Doug Brunk

SAN DIEGO – Though progress has been made in reducing the burden of disease, disability, and death caused by tobacco use since the 1964 Surgeon General’s Report on Smoking and Health debuted, much work remains to be done, according to Robert T. Croyle, Ph.D.

According to data from the Department of Health & Human Services, more than 42 million adults and more than 3.5 million middle and high school students continue to smoke tobacco. "We’re in a bizarre situation where we have a legal product on the market, which is responsible for about a half a million deaths," Dr. Croyle, director of division of cancer control and population sciences at the National Cancer Institute (NCI), said during a press briefing at the annual meeting of the American Association for Cancer Research marking the 50th anniversary of the Surgeon General’s Report on Smoking and Health. "In any other circumstance, without this long, strange history, we’d feel there would be a lot more engagement by the scientific community, by clinicians, and by organizations in marshalling every effort to address the problem."

© AACR/Vera LaMarche 2014

One recurring problem, he said, is the high use of tobacco products by subpopulations of Americans, especially those with low levels of income and education. "This is a challenge, because if you are a college-educated, wealthy individual living in the state of California, you may assume and believe that the tobacco problem is largely one of the past," he said. "But for many of us, we clearly see that across the United States, there are populations where this is still an overwhelming problem that individuals face in their families."

At the same time, Dr. Croyle said, "a rapid uptake" of tobacco use is taking place in many countries around the world. "We have some alarming concerns about the trajectory of tobacco use and the burden of cancer globally," he said. "That’s led us to support more research on global tobacco control and for the NCI to collaborate with international organizations."

In the United States, the National Institutes of Health formed a unique partnership aimed at bringing together expertise from scientists from a variety of disciplines to address the use of tobacco and other addictive substances. According to its website, the goal of Collaborative Research on Addiction at NIH is "to provide a strong collaborative framework to enable the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NCI to integrate resources and expertise to advance substance use, abuse, and addiction research and public health outcomes."

The time is right for such a partnership, Dr. Croyle said, because many current smokers also use alcohol and other drugs. "Unfortunately, even though scientists for many years have been calling for more research on these comorbid risk factors, the research lags behind what we need to inform clinical practice, so we’re paying special attention to issues of mental health," he said. "For example, tobacco use is incredibly high among those with schizophrenia. We’re also concerned about comorbid [tobacco] use and alcohol use, for example, among college students, where we see huge binge drinking problems that co-occur with tobacco use. We also have a concern about the introduction of electronic cigarettes and the fact that we desperately need a lot more evidence in that domain."

Mr. Croyle had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Though progress has been made in reducing the burden of disease, disability, and death caused by tobacco use since the 1964 Surgeon General’s Report on Smoking and Health debuted, much work remains to be done, according to Robert T. Croyle, Ph.D.

According to data from the Department of Health & Human Services, more than 42 million adults and more than 3.5 million middle and high school students continue to smoke tobacco. "We’re in a bizarre situation where we have a legal product on the market, which is responsible for about a half a million deaths," Dr. Croyle, director of division of cancer control and population sciences at the National Cancer Institute (NCI), said during a press briefing at the annual meeting of the American Association for Cancer Research marking the 50th anniversary of the Surgeon General’s Report on Smoking and Health. "In any other circumstance, without this long, strange history, we’d feel there would be a lot more engagement by the scientific community, by clinicians, and by organizations in marshalling every effort to address the problem."

© AACR/Vera LaMarche 2014

One recurring problem, he said, is the high use of tobacco products by subpopulations of Americans, especially those with low levels of income and education. "This is a challenge, because if you are a college-educated, wealthy individual living in the state of California, you may assume and believe that the tobacco problem is largely one of the past," he said. "But for many of us, we clearly see that across the United States, there are populations where this is still an overwhelming problem that individuals face in their families."

At the same time, Dr. Croyle said, "a rapid uptake" of tobacco use is taking place in many countries around the world. "We have some alarming concerns about the trajectory of tobacco use and the burden of cancer globally," he said. "That’s led us to support more research on global tobacco control and for the NCI to collaborate with international organizations."

In the United States, the National Institutes of Health formed a unique partnership aimed at bringing together expertise from scientists from a variety of disciplines to address the use of tobacco and other addictive substances. According to its website, the goal of Collaborative Research on Addiction at NIH is "to provide a strong collaborative framework to enable the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NCI to integrate resources and expertise to advance substance use, abuse, and addiction research and public health outcomes."

The time is right for such a partnership, Dr. Croyle said, because many current smokers also use alcohol and other drugs. "Unfortunately, even though scientists for many years have been calling for more research on these comorbid risk factors, the research lags behind what we need to inform clinical practice, so we’re paying special attention to issues of mental health," he said. "For example, tobacco use is incredibly high among those with schizophrenia. We’re also concerned about comorbid [tobacco] use and alcohol use, for example, among college students, where we see huge binge drinking problems that co-occur with tobacco use. We also have a concern about the introduction of electronic cigarettes and the fact that we desperately need a lot more evidence in that domain."

Mr. Croyle had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Though progress has been made in reducing the burden of disease, disability, and death caused by tobacco use since the 1964 Surgeon General’s Report on Smoking and Health debuted, much work remains to be done, according to Robert T. Croyle, Ph.D.

According to data from the Department of Health & Human Services, more than 42 million adults and more than 3.5 million middle and high school students continue to smoke tobacco. "We’re in a bizarre situation where we have a legal product on the market, which is responsible for about a half a million deaths," Dr. Croyle, director of division of cancer control and population sciences at the National Cancer Institute (NCI), said during a press briefing at the annual meeting of the American Association for Cancer Research marking the 50th anniversary of the Surgeon General’s Report on Smoking and Health. "In any other circumstance, without this long, strange history, we’d feel there would be a lot more engagement by the scientific community, by clinicians, and by organizations in marshalling every effort to address the problem."

© AACR/Vera LaMarche 2014

One recurring problem, he said, is the high use of tobacco products by subpopulations of Americans, especially those with low levels of income and education. "This is a challenge, because if you are a college-educated, wealthy individual living in the state of California, you may assume and believe that the tobacco problem is largely one of the past," he said. "But for many of us, we clearly see that across the United States, there are populations where this is still an overwhelming problem that individuals face in their families."

At the same time, Dr. Croyle said, "a rapid uptake" of tobacco use is taking place in many countries around the world. "We have some alarming concerns about the trajectory of tobacco use and the burden of cancer globally," he said. "That’s led us to support more research on global tobacco control and for the NCI to collaborate with international organizations."

In the United States, the National Institutes of Health formed a unique partnership aimed at bringing together expertise from scientists from a variety of disciplines to address the use of tobacco and other addictive substances. According to its website, the goal of Collaborative Research on Addiction at NIH is "to provide a strong collaborative framework to enable the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NCI to integrate resources and expertise to advance substance use, abuse, and addiction research and public health outcomes."

The time is right for such a partnership, Dr. Croyle said, because many current smokers also use alcohol and other drugs. "Unfortunately, even though scientists for many years have been calling for more research on these comorbid risk factors, the research lags behind what we need to inform clinical practice, so we’re paying special attention to issues of mental health," he said. "For example, tobacco use is incredibly high among those with schizophrenia. We’re also concerned about comorbid [tobacco] use and alcohol use, for example, among college students, where we see huge binge drinking problems that co-occur with tobacco use. We also have a concern about the introduction of electronic cigarettes and the fact that we desperately need a lot more evidence in that domain."

Mr. Croyle had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

The Food and Drug Administration approval of Hemangeol, a pediatric formulation of propranolol, should reduce the potential for error in increment dosing conversions when treating proliferating infantile hemangiomas that require systemic therapy, according to Dr. Adelaide A. Hebert.

"This represents a real milestone in therapy for patients who have hemangiomas," Dr. Hebert, professor and director of pediatric dermatology at the University of Texas Health Science Center at Houston, said in an interview. "It’s a wonderful step forward for all of us who care for children in the earliest months of life."

Pediatric dermatologists have been using generic propranolol to treat infantile hemangioma for several years. In doing so, "I as well as other pediatric dermatologists have found occasionally that the pharmacist was not as mindful as I wished them to be," said Dr. Hebert, who said that to date she does not have clinical experience with Hemangeol. "There were conversions that were not accurate in the dosing, so the patient occasionally got too much medicine or too little medicine. It was a human error. We picked up on these. With this new medicine, we won’t have that problem. It’s my understanding that [Hemangeol] will go through a specialty pharmacy. It will come with a special syringe to measure how much [drug you’re using]. There’s only one concentration, so I believe that the risk of error will be reduced."

In pivotal, randomized, placebo-controlled multicenter trials, researchers compared four Hemangeol treatment protocols (1 or 3 mg/kg per day for 3 or 6 months) versus placebo in an effort to reach the primary endpoint: complete or nearly complete resolution of the target hemangioma.

In a cohort of 456 infants aged 5 weeks to 5 months with a proliferative infantile hemangioma that required systemic treatment, the investigators found that the treatment dose of 3 mg/kg per day for 6 months had a 60.4% success rate, compared with 3.6% in the placebo group (P less than .0001). They also found that 11.4% of patients required retreatment after initial Hemangeol treatment was stopped.

"It’s unique when we have a situation where we have a drug that was available off label but then gets approved as a new medication," said Dr. Lawrence F. Eichenfield, chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego, which served as one of the Hemangeol study sites. "Propranolol for the treatment of hemangiomas is both a fascinating story and a tremendous breakthrough. The observation was that propranolol was incredibly effective at minimizing the growth and/or shrinking down the blood vessel tumors. This drug approval reflects a very large effort to study both the utility and safety of the drug."

In clinical trials, the most commonly reported adverse events among treated infants were sleep disorders; aggravated respiratory tract infections such as bronchitis and bronchiolitis associated with cough and fever; diarrhea; and vomiting. Adverse reactions resulted in treatment being stopped in less than 2% of treated patients.

"The FDA has been more conservative in recent years, so to get a drug that’s available and approved for small children is an enormous accomplishment," Dr. Hebert said. "It acknowledges that this is a significant part of health care in this pediatric population. I think each of us feels even more comfortable using a medicine specifically designed to meet this unmet need. The greatest challenge will be not the efficacy of the medicine, but difficulty getting it through [health] insurance [plans]."

Hemangeol is expected to be available in June 2014 and is marketed by Pierre Fabre Dermatologie in Castres, France. Dr. Eichenfield reported having served as a clinical investigator for, and/or consultant to, Pierre Fabre. Dr. Hebert disclosed that she has received one honorarium from Pierre Fabre for a single advisory board.

dbrunk@frontlinemedcom.com

The Food and Drug Administration approval of Hemangeol, a pediatric formulation of propranolol, should reduce the potential for error in increment dosing conversions when treating proliferating infantile hemangiomas that require systemic therapy, according to Dr. Adelaide A. Hebert.

"This represents a real milestone in therapy for patients who have hemangiomas," Dr. Hebert, professor and director of pediatric dermatology at the University of Texas Health Science Center at Houston, said in an interview. "It’s a wonderful step forward for all of us who care for children in the earliest months of life."

Pediatric dermatologists have been using generic propranolol to treat infantile hemangioma for several years. In doing so, "I as well as other pediatric dermatologists have found occasionally that the pharmacist was not as mindful as I wished them to be," said Dr. Hebert, who said that to date she does not have clinical experience with Hemangeol. "There were conversions that were not accurate in the dosing, so the patient occasionally got too much medicine or too little medicine. It was a human error. We picked up on these. With this new medicine, we won’t have that problem. It’s my understanding that [Hemangeol] will go through a specialty pharmacy. It will come with a special syringe to measure how much [drug you’re using]. There’s only one concentration, so I believe that the risk of error will be reduced."

In pivotal, randomized, placebo-controlled multicenter trials, researchers compared four Hemangeol treatment protocols (1 or 3 mg/kg per day for 3 or 6 months) versus placebo in an effort to reach the primary endpoint: complete or nearly complete resolution of the target hemangioma.

In a cohort of 456 infants aged 5 weeks to 5 months with a proliferative infantile hemangioma that required systemic treatment, the investigators found that the treatment dose of 3 mg/kg per day for 6 months had a 60.4% success rate, compared with 3.6% in the placebo group (P less than .0001). They also found that 11.4% of patients required retreatment after initial Hemangeol treatment was stopped.

"It’s unique when we have a situation where we have a drug that was available off label but then gets approved as a new medication," said Dr. Lawrence F. Eichenfield, chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego, which served as one of the Hemangeol study sites. "Propranolol for the treatment of hemangiomas is both a fascinating story and a tremendous breakthrough. The observation was that propranolol was incredibly effective at minimizing the growth and/or shrinking down the blood vessel tumors. This drug approval reflects a very large effort to study both the utility and safety of the drug."

In clinical trials, the most commonly reported adverse events among treated infants were sleep disorders; aggravated respiratory tract infections such as bronchitis and bronchiolitis associated with cough and fever; diarrhea; and vomiting. Adverse reactions resulted in treatment being stopped in less than 2% of treated patients.

"The FDA has been more conservative in recent years, so to get a drug that’s available and approved for small children is an enormous accomplishment," Dr. Hebert said. "It acknowledges that this is a significant part of health care in this pediatric population. I think each of us feels even more comfortable using a medicine specifically designed to meet this unmet need. The greatest challenge will be not the efficacy of the medicine, but difficulty getting it through [health] insurance [plans]."

Hemangeol is expected to be available in June 2014 and is marketed by Pierre Fabre Dermatologie in Castres, France. Dr. Eichenfield reported having served as a clinical investigator for, and/or consultant to, Pierre Fabre. Dr. Hebert disclosed that she has received one honorarium from Pierre Fabre for a single advisory board.

dbrunk@frontlinemedcom.com

The Food and Drug Administration approval of Hemangeol, a pediatric formulation of propranolol, should reduce the potential for error in increment dosing conversions when treating proliferating infantile hemangiomas that require systemic therapy, according to Dr. Adelaide A. Hebert.

"This represents a real milestone in therapy for patients who have hemangiomas," Dr. Hebert, professor and director of pediatric dermatology at the University of Texas Health Science Center at Houston, said in an interview. "It’s a wonderful step forward for all of us who care for children in the earliest months of life."

Pediatric dermatologists have been using generic propranolol to treat infantile hemangioma for several years. In doing so, "I as well as other pediatric dermatologists have found occasionally that the pharmacist was not as mindful as I wished them to be," said Dr. Hebert, who said that to date she does not have clinical experience with Hemangeol. "There were conversions that were not accurate in the dosing, so the patient occasionally got too much medicine or too little medicine. It was a human error. We picked up on these. With this new medicine, we won’t have that problem. It’s my understanding that [Hemangeol] will go through a specialty pharmacy. It will come with a special syringe to measure how much [drug you’re using]. There’s only one concentration, so I believe that the risk of error will be reduced."

In pivotal, randomized, placebo-controlled multicenter trials, researchers compared four Hemangeol treatment protocols (1 or 3 mg/kg per day for 3 or 6 months) versus placebo in an effort to reach the primary endpoint: complete or nearly complete resolution of the target hemangioma.

In a cohort of 456 infants aged 5 weeks to 5 months with a proliferative infantile hemangioma that required systemic treatment, the investigators found that the treatment dose of 3 mg/kg per day for 6 months had a 60.4% success rate, compared with 3.6% in the placebo group (P less than .0001). They also found that 11.4% of patients required retreatment after initial Hemangeol treatment was stopped.

"It’s unique when we have a situation where we have a drug that was available off label but then gets approved as a new medication," said Dr. Lawrence F. Eichenfield, chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego, which served as one of the Hemangeol study sites. "Propranolol for the treatment of hemangiomas is both a fascinating story and a tremendous breakthrough. The observation was that propranolol was incredibly effective at minimizing the growth and/or shrinking down the blood vessel tumors. This drug approval reflects a very large effort to study both the utility and safety of the drug."

In clinical trials, the most commonly reported adverse events among treated infants were sleep disorders; aggravated respiratory tract infections such as bronchitis and bronchiolitis associated with cough and fever; diarrhea; and vomiting. Adverse reactions resulted in treatment being stopped in less than 2% of treated patients.

"The FDA has been more conservative in recent years, so to get a drug that’s available and approved for small children is an enormous accomplishment," Dr. Hebert said. "It acknowledges that this is a significant part of health care in this pediatric population. I think each of us feels even more comfortable using a medicine specifically designed to meet this unmet need. The greatest challenge will be not the efficacy of the medicine, but difficulty getting it through [health] insurance [plans]."

Hemangeol is expected to be available in June 2014 and is marketed by Pierre Fabre Dermatologie in Castres, France. Dr. Eichenfield reported having served as a clinical investigator for, and/or consultant to, Pierre Fabre. Dr. Hebert disclosed that she has received one honorarium from Pierre Fabre for a single advisory board.

dbrunk@frontlinemedcom.com

SAN DIEGO – Efficacy results from an adaptive trial demonstrated that the investigational pan-HER inhibitor neratinib in combination with standard chemotherapy benefited patients with newly diagnosed hormone receptor–negative, HER2-positive primary breast cancer.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. John W. Park said that neratinib, an investigational agent being developed by Los Angeles–based Puma Biotechnology, "graduated" in the HR-negative/HER-positive signature, with a 79% probability of success in a phase III study of neratinib plus paclitaxel vs. trastuzumab plus paclitaxel. In addition, the Bayesian probability of superiority for the neratinib-containing regimen, compared with standard therapy, is 95% (P = .051).

©2014 AACR/Todd Buchanan

The findings come from the I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) trial, a randomized, phase II clinical study of women with newly diagnosed stage II breast cancer with a tumor size of at least 2.5 cm and who are considered to be at high risk for recurrence via MammaPrint test.

I-SPY 2 is designed to investigate whether adding investigational drugs such as neratinib to standard chemotherapy is better than standard therapy alone, said Dr. Park, one of the study investigators who is professor of medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

The study’s primary endpoint is pathological complete response (pCR) in the breast and in the lymph nodes at the time of surgery. The trial employs an adaptive design based on Bayesian predictive probability that a regimen will be shown to be statistically superior to standard therapy in an equally randomized 300-patient confirmatory trial. "If at any point in the trial this endpoint is not met, the trial continues to learn from the responses obtained to date, and the randomization is revised to reflect the results that have been obtained thus far," Dr. Park explained. "The trial continues to accrue patients in this weighted randomization fashion until graduation or futility is the result."

Dr. Park presented findings from 115 patients (median age, 51 years) who were assigned to receive paclitaxel plus neratinib (followed by doxorubicin and cyclophosphamide). The rates of pCR in the neratinib arm were compared with those of 78 patients (median age, 48 years) who were concurrently randomized to the control arm containing standard chemotherapy, which consisted of paclitaxel plus trastuzumab (followed by doxorubicin and cyclophosphamide). The researchers also compared 10 biomarker signatures prospectively defined by categories of HR, HER2, and MammaPrint.

Among patients with HR-negative, HER2-positive breast cancer (one of the 10 biomarker signatures), the estimated pCR rate was 56% for the neratinib-containing regimen, compared with 33% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 79%.

Among the 65 patients in the neratinib-containing regimen who were HER2-positive (a separate biomarker signature), the estimated pCR rate was 39% for the neratinib-containing regimen, compared with 23% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 73%.

Neratinib was "largely well tolerated," Dr. Park said, but 39% of patients in the neratinib arm experienced grade 3 or 4 diarrhea, compared with 4% of patients in the control arm. "There was not a particular cardiac safety event that was frequent in either arm, and there are no congestive heart failure events noted to date," he said.

After noticing high rates of diarrhea symptoms, the trial investigators modified the diarrhea supportive care guideline "to include vigorous patient monitoring and early institution of supportive care, which appeared to make a difference in terms of the frequency of diarrhea and amelioration of that side effect," Dr. Park said. "Further to that, there was also the institution of a prophylactic loperamide regimen, which was also instituted later in the trial."

There was no apparent difference in the time to surgery from initiation of treatment in the control versus the neratinib-treated groups (a median of 168 days for both). "Early discontinuation was somewhat more frequently observed with neratinib, primarily due to toxicity, whereas early discontinuation due to progression was observed more frequently in the control group," Dr. Park said.

He concluded his remarks by noting that I-SPY 2 "is a biomarker-rich trial. Additional response predictors and biomarker developments are under investigation, and we anticipate they will be reported in a subsequent forum. Based on these results, neratinib is under consideration for phase III testing in the neoadjuvant population."

In an interview, Dr. Thomas Lynch, director of the Yale Cancer Center in New Haven, Conn., and a member of the American Association for Cancer Research’s annual meeting program committee, praised the novel design of the I-SPY 2 trial, "the fact that it allows rapid evaluation of both biomarkers and new drugs and the interaction between biomarkers and new drugs.

"It’s not a definitive [trial] design; it’s not going to lead to drug approval in and of itself. But it does have a lot of power to sort out which biomarkers and which agents are the most important to combine and look at in putting together treatments for patients," Dr. Lynch said.

He went on to describe the findings regarding neratinib as "intriguing, but I have to see a bigger study to have a sense of magnitude of benefit. What the interaction of the biomarker is, is hard to know."

The study is sponsored by the QuantumLeap Healthcare Collaborative, a 501(3) charitable foundation. Dr. Park said that he had no relevant financial conflicts to disclose. Dr. Lynch disclosed that he is on the board of directors of Bristol-Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board of Arvinas and receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation testing patent and receives royalties.

dbrunk@frontlinemedcom.com

SAN DIEGO – Efficacy results from an adaptive trial demonstrated that the investigational pan-HER inhibitor neratinib in combination with standard chemotherapy benefited patients with newly diagnosed hormone receptor–negative, HER2-positive primary breast cancer.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. John W. Park said that neratinib, an investigational agent being developed by Los Angeles–based Puma Biotechnology, "graduated" in the HR-negative/HER-positive signature, with a 79% probability of success in a phase III study of neratinib plus paclitaxel vs. trastuzumab plus paclitaxel. In addition, the Bayesian probability of superiority for the neratinib-containing regimen, compared with standard therapy, is 95% (P = .051).

©2014 AACR/Todd Buchanan

The findings come from the I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) trial, a randomized, phase II clinical study of women with newly diagnosed stage II breast cancer with a tumor size of at least 2.5 cm and who are considered to be at high risk for recurrence via MammaPrint test.

I-SPY 2 is designed to investigate whether adding investigational drugs such as neratinib to standard chemotherapy is better than standard therapy alone, said Dr. Park, one of the study investigators who is professor of medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

The study’s primary endpoint is pathological complete response (pCR) in the breast and in the lymph nodes at the time of surgery. The trial employs an adaptive design based on Bayesian predictive probability that a regimen will be shown to be statistically superior to standard therapy in an equally randomized 300-patient confirmatory trial. "If at any point in the trial this endpoint is not met, the trial continues to learn from the responses obtained to date, and the randomization is revised to reflect the results that have been obtained thus far," Dr. Park explained. "The trial continues to accrue patients in this weighted randomization fashion until graduation or futility is the result."

Dr. Park presented findings from 115 patients (median age, 51 years) who were assigned to receive paclitaxel plus neratinib (followed by doxorubicin and cyclophosphamide). The rates of pCR in the neratinib arm were compared with those of 78 patients (median age, 48 years) who were concurrently randomized to the control arm containing standard chemotherapy, which consisted of paclitaxel plus trastuzumab (followed by doxorubicin and cyclophosphamide). The researchers also compared 10 biomarker signatures prospectively defined by categories of HR, HER2, and MammaPrint.

Among patients with HR-negative, HER2-positive breast cancer (one of the 10 biomarker signatures), the estimated pCR rate was 56% for the neratinib-containing regimen, compared with 33% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 79%.

Among the 65 patients in the neratinib-containing regimen who were HER2-positive (a separate biomarker signature), the estimated pCR rate was 39% for the neratinib-containing regimen, compared with 23% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 73%.

Neratinib was "largely well tolerated," Dr. Park said, but 39% of patients in the neratinib arm experienced grade 3 or 4 diarrhea, compared with 4% of patients in the control arm. "There was not a particular cardiac safety event that was frequent in either arm, and there are no congestive heart failure events noted to date," he said.

After noticing high rates of diarrhea symptoms, the trial investigators modified the diarrhea supportive care guideline "to include vigorous patient monitoring and early institution of supportive care, which appeared to make a difference in terms of the frequency of diarrhea and amelioration of that side effect," Dr. Park said. "Further to that, there was also the institution of a prophylactic loperamide regimen, which was also instituted later in the trial."

There was no apparent difference in the time to surgery from initiation of treatment in the control versus the neratinib-treated groups (a median of 168 days for both). "Early discontinuation was somewhat more frequently observed with neratinib, primarily due to toxicity, whereas early discontinuation due to progression was observed more frequently in the control group," Dr. Park said.

He concluded his remarks by noting that I-SPY 2 "is a biomarker-rich trial. Additional response predictors and biomarker developments are under investigation, and we anticipate they will be reported in a subsequent forum. Based on these results, neratinib is under consideration for phase III testing in the neoadjuvant population."

In an interview, Dr. Thomas Lynch, director of the Yale Cancer Center in New Haven, Conn., and a member of the American Association for Cancer Research’s annual meeting program committee, praised the novel design of the I-SPY 2 trial, "the fact that it allows rapid evaluation of both biomarkers and new drugs and the interaction between biomarkers and new drugs.

"It’s not a definitive [trial] design; it’s not going to lead to drug approval in and of itself. But it does have a lot of power to sort out which biomarkers and which agents are the most important to combine and look at in putting together treatments for patients," Dr. Lynch said.

He went on to describe the findings regarding neratinib as "intriguing, but I have to see a bigger study to have a sense of magnitude of benefit. What the interaction of the biomarker is, is hard to know."

The study is sponsored by the QuantumLeap Healthcare Collaborative, a 501(3) charitable foundation. Dr. Park said that he had no relevant financial conflicts to disclose. Dr. Lynch disclosed that he is on the board of directors of Bristol-Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board of Arvinas and receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation testing patent and receives royalties.

dbrunk@frontlinemedcom.com

SAN DIEGO – Efficacy results from an adaptive trial demonstrated that the investigational pan-HER inhibitor neratinib in combination with standard chemotherapy benefited patients with newly diagnosed hormone receptor–negative, HER2-positive primary breast cancer.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. John W. Park said that neratinib, an investigational agent being developed by Los Angeles–based Puma Biotechnology, "graduated" in the HR-negative/HER-positive signature, with a 79% probability of success in a phase III study of neratinib plus paclitaxel vs. trastuzumab plus paclitaxel. In addition, the Bayesian probability of superiority for the neratinib-containing regimen, compared with standard therapy, is 95% (P = .051).

©2014 AACR/Todd Buchanan

The findings come from the I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) trial, a randomized, phase II clinical study of women with newly diagnosed stage II breast cancer with a tumor size of at least 2.5 cm and who are considered to be at high risk for recurrence via MammaPrint test.

I-SPY 2 is designed to investigate whether adding investigational drugs such as neratinib to standard chemotherapy is better than standard therapy alone, said Dr. Park, one of the study investigators who is professor of medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

The study’s primary endpoint is pathological complete response (pCR) in the breast and in the lymph nodes at the time of surgery. The trial employs an adaptive design based on Bayesian predictive probability that a regimen will be shown to be statistically superior to standard therapy in an equally randomized 300-patient confirmatory trial. "If at any point in the trial this endpoint is not met, the trial continues to learn from the responses obtained to date, and the randomization is revised to reflect the results that have been obtained thus far," Dr. Park explained. "The trial continues to accrue patients in this weighted randomization fashion until graduation or futility is the result."

Dr. Park presented findings from 115 patients (median age, 51 years) who were assigned to receive paclitaxel plus neratinib (followed by doxorubicin and cyclophosphamide). The rates of pCR in the neratinib arm were compared with those of 78 patients (median age, 48 years) who were concurrently randomized to the control arm containing standard chemotherapy, which consisted of paclitaxel plus trastuzumab (followed by doxorubicin and cyclophosphamide). The researchers also compared 10 biomarker signatures prospectively defined by categories of HR, HER2, and MammaPrint.

Among patients with HR-negative, HER2-positive breast cancer (one of the 10 biomarker signatures), the estimated pCR rate was 56% for the neratinib-containing regimen, compared with 33% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 79%.

Among the 65 patients in the neratinib-containing regimen who were HER2-positive (a separate biomarker signature), the estimated pCR rate was 39% for the neratinib-containing regimen, compared with 23% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 73%.

Neratinib was "largely well tolerated," Dr. Park said, but 39% of patients in the neratinib arm experienced grade 3 or 4 diarrhea, compared with 4% of patients in the control arm. "There was not a particular cardiac safety event that was frequent in either arm, and there are no congestive heart failure events noted to date," he said.

After noticing high rates of diarrhea symptoms, the trial investigators modified the diarrhea supportive care guideline "to include vigorous patient monitoring and early institution of supportive care, which appeared to make a difference in terms of the frequency of diarrhea and amelioration of that side effect," Dr. Park said. "Further to that, there was also the institution of a prophylactic loperamide regimen, which was also instituted later in the trial."

There was no apparent difference in the time to surgery from initiation of treatment in the control versus the neratinib-treated groups (a median of 168 days for both). "Early discontinuation was somewhat more frequently observed with neratinib, primarily due to toxicity, whereas early discontinuation due to progression was observed more frequently in the control group," Dr. Park said.

He concluded his remarks by noting that I-SPY 2 "is a biomarker-rich trial. Additional response predictors and biomarker developments are under investigation, and we anticipate they will be reported in a subsequent forum. Based on these results, neratinib is under consideration for phase III testing in the neoadjuvant population."

In an interview, Dr. Thomas Lynch, director of the Yale Cancer Center in New Haven, Conn., and a member of the American Association for Cancer Research’s annual meeting program committee, praised the novel design of the I-SPY 2 trial, "the fact that it allows rapid evaluation of both biomarkers and new drugs and the interaction between biomarkers and new drugs.

"It’s not a definitive [trial] design; it’s not going to lead to drug approval in and of itself. But it does have a lot of power to sort out which biomarkers and which agents are the most important to combine and look at in putting together treatments for patients," Dr. Lynch said.

He went on to describe the findings regarding neratinib as "intriguing, but I have to see a bigger study to have a sense of magnitude of benefit. What the interaction of the biomarker is, is hard to know."

The study is sponsored by the QuantumLeap Healthcare Collaborative, a 501(3) charitable foundation. Dr. Park said that he had no relevant financial conflicts to disclose. Dr. Lynch disclosed that he is on the board of directors of Bristol-Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board of Arvinas and receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation testing patent and receives royalties.

dbrunk@frontlinemedcom.com

SAN DIEGO – DEDN6526A, a new anti–endothelin B receptor antibody-drug conjugate, demonstrated safety, tolerability, and hints of clinical efficacy against different types of metastatic or unresectable melanoma, results from a phase I trial showed.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. Jeffrey R. Infante said that anti–endothelin B receptor (ETBR), a G-protein–coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma, compared with normal skin. Developed by Genentech using Seattle Genetics antibody-drug conjugate (ADC) technology, DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin E (MMAE) linked to the humanized IgG1 anti-ETBR antibody and represents a targeted chemotherapy to melanoma. ETBR "regulates migration and proliferation of melanocyte precursors from the neural crest during embryonic development," explained Dr. Infante, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tenn. "It is associated with malignant transformation of melanocytes and with potentiation of metastatic spread."

©2014 AACR/Todd Buchanan

A prototype ETBR assay is being developed as a potential comparison diagnostic in melanoma. The assay is used on formalin-fixed, paraffin-embedded melanoma.

In an effort to determine the maximum tolerated dose of DEDN6526A, 28 patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma received the intravenous agent every 3 weeks. The researchers collected pharmacokinetic samples and assessed tumor tissue for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1. (Response Evaluation Criteria in Solid Tumors version 1.1).

Dr. Infante reported that more than half of study participants had more than three prior therapies and 70% had two or more prior therapies. Eight of the patients had ocular melanoma and three of them had mucosal melanoma. Dose escalation started at 0.3 mg/kg and patients received a median of six doses of the agent. The maximum tolerated dose was determined to be 2.4 mg/kg, which is currently being tested in the expansion phase of the trial.

The most common adverse event of any grade was fatigue (57%), followed by chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), and infusion-related reaction (25%). Neutropenia was the most frequent grade 3 or 4 event. "It often did not require a dose reduction, so it was manageable," Dr. Infante said.

Complete radiographic data were available on 24 patients. Among these, clinical benefit was observed in 12 of the 19 patients who were assigned to a dosing regimen of 1.8 g/kg of DEDN6526A or more. Four of the 12 patients achieved complete response (two were cases of cutaneous melanoma and two were cases of mucosal melanoma). "It did not seem to depend on whether they had a BRAF mutation or had prior treatment with ipilimumab," Dr. Infante said. The other eight patients had stable disease for at least 6 months. "If you can stay on drug for 6 months, that’s probably meaningful benefit in an early phase I trial," he commented.

Dr. Thomas Lynch, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital at Yale University, New Haven, Conn., who moderated the press briefing, noted that while antibody-drug conjugates such as DEDN6526A "look very promising," the biomarker used in the trial is not fully developed yet. "It may well be that with a mature biomarker, it turns out to have good predictive value," he said.

In an unrelated presentation at the meeting, Dr. Mark Middleton presented findings from a phase I trial of IMCgp100, an investigational agent being developed by Immunocore that is comprised of an affinity-enhanced T-cell receptor specific for the HLA-A2 restricted melanoma gp100 peptide fused to an anti-CD3 antibody fragment. "What’s important about this method of targeting is that it’s very different from a lot of immunotherapies that have been reported," said Dr. Middleton, the study’s principal investigator who is professor of experimental cancer medicine at the University of Oxford (England). "Rather than targeting cell surface proteins, this is targeting the peptide HLA complex, and therefore brings in intracellular protein targets. The premise is that high affinity binding of the T-cell receptor portions of the cancer cell then leads to recruitment of T cells, formation of an immune synapse, and the release of lytic granules leading to apoptotic cell death of the cancer cell."

He and his associates conducted a phase I dose-escalation study using a standard 3+3 cohort design in melanoma patients who had disease in a variety of sites, including the lung, liver, lymphatic system, and various soft tissues. All patients received a single, 5 ng/kg dose of IMCgp100 followed by 30 days of observation. After this 30-day observation period patients could go on to have six weekly infusions followed by 4 weeks of rest if they continued to derive clinical benefit. "On establishment of the maximum tolerated dose, we specified that we would conduct an expansion cohort to explore pharmacodynamics, clinical efficacy, and safety in more detail," Dr. Middleton said, noting that a total of eight cohorts were studied. Patients had to have stage 4 or unresectable stage 3 melanoma, had to be HLA-A2 positive and have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.

The researchers administered IMCgp100 as a 4-hour infusion followed by 48 hours of in-patient observation. Over that 48-hour period they conducted extensive safety evaluations and pharmacokinetic and pharmacodynamic analysis, including detailed audiometric and ophthalmic review. "Because we started with such a low dose we said that we would triple the dose in the absence of toxicity, moving to smaller increments according to safety and pharmacokinetic profile," he said.

Dose-limiting toxicities were defined as drug-related toxicities that occurred within 8 days of drug administration. Anything grade 3 or higher would be deemed as a dose-limiting toxicity.

Among the 40 patients in the trial, the mean age was 59 years and 23 were male. The researchers started to see toxicity at a dose of 45 ng/kg, "which would manifest as a rash that would endure for a few hours, perhaps into the next day," Dr. Middleton said. "At a dose of 135 ng/kg this became more widespread, albeit transient, and we therefore slowed the rate of increase between cohorts." One patient in the 405 ng/kg cohort and two patients in the 900 ng/kg cohort developed grade 3 hypotension 10-12 hours after drug administration. This in part led the researchers to declare a nontolerated dose of 900 ng/kg and a maximum tolerated dose of 600 ng/kg.

Among the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg, the most common adverse event was an itchy rash, "which is often widespread, and associated with edema, which can be periorbital and more widespread," Dr. Middleton said. "This is transient; it usually settles down within 48-72 hours and is not as severe with subsequent administration of the drug." One case of hypotension occurred. The patient recovered after intensive supportive care. Evaluation of pharmacokinetics showed evidence of lymphocyte trafficking, neutrophilia, and a rise in C-reactive protein.

Efficacy results from 10 of the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg showed evidence of "significant and durable clinical responses, particularly in two patients who were treated in the dose escalation phase," he said. Those two patients met the RECIST criteria for response.

Dr. Middleton and his associates are continuing study expansion at the current dose level, with mandated tumor biopsies before treatment, and testing a weekly dosing arm. The goal is to identify the optimal dosing regimen for IMCgp100. The trial is expected to be complete in 2015.

The study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium, and Roche.

The study of DEDN6526A was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose.

Dr. Lynch disclosed that he is on the board of directors for Bristol Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and he receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation–testing patent and receives royalties.

dbrunk@frontlinemedcom.com

SAN DIEGO – DEDN6526A, a new anti–endothelin B receptor antibody-drug conjugate, demonstrated safety, tolerability, and hints of clinical efficacy against different types of metastatic or unresectable melanoma, results from a phase I trial showed.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. Jeffrey R. Infante said that anti–endothelin B receptor (ETBR), a G-protein–coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma, compared with normal skin. Developed by Genentech using Seattle Genetics antibody-drug conjugate (ADC) technology, DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin E (MMAE) linked to the humanized IgG1 anti-ETBR antibody and represents a targeted chemotherapy to melanoma. ETBR "regulates migration and proliferation of melanocyte precursors from the neural crest during embryonic development," explained Dr. Infante, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tenn. "It is associated with malignant transformation of melanocytes and with potentiation of metastatic spread."

©2014 AACR/Todd Buchanan

A prototype ETBR assay is being developed as a potential comparison diagnostic in melanoma. The assay is used on formalin-fixed, paraffin-embedded melanoma.

In an effort to determine the maximum tolerated dose of DEDN6526A, 28 patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma received the intravenous agent every 3 weeks. The researchers collected pharmacokinetic samples and assessed tumor tissue for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1. (Response Evaluation Criteria in Solid Tumors version 1.1).

Dr. Infante reported that more than half of study participants had more than three prior therapies and 70% had two or more prior therapies. Eight of the patients had ocular melanoma and three of them had mucosal melanoma. Dose escalation started at 0.3 mg/kg and patients received a median of six doses of the agent. The maximum tolerated dose was determined to be 2.4 mg/kg, which is currently being tested in the expansion phase of the trial.

The most common adverse event of any grade was fatigue (57%), followed by chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), and infusion-related reaction (25%). Neutropenia was the most frequent grade 3 or 4 event. "It often did not require a dose reduction, so it was manageable," Dr. Infante said.

Complete radiographic data were available on 24 patients. Among these, clinical benefit was observed in 12 of the 19 patients who were assigned to a dosing regimen of 1.8 g/kg of DEDN6526A or more. Four of the 12 patients achieved complete response (two were cases of cutaneous melanoma and two were cases of mucosal melanoma). "It did not seem to depend on whether they had a BRAF mutation or had prior treatment with ipilimumab," Dr. Infante said. The other eight patients had stable disease for at least 6 months. "If you can stay on drug for 6 months, that’s probably meaningful benefit in an early phase I trial," he commented.

Dr. Thomas Lynch, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital at Yale University, New Haven, Conn., who moderated the press briefing, noted that while antibody-drug conjugates such as DEDN6526A "look very promising," the biomarker used in the trial is not fully developed yet. "It may well be that with a mature biomarker, it turns out to have good predictive value," he said.

In an unrelated presentation at the meeting, Dr. Mark Middleton presented findings from a phase I trial of IMCgp100, an investigational agent being developed by Immunocore that is comprised of an affinity-enhanced T-cell receptor specific for the HLA-A2 restricted melanoma gp100 peptide fused to an anti-CD3 antibody fragment. "What’s important about this method of targeting is that it’s very different from a lot of immunotherapies that have been reported," said Dr. Middleton, the study’s principal investigator who is professor of experimental cancer medicine at the University of Oxford (England). "Rather than targeting cell surface proteins, this is targeting the peptide HLA complex, and therefore brings in intracellular protein targets. The premise is that high affinity binding of the T-cell receptor portions of the cancer cell then leads to recruitment of T cells, formation of an immune synapse, and the release of lytic granules leading to apoptotic cell death of the cancer cell."

He and his associates conducted a phase I dose-escalation study using a standard 3+3 cohort design in melanoma patients who had disease in a variety of sites, including the lung, liver, lymphatic system, and various soft tissues. All patients received a single, 5 ng/kg dose of IMCgp100 followed by 30 days of observation. After this 30-day observation period patients could go on to have six weekly infusions followed by 4 weeks of rest if they continued to derive clinical benefit. "On establishment of the maximum tolerated dose, we specified that we would conduct an expansion cohort to explore pharmacodynamics, clinical efficacy, and safety in more detail," Dr. Middleton said, noting that a total of eight cohorts were studied. Patients had to have stage 4 or unresectable stage 3 melanoma, had to be HLA-A2 positive and have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.

The researchers administered IMCgp100 as a 4-hour infusion followed by 48 hours of in-patient observation. Over that 48-hour period they conducted extensive safety evaluations and pharmacokinetic and pharmacodynamic analysis, including detailed audiometric and ophthalmic review. "Because we started with such a low dose we said that we would triple the dose in the absence of toxicity, moving to smaller increments according to safety and pharmacokinetic profile," he said.

Dose-limiting toxicities were defined as drug-related toxicities that occurred within 8 days of drug administration. Anything grade 3 or higher would be deemed as a dose-limiting toxicity.

Among the 40 patients in the trial, the mean age was 59 years and 23 were male. The researchers started to see toxicity at a dose of 45 ng/kg, "which would manifest as a rash that would endure for a few hours, perhaps into the next day," Dr. Middleton said. "At a dose of 135 ng/kg this became more widespread, albeit transient, and we therefore slowed the rate of increase between cohorts." One patient in the 405 ng/kg cohort and two patients in the 900 ng/kg cohort developed grade 3 hypotension 10-12 hours after drug administration. This in part led the researchers to declare a nontolerated dose of 900 ng/kg and a maximum tolerated dose of 600 ng/kg.

Among the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg, the most common adverse event was an itchy rash, "which is often widespread, and associated with edema, which can be periorbital and more widespread," Dr. Middleton said. "This is transient; it usually settles down within 48-72 hours and is not as severe with subsequent administration of the drug." One case of hypotension occurred. The patient recovered after intensive supportive care. Evaluation of pharmacokinetics showed evidence of lymphocyte trafficking, neutrophilia, and a rise in C-reactive protein.

Efficacy results from 10 of the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg showed evidence of "significant and durable clinical responses, particularly in two patients who were treated in the dose escalation phase," he said. Those two patients met the RECIST criteria for response.

Dr. Middleton and his associates are continuing study expansion at the current dose level, with mandated tumor biopsies before treatment, and testing a weekly dosing arm. The goal is to identify the optimal dosing regimen for IMCgp100. The trial is expected to be complete in 2015.

The study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium, and Roche.

The study of DEDN6526A was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose.

Dr. Lynch disclosed that he is on the board of directors for Bristol Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and he receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation–testing patent and receives royalties.

dbrunk@frontlinemedcom.com

SAN DIEGO – DEDN6526A, a new anti–endothelin B receptor antibody-drug conjugate, demonstrated safety, tolerability, and hints of clinical efficacy against different types of metastatic or unresectable melanoma, results from a phase I trial showed.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. Jeffrey R. Infante said that anti–endothelin B receptor (ETBR), a G-protein–coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma, compared with normal skin. Developed by Genentech using Seattle Genetics antibody-drug conjugate (ADC) technology, DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin E (MMAE) linked to the humanized IgG1 anti-ETBR antibody and represents a targeted chemotherapy to melanoma. ETBR "regulates migration and proliferation of melanocyte precursors from the neural crest during embryonic development," explained Dr. Infante, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tenn. "It is associated with malignant transformation of melanocytes and with potentiation of metastatic spread."

©2014 AACR/Todd Buchanan

A prototype ETBR assay is being developed as a potential comparison diagnostic in melanoma. The assay is used on formalin-fixed, paraffin-embedded melanoma.

In an effort to determine the maximum tolerated dose of DEDN6526A, 28 patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma received the intravenous agent every 3 weeks. The researchers collected pharmacokinetic samples and assessed tumor tissue for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1. (Response Evaluation Criteria in Solid Tumors version 1.1).

Dr. Infante reported that more than half of study participants had more than three prior therapies and 70% had two or more prior therapies. Eight of the patients had ocular melanoma and three of them had mucosal melanoma. Dose escalation started at 0.3 mg/kg and patients received a median of six doses of the agent. The maximum tolerated dose was determined to be 2.4 mg/kg, which is currently being tested in the expansion phase of the trial.

The most common adverse event of any grade was fatigue (57%), followed by chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), and infusion-related reaction (25%). Neutropenia was the most frequent grade 3 or 4 event. "It often did not require a dose reduction, so it was manageable," Dr. Infante said.

Complete radiographic data were available on 24 patients. Among these, clinical benefit was observed in 12 of the 19 patients who were assigned to a dosing regimen of 1.8 g/kg of DEDN6526A or more. Four of the 12 patients achieved complete response (two were cases of cutaneous melanoma and two were cases of mucosal melanoma). "It did not seem to depend on whether they had a BRAF mutation or had prior treatment with ipilimumab," Dr. Infante said. The other eight patients had stable disease for at least 6 months. "If you can stay on drug for 6 months, that’s probably meaningful benefit in an early phase I trial," he commented.

Dr. Thomas Lynch, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital at Yale University, New Haven, Conn., who moderated the press briefing, noted that while antibody-drug conjugates such as DEDN6526A "look very promising," the biomarker used in the trial is not fully developed yet. "It may well be that with a mature biomarker, it turns out to have good predictive value," he said.

In an unrelated presentation at the meeting, Dr. Mark Middleton presented findings from a phase I trial of IMCgp100, an investigational agent being developed by Immunocore that is comprised of an affinity-enhanced T-cell receptor specific for the HLA-A2 restricted melanoma gp100 peptide fused to an anti-CD3 antibody fragment. "What’s important about this method of targeting is that it’s very different from a lot of immunotherapies that have been reported," said Dr. Middleton, the study’s principal investigator who is professor of experimental cancer medicine at the University of Oxford (England). "Rather than targeting cell surface proteins, this is targeting the peptide HLA complex, and therefore brings in intracellular protein targets. The premise is that high affinity binding of the T-cell receptor portions of the cancer cell then leads to recruitment of T cells, formation of an immune synapse, and the release of lytic granules leading to apoptotic cell death of the cancer cell."

He and his associates conducted a phase I dose-escalation study using a standard 3+3 cohort design in melanoma patients who had disease in a variety of sites, including the lung, liver, lymphatic system, and various soft tissues. All patients received a single, 5 ng/kg dose of IMCgp100 followed by 30 days of observation. After this 30-day observation period patients could go on to have six weekly infusions followed by 4 weeks of rest if they continued to derive clinical benefit. "On establishment of the maximum tolerated dose, we specified that we would conduct an expansion cohort to explore pharmacodynamics, clinical efficacy, and safety in more detail," Dr. Middleton said, noting that a total of eight cohorts were studied. Patients had to have stage 4 or unresectable stage 3 melanoma, had to be HLA-A2 positive and have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.

The researchers administered IMCgp100 as a 4-hour infusion followed by 48 hours of in-patient observation. Over that 48-hour period they conducted extensive safety evaluations and pharmacokinetic and pharmacodynamic analysis, including detailed audiometric and ophthalmic review. "Because we started with such a low dose we said that we would triple the dose in the absence of toxicity, moving to smaller increments according to safety and pharmacokinetic profile," he said.

Dose-limiting toxicities were defined as drug-related toxicities that occurred within 8 days of drug administration. Anything grade 3 or higher would be deemed as a dose-limiting toxicity.

Among the 40 patients in the trial, the mean age was 59 years and 23 were male. The researchers started to see toxicity at a dose of 45 ng/kg, "which would manifest as a rash that would endure for a few hours, perhaps into the next day," Dr. Middleton said. "At a dose of 135 ng/kg this became more widespread, albeit transient, and we therefore slowed the rate of increase between cohorts." One patient in the 405 ng/kg cohort and two patients in the 900 ng/kg cohort developed grade 3 hypotension 10-12 hours after drug administration. This in part led the researchers to declare a nontolerated dose of 900 ng/kg and a maximum tolerated dose of 600 ng/kg.

Among the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg, the most common adverse event was an itchy rash, "which is often widespread, and associated with edema, which can be periorbital and more widespread," Dr. Middleton said. "This is transient; it usually settles down within 48-72 hours and is not as severe with subsequent administration of the drug." One case of hypotension occurred. The patient recovered after intensive supportive care. Evaluation of pharmacokinetics showed evidence of lymphocyte trafficking, neutrophilia, and a rise in C-reactive protein.

Efficacy results from 10 of the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg showed evidence of "significant and durable clinical responses, particularly in two patients who were treated in the dose escalation phase," he said. Those two patients met the RECIST criteria for response.

Dr. Middleton and his associates are continuing study expansion at the current dose level, with mandated tumor biopsies before treatment, and testing a weekly dosing arm. The goal is to identify the optimal dosing regimen for IMCgp100. The trial is expected to be complete in 2015.

The study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium, and Roche.

The study of DEDN6526A was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose.

Dr. Lynch disclosed that he is on the board of directors for Bristol Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and he receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation–testing patent and receives royalties.

dbrunk@frontlinemedcom.com

SAN DIEGO – OTX015, an investigational agent that blocks the activity of bromodomain and extraterminal bromodomain proteins, demonstrated activity against a variety of hematologic cancers, preliminary results from a phase I trial demonstrated.

The finding is believed to be the first clinical proof that BET bromodomain inhibitors, a new class of anticancer agents that intervene with the down-regulation of the critical oncogene MYC may play a role in the treatment of human malignancies.

©2014 AACR/Todd Buchanan

"We are seeing things that we did not expect to see," Dr. Esteban Cvitkovic, chief scientific officer of Lausanne, Switzerland–based OncoEthix, said during a press briefing at the annual meeting of the American Association for Cancer Research. OncoEthix is developing OTX015, an orally available molecule.

Dr. Cvitkovic presented findings from 42 patients with hematologic malignancies who were enrolled in a trial designed to determine the recommended dose and schedule of OTX015 to be given orally as a single agent. Of the 42 patients, 21 had acute leukemia – primarily acute myelogenous leukemia – and the remaining 21 had other hematologic malignancies, including diffuse large B-cell lymphoma and multiple myeloma. The researchers assigned study participants to a single dose of 10, 20, 40, or 80 mg of OTX015 daily, or to two 40-mg doses of OTX015 daily. Each dosing regimen included three to six patients with acute leukemia and three to six patients with another hematologic malignancy. The drug was administered in 21-day cycles, with a 14 days on, 7 days off regimen for acute leukemia patients and a continuous dosing regimen for patients with other hematologic malignancies.

The mean age of patients was 69 years and 60% were male. Complete data were available on 38 patients. Among these, the researchers observed significant clinical activity in seven patients: four with acute myelogenous leukemia (including one case of complete remission) and three with lymphoma. Of the seven patients, four received a single dose of 80 mg OTX015 daily, one received 10 mg daily, and the other two received 40 mg daily.

"The drug was very well tolerated, and half of the patients had at least three cycles [of the drug]," Dr. Cvitkovic said. Among acute leukemia patients, no dose-limiting toxicity was observed; the maximum tolerated dose was not reached at the 80-mg everyday or 40-mg b.i.d. doses.

Among patients with other hematologic malignancies, thrombocytopenia is emerging as a dose-related toxicity. "Thrombocytopenia is very peculiar, because as with this and any other adverse events, we stopped the drug and within 3 or 4 days everything went back to normal," Dr. Cvitkovic said. "Every adverse event is reversible upon discontinuation of the drug." Enrollment in the trial is continuing, and dose escalation with single doses of 120 mg OTX015 daily is being explored.

Other adverse events reported to date included increased blood glucose levels in previously diabetic patients, mild to moderate digestive symptoms, and declining platelet counts. No cumulative toxicity has been observed, Dr. Cvitkovic said.

"You look at cancer right now, and you look at tumors that are driven by c-Myc, RAS, RB, and p53," Dr. Thomas Lynch, director of the Yale Cancer Center, New Haven, Conn., said at the briefing. "Those are the four big actors in cancer, and we can do [nothing] for all of those major genetic abnormalities. If this approach works, and this is a way of targeting C-Myc or related genes, this would be a major breakthrough. If it works, it offers a [treatment for a] huge unmet medical need."

The study was supported by OncoEthix. Dr. Cvitkovic is chief scientific officer of the company. Dr. Lynch disclosed that he is on the board of directors for Bristol-Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation testing patent and receives royalties.

dbrunk@frontlinemedcom.com

SAN DIEGO – OTX015, an investigational agent that blocks the activity of bromodomain and extraterminal bromodomain proteins, demonstrated activity against a variety of hematologic cancers, preliminary results from a phase I trial demonstrated.

The finding is believed to be the first clinical proof that BET bromodomain inhibitors, a new class of anticancer agents that intervene with the down-regulation of the critical oncogene MYC may play a role in the treatment of human malignancies.

©2014 AACR/Todd Buchanan

"We are seeing things that we did not expect to see," Dr. Esteban Cvitkovic, chief scientific officer of Lausanne, Switzerland–based OncoEthix, said during a press briefing at the annual meeting of the American Association for Cancer Research. OncoEthix is developing OTX015, an orally available molecule.

Dr. Cvitkovic presented findings from 42 patients with hematologic malignancies who were enrolled in a trial designed to determine the recommended dose and schedule of OTX015 to be given orally as a single agent. Of the 42 patients, 21 had acute leukemia – primarily acute myelogenous leukemia – and the remaining 21 had other hematologic malignancies, including diffuse large B-cell lymphoma and multiple myeloma. The researchers assigned study participants to a single dose of 10, 20, 40, or 80 mg of OTX015 daily, or to two 40-mg doses of OTX015 daily. Each dosing regimen included three to six patients with acute leukemia and three to six patients with another hematologic malignancy. The drug was administered in 21-day cycles, with a 14 days on, 7 days off regimen for acute leukemia patients and a continuous dosing regimen for patients with other hematologic malignancies.

The mean age of patients was 69 years and 60% were male. Complete data were available on 38 patients. Among these, the researchers observed significant clinical activity in seven patients: four with acute myelogenous leukemia (including one case of complete remission) and three with lymphoma. Of the seven patients, four received a single dose of 80 mg OTX015 daily, one received 10 mg daily, and the other two received 40 mg daily.

"The drug was very well tolerated, and half of the patients had at least three cycles [of the drug]," Dr. Cvitkovic said. Among acute leukemia patients, no dose-limiting toxicity was observed; the maximum tolerated dose was not reached at the 80-mg everyday or 40-mg b.i.d. doses.

Among patients with other hematologic malignancies, thrombocytopenia is emerging as a dose-related toxicity. "Thrombocytopenia is very peculiar, because as with this and any other adverse events, we stopped the drug and within 3 or 4 days everything went back to normal," Dr. Cvitkovic said. "Every adverse event is reversible upon discontinuation of the drug." Enrollment in the trial is continuing, and dose escalation with single doses of 120 mg OTX015 daily is being explored.

Other adverse events reported to date included increased blood glucose levels in previously diabetic patients, mild to moderate digestive symptoms, and declining platelet counts. No cumulative toxicity has been observed, Dr. Cvitkovic said.

"You look at cancer right now, and you look at tumors that are driven by c-Myc, RAS, RB, and p53," Dr. Thomas Lynch, director of the Yale Cancer Center, New Haven, Conn., said at the briefing. "Those are the four big actors in cancer, and we can do [nothing] for all of those major genetic abnormalities. If this approach works, and this is a way of targeting C-Myc or related genes, this would be a major breakthrough. If it works, it offers a [treatment for a] huge unmet medical need."

The study was supported by OncoEthix. Dr. Cvitkovic is chief scientific officer of the company. Dr. Lynch disclosed that he is on the board of directors for Bristol-Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation testing patent and receives royalties.

dbrunk@frontlinemedcom.com

SAN DIEGO – OTX015, an investigational agent that blocks the activity of bromodomain and extraterminal bromodomain proteins, demonstrated activity against a variety of hematologic cancers, preliminary results from a phase I trial demonstrated.

The finding is believed to be the first clinical proof that BET bromodomain inhibitors, a new class of anticancer agents that intervene with the down-regulation of the critical oncogene MYC may play a role in the treatment of human malignancies.

©2014 AACR/Todd Buchanan

"We are seeing things that we did not expect to see," Dr. Esteban Cvitkovic, chief scientific officer of Lausanne, Switzerland–based OncoEthix, said during a press briefing at the annual meeting of the American Association for Cancer Research. OncoEthix is developing OTX015, an orally available molecule.

Dr. Cvitkovic presented findings from 42 patients with hematologic malignancies who were enrolled in a trial designed to determine the recommended dose and schedule of OTX015 to be given orally as a single agent. Of the 42 patients, 21 had acute leukemia – primarily acute myelogenous leukemia – and the remaining 21 had other hematologic malignancies, including diffuse large B-cell lymphoma and multiple myeloma. The researchers assigned study participants to a single dose of 10, 20, 40, or 80 mg of OTX015 daily, or to two 40-mg doses of OTX015 daily. Each dosing regimen included three to six patients with acute leukemia and three to six patients with another hematologic malignancy. The drug was administered in 21-day cycles, with a 14 days on, 7 days off regimen for acute leukemia patients and a continuous dosing regimen for patients with other hematologic malignancies.

The mean age of patients was 69 years and 60% were male. Complete data were available on 38 patients. Among these, the researchers observed significant clinical activity in seven patients: four with acute myelogenous leukemia (including one case of complete remission) and three with lymphoma. Of the seven patients, four received a single dose of 80 mg OTX015 daily, one received 10 mg daily, and the other two received 40 mg daily.

"The drug was very well tolerated, and half of the patients had at least three cycles [of the drug]," Dr. Cvitkovic said. Among acute leukemia patients, no dose-limiting toxicity was observed; the maximum tolerated dose was not reached at the 80-mg everyday or 40-mg b.i.d. doses.

Among patients with other hematologic malignancies, thrombocytopenia is emerging as a dose-related toxicity. "Thrombocytopenia is very peculiar, because as with this and any other adverse events, we stopped the drug and within 3 or 4 days everything went back to normal," Dr. Cvitkovic said. "Every adverse event is reversible upon discontinuation of the drug." Enrollment in the trial is continuing, and dose escalation with single doses of 120 mg OTX015 daily is being explored.

Other adverse events reported to date included increased blood glucose levels in previously diabetic patients, mild to moderate digestive symptoms, and declining platelet counts. No cumulative toxicity has been observed, Dr. Cvitkovic said.

"You look at cancer right now, and you look at tumors that are driven by c-Myc, RAS, RB, and p53," Dr. Thomas Lynch, director of the Yale Cancer Center, New Haven, Conn., said at the briefing. "Those are the four big actors in cancer, and we can do [nothing] for all of those major genetic abnormalities. If this approach works, and this is a way of targeting C-Myc or related genes, this would be a major breakthrough. If it works, it offers a [treatment for a] huge unmet medical need."

The study was supported by OncoEthix. Dr. Cvitkovic is chief scientific officer of the company. Dr. Lynch disclosed that he is on the board of directors for Bristol-Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation testing patent and receives royalties.

dbrunk@frontlinemedcom.com

SAN DIEGO – Palbociclib, a first-in-class cyclin-dependent kinase 4/6 inhibitor, in combination with letrozole, significantly improved median progression-free survival in patients with advanced estrogen receptor–positive, human epidermal growth factor receptor 2–negative breast cancer in the first-line setting.

In preclinical studies, palbociclib, previously known as PD 0332991, "has been shown to block the transition from G1 to S in the cell cycle," Dr. Richard S. Finn said during a press briefing at the annual meeting of the American Association for Cancer Research. "That’s a place where CDK 4 and 6 play a critical role in regulating cell metabolism. What is important to note is that palbociclib, unlike prior CDK inhibitors, is very specific for CDK 4 and 6. Earlier [nonspecific] CDK inhibitors had trouble in clinical development."

In a study supported by Pfizer Inc., which is developing palbociclib, Dr. Finn of the University of California, Los Angeles, and his associates conducted an open-label, randomized, phase II study of palbociclib in combination with letrozole vs. letrozole alone for first-line treatment of ER-positive, HER2-negative advanced breast cancer.

©2014 AACR/Todd Buchanan

The study, known as PALOMA-1, included 165 patients and was conducted in two parts. Part one included 66 postmenopausal women with ER-positive/HER2-negative breast cancer, while part two included 99 postmenopausal women with the same cancer subtype who were additionally screened for CCND1 amplification and/or loss of p16. Women in both study arms were randomized 1:1 open label to letrozole vs. palbociclib 125 mg on a 3-week-on, 3-week-off course and were followed for tumor assessments every 2 months. The primary endpoint was investigator-assessed progression-free survival defined as the time from randomization to objective progression or death.

The median age of the patients was 64 years, and about one-third had received prior hormone replacement therapy in the adjuvant setting. The median progression-free survival was 10.2 months among patients who received letrozole alone, compared with 20.2 months among patients who received letrozole plus palbociclib. This difference reached statistical significance with a hazard ratio of 0.488, or a 51% decrease in the risk of progression with the addition of palbociclib (P = .0004), Dr. Finn reported.

In secondary measures, the researchers observed a benefit of letrozole plus palbociclib, compared with letrozole only, in terms of the objective response rate among all randomized patients (43% vs. 33%, respectively), the objective response rate among patients with measurable disease (55% vs. 39%), and in the clinical benefit rate (81% vs. 58%).

The median overall survival increased from 33.3 months among patients in the letrozole-only arm to 37.5 months among patients in the letrozole-plus-palbociclib arm. That translated into a hazard ratio of 0.813, "which at this time is not statistically significant," Dr. Finn noted.

The most common adverse events were neutropenia, leukopenia, and fatigue. "This neutropenia is not the type we see with chemotherapy," he said. "It is self limited and recovers quickly. We did not see neutropenic fever."

A randomized phase III study is under way to confirm these findings in a similar patient population.

In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, characterized the findings as impressive. "This is just as impressive as the everolimus data that led to a subsequent phase III [trial] that led to subsequent approval of that drug," she said.

The study was supported by Pfizer. Dr. Finn disclosed that he has received research support from the company. Dr. LoRusso disclosed that she has received research funding from Agios Pharmaceuticals.

dbrunk@frontlinemedcom.com

SAN DIEGO – Palbociclib, a first-in-class cyclin-dependent kinase 4/6 inhibitor, in combination with letrozole, significantly improved median progression-free survival in patients with advanced estrogen receptor–positive, human epidermal growth factor receptor 2–negative breast cancer in the first-line setting.

In preclinical studies, palbociclib, previously known as PD 0332991, "has been shown to block the transition from G1 to S in the cell cycle," Dr. Richard S. Finn said during a press briefing at the annual meeting of the American Association for Cancer Research. "That’s a place where CDK 4 and 6 play a critical role in regulating cell metabolism. What is important to note is that palbociclib, unlike prior CDK inhibitors, is very specific for CDK 4 and 6. Earlier [nonspecific] CDK inhibitors had trouble in clinical development."

In a study supported by Pfizer Inc., which is developing palbociclib, Dr. Finn of the University of California, Los Angeles, and his associates conducted an open-label, randomized, phase II study of palbociclib in combination with letrozole vs. letrozole alone for first-line treatment of ER-positive, HER2-negative advanced breast cancer.

©2014 AACR/Todd Buchanan

The study, known as PALOMA-1, included 165 patients and was conducted in two parts. Part one included 66 postmenopausal women with ER-positive/HER2-negative breast cancer, while part two included 99 postmenopausal women with the same cancer subtype who were additionally screened for CCND1 amplification and/or loss of p16. Women in both study arms were randomized 1:1 open label to letrozole vs. palbociclib 125 mg on a 3-week-on, 3-week-off course and were followed for tumor assessments every 2 months. The primary endpoint was investigator-assessed progression-free survival defined as the time from randomization to objective progression or death.

The median age of the patients was 64 years, and about one-third had received prior hormone replacement therapy in the adjuvant setting. The median progression-free survival was 10.2 months among patients who received letrozole alone, compared with 20.2 months among patients who received letrozole plus palbociclib. This difference reached statistical significance with a hazard ratio of 0.488, or a 51% decrease in the risk of progression with the addition of palbociclib (P = .0004), Dr. Finn reported.

In secondary measures, the researchers observed a benefit of letrozole plus palbociclib, compared with letrozole only, in terms of the objective response rate among all randomized patients (43% vs. 33%, respectively), the objective response rate among patients with measurable disease (55% vs. 39%), and in the clinical benefit rate (81% vs. 58%).

The median overall survival increased from 33.3 months among patients in the letrozole-only arm to 37.5 months among patients in the letrozole-plus-palbociclib arm. That translated into a hazard ratio of 0.813, "which at this time is not statistically significant," Dr. Finn noted.

The most common adverse events were neutropenia, leukopenia, and fatigue. "This neutropenia is not the type we see with chemotherapy," he said. "It is self limited and recovers quickly. We did not see neutropenic fever."

A randomized phase III study is under way to confirm these findings in a similar patient population.

In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, characterized the findings as impressive. "This is just as impressive as the everolimus data that led to a subsequent phase III [trial] that led to subsequent approval of that drug," she said.

The study was supported by Pfizer. Dr. Finn disclosed that he has received research support from the company. Dr. LoRusso disclosed that she has received research funding from Agios Pharmaceuticals.

dbrunk@frontlinemedcom.com

SAN DIEGO – Palbociclib, a first-in-class cyclin-dependent kinase 4/6 inhibitor, in combination with letrozole, significantly improved median progression-free survival in patients with advanced estrogen receptor–positive, human epidermal growth factor receptor 2–negative breast cancer in the first-line setting.

In preclinical studies, palbociclib, previously known as PD 0332991, "has been shown to block the transition from G1 to S in the cell cycle," Dr. Richard S. Finn said during a press briefing at the annual meeting of the American Association for Cancer Research. "That’s a place where CDK 4 and 6 play a critical role in regulating cell metabolism. What is important to note is that palbociclib, unlike prior CDK inhibitors, is very specific for CDK 4 and 6. Earlier [nonspecific] CDK inhibitors had trouble in clinical development."

In a study supported by Pfizer Inc., which is developing palbociclib, Dr. Finn of the University of California, Los Angeles, and his associates conducted an open-label, randomized, phase II study of palbociclib in combination with letrozole vs. letrozole alone for first-line treatment of ER-positive, HER2-negative advanced breast cancer.

©2014 AACR/Todd Buchanan

The study, known as PALOMA-1, included 165 patients and was conducted in two parts. Part one included 66 postmenopausal women with ER-positive/HER2-negative breast cancer, while part two included 99 postmenopausal women with the same cancer subtype who were additionally screened for CCND1 amplification and/or loss of p16. Women in both study arms were randomized 1:1 open label to letrozole vs. palbociclib 125 mg on a 3-week-on, 3-week-off course and were followed for tumor assessments every 2 months. The primary endpoint was investigator-assessed progression-free survival defined as the time from randomization to objective progression or death.

The median age of the patients was 64 years, and about one-third had received prior hormone replacement therapy in the adjuvant setting. The median progression-free survival was 10.2 months among patients who received letrozole alone, compared with 20.2 months among patients who received letrozole plus palbociclib. This difference reached statistical significance with a hazard ratio of 0.488, or a 51% decrease in the risk of progression with the addition of palbociclib (P = .0004), Dr. Finn reported.

In secondary measures, the researchers observed a benefit of letrozole plus palbociclib, compared with letrozole only, in terms of the objective response rate among all randomized patients (43% vs. 33%, respectively), the objective response rate among patients with measurable disease (55% vs. 39%), and in the clinical benefit rate (81% vs. 58%).

The median overall survival increased from 33.3 months among patients in the letrozole-only arm to 37.5 months among patients in the letrozole-plus-palbociclib arm. That translated into a hazard ratio of 0.813, "which at this time is not statistically significant," Dr. Finn noted.

The most common adverse events were neutropenia, leukopenia, and fatigue. "This neutropenia is not the type we see with chemotherapy," he said. "It is self limited and recovers quickly. We did not see neutropenic fever."

A randomized phase III study is under way to confirm these findings in a similar patient population.

In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, characterized the findings as impressive. "This is just as impressive as the everolimus data that led to a subsequent phase III [trial] that led to subsequent approval of that drug," she said.

The study was supported by Pfizer. Dr. Finn disclosed that he has received research support from the company. Dr. LoRusso disclosed that she has received research funding from Agios Pharmaceuticals.

dbrunk@frontlinemedcom.com

SAN DIEGO - About 30% of nodules detected by CT screening fit the criteria for an indeterminate pulmonary nodule. Very few of those nodules represent cancer, and the question is, what do you recommend for those patients in terms of follow-up?

"We're encountering more and more patients with lung nodules in the clinic, and with the advance of screening, it will become even more of a problem. The numbers are tremendous," Dr. Pierre P. Massion stated at the Joint Conference on the Molecular Origins of Lung Cancer, sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Massion, the Ingram Professor of Cancer Research at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said it's important to differentiate - early, accurately, and noninvasively - benign lesions from cancer. "There is a race for early diagnosis, because surgery is the best chance for cure ... but we also need to decrease the number of thoracotomies performed for benign disease."

Data from eight large trials of lung cancer screening examined the relationship between lesion size and the probability of lung cancer (Chest 2007;132[3 Suppl]:94S-107S). The probability of cancer was 0-1% for lesions less than 5 mm in diameter; 6%-28% for those 5-10 mm, 33%-60% for those 11-20 mm, and 64%-82% for those 21-30 mm.

"The bigger the nodule, the greater the probability of cancer. In fact, however, the number of large nodules is very small," Dr. Massion said. "The indeterminate ones are between 5 and 15 mm in diameter, and these are the ones we struggle with how best to handle." The probability of cancer from indeterminate pulmonary nodules ranges from 6% to 60%, which is a large range.

The shape of the nodule provides additional information, Dr. Massion said. Triangular shape abutting a fissure and central calcification are generally indicators of benign disease and typically do not require follow-up. Alternatively, solid, noncalcified spiculated nodules have a high likelihood of being cancer. Part solid nodules are "very worrisome," he said. "These are most likely to contain malignancy. Nonsolid lesions, also called ground-glass opacities, are troublesome and difficult to assess. They represent about a 20% probability of disease."

The rate of growth of small nodules over time "is probably one of the best imaging markers, [but] for small nodules such as those 5 mm in diameter, the volumetric analysis has a large coefficient of variance," he said.

Prediction models are important to the evaluation of lung nodules, yet even with existing tools "we're wrong about 30% of the time," he said. The best three prediction models come from studies of patients at the Mayo Clinic (Arch. Intern. Med. 1997;157:849-55) and the Veterans Affairs department (Chest 2007;131:383-88), and from patients enrolled in the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial (N. Engl. J. Med. 2013;368:728-36). These prediction models are now recommended for use on nodules greater than 8 mm in diameter in the ACCP 2013 guidelines for evaluation of lung nodules (Chest 2013;143[5 Suppl]:e93S-120S).

"We have no models for never-smokers, which is a huge problem in the community at the moment."

Dr. Massion predicted that serum biomarkers might "come to the rescue" for deciding which patients with indeterminate pulmonary nodules might need to go for a biopsy or resection and which can be carefully watched over time.

In a separate study of 62 lung nodules that integrated clinical, imaging, and protein biomarker findings, clinical information alone resulted in about 50% sensitivity for predicting disease, "which is not great," said Dr. Massion, who was the principal investigator (Cancer Epidemiol. Biomarkers Prev. 2012;21:786-92). The addition of CT imaging increased the area under the curve to about 61%. Adding biomarkers in the blood raised the bar to about 69%.

"It's not a panacea, but we show a trend toward improvement of classification of these nodules, which is where I think this field is going - integrating information from the clinic, imaging, and the discriminatory power of biomarkers."

Dr. Massion said that he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO - About 30% of nodules detected by CT screening fit the criteria for an indeterminate pulmonary nodule. Very few of those nodules represent cancer, and the question is, what do you recommend for those patients in terms of follow-up?

"We're encountering more and more patients with lung nodules in the clinic, and with the advance of screening, it will become even more of a problem. The numbers are tremendous," Dr. Pierre P. Massion stated at the Joint Conference on the Molecular Origins of Lung Cancer, sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Massion, the Ingram Professor of Cancer Research at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said it's important to differentiate - early, accurately, and noninvasively - benign lesions from cancer. "There is a race for early diagnosis, because surgery is the best chance for cure ... but we also need to decrease the number of thoracotomies performed for benign disease."

Data from eight large trials of lung cancer screening examined the relationship between lesion size and the probability of lung cancer (Chest 2007;132[3 Suppl]:94S-107S). The probability of cancer was 0-1% for lesions less than 5 mm in diameter; 6%-28% for those 5-10 mm, 33%-60% for those 11-20 mm, and 64%-82% for those 21-30 mm.

"The bigger the nodule, the greater the probability of cancer. In fact, however, the number of large nodules is very small," Dr. Massion said. "The indeterminate ones are between 5 and 15 mm in diameter, and these are the ones we struggle with how best to handle." The probability of cancer from indeterminate pulmonary nodules ranges from 6% to 60%, which is a large range.

The shape of the nodule provides additional information, Dr. Massion said. Triangular shape abutting a fissure and central calcification are generally indicators of benign disease and typically do not require follow-up. Alternatively, solid, noncalcified spiculated nodules have a high likelihood of being cancer. Part solid nodules are "very worrisome," he said. "These are most likely to contain malignancy. Nonsolid lesions, also called ground-glass opacities, are troublesome and difficult to assess. They represent about a 20% probability of disease."

The rate of growth of small nodules over time "is probably one of the best imaging markers, [but] for small nodules such as those 5 mm in diameter, the volumetric analysis has a large coefficient of variance," he said.

Prediction models are important to the evaluation of lung nodules, yet even with existing tools "we're wrong about 30% of the time," he said. The best three prediction models come from studies of patients at the Mayo Clinic (Arch. Intern. Med. 1997;157:849-55) and the Veterans Affairs department (Chest 2007;131:383-88), and from patients enrolled in the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial (N. Engl. J. Med. 2013;368:728-36). These prediction models are now recommended for use on nodules greater than 8 mm in diameter in the ACCP 2013 guidelines for evaluation of lung nodules (Chest 2013;143[5 Suppl]:e93S-120S).

"We have no models for never-smokers, which is a huge problem in the community at the moment."

Dr. Massion predicted that serum biomarkers might "come to the rescue" for deciding which patients with indeterminate pulmonary nodules might need to go for a biopsy or resection and which can be carefully watched over time.

In a separate study of 62 lung nodules that integrated clinical, imaging, and protein biomarker findings, clinical information alone resulted in about 50% sensitivity for predicting disease, "which is not great," said Dr. Massion, who was the principal investigator (Cancer Epidemiol. Biomarkers Prev. 2012;21:786-92). The addition of CT imaging increased the area under the curve to about 61%. Adding biomarkers in the blood raised the bar to about 69%.

"It's not a panacea, but we show a trend toward improvement of classification of these nodules, which is where I think this field is going - integrating information from the clinic, imaging, and the discriminatory power of biomarkers."

Dr. Massion said that he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO - About 30% of nodules detected by CT screening fit the criteria for an indeterminate pulmonary nodule. Very few of those nodules represent cancer, and the question is, what do you recommend for those patients in terms of follow-up?

"We're encountering more and more patients with lung nodules in the clinic, and with the advance of screening, it will become even more of a problem. The numbers are tremendous," Dr. Pierre P. Massion stated at the Joint Conference on the Molecular Origins of Lung Cancer, sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Massion, the Ingram Professor of Cancer Research at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said it's important to differentiate - early, accurately, and noninvasively - benign lesions from cancer. "There is a race for early diagnosis, because surgery is the best chance for cure ... but we also need to decrease the number of thoracotomies performed for benign disease."

Data from eight large trials of lung cancer screening examined the relationship between lesion size and the probability of lung cancer (Chest 2007;132[3 Suppl]:94S-107S). The probability of cancer was 0-1% for lesions less than 5 mm in diameter; 6%-28% for those 5-10 mm, 33%-60% for those 11-20 mm, and 64%-82% for those 21-30 mm.

"The bigger the nodule, the greater the probability of cancer. In fact, however, the number of large nodules is very small," Dr. Massion said. "The indeterminate ones are between 5 and 15 mm in diameter, and these are the ones we struggle with how best to handle." The probability of cancer from indeterminate pulmonary nodules ranges from 6% to 60%, which is a large range.

The shape of the nodule provides additional information, Dr. Massion said. Triangular shape abutting a fissure and central calcification are generally indicators of benign disease and typically do not require follow-up. Alternatively, solid, noncalcified spiculated nodules have a high likelihood of being cancer. Part solid nodules are "very worrisome," he said. "These are most likely to contain malignancy. Nonsolid lesions, also called ground-glass opacities, are troublesome and difficult to assess. They represent about a 20% probability of disease."

The rate of growth of small nodules over time "is probably one of the best imaging markers, [but] for small nodules such as those 5 mm in diameter, the volumetric analysis has a large coefficient of variance," he said.

Prediction models are important to the evaluation of lung nodules, yet even with existing tools "we're wrong about 30% of the time," he said. The best three prediction models come from studies of patients at the Mayo Clinic (Arch. Intern. Med. 1997;157:849-55) and the Veterans Affairs department (Chest 2007;131:383-88), and from patients enrolled in the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial (N. Engl. J. Med. 2013;368:728-36). These prediction models are now recommended for use on nodules greater than 8 mm in diameter in the ACCP 2013 guidelines for evaluation of lung nodules (Chest 2013;143[5 Suppl]:e93S-120S).

"We have no models for never-smokers, which is a huge problem in the community at the moment."

Dr. Massion predicted that serum biomarkers might "come to the rescue" for deciding which patients with indeterminate pulmonary nodules might need to go for a biopsy or resection and which can be carefully watched over time.

In a separate study of 62 lung nodules that integrated clinical, imaging, and protein biomarker findings, clinical information alone resulted in about 50% sensitivity for predicting disease, "which is not great," said Dr. Massion, who was the principal investigator (Cancer Epidemiol. Biomarkers Prev. 2012;21:786-92). The addition of CT imaging increased the area under the curve to about 61%. Adding biomarkers in the blood raised the bar to about 69%.

"It's not a panacea, but we show a trend toward improvement of classification of these nodules, which is where I think this field is going - integrating information from the clinic, imaging, and the discriminatory power of biomarkers."

Dr. Massion said that he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Expect an expanded role of immunotherapy in patients with non–small cell lung cancer, Dr. Roy S. Herbst predicted at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Herbst, who is a professor of medical oncology at Yale University, New Haven, Conn., characterized immunotherapy as "probably the most exciting new and specific therapies we have for NSCLC. The extent in its response is impressive, and this is a therapy that has memory. The adaptability of immunotherapy is important as well."

He advised researchers and clinicians to consider using immunotherapy that includes CTLA-4 antibodies, PD-1 antibodies, and PD-L1 antibodies alone or together in patients with earlier stages of lung disease. Clinical studies of immunotherapy in NSCLC patients suggest that some patients don’t get better with immunotherapy, "but a lot of patients do," said Dr. Herbst.

"We want to figure out who those patients are. When we see activity like this, we think, can we bring this therapy to earlier disease? These agents might have a role in maintenance therapy and adjuvant/neoadjuvant therapy. Of course, we worry about side effects such as pneumonitis, which occurs rarely, but we still hope these agents will have a benefit in the adjuvant setting. The biology speaks to that. But what about using these agents as maintenance therapy? I think that needs to be explored."

Using immunotherapy as frontline treatment in patients with stage IV lung cancer is also feasible, he said. "I’d feel much better about it if we had a marker, but we should think about some single-agent trials," he said.

"Other possibilities in stage IV disease include using immunotherapy with chemotherapy and with tyrosine kinase inhibitors."

Immunotherapy-related adverse events are "not overwhelming, but they’re different than what we see with chemotherapy," Dr. Herbst continued. "For example, some of the endocrine events are not something we often see. We are working on ways to manage this."

Use of biomarkers and immune monitoring can also help clinicians gauge the efficacy of immunotherapy in their NSCLC patients.

Dr. Herbst and his associates at Yale Cancer Center follow these patients with biopsies at baseline, during therapy, and at the end of therapy, "because after their therapy at 1 year or more, you wonder: Is this active tumor? Or is this necrotic tissue?" he said. "We now have ways to figure out who is responding and why they’re responding."

Another trend being seen in the future of immunotherapy involves combining with other agents that address key mechanisms in positive and negative regulation of the immune system.

Dr. Herbst explained that the biological goal of combinations with a checkpoint inhibitor include the ability to induce antigen-specific T cells, provide more antigen-presenting cells (APCs), activation/modulation of APCs, drive T-cell expansion to expand the pool of antigen-specific cells, and remove other regulatory checkpoints/suppressive factors for T-cell activation/expansion in periphery.

"The current challenge is to identify the critical deficiencies in individual patients," he said.

"We have to continue to investigate the biologic significance of all potential ligand-receptor interactions in the tumor microenvironment."

Dr. Herbst disclosed that he is on the scientific advisory boards of Biothera, Diatech, Kolltan, N of 1, Novarx, and Quintiles. He also has done consulting for Ariad, Astellas, and other companies.

dbrunk@frontlinemedcom.com

SAN DIEGO – Expect an expanded role of immunotherapy in patients with non–small cell lung cancer, Dr. Roy S. Herbst predicted at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Herbst, who is a professor of medical oncology at Yale University, New Haven, Conn., characterized immunotherapy as "probably the most exciting new and specific therapies we have for NSCLC. The extent in its response is impressive, and this is a therapy that has memory. The adaptability of immunotherapy is important as well."

He advised researchers and clinicians to consider using immunotherapy that includes CTLA-4 antibodies, PD-1 antibodies, and PD-L1 antibodies alone or together in patients with earlier stages of lung disease. Clinical studies of immunotherapy in NSCLC patients suggest that some patients don’t get better with immunotherapy, "but a lot of patients do," said Dr. Herbst.

"We want to figure out who those patients are. When we see activity like this, we think, can we bring this therapy to earlier disease? These agents might have a role in maintenance therapy and adjuvant/neoadjuvant therapy. Of course, we worry about side effects such as pneumonitis, which occurs rarely, but we still hope these agents will have a benefit in the adjuvant setting. The biology speaks to that. But what about using these agents as maintenance therapy? I think that needs to be explored."

Using immunotherapy as frontline treatment in patients with stage IV lung cancer is also feasible, he said. "I’d feel much better about it if we had a marker, but we should think about some single-agent trials," he said.

"Other possibilities in stage IV disease include using immunotherapy with chemotherapy and with tyrosine kinase inhibitors."

Immunotherapy-related adverse events are "not overwhelming, but they’re different than what we see with chemotherapy," Dr. Herbst continued. "For example, some of the endocrine events are not something we often see. We are working on ways to manage this."

Use of biomarkers and immune monitoring can also help clinicians gauge the efficacy of immunotherapy in their NSCLC patients.

Dr. Herbst and his associates at Yale Cancer Center follow these patients with biopsies at baseline, during therapy, and at the end of therapy, "because after their therapy at 1 year or more, you wonder: Is this active tumor? Or is this necrotic tissue?" he said. "We now have ways to figure out who is responding and why they’re responding."

Another trend being seen in the future of immunotherapy involves combining with other agents that address key mechanisms in positive and negative regulation of the immune system.

Dr. Herbst explained that the biological goal of combinations with a checkpoint inhibitor include the ability to induce antigen-specific T cells, provide more antigen-presenting cells (APCs), activation/modulation of APCs, drive T-cell expansion to expand the pool of antigen-specific cells, and remove other regulatory checkpoints/suppressive factors for T-cell activation/expansion in periphery.

"The current challenge is to identify the critical deficiencies in individual patients," he said.

"We have to continue to investigate the biologic significance of all potential ligand-receptor interactions in the tumor microenvironment."

Dr. Herbst disclosed that he is on the scientific advisory boards of Biothera, Diatech, Kolltan, N of 1, Novarx, and Quintiles. He also has done consulting for Ariad, Astellas, and other companies.

dbrunk@frontlinemedcom.com

SAN DIEGO – Expect an expanded role of immunotherapy in patients with non–small cell lung cancer, Dr. Roy S. Herbst predicted at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Herbst, who is a professor of medical oncology at Yale University, New Haven, Conn., characterized immunotherapy as "probably the most exciting new and specific therapies we have for NSCLC. The extent in its response is impressive, and this is a therapy that has memory. The adaptability of immunotherapy is important as well."

He advised researchers and clinicians to consider using immunotherapy that includes CTLA-4 antibodies, PD-1 antibodies, and PD-L1 antibodies alone or together in patients with earlier stages of lung disease. Clinical studies of immunotherapy in NSCLC patients suggest that some patients don’t get better with immunotherapy, "but a lot of patients do," said Dr. Herbst.

"We want to figure out who those patients are. When we see activity like this, we think, can we bring this therapy to earlier disease? These agents might have a role in maintenance therapy and adjuvant/neoadjuvant therapy. Of course, we worry about side effects such as pneumonitis, which occurs rarely, but we still hope these agents will have a benefit in the adjuvant setting. The biology speaks to that. But what about using these agents as maintenance therapy? I think that needs to be explored."

Using immunotherapy as frontline treatment in patients with stage IV lung cancer is also feasible, he said. "I’d feel much better about it if we had a marker, but we should think about some single-agent trials," he said.

"Other possibilities in stage IV disease include using immunotherapy with chemotherapy and with tyrosine kinase inhibitors."

Immunotherapy-related adverse events are "not overwhelming, but they’re different than what we see with chemotherapy," Dr. Herbst continued. "For example, some of the endocrine events are not something we often see. We are working on ways to manage this."

Use of biomarkers and immune monitoring can also help clinicians gauge the efficacy of immunotherapy in their NSCLC patients.

Dr. Herbst and his associates at Yale Cancer Center follow these patients with biopsies at baseline, during therapy, and at the end of therapy, "because after their therapy at 1 year or more, you wonder: Is this active tumor? Or is this necrotic tissue?" he said. "We now have ways to figure out who is responding and why they’re responding."

Another trend being seen in the future of immunotherapy involves combining with other agents that address key mechanisms in positive and negative regulation of the immune system.

Dr. Herbst explained that the biological goal of combinations with a checkpoint inhibitor include the ability to induce antigen-specific T cells, provide more antigen-presenting cells (APCs), activation/modulation of APCs, drive T-cell expansion to expand the pool of antigen-specific cells, and remove other regulatory checkpoints/suppressive factors for T-cell activation/expansion in periphery.

"The current challenge is to identify the critical deficiencies in individual patients," he said.

"We have to continue to investigate the biologic significance of all potential ligand-receptor interactions in the tumor microenvironment."

Dr. Herbst disclosed that he is on the scientific advisory boards of Biothera, Diatech, Kolltan, N of 1, Novarx, and Quintiles. He also has done consulting for Ariad, Astellas, and other companies.

dbrunk@frontlinemedcom.com

SAN DIEGO – The country’s leading regulatory agency has as many questions about the potential health effects of electronic cigarettes as concerned clinicians do.

According to Mitchell Zeller, J.D., director of the Food and Drug Administration’s (FDA’s) Center for Tobacco Products, two key behavioral questions are who is using them and how they are being used.

© -goldy-/Thinkstockphotos.com

"The only way to get answers to that is to fund the research to do it," he said during a press briefing at the annual meeting of the American Association for Cancer Research. "We’ve been funding research on e-cigarettes for a while and will continue to do that. As a regulatory maker, we’ll then make regulatory policy decisions based on what the science tells us."

The FDA does not currently regulate e-cigarettes, but the agency intends to issue a proposed rule extending its product authorities beyond cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco. "We’re very close to being able to announce [that] proposed rule," Mr. Zeller said.

He noted that if the subset of current smokers who are unable or unwilling to quit, substitute conventional cigarettes for e-cigarettes, "there’s a chance there could be a positive impact on public health. But the standard that Congress has given the FDA to implement and enforce – when that day comes that we do regulate e cigarettes – it’s going to be about the net population [impact], not just the subset of smokers unable or unwilling to quit. What if it turns out that the use pattern is not complete substitution but situational substitution, where an otherwise health-concerned, interested-in-quitting smoker is using e-cigarettes as a bridge to get from their last cigarette to their next cigarette? That would have a net negative impact on public health. It’s going to be the FDA’s job to figure out what the net of all of that is, but right now all of us in government and research have far more questions than answers when it comes to e- cigarettes."

"We understand that there are a lot of impatience and urgency around the issue," said Robert T. Croyle, Ph.D., director of the National Cancer Institute’s Division of Cancer Control and Population Sciences. Investigating the health effect of e-cigarettes poses certain challenges, "but we’re dedicated to expanding work in this area," he said.

Neither Mr. Zeller nor Dr. Croyle had relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – The country’s leading regulatory agency has as many questions about the potential health effects of electronic cigarettes as concerned clinicians do.

According to Mitchell Zeller, J.D., director of the Food and Drug Administration’s (FDA’s) Center for Tobacco Products, two key behavioral questions are who is using them and how they are being used.

© -goldy-/Thinkstockphotos.com

"The only way to get answers to that is to fund the research to do it," he said during a press briefing at the annual meeting of the American Association for Cancer Research. "We’ve been funding research on e-cigarettes for a while and will continue to do that. As a regulatory maker, we’ll then make regulatory policy decisions based on what the science tells us."

The FDA does not currently regulate e-cigarettes, but the agency intends to issue a proposed rule extending its product authorities beyond cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco. "We’re very close to being able to announce [that] proposed rule," Mr. Zeller said.

He noted that if the subset of current smokers who are unable or unwilling to quit, substitute conventional cigarettes for e-cigarettes, "there’s a chance there could be a positive impact on public health. But the standard that Congress has given the FDA to implement and enforce – when that day comes that we do regulate e cigarettes – it’s going to be about the net population [impact], not just the subset of smokers unable or unwilling to quit. What if it turns out that the use pattern is not complete substitution but situational substitution, where an otherwise health-concerned, interested-in-quitting smoker is using e-cigarettes as a bridge to get from their last cigarette to their next cigarette? That would have a net negative impact on public health. It’s going to be the FDA’s job to figure out what the net of all of that is, but right now all of us in government and research have far more questions than answers when it comes to e- cigarettes."

"We understand that there are a lot of impatience and urgency around the issue," said Robert T. Croyle, Ph.D., director of the National Cancer Institute’s Division of Cancer Control and Population Sciences. Investigating the health effect of e-cigarettes poses certain challenges, "but we’re dedicated to expanding work in this area," he said.

Neither Mr. Zeller nor Dr. Croyle had relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – The country’s leading regulatory agency has as many questions about the potential health effects of electronic cigarettes as concerned clinicians do.

According to Mitchell Zeller, J.D., director of the Food and Drug Administration’s (FDA’s) Center for Tobacco Products, two key behavioral questions are who is using them and how they are being used.

© -goldy-/Thinkstockphotos.com

"The only way to get answers to that is to fund the research to do it," he said during a press briefing at the annual meeting of the American Association for Cancer Research. "We’ve been funding research on e-cigarettes for a while and will continue to do that. As a regulatory maker, we’ll then make regulatory policy decisions based on what the science tells us."

The FDA does not currently regulate e-cigarettes, but the agency intends to issue a proposed rule extending its product authorities beyond cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco. "We’re very close to being able to announce [that] proposed rule," Mr. Zeller said.

He noted that if the subset of current smokers who are unable or unwilling to quit, substitute conventional cigarettes for e-cigarettes, "there’s a chance there could be a positive impact on public health. But the standard that Congress has given the FDA to implement and enforce – when that day comes that we do regulate e cigarettes – it’s going to be about the net population [impact], not just the subset of smokers unable or unwilling to quit. What if it turns out that the use pattern is not complete substitution but situational substitution, where an otherwise health-concerned, interested-in-quitting smoker is using e-cigarettes as a bridge to get from their last cigarette to their next cigarette? That would have a net negative impact on public health. It’s going to be the FDA’s job to figure out what the net of all of that is, but right now all of us in government and research have far more questions than answers when it comes to e- cigarettes."

"We understand that there are a lot of impatience and urgency around the issue," said Robert T. Croyle, Ph.D., director of the National Cancer Institute’s Division of Cancer Control and Population Sciences. Investigating the health effect of e-cigarettes poses certain challenges, "but we’re dedicated to expanding work in this area," he said.

Neither Mr. Zeller nor Dr. Croyle had relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Asthma and airway hyperresponsiveness may be underrecognized in children with eosinophilic esophagitis, results from a controlled cross-sectional study demonstrated.

While previous studies have estimated the prevalence of asthma in children with eosinophilic esophagitis (EoE), to range from 24-42%, a recent analysis presented during a late-breaker abstract session at annual meeting of the American Academy of Allergy, Asthma, and Immunology found that up to 70% of children with EoE may suffer from asthma.

pelvidge/thinkstockphotos.com

"Clinicians treating children with eosinophilic esophagitis should consider asking additional history questions related to asthma symptoms and may also want to consider pulmonary function testing or referral to an asthma specialist for evaluation," lead author Dr. Nadia L. Krupp said in an interview prior to the meeting. "This is the first study to formally evaluate lung function and airway hyperresponsiveness in children with EoE. Prior estimations of asthma have solely come from patient/parent report."

Dr. Krupp, director of the Riley Asthma Care Center in the section of pulmonology, allergy, and critical care medicine at Riley Hospital Children, Indianapolis, and her associates conducted a cross-sectional study of 33 children aged 6-18 years with EoE and 37 healthy controls. The researchers performed methacholine challenge (airway hyperresponsiveness defined as provocative concentration of methacholine less than 8mg/mL), and exhaled nitric oxide. They also analyzed peripheral blood for total IgE, eosinophil count, eotaxin, and serum cytokines.

Baseline spirometry did not significantly differ between EoE subjects and healthy controls. However, airway hyperresponsiveness was present in 33% of children with EoE, compared with only 10.8% of healthy controls (P = .04). In addition, 20% of the 15 EoE subjects with asthma had airway hyperresponsiveness, compared with 44% of the 18 EoE subjects without asthma. Overall, 69.7% of EoE subjects had either asthma or airway hyperresponsiveness.

The researchers found that airway hyperresponsiveness correlated strongly with serum IgE (P less than .0001) and exhaled nitric oxide (P = .0002), while epidermal growth factor (EGF) and fibroblastic growth factor–2 (FGF-2) were elevated in subjects with EoE and asthma, compared to healthy controls and those with EoE but no asthma (P less than .05). In addition, subjects with EoE and asthma who were on asthma controller medications had similar levels of EGF and FGF-2 as healthy controls, while Th2 cytokines and eotaxin did not differ significantly among any groups.

Dr. Krupp said she was surprised "by the fact that airway hyperresponsiveness was more prevalent in those subjects without a history of asthma than those with a known diagnosis, and the fact that Th2-related cytokines were not significantly different between healthy controls and EoE subjects."

She acknowledged certain limitations of the study, including its cross-sectional design and "the fact EoE subjects may have had significant variability in the current activity of their esophageal disease at the time of enrollment."

The study was partially funded by Aerocrine. Dr. Krupp said that she had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Asthma and airway hyperresponsiveness may be underrecognized in children with eosinophilic esophagitis, results from a controlled cross-sectional study demonstrated.

While previous studies have estimated the prevalence of asthma in children with eosinophilic esophagitis (EoE), to range from 24-42%, a recent analysis presented during a late-breaker abstract session at annual meeting of the American Academy of Allergy, Asthma, and Immunology found that up to 70% of children with EoE may suffer from asthma.

pelvidge/thinkstockphotos.com

"Clinicians treating children with eosinophilic esophagitis should consider asking additional history questions related to asthma symptoms and may also want to consider pulmonary function testing or referral to an asthma specialist for evaluation," lead author Dr. Nadia L. Krupp said in an interview prior to the meeting. "This is the first study to formally evaluate lung function and airway hyperresponsiveness in children with EoE. Prior estimations of asthma have solely come from patient/parent report."

Dr. Krupp, director of the Riley Asthma Care Center in the section of pulmonology, allergy, and critical care medicine at Riley Hospital Children, Indianapolis, and her associates conducted a cross-sectional study of 33 children aged 6-18 years with EoE and 37 healthy controls. The researchers performed methacholine challenge (airway hyperresponsiveness defined as provocative concentration of methacholine less than 8mg/mL), and exhaled nitric oxide. They also analyzed peripheral blood for total IgE, eosinophil count, eotaxin, and serum cytokines.

Baseline spirometry did not significantly differ between EoE subjects and healthy controls. However, airway hyperresponsiveness was present in 33% of children with EoE, compared with only 10.8% of healthy controls (P = .04). In addition, 20% of the 15 EoE subjects with asthma had airway hyperresponsiveness, compared with 44% of the 18 EoE subjects without asthma. Overall, 69.7% of EoE subjects had either asthma or airway hyperresponsiveness.

The researchers found that airway hyperresponsiveness correlated strongly with serum IgE (P less than .0001) and exhaled nitric oxide (P = .0002), while epidermal growth factor (EGF) and fibroblastic growth factor–2 (FGF-2) were elevated in subjects with EoE and asthma, compared to healthy controls and those with EoE but no asthma (P less than .05). In addition, subjects with EoE and asthma who were on asthma controller medications had similar levels of EGF and FGF-2 as healthy controls, while Th2 cytokines and eotaxin did not differ significantly among any groups.

Dr. Krupp said she was surprised "by the fact that airway hyperresponsiveness was more prevalent in those subjects without a history of asthma than those with a known diagnosis, and the fact that Th2-related cytokines were not significantly different between healthy controls and EoE subjects."

She acknowledged certain limitations of the study, including its cross-sectional design and "the fact EoE subjects may have had significant variability in the current activity of their esophageal disease at the time of enrollment."

The study was partially funded by Aerocrine. Dr. Krupp said that she had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Asthma and airway hyperresponsiveness may be underrecognized in children with eosinophilic esophagitis, results from a controlled cross-sectional study demonstrated.

While previous studies have estimated the prevalence of asthma in children with eosinophilic esophagitis (EoE), to range from 24-42%, a recent analysis presented during a late-breaker abstract session at annual meeting of the American Academy of Allergy, Asthma, and Immunology found that up to 70% of children with EoE may suffer from asthma.

pelvidge/thinkstockphotos.com

"Clinicians treating children with eosinophilic esophagitis should consider asking additional history questions related to asthma symptoms and may also want to consider pulmonary function testing or referral to an asthma specialist for evaluation," lead author Dr. Nadia L. Krupp said in an interview prior to the meeting. "This is the first study to formally evaluate lung function and airway hyperresponsiveness in children with EoE. Prior estimations of asthma have solely come from patient/parent report."

Dr. Krupp, director of the Riley Asthma Care Center in the section of pulmonology, allergy, and critical care medicine at Riley Hospital Children, Indianapolis, and her associates conducted a cross-sectional study of 33 children aged 6-18 years with EoE and 37 healthy controls. The researchers performed methacholine challenge (airway hyperresponsiveness defined as provocative concentration of methacholine less than 8mg/mL), and exhaled nitric oxide. They also analyzed peripheral blood for total IgE, eosinophil count, eotaxin, and serum cytokines.

Baseline spirometry did not significantly differ between EoE subjects and healthy controls. However, airway hyperresponsiveness was present in 33% of children with EoE, compared with only 10.8% of healthy controls (P = .04). In addition, 20% of the 15 EoE subjects with asthma had airway hyperresponsiveness, compared with 44% of the 18 EoE subjects without asthma. Overall, 69.7% of EoE subjects had either asthma or airway hyperresponsiveness.

The researchers found that airway hyperresponsiveness correlated strongly with serum IgE (P less than .0001) and exhaled nitric oxide (P = .0002), while epidermal growth factor (EGF) and fibroblastic growth factor–2 (FGF-2) were elevated in subjects with EoE and asthma, compared to healthy controls and those with EoE but no asthma (P less than .05). In addition, subjects with EoE and asthma who were on asthma controller medications had similar levels of EGF and FGF-2 as healthy controls, while Th2 cytokines and eotaxin did not differ significantly among any groups.

Dr. Krupp said she was surprised "by the fact that airway hyperresponsiveness was more prevalent in those subjects without a history of asthma than those with a known diagnosis, and the fact that Th2-related cytokines were not significantly different between healthy controls and EoE subjects."

She acknowledged certain limitations of the study, including its cross-sectional design and "the fact EoE subjects may have had significant variability in the current activity of their esophageal disease at the time of enrollment."

The study was partially funded by Aerocrine. Dr. Krupp said that she had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com