instance of a checkpoint inhibitor leading to this kind of simultaneous regression, reported Benjamin Musher, MD, of Baylor College of Medicine, Houston, and his coauthors.

The patient was a 55-year-old woman with a family history of gastric, uterine, and colon cancer. After presenting with weight loss, fatigue, and abdominal pain, colonoscopy showed a 5-cm mucosal lesion. A subsequent PET-CT scan revealed a 12-cm hepatic mass with multiple other liver masses, and bulky lymph nodes nearby. Site biopsies showed two primary cancer types: colonic adenocarcinoma and intrahepatic cholangiocarcinoma.

“Additional staining ... for proteins that repair mismatched DNA showed an absence of MLH1 expression. Sequencing of the patient’s DNA revealed a deleterious mutation in MLH1, which confirmed that Lynch syndrome caused both types of cancer,” the authors wrote in Annals of Internal Medicine.

Lynch syndrome (also called hereditary nonpolyposis colorectal cancer), is an autosomal dominant condition that incurs a high risk of colorectal, pancreatic, bile duct, ovarian, gastric, and uterine cancer. Patients may present with more than one type of cancer simultaneously, as occurred in this case study.

Following diagnosis, the patient started pembrolizumab monotherapy (200 mg IV Q3W). After 16 months the tumors were undetectable by colonoscopy or PET-CT; 2 months later the patient was free of cancer symptoms.

“To our knowledge, our case report is the first to document complete regression of 2 simultaneous types of cancer after treatment with an immune checkpoint inhibitor,” the authors wrote.

But why the dramatic response?

“The types of cancer that develop because of a mismatch repair deficiency contain more mutations than most other kinds of cancer,” the authors explained. These highly mutated cells are recognized by the host immune system, but responses are limited, in part, by programmed cell death proteins. “These events make checkpoint inhibition an attractive and potentially effective treatment for mismatch repair deficient cancer.

“We believe that this case emphasizes the importance of eliciting a thorough family history in patients with cancer and considering the presence of multiple types of primary cancer in a patient with an extensive family history of cancer,” the authors concluded. “It also shows the value of identifying mismatch repair deficiency, [in which] immunotherapy can yield dramatic and durable benefit.”

Dr. Musher reported compensation from LOKON pharmaceuticals.
 

SOURCE: Musher et al. Ann Intern Med. 2018 Sep 24. doi: 10.7326/L18-0360.

A woman with two distinct primary tumors achieved complete regression of both after pembrolizumab therapy, investigators report.

This is the first documented instance of a checkpoint inhibitor leading to this kind of simultaneous regression, reported Benjamin Musher, MD, of Baylor College of Medicine, Houston, and his coauthors.

The patient was a 55-year-old woman with a family history of gastric, uterine, and colon cancer. After presenting with weight loss, fatigue, and abdominal pain, colonoscopy showed a 5-cm mucosal lesion. A subsequent PET-CT scan revealed a 12-cm hepatic mass with multiple other liver masses, and bulky lymph nodes nearby. Site biopsies showed two primary cancer types: colonic adenocarcinoma and intrahepatic cholangiocarcinoma.

“Additional staining ... for proteins that repair mismatched DNA showed an absence of MLH1 expression. Sequencing of the patient’s DNA revealed a deleterious mutation in MLH1, which confirmed that Lynch syndrome caused both types of cancer,” the authors wrote in Annals of Internal Medicine.

Lynch syndrome (also called hereditary nonpolyposis colorectal cancer), is an autosomal dominant condition that incurs a high risk of colorectal, pancreatic, bile duct, ovarian, gastric, and uterine cancer. Patients may present with more than one type of cancer simultaneously, as occurred in this case study.

Following diagnosis, the patient started pembrolizumab monotherapy (200 mg IV Q3W). After 16 months the tumors were undetectable by colonoscopy or PET-CT; 2 months later the patient was free of cancer symptoms.

“To our knowledge, our case report is the first to document complete regression of 2 simultaneous types of cancer after treatment with an immune checkpoint inhibitor,” the authors wrote.

But why the dramatic response?

“The types of cancer that develop because of a mismatch repair deficiency contain more mutations than most other kinds of cancer,” the authors explained. These highly mutated cells are recognized by the host immune system, but responses are limited, in part, by programmed cell death proteins. “These events make checkpoint inhibition an attractive and potentially effective treatment for mismatch repair deficient cancer.

“We believe that this case emphasizes the importance of eliciting a thorough family history in patients with cancer and considering the presence of multiple types of primary cancer in a patient with an extensive family history of cancer,” the authors concluded. “It also shows the value of identifying mismatch repair deficiency, [in which] immunotherapy can yield dramatic and durable benefit.”

Dr. Musher reported compensation from LOKON pharmaceuticals.
 

SOURCE: Musher et al. Ann Intern Med. 2018 Sep 24. doi: 10.7326/L18-0360.

A woman with two distinct primary tumors achieved complete regression of both after pembrolizumab therapy, investigators report.

This is the first documented instance of a checkpoint inhibitor leading to this kind of simultaneous regression, reported Benjamin Musher, MD, of Baylor College of Medicine, Houston, and his coauthors.

The patient was a 55-year-old woman with a family history of gastric, uterine, and colon cancer. After presenting with weight loss, fatigue, and abdominal pain, colonoscopy showed a 5-cm mucosal lesion. A subsequent PET-CT scan revealed a 12-cm hepatic mass with multiple other liver masses, and bulky lymph nodes nearby. Site biopsies showed two primary cancer types: colonic adenocarcinoma and intrahepatic cholangiocarcinoma.

“Additional staining ... for proteins that repair mismatched DNA showed an absence of MLH1 expression. Sequencing of the patient’s DNA revealed a deleterious mutation in MLH1, which confirmed that Lynch syndrome caused both types of cancer,” the authors wrote in Annals of Internal Medicine.

Lynch syndrome (also called hereditary nonpolyposis colorectal cancer), is an autosomal dominant condition that incurs a high risk of colorectal, pancreatic, bile duct, ovarian, gastric, and uterine cancer. Patients may present with more than one type of cancer simultaneously, as occurred in this case study.

Following diagnosis, the patient started pembrolizumab monotherapy (200 mg IV Q3W). After 16 months the tumors were undetectable by colonoscopy or PET-CT; 2 months later the patient was free of cancer symptoms.

“To our knowledge, our case report is the first to document complete regression of 2 simultaneous types of cancer after treatment with an immune checkpoint inhibitor,” the authors wrote.

But why the dramatic response?

“The types of cancer that develop because of a mismatch repair deficiency contain more mutations than most other kinds of cancer,” the authors explained. These highly mutated cells are recognized by the host immune system, but responses are limited, in part, by programmed cell death proteins. “These events make checkpoint inhibition an attractive and potentially effective treatment for mismatch repair deficient cancer.

“We believe that this case emphasizes the importance of eliciting a thorough family history in patients with cancer and considering the presence of multiple types of primary cancer in a patient with an extensive family history of cancer,” the authors concluded. “It also shows the value of identifying mismatch repair deficiency, [in which] immunotherapy can yield dramatic and durable benefit.”

Dr. Musher reported compensation from LOKON pharmaceuticals.
 

SOURCE: Musher et al. Ann Intern Med. 2018 Sep 24. doi: 10.7326/L18-0360.

Hyperprogressive disease is a new pattern of progression that may be more prevalent in patients with non–small-cell lung cancer receiving treatment with PD-1/PD-L1 inhibitors than in those receiving chemotherapy, results of a multicenter retrospective study suggest.

Nearly 14% of patients treated with PD/1/PD-L1 inhibitors had hyperprogressive disease in the study, compared with about 5% of patients treated with chemotherapy, the investigators reported.

This acceleration of tumor growth during therapy was associated with a high metastatic burden before treatment, and with a poor prognosis after treatment, wrote Benjamin Besse, MD, PhD, of the cancer medicine department at Gustave Roussy, Villejuif, France, and his colleagues.

Based on these findings, disease evolution should be carefully monitored to identify “hyperprogressors” among non–small-cell lung cancer (NSCLC) patients receiving PD-1/PD-L1 inhibitors, Dr. Besse and his colleagues said.

“Because of the poor overall survival associated with hyperprogressive disease, an early switch to salvage chemotherapy in these patients should be considered,” they wrote in JAMA Oncology.

This is believed to be the first study to look at incidence of hyperprogressive disease after PD-1/PD-L1 therapy specifically in NSCLC patients, and the first in any tumor type to include a chemotherapy treatment control group, according to Dr. Besse and his coauthors.

In one other recent report, hyperprogressive disease was seen in 9% of advanced cancers, and in a second recent investigation, it was seen in 29% of head and neck cancer patients, they said.

Although those proportions appear different, that could be due to differing interpretations of hyperprogressive disease, as there is no consensus on the optimal definition, they noted.

In this study, which included 406 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors and 59 treated with chemotherapy, hyperprogressive disease was defined as progressive disease observed at the first computed tomography scan and an absolute increase in tumor growth rate of 50% or more per month.

A total of 56 patients (13.8%) in the PD-1/PD-L1 treatment group met that definition for hyperprogressive disease, the investigators found. By comparison, three patients (5.1%) in the chemotherapy treatment group had hyperprogressive disease.

With a median follow-up of 12.1 months in the PD-1/PD-L1 group, the median overall survival was 13.4 months. Median overall survival for those with progressive disease was 6.2 months, and significantly lower at 3.4 months for those who had experienced hyperprogressive disease (P = .002), Dr. Besse and his coinvestigators found.

Moreover, 42.6% patients with progressive disease had two or more metastatic sites, compared with 62.5% of patients with hyperprogressive disease (P = .006), they reported.

The phenomenon of hyperprogressive disease might explain the initial excess in deaths seen in some phase 3 trials, Dr. Besse said in an interview posted on the JAMA Oncology website.

“In most of the second-line trials that compared single-agent immunotherapy to single-agent chemotherapy, overall survival curves crossed, meaning that there were an extra number of deaths in the immunotherapy arm,” he said in the interview. “That led us to evaluate the speed of progression.”

Based on the study results, Dr. Besse recommends early assessment by CT scan at 6 or 8 weeks after the start of immunotherapy. “If a patient has hyperprogressive disease, you don’t have much time to react,” he said. “You have to switch to a new treatment quite early.”

Dr. Besse reported receiving research funding from AstraZeneca, Boehringer, Bristol-Myers Squibb, Clovis Oncology, GlaxoSmithKline, Eli Lilly, Inivata, Merck Sharp & Dohme, Onxeo, OSE Pharma, Pfizer, Roche/Genentech, and Servier.
 

SOURCE: Ferrara R et al. JAMA Oncol. 2018 Sep 6. doi: 10.1001/jamaoncol.2018.3676.

Hyperprogressive disease is a new pattern of progression that may be more prevalent in patients with non–small-cell lung cancer receiving treatment with PD-1/PD-L1 inhibitors than in those receiving chemotherapy, results of a multicenter retrospective study suggest.

Nearly 14% of patients treated with PD/1/PD-L1 inhibitors had hyperprogressive disease in the study, compared with about 5% of patients treated with chemotherapy, the investigators reported.

This acceleration of tumor growth during therapy was associated with a high metastatic burden before treatment, and with a poor prognosis after treatment, wrote Benjamin Besse, MD, PhD, of the cancer medicine department at Gustave Roussy, Villejuif, France, and his colleagues.

Based on these findings, disease evolution should be carefully monitored to identify “hyperprogressors” among non–small-cell lung cancer (NSCLC) patients receiving PD-1/PD-L1 inhibitors, Dr. Besse and his colleagues said.

“Because of the poor overall survival associated with hyperprogressive disease, an early switch to salvage chemotherapy in these patients should be considered,” they wrote in JAMA Oncology.

This is believed to be the first study to look at incidence of hyperprogressive disease after PD-1/PD-L1 therapy specifically in NSCLC patients, and the first in any tumor type to include a chemotherapy treatment control group, according to Dr. Besse and his coauthors.

In one other recent report, hyperprogressive disease was seen in 9% of advanced cancers, and in a second recent investigation, it was seen in 29% of head and neck cancer patients, they said.

Although those proportions appear different, that could be due to differing interpretations of hyperprogressive disease, as there is no consensus on the optimal definition, they noted.

In this study, which included 406 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors and 59 treated with chemotherapy, hyperprogressive disease was defined as progressive disease observed at the first computed tomography scan and an absolute increase in tumor growth rate of 50% or more per month.

A total of 56 patients (13.8%) in the PD-1/PD-L1 treatment group met that definition for hyperprogressive disease, the investigators found. By comparison, three patients (5.1%) in the chemotherapy treatment group had hyperprogressive disease.

With a median follow-up of 12.1 months in the PD-1/PD-L1 group, the median overall survival was 13.4 months. Median overall survival for those with progressive disease was 6.2 months, and significantly lower at 3.4 months for those who had experienced hyperprogressive disease (P = .002), Dr. Besse and his coinvestigators found.

Moreover, 42.6% patients with progressive disease had two or more metastatic sites, compared with 62.5% of patients with hyperprogressive disease (P = .006), they reported.

The phenomenon of hyperprogressive disease might explain the initial excess in deaths seen in some phase 3 trials, Dr. Besse said in an interview posted on the JAMA Oncology website.

“In most of the second-line trials that compared single-agent immunotherapy to single-agent chemotherapy, overall survival curves crossed, meaning that there were an extra number of deaths in the immunotherapy arm,” he said in the interview. “That led us to evaluate the speed of progression.”

Based on the study results, Dr. Besse recommends early assessment by CT scan at 6 or 8 weeks after the start of immunotherapy. “If a patient has hyperprogressive disease, you don’t have much time to react,” he said. “You have to switch to a new treatment quite early.”

Dr. Besse reported receiving research funding from AstraZeneca, Boehringer, Bristol-Myers Squibb, Clovis Oncology, GlaxoSmithKline, Eli Lilly, Inivata, Merck Sharp & Dohme, Onxeo, OSE Pharma, Pfizer, Roche/Genentech, and Servier.
 

SOURCE: Ferrara R et al. JAMA Oncol. 2018 Sep 6. doi: 10.1001/jamaoncol.2018.3676.

Hyperprogressive disease is a new pattern of progression that may be more prevalent in patients with non–small-cell lung cancer receiving treatment with PD-1/PD-L1 inhibitors than in those receiving chemotherapy, results of a multicenter retrospective study suggest.

Nearly 14% of patients treated with PD/1/PD-L1 inhibitors had hyperprogressive disease in the study, compared with about 5% of patients treated with chemotherapy, the investigators reported.

This acceleration of tumor growth during therapy was associated with a high metastatic burden before treatment, and with a poor prognosis after treatment, wrote Benjamin Besse, MD, PhD, of the cancer medicine department at Gustave Roussy, Villejuif, France, and his colleagues.

Based on these findings, disease evolution should be carefully monitored to identify “hyperprogressors” among non–small-cell lung cancer (NSCLC) patients receiving PD-1/PD-L1 inhibitors, Dr. Besse and his colleagues said.

“Because of the poor overall survival associated with hyperprogressive disease, an early switch to salvage chemotherapy in these patients should be considered,” they wrote in JAMA Oncology.

This is believed to be the first study to look at incidence of hyperprogressive disease after PD-1/PD-L1 therapy specifically in NSCLC patients, and the first in any tumor type to include a chemotherapy treatment control group, according to Dr. Besse and his coauthors.

In one other recent report, hyperprogressive disease was seen in 9% of advanced cancers, and in a second recent investigation, it was seen in 29% of head and neck cancer patients, they said.

Although those proportions appear different, that could be due to differing interpretations of hyperprogressive disease, as there is no consensus on the optimal definition, they noted.

In this study, which included 406 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors and 59 treated with chemotherapy, hyperprogressive disease was defined as progressive disease observed at the first computed tomography scan and an absolute increase in tumor growth rate of 50% or more per month.

A total of 56 patients (13.8%) in the PD-1/PD-L1 treatment group met that definition for hyperprogressive disease, the investigators found. By comparison, three patients (5.1%) in the chemotherapy treatment group had hyperprogressive disease.

With a median follow-up of 12.1 months in the PD-1/PD-L1 group, the median overall survival was 13.4 months. Median overall survival for those with progressive disease was 6.2 months, and significantly lower at 3.4 months for those who had experienced hyperprogressive disease (P = .002), Dr. Besse and his coinvestigators found.

Moreover, 42.6% patients with progressive disease had two or more metastatic sites, compared with 62.5% of patients with hyperprogressive disease (P = .006), they reported.

The phenomenon of hyperprogressive disease might explain the initial excess in deaths seen in some phase 3 trials, Dr. Besse said in an interview posted on the JAMA Oncology website.

“In most of the second-line trials that compared single-agent immunotherapy to single-agent chemotherapy, overall survival curves crossed, meaning that there were an extra number of deaths in the immunotherapy arm,” he said in the interview. “That led us to evaluate the speed of progression.”

Based on the study results, Dr. Besse recommends early assessment by CT scan at 6 or 8 weeks after the start of immunotherapy. “If a patient has hyperprogressive disease, you don’t have much time to react,” he said. “You have to switch to a new treatment quite early.”

Dr. Besse reported receiving research funding from AstraZeneca, Boehringer, Bristol-Myers Squibb, Clovis Oncology, GlaxoSmithKline, Eli Lilly, Inivata, Merck Sharp & Dohme, Onxeo, OSE Pharma, Pfizer, Roche/Genentech, and Servier.
 

SOURCE: Ferrara R et al. JAMA Oncol. 2018 Sep 6. doi: 10.1001/jamaoncol.2018.3676.

Fatal adverse events are uncommon with immune checkpoint inhibitors (ICI), but they are not unknown, and it’s important to recognize rare, potentially lethal side effects with these agents, investigators say.

A systematic review and meta-analysis of records from academic medical centers and from a pharmacovigilance database found that fatal side adverse events varied in nature and severity according to the agent and immune checkpoint targeted, reported Daniel Y. Wang, MD, of Vanderbilt University Medical Center, Nashville, Tenn., and his colleagues.

“This study underscores that the risk of death associated with complications of ICI therapy is real, but within or well below fatality rates for common oncologic interventions,” they wrote in JAMA Oncology.

In their study, rates of fatal toxic effects associated with immune checkpoint inhibitors ranged from 0.3% to 1.3%. In contrast, the investigators noted, platinum doublet chemotherapy is associated with a 0.9% rate of fatal toxicities, targeted therapies with angiogenesis inhibitors or tyrosine kinase inhibitors have had fatal toxicity rates up to 4%, and allogeneic hematopoietic stem cell transplants are associated with a fatal adverse event rate of approximately 15%. In addition, the death rate associated with complex oncologic surgeries such as the Whipple procedure or esophagectomy ranges from 1% to 10%.

The authors queried the World Health Organization pharmacovigilance database, called Vigilyze, which contains data on more than 16 million adverse drug reactions; records from patients treated with checkpoint inhibitors in seven academic centers in the United States, Germany, and Australia; and published clinical trials.

They combed through the data to identify fatal toxic effects associated with the anti-programmed death 1/ligand-1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), and with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors ipilimumab (Yervoy) and tremelimumab (investigational).

They found in the Vigilyze data that of 193 deaths attributed to CTLA-4 inhibitors, 70% were from colitis, 16% from hepatitis, 8% from pneumonitis, and the remainder from other causes. In contrast, the most common fatal toxicities associated with PD-1/PD-L1 inhibitors were pneumonitis in 35%, hepatitis in 22%, colitis in 17%, and the remainder from other causes.

With the two classes of ICIs used in combination, primarily for treatment of malignant melanoma, colitis accounted for 37% of toxic fatal events, followed by myocarditis in 25%, hepatitis in 22%, pneumonitis in 14%, and others.

The events occurred early in the course of therapy, at a median of 14.5 days from the start of therapy for combination treatment, and 40 days each for anti-PD-1/PD-L1 and anti-CTLA-4 agents.

The complication with highest fatality rate was myocarditis, which killed 39.7% of affected patients. In contrast, endocrine events and colitis were fatal in only 2%-5% of cases. The fatality rates associated with toxic effects in other organ systems ranged from 10% to 17%.

A review of data on 3,545 patients treated with immune checkpoint inhibitors at the seven academic centers found a 0.6% fatality rate, with cardiac and neurologic events accounting for 43% of the deaths.

The investigators also conducted a meta-analysis of data from 112 clinical trials with a total of 19,217 patients treated with ICIs. In these studies, anti-PD-1 agents were associated with a 0.36% rate of fatal toxicities, anti-PD-L1 agents were associated with a 0.38% rate, anti-CTLA-4 agents were linked to a 1.08% rate, and combined PD-1/PD-L1 and CTLA-4 therapy was associated with a 1.23% fatal toxicity rate.

“Each database largely validated the patterns of death from distinct regimens with a few exceptions. Intriguingly, our retrospective analysis at large, experienced academic centers suggested that neurologic and cardiac toxic effects comprised nearly half of deaths. Thus, we surmise that more optimized treatment of these events is urgently needed. In addition, persistent deaths from colitis and pneumonitis, events with standardized treatment algorithms and clear symptoms, suggests that patient and physician education remains a critical objective,” the investigators wrote.

SOURCE: Wang DY et al. JAMA Oncol. 2018 Sept 13. doi: 10.1001/jamaoncol.2018.3923.

Fatal adverse events are uncommon with immune checkpoint inhibitors (ICI), but they are not unknown, and it’s important to recognize rare, potentially lethal side effects with these agents, investigators say.

A systematic review and meta-analysis of records from academic medical centers and from a pharmacovigilance database found that fatal side adverse events varied in nature and severity according to the agent and immune checkpoint targeted, reported Daniel Y. Wang, MD, of Vanderbilt University Medical Center, Nashville, Tenn., and his colleagues.

“This study underscores that the risk of death associated with complications of ICI therapy is real, but within or well below fatality rates for common oncologic interventions,” they wrote in JAMA Oncology.

In their study, rates of fatal toxic effects associated with immune checkpoint inhibitors ranged from 0.3% to 1.3%. In contrast, the investigators noted, platinum doublet chemotherapy is associated with a 0.9% rate of fatal toxicities, targeted therapies with angiogenesis inhibitors or tyrosine kinase inhibitors have had fatal toxicity rates up to 4%, and allogeneic hematopoietic stem cell transplants are associated with a fatal adverse event rate of approximately 15%. In addition, the death rate associated with complex oncologic surgeries such as the Whipple procedure or esophagectomy ranges from 1% to 10%.

The authors queried the World Health Organization pharmacovigilance database, called Vigilyze, which contains data on more than 16 million adverse drug reactions; records from patients treated with checkpoint inhibitors in seven academic centers in the United States, Germany, and Australia; and published clinical trials.

They combed through the data to identify fatal toxic effects associated with the anti-programmed death 1/ligand-1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), and with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors ipilimumab (Yervoy) and tremelimumab (investigational).

They found in the Vigilyze data that of 193 deaths attributed to CTLA-4 inhibitors, 70% were from colitis, 16% from hepatitis, 8% from pneumonitis, and the remainder from other causes. In contrast, the most common fatal toxicities associated with PD-1/PD-L1 inhibitors were pneumonitis in 35%, hepatitis in 22%, colitis in 17%, and the remainder from other causes.

With the two classes of ICIs used in combination, primarily for treatment of malignant melanoma, colitis accounted for 37% of toxic fatal events, followed by myocarditis in 25%, hepatitis in 22%, pneumonitis in 14%, and others.

The events occurred early in the course of therapy, at a median of 14.5 days from the start of therapy for combination treatment, and 40 days each for anti-PD-1/PD-L1 and anti-CTLA-4 agents.

The complication with highest fatality rate was myocarditis, which killed 39.7% of affected patients. In contrast, endocrine events and colitis were fatal in only 2%-5% of cases. The fatality rates associated with toxic effects in other organ systems ranged from 10% to 17%.

A review of data on 3,545 patients treated with immune checkpoint inhibitors at the seven academic centers found a 0.6% fatality rate, with cardiac and neurologic events accounting for 43% of the deaths.

The investigators also conducted a meta-analysis of data from 112 clinical trials with a total of 19,217 patients treated with ICIs. In these studies, anti-PD-1 agents were associated with a 0.36% rate of fatal toxicities, anti-PD-L1 agents were associated with a 0.38% rate, anti-CTLA-4 agents were linked to a 1.08% rate, and combined PD-1/PD-L1 and CTLA-4 therapy was associated with a 1.23% fatal toxicity rate.

“Each database largely validated the patterns of death from distinct regimens with a few exceptions. Intriguingly, our retrospective analysis at large, experienced academic centers suggested that neurologic and cardiac toxic effects comprised nearly half of deaths. Thus, we surmise that more optimized treatment of these events is urgently needed. In addition, persistent deaths from colitis and pneumonitis, events with standardized treatment algorithms and clear symptoms, suggests that patient and physician education remains a critical objective,” the investigators wrote.

SOURCE: Wang DY et al. JAMA Oncol. 2018 Sept 13. doi: 10.1001/jamaoncol.2018.3923.

Fatal adverse events are uncommon with immune checkpoint inhibitors (ICI), but they are not unknown, and it’s important to recognize rare, potentially lethal side effects with these agents, investigators say.

A systematic review and meta-analysis of records from academic medical centers and from a pharmacovigilance database found that fatal side adverse events varied in nature and severity according to the agent and immune checkpoint targeted, reported Daniel Y. Wang, MD, of Vanderbilt University Medical Center, Nashville, Tenn., and his colleagues.

“This study underscores that the risk of death associated with complications of ICI therapy is real, but within or well below fatality rates for common oncologic interventions,” they wrote in JAMA Oncology.

In their study, rates of fatal toxic effects associated with immune checkpoint inhibitors ranged from 0.3% to 1.3%. In contrast, the investigators noted, platinum doublet chemotherapy is associated with a 0.9% rate of fatal toxicities, targeted therapies with angiogenesis inhibitors or tyrosine kinase inhibitors have had fatal toxicity rates up to 4%, and allogeneic hematopoietic stem cell transplants are associated with a fatal adverse event rate of approximately 15%. In addition, the death rate associated with complex oncologic surgeries such as the Whipple procedure or esophagectomy ranges from 1% to 10%.

The authors queried the World Health Organization pharmacovigilance database, called Vigilyze, which contains data on more than 16 million adverse drug reactions; records from patients treated with checkpoint inhibitors in seven academic centers in the United States, Germany, and Australia; and published clinical trials.

They combed through the data to identify fatal toxic effects associated with the anti-programmed death 1/ligand-1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), and with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors ipilimumab (Yervoy) and tremelimumab (investigational).

They found in the Vigilyze data that of 193 deaths attributed to CTLA-4 inhibitors, 70% were from colitis, 16% from hepatitis, 8% from pneumonitis, and the remainder from other causes. In contrast, the most common fatal toxicities associated with PD-1/PD-L1 inhibitors were pneumonitis in 35%, hepatitis in 22%, colitis in 17%, and the remainder from other causes.

With the two classes of ICIs used in combination, primarily for treatment of malignant melanoma, colitis accounted for 37% of toxic fatal events, followed by myocarditis in 25%, hepatitis in 22%, pneumonitis in 14%, and others.

The events occurred early in the course of therapy, at a median of 14.5 days from the start of therapy for combination treatment, and 40 days each for anti-PD-1/PD-L1 and anti-CTLA-4 agents.

The complication with highest fatality rate was myocarditis, which killed 39.7% of affected patients. In contrast, endocrine events and colitis were fatal in only 2%-5% of cases. The fatality rates associated with toxic effects in other organ systems ranged from 10% to 17%.

A review of data on 3,545 patients treated with immune checkpoint inhibitors at the seven academic centers found a 0.6% fatality rate, with cardiac and neurologic events accounting for 43% of the deaths.

The investigators also conducted a meta-analysis of data from 112 clinical trials with a total of 19,217 patients treated with ICIs. In these studies, anti-PD-1 agents were associated with a 0.36% rate of fatal toxicities, anti-PD-L1 agents were associated with a 0.38% rate, anti-CTLA-4 agents were linked to a 1.08% rate, and combined PD-1/PD-L1 and CTLA-4 therapy was associated with a 1.23% fatal toxicity rate.

“Each database largely validated the patterns of death from distinct regimens with a few exceptions. Intriguingly, our retrospective analysis at large, experienced academic centers suggested that neurologic and cardiac toxic effects comprised nearly half of deaths. Thus, we surmise that more optimized treatment of these events is urgently needed. In addition, persistent deaths from colitis and pneumonitis, events with standardized treatment algorithms and clear symptoms, suggests that patient and physician education remains a critical objective,” the investigators wrote.

SOURCE: Wang DY et al. JAMA Oncol. 2018 Sept 13. doi: 10.1001/jamaoncol.2018.3923.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

Signs of efficacy of anti-cancer therapies may be only skin deep, results of a retrospective review indicate.

Cutaneous toxicities such as vitiligo, rash, alopecia, and nail toxicities may be early signs of efficacy of targeted therapies, immunotherapy, or cytotoxic chemotherapy, according to Alexandra K. Rzepecki, of the University of Michigan, and her coauthors from Albert Einstein Medical College in the Bronx, New York.

“Because cutaneous toxicities are a clinically visible parameter, they may alert clinicians to the possibility of treatment success or failure in a rapid, cost-effective, and noninvasive manner,” they wrote. The report is in the Journal of the American Academy of Dermatology.

The investigators reviewed the medical literature for clinical studies of three major classes of anti-cancer therapies that included data on associations between cutaneous toxicities and clinical outcomes such progression-free survival (PFS) overall survival (OS).

The drug classes and their associations with cutaneous toxicities and clinical outcomes were as follows:

• Targeted therapies, including tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) such as cetuximab (Erbitux) and erlotinib (Tarceva), and multikinase targeted agents such as sorafenib (Nexavar) and sunitinib (Sutent). Toxicities associated with clinical benefit from EGFR inhibitors include rash, xerosis, leukocytoclastic vasculitis, paronychia, and pruritus, whereas skin toxicities associated with the multikinase inhibitors trended toward the hand-foot syndrome and hand-foot skin reaction.
• Immunotherapies included blockers of cytotoxic T-lymphocyte associated protein 4 (CTLA4) such as ipilimumab (Yervoy) and inhibitors of programmed death 1 protein (PD-1) and its ligand 1 (PD-L1) such as nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). In studies of pembrolizumab for various malignancies, rash or vitiligo was an independent prognostic factor for longer OS, a higher proportion of objective responses, and longer PFS. Similar associations were seen with nivolumab, with the additional association of hair repigmentation among patients with non–small-cell lung cancer being associated with stable disease responses or better. Among patients with melanoma treated with ipilimumab, hair depigmentation correlated with durable responses.
• Cytotoxic chemotherapy agents included the anthracycline doxorubicin, taxanes such as paclitaxel and docetaxel, platinum agents (cisplatin and carboplatin), and fluoropyrimidines such as capecitabine. Patients treated for various cancers with doxorubicin who had alopecia were significantly more likely to have clinical remissions than were patients who did not lose their hair, and patients treated with this agent who developed hand-foot syndrome had significantly longer PFS. For patients treated with docetaxel, severity of nail changes and/or development of nail alterations were associated with both improved OS and PFS. Patients treated with the combination of paclitaxel and a platinum agent who developed grade 2 or greater alopecia up to cycle 3 had significantly longer OS than did patients who had hair loss later in the course of therapy. Patients treated with capecitabine who developed had hand-foot skin reactions had improved progression-free and disease-free survival.

“Although further studies are needed to better evaluate these promising associations, vigilant monitoring of cutaneous toxicities should be a priority, as their development may indicate a favorable response to treatment. Dermatologists have a unique opportunity to collaborate with oncologists to help identify and manage these toxicities, thereby allowing patients to receive life-prolonging anticancer therapy while minimizing dose reduction or interruption of their treatment,” the authors wrote.

They reported no study funding source and no conflicts of interest.

SOURCE: Rzepecki A, et al. J Am Acad Dermatol. 2018;79:545-555.

Signs of efficacy of anti-cancer therapies may be only skin deep, results of a retrospective review indicate.

Cutaneous toxicities such as vitiligo, rash, alopecia, and nail toxicities may be early signs of efficacy of targeted therapies, immunotherapy, or cytotoxic chemotherapy, according to Alexandra K. Rzepecki, of the University of Michigan, and her coauthors from Albert Einstein Medical College in the Bronx, New York.

“Because cutaneous toxicities are a clinically visible parameter, they may alert clinicians to the possibility of treatment success or failure in a rapid, cost-effective, and noninvasive manner,” they wrote. The report is in the Journal of the American Academy of Dermatology.

The investigators reviewed the medical literature for clinical studies of three major classes of anti-cancer therapies that included data on associations between cutaneous toxicities and clinical outcomes such progression-free survival (PFS) overall survival (OS).

The drug classes and their associations with cutaneous toxicities and clinical outcomes were as follows:

• Targeted therapies, including tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) such as cetuximab (Erbitux) and erlotinib (Tarceva), and multikinase targeted agents such as sorafenib (Nexavar) and sunitinib (Sutent). Toxicities associated with clinical benefit from EGFR inhibitors include rash, xerosis, leukocytoclastic vasculitis, paronychia, and pruritus, whereas skin toxicities associated with the multikinase inhibitors trended toward the hand-foot syndrome and hand-foot skin reaction.
• Immunotherapies included blockers of cytotoxic T-lymphocyte associated protein 4 (CTLA4) such as ipilimumab (Yervoy) and inhibitors of programmed death 1 protein (PD-1) and its ligand 1 (PD-L1) such as nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). In studies of pembrolizumab for various malignancies, rash or vitiligo was an independent prognostic factor for longer OS, a higher proportion of objective responses, and longer PFS. Similar associations were seen with nivolumab, with the additional association of hair repigmentation among patients with non–small-cell lung cancer being associated with stable disease responses or better. Among patients with melanoma treated with ipilimumab, hair depigmentation correlated with durable responses.
• Cytotoxic chemotherapy agents included the anthracycline doxorubicin, taxanes such as paclitaxel and docetaxel, platinum agents (cisplatin and carboplatin), and fluoropyrimidines such as capecitabine. Patients treated for various cancers with doxorubicin who had alopecia were significantly more likely to have clinical remissions than were patients who did not lose their hair, and patients treated with this agent who developed hand-foot syndrome had significantly longer PFS. For patients treated with docetaxel, severity of nail changes and/or development of nail alterations were associated with both improved OS and PFS. Patients treated with the combination of paclitaxel and a platinum agent who developed grade 2 or greater alopecia up to cycle 3 had significantly longer OS than did patients who had hair loss later in the course of therapy. Patients treated with capecitabine who developed had hand-foot skin reactions had improved progression-free and disease-free survival.

“Although further studies are needed to better evaluate these promising associations, vigilant monitoring of cutaneous toxicities should be a priority, as their development may indicate a favorable response to treatment. Dermatologists have a unique opportunity to collaborate with oncologists to help identify and manage these toxicities, thereby allowing patients to receive life-prolonging anticancer therapy while minimizing dose reduction or interruption of their treatment,” the authors wrote.

They reported no study funding source and no conflicts of interest.

SOURCE: Rzepecki A, et al. J Am Acad Dermatol. 2018;79:545-555.

Signs of efficacy of anti-cancer therapies may be only skin deep, results of a retrospective review indicate.

Cutaneous toxicities such as vitiligo, rash, alopecia, and nail toxicities may be early signs of efficacy of targeted therapies, immunotherapy, or cytotoxic chemotherapy, according to Alexandra K. Rzepecki, of the University of Michigan, and her coauthors from Albert Einstein Medical College in the Bronx, New York.

“Because cutaneous toxicities are a clinically visible parameter, they may alert clinicians to the possibility of treatment success or failure in a rapid, cost-effective, and noninvasive manner,” they wrote. The report is in the Journal of the American Academy of Dermatology.

The investigators reviewed the medical literature for clinical studies of three major classes of anti-cancer therapies that included data on associations between cutaneous toxicities and clinical outcomes such progression-free survival (PFS) overall survival (OS).

The drug classes and their associations with cutaneous toxicities and clinical outcomes were as follows:

• Targeted therapies, including tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) such as cetuximab (Erbitux) and erlotinib (Tarceva), and multikinase targeted agents such as sorafenib (Nexavar) and sunitinib (Sutent). Toxicities associated with clinical benefit from EGFR inhibitors include rash, xerosis, leukocytoclastic vasculitis, paronychia, and pruritus, whereas skin toxicities associated with the multikinase inhibitors trended toward the hand-foot syndrome and hand-foot skin reaction.
• Immunotherapies included blockers of cytotoxic T-lymphocyte associated protein 4 (CTLA4) such as ipilimumab (Yervoy) and inhibitors of programmed death 1 protein (PD-1) and its ligand 1 (PD-L1) such as nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). In studies of pembrolizumab for various malignancies, rash or vitiligo was an independent prognostic factor for longer OS, a higher proportion of objective responses, and longer PFS. Similar associations were seen with nivolumab, with the additional association of hair repigmentation among patients with non–small-cell lung cancer being associated with stable disease responses or better. Among patients with melanoma treated with ipilimumab, hair depigmentation correlated with durable responses.
• Cytotoxic chemotherapy agents included the anthracycline doxorubicin, taxanes such as paclitaxel and docetaxel, platinum agents (cisplatin and carboplatin), and fluoropyrimidines such as capecitabine. Patients treated for various cancers with doxorubicin who had alopecia were significantly more likely to have clinical remissions than were patients who did not lose their hair, and patients treated with this agent who developed hand-foot syndrome had significantly longer PFS. For patients treated with docetaxel, severity of nail changes and/or development of nail alterations were associated with both improved OS and PFS. Patients treated with the combination of paclitaxel and a platinum agent who developed grade 2 or greater alopecia up to cycle 3 had significantly longer OS than did patients who had hair loss later in the course of therapy. Patients treated with capecitabine who developed had hand-foot skin reactions had improved progression-free and disease-free survival.

“Although further studies are needed to better evaluate these promising associations, vigilant monitoring of cutaneous toxicities should be a priority, as their development may indicate a favorable response to treatment. Dermatologists have a unique opportunity to collaborate with oncologists to help identify and manage these toxicities, thereby allowing patients to receive life-prolonging anticancer therapy while minimizing dose reduction or interruption of their treatment,” the authors wrote.

They reported no study funding source and no conflicts of interest.

SOURCE: Rzepecki A, et al. J Am Acad Dermatol. 2018;79:545-555.

Checkpoint inhibitor therapy is effective for patients with HIV-associated Kaposi sarcoma (KS), a recent study has found.

Partial or complete remission was achieved by a majority of patients; others currently have stable disease lasting longer than 6 months, reported Natalie Galanina, MD, of Rebecca and John Moores Cancer Center at the University of California, San Diego, and her colleagues. Earlier this year, investigators reported similar responses to checkpoint inhibitors in two patients with KS that wasn’t associated with HIV.

“An association has been demonstrated between chronic viral infection, malignancy, and up-regulation of programmed death receptor 1 (PD-1) on CD8+ cytotoxic T-lymphocytes,” the authors wrote in Cancer Immunology Research. In particular, “HIV-specific CD8+ T cells have increased PD-1 expression, which … promotes a cellular milieu conducive to oncogenesis.” These factors, together with the results from the previous study, have suggested that checkpoint inhibitors may be effective for patients with HIV-associated KS.

The retrospective study involved 320 patients treated with immunotherapy at Moores Cancer Center from August 2013 through December 2017. From this group, nine cases of HIV-associated KS were found. Median CD4 count was 256 cells/mcL and median viral load was 20 copies/mL. Eight patients were treated with nivolumab and one was treated with pembrolizumab. Median age was 44 years. All patients were male and receiving antiretroviral therapy.

Six patients (67%) achieved remission, with five attaining partial remission and one attaining complete remission (gastrointestinal disease). Of the remaining three patients, two currently have stable disease lasting longer than 6 months, and one has stable disease lasting longer than 3 months.

Muscle aches, pruritus, and low-grade fever were the most common adverse events. No grade 3 or higher drug-related adverse events occurred.

“Most of our patients received one to four prior lines of therapy but still responded to checkpoint blockade,” the authors wrote. “Our observations suggest that patients with HIV-associated KS have high [response rates] to PD-1 checkpoint blockade, without significant toxicity, even in the presence of low [tumor mutational burden] and/or lack of PD-L1 expression.”

Authors reported compensation from Incyte, Genentech, Merck, Pfizer, and others.

SOURCE: Galanina et al. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-18-0121.

Checkpoint inhibitor therapy is effective for patients with HIV-associated Kaposi sarcoma (KS), a recent study has found.

Partial or complete remission was achieved by a majority of patients; others currently have stable disease lasting longer than 6 months, reported Natalie Galanina, MD, of Rebecca and John Moores Cancer Center at the University of California, San Diego, and her colleagues. Earlier this year, investigators reported similar responses to checkpoint inhibitors in two patients with KS that wasn’t associated with HIV.

“An association has been demonstrated between chronic viral infection, malignancy, and up-regulation of programmed death receptor 1 (PD-1) on CD8+ cytotoxic T-lymphocytes,” the authors wrote in Cancer Immunology Research. In particular, “HIV-specific CD8+ T cells have increased PD-1 expression, which … promotes a cellular milieu conducive to oncogenesis.” These factors, together with the results from the previous study, have suggested that checkpoint inhibitors may be effective for patients with HIV-associated KS.

The retrospective study involved 320 patients treated with immunotherapy at Moores Cancer Center from August 2013 through December 2017. From this group, nine cases of HIV-associated KS were found. Median CD4 count was 256 cells/mcL and median viral load was 20 copies/mL. Eight patients were treated with nivolumab and one was treated with pembrolizumab. Median age was 44 years. All patients were male and receiving antiretroviral therapy.

Six patients (67%) achieved remission, with five attaining partial remission and one attaining complete remission (gastrointestinal disease). Of the remaining three patients, two currently have stable disease lasting longer than 6 months, and one has stable disease lasting longer than 3 months.

Muscle aches, pruritus, and low-grade fever were the most common adverse events. No grade 3 or higher drug-related adverse events occurred.

“Most of our patients received one to four prior lines of therapy but still responded to checkpoint blockade,” the authors wrote. “Our observations suggest that patients with HIV-associated KS have high [response rates] to PD-1 checkpoint blockade, without significant toxicity, even in the presence of low [tumor mutational burden] and/or lack of PD-L1 expression.”

Authors reported compensation from Incyte, Genentech, Merck, Pfizer, and others.

SOURCE: Galanina et al. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-18-0121.

Checkpoint inhibitor therapy is effective for patients with HIV-associated Kaposi sarcoma (KS), a recent study has found.

Partial or complete remission was achieved by a majority of patients; others currently have stable disease lasting longer than 6 months, reported Natalie Galanina, MD, of Rebecca and John Moores Cancer Center at the University of California, San Diego, and her colleagues. Earlier this year, investigators reported similar responses to checkpoint inhibitors in two patients with KS that wasn’t associated with HIV.

“An association has been demonstrated between chronic viral infection, malignancy, and up-regulation of programmed death receptor 1 (PD-1) on CD8+ cytotoxic T-lymphocytes,” the authors wrote in Cancer Immunology Research. In particular, “HIV-specific CD8+ T cells have increased PD-1 expression, which … promotes a cellular milieu conducive to oncogenesis.” These factors, together with the results from the previous study, have suggested that checkpoint inhibitors may be effective for patients with HIV-associated KS.

The retrospective study involved 320 patients treated with immunotherapy at Moores Cancer Center from August 2013 through December 2017. From this group, nine cases of HIV-associated KS were found. Median CD4 count was 256 cells/mcL and median viral load was 20 copies/mL. Eight patients were treated with nivolumab and one was treated with pembrolizumab. Median age was 44 years. All patients were male and receiving antiretroviral therapy.

Six patients (67%) achieved remission, with five attaining partial remission and one attaining complete remission (gastrointestinal disease). Of the remaining three patients, two currently have stable disease lasting longer than 6 months, and one has stable disease lasting longer than 3 months.

Muscle aches, pruritus, and low-grade fever were the most common adverse events. No grade 3 or higher drug-related adverse events occurred.

“Most of our patients received one to four prior lines of therapy but still responded to checkpoint blockade,” the authors wrote. “Our observations suggest that patients with HIV-associated KS have high [response rates] to PD-1 checkpoint blockade, without significant toxicity, even in the presence of low [tumor mutational burden] and/or lack of PD-L1 expression.”

Authors reported compensation from Incyte, Genentech, Merck, Pfizer, and others.

SOURCE: Galanina et al. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-18-0121.

Expression of programmed death-1 (PD1) mRNA may predict outcomes after anti-PD1 therapy across cancer types, according to investigators.

High levels of PD1 mRNA were significantly associated with response to anti-PD1 monotherapy, investigators found in an analysis of tumor samples from 117 patients with advanced cancers who had received either nivolumab or pembrolizumab.

Further validation of PD1 mRNA is warranted to help select patients who might benefit from an anti-PD1 treatment strategy, wrote investigator Aleix Prat, MD, PhD, of Hospital Clínic of Barcelona, and his coinvestigators.

“Identification of reproducible biomarkers that can be applied to predict benefit of anti-PD1 monotherapy might be of clinical value,” Dr. Prat and his coinvestigators note. The report is in Annals of Oncology.

Previous studies support use of PDL1 expression by immunohistochemistry as a biomarker for pembrolizumab in non–small-cell lung cancer; however, that biomarker has some technical limitations, and has not been predictive in other cancer types and with other anti-PD1 drugs including nivolumab, Dr. Prat and his coinvestigators said.

The 117 tumor samples evaluated for PD1 mRNA expression comprised 59 advanced melanomas, 32 non–small-cell lung cancers, 14 renal cell cancers, and 12 other tumors, according to the report. Sixty-two of the patients had been treated with pembrolizumab, and 55 received nivolumab.

About one-quarter of the samples (28.2%) were classified as “PD1-high” with a preestablished cutoff value developed by Dr. Prat and his coinvestigators.

The overall response rate was 51.5% for the patients who had PD1-high tumors, versus 23.8% for the remaining tumors (P less than .001). Those non-PD1-high tumors, when grouped as PD1-intermediate and PD1-low, had overall response rates of 26.6% and 15.0%, respectively.

Median progression-free survival was 8.17 months for PD1-high tumors and 3.18 months for the rest of the tumors (P = .011), the report shows. Similarly, overall survival was a median of 23.4 months for PD1-high tumors and 14.9 months for the rest (P = .330).

Dr. Prat and his colleagues detailed earlier investigations validating PD1 mRNA as a biomarker, including an analysis of PD1 and immune-related gene expression in 10,078 samples from 34 cancer types in The Cancer Genome Atlas.

In that analysis, PD1 was strongly correlated with a group of 30 genes that were “significantly enriched” in biological processes including CD8-T-cell activation, the investigators said.

Moreover, high levels of PD1 mRNA expression were strongly correlated with overall response rates reported in the literature for anti-PD1 monotherapy, they added.

They also reported results of an analysis they used to develop the PD1-high cutoff value. That analysis was based on PD1 mRNA expression in 773 tumor samples across 17 tumor types.

“Our results are consistent with the hypothesis that identification of a preexisting and stable adaptive immune response using PD1 mRNA expression predicts outcome across cancer-types following anti-PD1 monotherapy,” the researchers wrote.

The work was partially sponsored by Instituto de Salud Carlos III, Spanish Society of Medical Oncology, Banco Bilbao Vizcaya Argentaria Foundation, Pas a Pas, Save the Mama, and the Breast Cancer Research Foundation. Dr. Prat disclosed an advisory role with Nanostring Technologies.

SOURCE: Paré L et al. Ann Oncol. 2018 Aug 27. doi: 10.1093/annonc/mdy335.

Expression of programmed death-1 (PD1) mRNA may predict outcomes after anti-PD1 therapy across cancer types, according to investigators.

High levels of PD1 mRNA were significantly associated with response to anti-PD1 monotherapy, investigators found in an analysis of tumor samples from 117 patients with advanced cancers who had received either nivolumab or pembrolizumab.

Further validation of PD1 mRNA is warranted to help select patients who might benefit from an anti-PD1 treatment strategy, wrote investigator Aleix Prat, MD, PhD, of Hospital Clínic of Barcelona, and his coinvestigators.

“Identification of reproducible biomarkers that can be applied to predict benefit of anti-PD1 monotherapy might be of clinical value,” Dr. Prat and his coinvestigators note. The report is in Annals of Oncology.

Previous studies support use of PDL1 expression by immunohistochemistry as a biomarker for pembrolizumab in non–small-cell lung cancer; however, that biomarker has some technical limitations, and has not been predictive in other cancer types and with other anti-PD1 drugs including nivolumab, Dr. Prat and his coinvestigators said.

The 117 tumor samples evaluated for PD1 mRNA expression comprised 59 advanced melanomas, 32 non–small-cell lung cancers, 14 renal cell cancers, and 12 other tumors, according to the report. Sixty-two of the patients had been treated with pembrolizumab, and 55 received nivolumab.

About one-quarter of the samples (28.2%) were classified as “PD1-high” with a preestablished cutoff value developed by Dr. Prat and his coinvestigators.

The overall response rate was 51.5% for the patients who had PD1-high tumors, versus 23.8% for the remaining tumors (P less than .001). Those non-PD1-high tumors, when grouped as PD1-intermediate and PD1-low, had overall response rates of 26.6% and 15.0%, respectively.

Median progression-free survival was 8.17 months for PD1-high tumors and 3.18 months for the rest of the tumors (P = .011), the report shows. Similarly, overall survival was a median of 23.4 months for PD1-high tumors and 14.9 months for the rest (P = .330).

Dr. Prat and his colleagues detailed earlier investigations validating PD1 mRNA as a biomarker, including an analysis of PD1 and immune-related gene expression in 10,078 samples from 34 cancer types in The Cancer Genome Atlas.

In that analysis, PD1 was strongly correlated with a group of 30 genes that were “significantly enriched” in biological processes including CD8-T-cell activation, the investigators said.

Moreover, high levels of PD1 mRNA expression were strongly correlated with overall response rates reported in the literature for anti-PD1 monotherapy, they added.

They also reported results of an analysis they used to develop the PD1-high cutoff value. That analysis was based on PD1 mRNA expression in 773 tumor samples across 17 tumor types.

“Our results are consistent with the hypothesis that identification of a preexisting and stable adaptive immune response using PD1 mRNA expression predicts outcome across cancer-types following anti-PD1 monotherapy,” the researchers wrote.

The work was partially sponsored by Instituto de Salud Carlos III, Spanish Society of Medical Oncology, Banco Bilbao Vizcaya Argentaria Foundation, Pas a Pas, Save the Mama, and the Breast Cancer Research Foundation. Dr. Prat disclosed an advisory role with Nanostring Technologies.

SOURCE: Paré L et al. Ann Oncol. 2018 Aug 27. doi: 10.1093/annonc/mdy335.

Expression of programmed death-1 (PD1) mRNA may predict outcomes after anti-PD1 therapy across cancer types, according to investigators.

High levels of PD1 mRNA were significantly associated with response to anti-PD1 monotherapy, investigators found in an analysis of tumor samples from 117 patients with advanced cancers who had received either nivolumab or pembrolizumab.

Further validation of PD1 mRNA is warranted to help select patients who might benefit from an anti-PD1 treatment strategy, wrote investigator Aleix Prat, MD, PhD, of Hospital Clínic of Barcelona, and his coinvestigators.

“Identification of reproducible biomarkers that can be applied to predict benefit of anti-PD1 monotherapy might be of clinical value,” Dr. Prat and his coinvestigators note. The report is in Annals of Oncology.

Previous studies support use of PDL1 expression by immunohistochemistry as a biomarker for pembrolizumab in non–small-cell lung cancer; however, that biomarker has some technical limitations, and has not been predictive in other cancer types and with other anti-PD1 drugs including nivolumab, Dr. Prat and his coinvestigators said.

The 117 tumor samples evaluated for PD1 mRNA expression comprised 59 advanced melanomas, 32 non–small-cell lung cancers, 14 renal cell cancers, and 12 other tumors, according to the report. Sixty-two of the patients had been treated with pembrolizumab, and 55 received nivolumab.

About one-quarter of the samples (28.2%) were classified as “PD1-high” with a preestablished cutoff value developed by Dr. Prat and his coinvestigators.

The overall response rate was 51.5% for the patients who had PD1-high tumors, versus 23.8% for the remaining tumors (P less than .001). Those non-PD1-high tumors, when grouped as PD1-intermediate and PD1-low, had overall response rates of 26.6% and 15.0%, respectively.

Median progression-free survival was 8.17 months for PD1-high tumors and 3.18 months for the rest of the tumors (P = .011), the report shows. Similarly, overall survival was a median of 23.4 months for PD1-high tumors and 14.9 months for the rest (P = .330).

Dr. Prat and his colleagues detailed earlier investigations validating PD1 mRNA as a biomarker, including an analysis of PD1 and immune-related gene expression in 10,078 samples from 34 cancer types in The Cancer Genome Atlas.

In that analysis, PD1 was strongly correlated with a group of 30 genes that were “significantly enriched” in biological processes including CD8-T-cell activation, the investigators said.

Moreover, high levels of PD1 mRNA expression were strongly correlated with overall response rates reported in the literature for anti-PD1 monotherapy, they added.

They also reported results of an analysis they used to develop the PD1-high cutoff value. That analysis was based on PD1 mRNA expression in 773 tumor samples across 17 tumor types.

“Our results are consistent with the hypothesis that identification of a preexisting and stable adaptive immune response using PD1 mRNA expression predicts outcome across cancer-types following anti-PD1 monotherapy,” the researchers wrote.

The work was partially sponsored by Instituto de Salud Carlos III, Spanish Society of Medical Oncology, Banco Bilbao Vizcaya Argentaria Foundation, Pas a Pas, Save the Mama, and the Breast Cancer Research Foundation. Dr. Prat disclosed an advisory role with Nanostring Technologies.

SOURCE: Paré L et al. Ann Oncol. 2018 Aug 27. doi: 10.1093/annonc/mdy335.

Drugmakers and physician groups expressed concern about connecting patient reported outcomes (PRO) to coverage decisions for chimeric antigen receptor T-cell therapy (CAR T) at a recent Medicare meeting.

copyright roobcio/Thinkstock

Despite these objections, members of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) generally expressed confidence in the use of PROs in a series of votes about PRO instruments’ use in cancer care trials.

MEDCAC opened a national coverage analysis in May 2018 at the request of UnitedHealthcare. The insurer had asked the Centers for Medicare & Medicaid Services to clarify the circumstances for coverage of the new CAR T therapies.

In presentations at an Aug. 22 MEDCAC meeting, representatives from the two manufacturers that have approved CAR T treatments on the market cautioned against using PROs in the context of coverage decisions, even though both companies used PRO data in their clinical trials and are collecting it in the postmarketing period.

“While Kite recognizes the importance of PROs in ... clinical trials, the PRO CAR T science, where these instruments are most appropriate for CAR T, remains a still to be determined and still is evolving and still quite early in the developments,” said William Go, MD, PhD, vice president of clinical development at Kite Pharmaceuticals, a Gilead company.

Despite PROs playing an active role in the ongoing development and clinical trials that Kite is running, in the context of CAR T, “we feel PROs are not quite ready for real-world coverage decisions at this time,” Dr. Go said.

A representative from Novartis agreed. “It is important to clearly define research objectives when considering whether to collect patient reported outcomes data, particularly given the burden associated with advanced disease experienced by the patients that are likely to receive this therapy,” Ilia Ferrusi, PhD, associate director, HEOR (CAR T Therapy), U.S. Oncology, Novartis, told the panel.

She noted that Novartis experienced challenges collecting PRO data, which resulted in risks to data quality and interpretation. “This could very well be amplified in larger trials or in real-world practice.”

The presenters’ comments were echoed by written comments submitted to the CMS prior to the MEDCAC meeting.

The American Society for Blood and Marrow Transplantation (ASBMT), despite supporting the collection of patient-reported outcomes, particularly in oncology, “strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR T therapy,” the organization said in a letter to the CMS.

Optimal PRO instruments and time points “are currently unknown” as the PROs used today were developed around chemotherapy use.

“Mandating the use of a current instrument or set of outcomes through NCD [national coverage determination] or CED [coverage with evidence development] will set a course of collecting data that is very likely to be inaccurate and inadequate,” they said.

The ASBMT also noted there is significant heterogeneity in the CAR T constructs and associated disease indications. “Products will utilize different scientific constructs and the time frames for clinical response and/or potential onset of toxicities may differ for each construct, which will challenge the establishment of set time points for data collection.”

And while presentations and comments focused on PROs in the context of CAR T, conversation and voting on the use of PROs was in the broader context of oncology clinical trials, not specific to CAR T, changing the nature of the debate and calling into question the point of the meeting and how it will inform the national coverage determination on CAR T specifically.

The June 15 meeting announcement published in the Federal Register stated that the advisory committee “will specifically focus on appraisal of evidence-based PRO assessments to provide information that impacts patients, their providers, and caregivers after a CAR T-cell therapy intervention for the patient’s cancer.”

However, the committee was asked to evaluate evidence on a number of potential PRO instruments in the broader context of oncology clinical trials without a cancer-specific or treatment-specific context, leading to a debate over how different types of cancer will have different kinds of PRO assessments related to them.

The CMS is expected to make a national coverage decision on CAR T-cell therapy by Feb. 16, 2019.

gtwachtman@mdedge.com

Drugmakers and physician groups expressed concern about connecting patient reported outcomes (PRO) to coverage decisions for chimeric antigen receptor T-cell therapy (CAR T) at a recent Medicare meeting.

copyright roobcio/Thinkstock

Despite these objections, members of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) generally expressed confidence in the use of PROs in a series of votes about PRO instruments’ use in cancer care trials.

MEDCAC opened a national coverage analysis in May 2018 at the request of UnitedHealthcare. The insurer had asked the Centers for Medicare & Medicaid Services to clarify the circumstances for coverage of the new CAR T therapies.

In presentations at an Aug. 22 MEDCAC meeting, representatives from the two manufacturers that have approved CAR T treatments on the market cautioned against using PROs in the context of coverage decisions, even though both companies used PRO data in their clinical trials and are collecting it in the postmarketing period.

“While Kite recognizes the importance of PROs in ... clinical trials, the PRO CAR T science, where these instruments are most appropriate for CAR T, remains a still to be determined and still is evolving and still quite early in the developments,” said William Go, MD, PhD, vice president of clinical development at Kite Pharmaceuticals, a Gilead company.

Despite PROs playing an active role in the ongoing development and clinical trials that Kite is running, in the context of CAR T, “we feel PROs are not quite ready for real-world coverage decisions at this time,” Dr. Go said.

A representative from Novartis agreed. “It is important to clearly define research objectives when considering whether to collect patient reported outcomes data, particularly given the burden associated with advanced disease experienced by the patients that are likely to receive this therapy,” Ilia Ferrusi, PhD, associate director, HEOR (CAR T Therapy), U.S. Oncology, Novartis, told the panel.

She noted that Novartis experienced challenges collecting PRO data, which resulted in risks to data quality and interpretation. “This could very well be amplified in larger trials or in real-world practice.”

The presenters’ comments were echoed by written comments submitted to the CMS prior to the MEDCAC meeting.

The American Society for Blood and Marrow Transplantation (ASBMT), despite supporting the collection of patient-reported outcomes, particularly in oncology, “strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR T therapy,” the organization said in a letter to the CMS.

Optimal PRO instruments and time points “are currently unknown” as the PROs used today were developed around chemotherapy use.

“Mandating the use of a current instrument or set of outcomes through NCD [national coverage determination] or CED [coverage with evidence development] will set a course of collecting data that is very likely to be inaccurate and inadequate,” they said.

The ASBMT also noted there is significant heterogeneity in the CAR T constructs and associated disease indications. “Products will utilize different scientific constructs and the time frames for clinical response and/or potential onset of toxicities may differ for each construct, which will challenge the establishment of set time points for data collection.”

And while presentations and comments focused on PROs in the context of CAR T, conversation and voting on the use of PROs was in the broader context of oncology clinical trials, not specific to CAR T, changing the nature of the debate and calling into question the point of the meeting and how it will inform the national coverage determination on CAR T specifically.

The June 15 meeting announcement published in the Federal Register stated that the advisory committee “will specifically focus on appraisal of evidence-based PRO assessments to provide information that impacts patients, their providers, and caregivers after a CAR T-cell therapy intervention for the patient’s cancer.”

However, the committee was asked to evaluate evidence on a number of potential PRO instruments in the broader context of oncology clinical trials without a cancer-specific or treatment-specific context, leading to a debate over how different types of cancer will have different kinds of PRO assessments related to them.

The CMS is expected to make a national coverage decision on CAR T-cell therapy by Feb. 16, 2019.

gtwachtman@mdedge.com

Drugmakers and physician groups expressed concern about connecting patient reported outcomes (PRO) to coverage decisions for chimeric antigen receptor T-cell therapy (CAR T) at a recent Medicare meeting.

copyright roobcio/Thinkstock

Despite these objections, members of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) generally expressed confidence in the use of PROs in a series of votes about PRO instruments’ use in cancer care trials.

MEDCAC opened a national coverage analysis in May 2018 at the request of UnitedHealthcare. The insurer had asked the Centers for Medicare & Medicaid Services to clarify the circumstances for coverage of the new CAR T therapies.

In presentations at an Aug. 22 MEDCAC meeting, representatives from the two manufacturers that have approved CAR T treatments on the market cautioned against using PROs in the context of coverage decisions, even though both companies used PRO data in their clinical trials and are collecting it in the postmarketing period.

“While Kite recognizes the importance of PROs in ... clinical trials, the PRO CAR T science, where these instruments are most appropriate for CAR T, remains a still to be determined and still is evolving and still quite early in the developments,” said William Go, MD, PhD, vice president of clinical development at Kite Pharmaceuticals, a Gilead company.

Despite PROs playing an active role in the ongoing development and clinical trials that Kite is running, in the context of CAR T, “we feel PROs are not quite ready for real-world coverage decisions at this time,” Dr. Go said.

A representative from Novartis agreed. “It is important to clearly define research objectives when considering whether to collect patient reported outcomes data, particularly given the burden associated with advanced disease experienced by the patients that are likely to receive this therapy,” Ilia Ferrusi, PhD, associate director, HEOR (CAR T Therapy), U.S. Oncology, Novartis, told the panel.

She noted that Novartis experienced challenges collecting PRO data, which resulted in risks to data quality and interpretation. “This could very well be amplified in larger trials or in real-world practice.”

The presenters’ comments were echoed by written comments submitted to the CMS prior to the MEDCAC meeting.

The American Society for Blood and Marrow Transplantation (ASBMT), despite supporting the collection of patient-reported outcomes, particularly in oncology, “strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR T therapy,” the organization said in a letter to the CMS.

Optimal PRO instruments and time points “are currently unknown” as the PROs used today were developed around chemotherapy use.

“Mandating the use of a current instrument or set of outcomes through NCD [national coverage determination] or CED [coverage with evidence development] will set a course of collecting data that is very likely to be inaccurate and inadequate,” they said.

The ASBMT also noted there is significant heterogeneity in the CAR T constructs and associated disease indications. “Products will utilize different scientific constructs and the time frames for clinical response and/or potential onset of toxicities may differ for each construct, which will challenge the establishment of set time points for data collection.”

And while presentations and comments focused on PROs in the context of CAR T, conversation and voting on the use of PROs was in the broader context of oncology clinical trials, not specific to CAR T, changing the nature of the debate and calling into question the point of the meeting and how it will inform the national coverage determination on CAR T specifically.

The June 15 meeting announcement published in the Federal Register stated that the advisory committee “will specifically focus on appraisal of evidence-based PRO assessments to provide information that impacts patients, their providers, and caregivers after a CAR T-cell therapy intervention for the patient’s cancer.”

However, the committee was asked to evaluate evidence on a number of potential PRO instruments in the broader context of oncology clinical trials without a cancer-specific or treatment-specific context, leading to a debate over how different types of cancer will have different kinds of PRO assessments related to them.

The CMS is expected to make a national coverage decision on CAR T-cell therapy by Feb. 16, 2019.

gtwachtman@mdedge.com

Treatment with nivolumab plus ipilimumab resulted in clinically meaningful efficacy for melanoma patients with asymptomatic, previously untreated brain metastases, results of an open-label, multicenter, phase 2 study have shown.

The combination of these two immune checkpoint inhibitors produced intracranial responses in more than half of the patients treated, and perhaps more importantly, according to the study investigators, the combination treatment prevented intracranial progression for more than 6 months in 64% of the study population.

“These results are relevant in a population in whom progression can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,” the study investigators wrote in the New England Journal of Medicine.

The investigators, led by Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer, Houston, initially enrolled 101 patients with histologically confirmed melanoma and metastases to the brain that were asymptomatic. All patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had not received systemic glucocorticoid therapy within 10 days of study treatment.

The primary endpoint of the study was the rate of intracranial benefit, defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months after starting treatment.

For 94 patients with at least 6 months of follow-up at the time of analysis (median follow-up, 14 months), the rate of intracranial benefit was 57%, including complete responses in 26%, partial responses in 30%, and stable disease in 2%, the investigators reported. The rate of extracranial benefit was similar, at 56%.

The 6-month rate of progression-free survival was 64.2% for intracranial assessments, while the 6-month overall survival rate was 92.3%, according to results of an initial assessment.

Grade 3 or 4 adverse events thought to be related to treatment occurred in 55% of patients and led to treatment discontinuation in 20%; the most common were increased levels of ALT and AST.

Dr. Tawbi and his colleagues said that, while cross-trial comparisons have inherent limitations, the rate of intracranial response seen in this trial is similar to what was seen in the COMBI-MB study of dabrafenib plus trametinib in patients with BRAF-mutant melanoma and brain metastases. However, in that study, published in 2017 in the Lancet, the combination of a BRAF inhibitor and MEK inhibitor had rates of intracranial response and progression-free survival that were “substantially shorter” than the rates of extracranial response and progression-free survival.

“In our study, the use of immunotherapy seemed capable of inducing intracranial responses that were very similar to extracranial responses in character, depth, and duration,” they wrote.

Dr. Tawbi and his coinvestigators enrolled an additional 20 symptomatic patients with brain metastases following a study protocol amendment; however, results from that cohort are not being reported yet because of inadequate follow-up length, they said.

The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. Dr. Tawbi reported disclosures related to Bristol-Myers Squibb, Merck, Genentech, and Novartis. His coauthors reported additional disclosures related to MedImmune, AstraZeneca, Dynavax Technologies, Genoptix, Exelixis, Acceleron Pharma, and Eisai, among others.

SOURCE: Tawbi HA et al. N Engl J Med. 2018 Aug 23. doi: 10.1056/NEJMoa1805453.

Treatment with nivolumab plus ipilimumab resulted in clinically meaningful efficacy for melanoma patients with asymptomatic, previously untreated brain metastases, results of an open-label, multicenter, phase 2 study have shown.

The combination of these two immune checkpoint inhibitors produced intracranial responses in more than half of the patients treated, and perhaps more importantly, according to the study investigators, the combination treatment prevented intracranial progression for more than 6 months in 64% of the study population.

“These results are relevant in a population in whom progression can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,” the study investigators wrote in the New England Journal of Medicine.

The investigators, led by Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer, Houston, initially enrolled 101 patients with histologically confirmed melanoma and metastases to the brain that were asymptomatic. All patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had not received systemic glucocorticoid therapy within 10 days of study treatment.

The primary endpoint of the study was the rate of intracranial benefit, defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months after starting treatment.

For 94 patients with at least 6 months of follow-up at the time of analysis (median follow-up, 14 months), the rate of intracranial benefit was 57%, including complete responses in 26%, partial responses in 30%, and stable disease in 2%, the investigators reported. The rate of extracranial benefit was similar, at 56%.

The 6-month rate of progression-free survival was 64.2% for intracranial assessments, while the 6-month overall survival rate was 92.3%, according to results of an initial assessment.

Grade 3 or 4 adverse events thought to be related to treatment occurred in 55% of patients and led to treatment discontinuation in 20%; the most common were increased levels of ALT and AST.

Dr. Tawbi and his colleagues said that, while cross-trial comparisons have inherent limitations, the rate of intracranial response seen in this trial is similar to what was seen in the COMBI-MB study of dabrafenib plus trametinib in patients with BRAF-mutant melanoma and brain metastases. However, in that study, published in 2017 in the Lancet, the combination of a BRAF inhibitor and MEK inhibitor had rates of intracranial response and progression-free survival that were “substantially shorter” than the rates of extracranial response and progression-free survival.

“In our study, the use of immunotherapy seemed capable of inducing intracranial responses that were very similar to extracranial responses in character, depth, and duration,” they wrote.

Dr. Tawbi and his coinvestigators enrolled an additional 20 symptomatic patients with brain metastases following a study protocol amendment; however, results from that cohort are not being reported yet because of inadequate follow-up length, they said.

The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. Dr. Tawbi reported disclosures related to Bristol-Myers Squibb, Merck, Genentech, and Novartis. His coauthors reported additional disclosures related to MedImmune, AstraZeneca, Dynavax Technologies, Genoptix, Exelixis, Acceleron Pharma, and Eisai, among others.

SOURCE: Tawbi HA et al. N Engl J Med. 2018 Aug 23. doi: 10.1056/NEJMoa1805453.

Treatment with nivolumab plus ipilimumab resulted in clinically meaningful efficacy for melanoma patients with asymptomatic, previously untreated brain metastases, results of an open-label, multicenter, phase 2 study have shown.

The combination of these two immune checkpoint inhibitors produced intracranial responses in more than half of the patients treated, and perhaps more importantly, according to the study investigators, the combination treatment prevented intracranial progression for more than 6 months in 64% of the study population.

“These results are relevant in a population in whom progression can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,” the study investigators wrote in the New England Journal of Medicine.

The investigators, led by Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer, Houston, initially enrolled 101 patients with histologically confirmed melanoma and metastases to the brain that were asymptomatic. All patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had not received systemic glucocorticoid therapy within 10 days of study treatment.

The primary endpoint of the study was the rate of intracranial benefit, defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months after starting treatment.

For 94 patients with at least 6 months of follow-up at the time of analysis (median follow-up, 14 months), the rate of intracranial benefit was 57%, including complete responses in 26%, partial responses in 30%, and stable disease in 2%, the investigators reported. The rate of extracranial benefit was similar, at 56%.

The 6-month rate of progression-free survival was 64.2% for intracranial assessments, while the 6-month overall survival rate was 92.3%, according to results of an initial assessment.

Grade 3 or 4 adverse events thought to be related to treatment occurred in 55% of patients and led to treatment discontinuation in 20%; the most common were increased levels of ALT and AST.

Dr. Tawbi and his colleagues said that, while cross-trial comparisons have inherent limitations, the rate of intracranial response seen in this trial is similar to what was seen in the COMBI-MB study of dabrafenib plus trametinib in patients with BRAF-mutant melanoma and brain metastases. However, in that study, published in 2017 in the Lancet, the combination of a BRAF inhibitor and MEK inhibitor had rates of intracranial response and progression-free survival that were “substantially shorter” than the rates of extracranial response and progression-free survival.

“In our study, the use of immunotherapy seemed capable of inducing intracranial responses that were very similar to extracranial responses in character, depth, and duration,” they wrote.

Dr. Tawbi and his coinvestigators enrolled an additional 20 symptomatic patients with brain metastases following a study protocol amendment; however, results from that cohort are not being reported yet because of inadequate follow-up length, they said.

The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. Dr. Tawbi reported disclosures related to Bristol-Myers Squibb, Merck, Genentech, and Novartis. His coauthors reported additional disclosures related to MedImmune, AstraZeneca, Dynavax Technologies, Genoptix, Exelixis, Acceleron Pharma, and Eisai, among others.

SOURCE: Tawbi HA et al. N Engl J Med. 2018 Aug 23. doi: 10.1056/NEJMoa1805453.

Among scenarios where immune checkpoint inhibitors (ICIs) might be combined, particular caution is needed in the setting of brain metastases, according to authors of a recent clinical review.

While evidence to date is mixed, some studies do suggest that adding ICIs to high-dose stereotactic intracranial radiotherapy for brain metastases might increase the risk of treatment-related brain necrosis, the authors said.

By contrast, the balance of evidence suggests ICIs can be safely combined with palliative radiotherapy without site-specific increases in adverse events, they added.

Likewise, in patients with non–small-cell lung cancer, ICIs do not appear to increase incidence of grade 3 or greater pneumonitis when given after definitive chemoradiotherapy, in both retrospective and prospective investigations.

Nevertheless, the addition of ICIs to radiotherapy requires careful further study because of the potential for increased type or severity of toxicities, including the immune-related adverse events associated with ICIs, wrote corresponding author Jay S. Loeffler, MD, of Massachusetts General Hospital, Boston, and his colleagues.

“Caution is warranted when combining radiotherapy and ICI, especially with intracranial radiotherapy,” the researchers wrote. Their report is in Nature Reviews Clinical Oncology.

Some studies have indicated a higher rate of treatment-associated brain necrosis when ICIs are combined with intracranial radiotherapy, while others have shown no such trend, the authors said.

In one single-institution experience involving 180 patients with brain metastases undergoing stereotactic radiotherapy, incidence of treatment-associated brain necrosis was significantly higher in patients receiving an ICI, with an odds ratio of 2.4 (95% confidence interval, 1.06-5.44; P = .03).

Similarly, a retrospective single institution 480-patient study showed an incidence of treatment-associated brain necrosis of 20% for ICIs plus stereotactic radiotherapy versus 7% for radiotherapy alone (P less than .001), but substantial differences in baseline characteristics between groups limited the strength of the study’s conclusions, according to the researchers.

Increased risk is primarily in the form of asymptomatic or minimally symptomatic episodes in some series, the authors noted. A retrospective, 54-patient report showed a rate of treatment-associated brain necrosis of 30% when ICIs were combined with stereotactic radiotherapy, versus 21% for radiotherapy alone (P = .08), but the incidence of symptomatic cases was 15% in both groups, they noted.

“Intriguingly, the findings of several studies have demonstrated an association between [treatment-associated brain necrosis] and improved survival outcomes in patients with melanoma brain metastases that is similar to the independent observations of an analogous relationship between risk of [immune-related adverse events] in general and responsiveness to ICI,” the researchers wrote.

Most of the Food and Drug Administration–approved indications for ICIs are in the metastatic setting, where palliative radiotherapy is frequently important, the authors noted.

In two retrospective studies of patients with metastatic cancers receiving palliative radiotherapy with ICIs, there was a lack of clear association between the irradiated site and specific immune-related adverse events; that lack of association suggests that any toxicities arising from interactions between palliative radiotherapy and ICIs are mainly systemic, rather than local, the authors wrote.

Several retrospective series in advanced-stage melanoma patients have suggested that palliative radiotherapy plus ICIs is safe and does not significantly increase incidence of immune-related adverse events. However, findings from one series showed a correlation between both the ICI and radiotherapy dose given and the incidence of immune-related adverse events.

Prospective studies will be essential to optimize the balance between disease control and risk of morbidity associated with ICIs and radiotherapy combinations, the authors concluded.

The researchers declared no competing interests related to their review article.

SOURCE: Hwang WL, et al. Nat Rev Clin Oncol. 2018 Aug;15(8):477-494.

Among scenarios where immune checkpoint inhibitors (ICIs) might be combined, particular caution is needed in the setting of brain metastases, according to authors of a recent clinical review.

While evidence to date is mixed, some studies do suggest that adding ICIs to high-dose stereotactic intracranial radiotherapy for brain metastases might increase the risk of treatment-related brain necrosis, the authors said.

By contrast, the balance of evidence suggests ICIs can be safely combined with palliative radiotherapy without site-specific increases in adverse events, they added.

Likewise, in patients with non–small-cell lung cancer, ICIs do not appear to increase incidence of grade 3 or greater pneumonitis when given after definitive chemoradiotherapy, in both retrospective and prospective investigations.

Nevertheless, the addition of ICIs to radiotherapy requires careful further study because of the potential for increased type or severity of toxicities, including the immune-related adverse events associated with ICIs, wrote corresponding author Jay S. Loeffler, MD, of Massachusetts General Hospital, Boston, and his colleagues.

“Caution is warranted when combining radiotherapy and ICI, especially with intracranial radiotherapy,” the researchers wrote. Their report is in Nature Reviews Clinical Oncology.

Some studies have indicated a higher rate of treatment-associated brain necrosis when ICIs are combined with intracranial radiotherapy, while others have shown no such trend, the authors said.

In one single-institution experience involving 180 patients with brain metastases undergoing stereotactic radiotherapy, incidence of treatment-associated brain necrosis was significantly higher in patients receiving an ICI, with an odds ratio of 2.4 (95% confidence interval, 1.06-5.44; P = .03).

Similarly, a retrospective single institution 480-patient study showed an incidence of treatment-associated brain necrosis of 20% for ICIs plus stereotactic radiotherapy versus 7% for radiotherapy alone (P less than .001), but substantial differences in baseline characteristics between groups limited the strength of the study’s conclusions, according to the researchers.

Increased risk is primarily in the form of asymptomatic or minimally symptomatic episodes in some series, the authors noted. A retrospective, 54-patient report showed a rate of treatment-associated brain necrosis of 30% when ICIs were combined with stereotactic radiotherapy, versus 21% for radiotherapy alone (P = .08), but the incidence of symptomatic cases was 15% in both groups, they noted.

“Intriguingly, the findings of several studies have demonstrated an association between [treatment-associated brain necrosis] and improved survival outcomes in patients with melanoma brain metastases that is similar to the independent observations of an analogous relationship between risk of [immune-related adverse events] in general and responsiveness to ICI,” the researchers wrote.

Most of the Food and Drug Administration–approved indications for ICIs are in the metastatic setting, where palliative radiotherapy is frequently important, the authors noted.

In two retrospective studies of patients with metastatic cancers receiving palliative radiotherapy with ICIs, there was a lack of clear association between the irradiated site and specific immune-related adverse events; that lack of association suggests that any toxicities arising from interactions between palliative radiotherapy and ICIs are mainly systemic, rather than local, the authors wrote.

Several retrospective series in advanced-stage melanoma patients have suggested that palliative radiotherapy plus ICIs is safe and does not significantly increase incidence of immune-related adverse events. However, findings from one series showed a correlation between both the ICI and radiotherapy dose given and the incidence of immune-related adverse events.

Prospective studies will be essential to optimize the balance between disease control and risk of morbidity associated with ICIs and radiotherapy combinations, the authors concluded.

The researchers declared no competing interests related to their review article.

SOURCE: Hwang WL, et al. Nat Rev Clin Oncol. 2018 Aug;15(8):477-494.

Among scenarios where immune checkpoint inhibitors (ICIs) might be combined, particular caution is needed in the setting of brain metastases, according to authors of a recent clinical review.

While evidence to date is mixed, some studies do suggest that adding ICIs to high-dose stereotactic intracranial radiotherapy for brain metastases might increase the risk of treatment-related brain necrosis, the authors said.

By contrast, the balance of evidence suggests ICIs can be safely combined with palliative radiotherapy without site-specific increases in adverse events, they added.

Likewise, in patients with non–small-cell lung cancer, ICIs do not appear to increase incidence of grade 3 or greater pneumonitis when given after definitive chemoradiotherapy, in both retrospective and prospective investigations.

Nevertheless, the addition of ICIs to radiotherapy requires careful further study because of the potential for increased type or severity of toxicities, including the immune-related adverse events associated with ICIs, wrote corresponding author Jay S. Loeffler, MD, of Massachusetts General Hospital, Boston, and his colleagues.

“Caution is warranted when combining radiotherapy and ICI, especially with intracranial radiotherapy,” the researchers wrote. Their report is in Nature Reviews Clinical Oncology.

Some studies have indicated a higher rate of treatment-associated brain necrosis when ICIs are combined with intracranial radiotherapy, while others have shown no such trend, the authors said.

In one single-institution experience involving 180 patients with brain metastases undergoing stereotactic radiotherapy, incidence of treatment-associated brain necrosis was significantly higher in patients receiving an ICI, with an odds ratio of 2.4 (95% confidence interval, 1.06-5.44; P = .03).

Similarly, a retrospective single institution 480-patient study showed an incidence of treatment-associated brain necrosis of 20% for ICIs plus stereotactic radiotherapy versus 7% for radiotherapy alone (P less than .001), but substantial differences in baseline characteristics between groups limited the strength of the study’s conclusions, according to the researchers.

Increased risk is primarily in the form of asymptomatic or minimally symptomatic episodes in some series, the authors noted. A retrospective, 54-patient report showed a rate of treatment-associated brain necrosis of 30% when ICIs were combined with stereotactic radiotherapy, versus 21% for radiotherapy alone (P = .08), but the incidence of symptomatic cases was 15% in both groups, they noted.

“Intriguingly, the findings of several studies have demonstrated an association between [treatment-associated brain necrosis] and improved survival outcomes in patients with melanoma brain metastases that is similar to the independent observations of an analogous relationship between risk of [immune-related adverse events] in general and responsiveness to ICI,” the researchers wrote.

Most of the Food and Drug Administration–approved indications for ICIs are in the metastatic setting, where palliative radiotherapy is frequently important, the authors noted.

In two retrospective studies of patients with metastatic cancers receiving palliative radiotherapy with ICIs, there was a lack of clear association between the irradiated site and specific immune-related adverse events; that lack of association suggests that any toxicities arising from interactions between palliative radiotherapy and ICIs are mainly systemic, rather than local, the authors wrote.

Several retrospective series in advanced-stage melanoma patients have suggested that palliative radiotherapy plus ICIs is safe and does not significantly increase incidence of immune-related adverse events. However, findings from one series showed a correlation between both the ICI and radiotherapy dose given and the incidence of immune-related adverse events.

Prospective studies will be essential to optimize the balance between disease control and risk of morbidity associated with ICIs and radiotherapy combinations, the authors concluded.

The researchers declared no competing interests related to their review article.

SOURCE: Hwang WL, et al. Nat Rev Clin Oncol. 2018 Aug;15(8):477-494.