AACR Annual Meeting 2011

ORLANDO - Ovarian cancer patients with BRCA1 or BRCA2 gene mutations have better survival than do those with neither mutation, and those with the BRCA2 mutation have better survival than do those with the BRCA1 mutation, according to the findings of a large, multicenter study.

The findings confirm the results of several prior smaller studies showing a survival advantage in mutation carriers vs. nonmutation carriers, and they provide the first direct evidence that BRCA1 and BRCA2 mutations have differing effects on survival, Kelly L. Bolton reported at the annual meeting of the American Association for Cancer Research.

She and her colleagues studied 3,531 women with invasive epithelial ovarian cancer who were enrolled in one of 24 studies in the United States, Europe, Israel, and Asia, and for whom survival data were available. They excluded patients who either were known or were likely not to have received platinum-based therapy. Included were 1,178 women with BRCA1, 367 with BRCA2, and 1,986 who were BRCA negative.

The 5-year survival was 36% in those with no mutation, 46% of those with the BRCA1 mutation, and 61% of those with the BRCA2 mutation, after adjustment for stage, grade, histology, and age at diagnosis, said Ms. Bolton, a predoctoral fellow at the National Cancer Institute.

The difference in survival between the BRCA1 mutation carriers and those with no mutation was modest, although not statistically significant (hazard ratio, 0.84). However, the difference between the BRCA2 mutation carriers and both the noncarriers and the BRCA1 mutation carriers (after adjustment for age at diagnosis) did reach statistical significance (HR, 0.57 and 0.69, respectively).

Even after the exclusion of all but high-grade, advanced-stage serous cases, the survival differences persisted, Ms. Bolton reported.

A possible explanation for the differences, based on in vitro work and some retrospective trials, may lie in patients’ responses to chemotherapy; those with the BRCA2 mutation may have an improved response, but unidentified biological differences among BRCA1 carriers, BRCA2 carriers, and noncarriers could also be driving the association, she said.

The BRCA1 and BRCA2 mutation carriers in this study did not differ in regard to tumor stage, grade, or histology. Compared with noncarriers, however, BRCA1 carriers were younger and BRCA2 carriers were older at diagnosis.

Furthermore, compared with noncarriers, BRCA1 and BRCA2 carriers were more likely to present with advanced-stage disease, high-grade disease, and serous disease.

"The findings don’t have any immediate impact on clinical practice, but they do have important implications [for both] clinical prediction and also trial design, particularly for clinical trials," Ms. Bolton said, noting that although germline mutations in the BRCA1 and BRCA2 genes (which are important in DNA damage repair and have distinct yet complementary functions) are rare in the general population, they are present in 10%-15% of those with ovarian cancer.

Indeed, the findings – which "may be a very faint silver lining" for mutation carriers with a terrible disease that still has terrible survival – do speak to the possibility that women with these mutations need to be identified in the setting of ovarian cancer, as the presence of mutations will affect thinking about treatment, said Dr. Judy E. Garber, the new AACR president and director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston. Dr. Garber moderated a press briefing where Ms. Bolton discussed her findings,

Ms. Bolton had no relevant disclosures.

ORLANDO - Ovarian cancer patients with BRCA1 or BRCA2 gene mutations have better survival than do those with neither mutation, and those with the BRCA2 mutation have better survival than do those with the BRCA1 mutation, according to the findings of a large, multicenter study.

The findings confirm the results of several prior smaller studies showing a survival advantage in mutation carriers vs. nonmutation carriers, and they provide the first direct evidence that BRCA1 and BRCA2 mutations have differing effects on survival, Kelly L. Bolton reported at the annual meeting of the American Association for Cancer Research.

She and her colleagues studied 3,531 women with invasive epithelial ovarian cancer who were enrolled in one of 24 studies in the United States, Europe, Israel, and Asia, and for whom survival data were available. They excluded patients who either were known or were likely not to have received platinum-based therapy. Included were 1,178 women with BRCA1, 367 with BRCA2, and 1,986 who were BRCA negative.

The 5-year survival was 36% in those with no mutation, 46% of those with the BRCA1 mutation, and 61% of those with the BRCA2 mutation, after adjustment for stage, grade, histology, and age at diagnosis, said Ms. Bolton, a predoctoral fellow at the National Cancer Institute.

The difference in survival between the BRCA1 mutation carriers and those with no mutation was modest, although not statistically significant (hazard ratio, 0.84). However, the difference between the BRCA2 mutation carriers and both the noncarriers and the BRCA1 mutation carriers (after adjustment for age at diagnosis) did reach statistical significance (HR, 0.57 and 0.69, respectively).

Even after the exclusion of all but high-grade, advanced-stage serous cases, the survival differences persisted, Ms. Bolton reported.

A possible explanation for the differences, based on in vitro work and some retrospective trials, may lie in patients’ responses to chemotherapy; those with the BRCA2 mutation may have an improved response, but unidentified biological differences among BRCA1 carriers, BRCA2 carriers, and noncarriers could also be driving the association, she said.

The BRCA1 and BRCA2 mutation carriers in this study did not differ in regard to tumor stage, grade, or histology. Compared with noncarriers, however, BRCA1 carriers were younger and BRCA2 carriers were older at diagnosis.

Furthermore, compared with noncarriers, BRCA1 and BRCA2 carriers were more likely to present with advanced-stage disease, high-grade disease, and serous disease.

"The findings don’t have any immediate impact on clinical practice, but they do have important implications [for both] clinical prediction and also trial design, particularly for clinical trials," Ms. Bolton said, noting that although germline mutations in the BRCA1 and BRCA2 genes (which are important in DNA damage repair and have distinct yet complementary functions) are rare in the general population, they are present in 10%-15% of those with ovarian cancer.

Indeed, the findings – which "may be a very faint silver lining" for mutation carriers with a terrible disease that still has terrible survival – do speak to the possibility that women with these mutations need to be identified in the setting of ovarian cancer, as the presence of mutations will affect thinking about treatment, said Dr. Judy E. Garber, the new AACR president and director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston. Dr. Garber moderated a press briefing where Ms. Bolton discussed her findings,

Ms. Bolton had no relevant disclosures.

ORLANDO - Ovarian cancer patients with BRCA1 or BRCA2 gene mutations have better survival than do those with neither mutation, and those with the BRCA2 mutation have better survival than do those with the BRCA1 mutation, according to the findings of a large, multicenter study.

The findings confirm the results of several prior smaller studies showing a survival advantage in mutation carriers vs. nonmutation carriers, and they provide the first direct evidence that BRCA1 and BRCA2 mutations have differing effects on survival, Kelly L. Bolton reported at the annual meeting of the American Association for Cancer Research.

She and her colleagues studied 3,531 women with invasive epithelial ovarian cancer who were enrolled in one of 24 studies in the United States, Europe, Israel, and Asia, and for whom survival data were available. They excluded patients who either were known or were likely not to have received platinum-based therapy. Included were 1,178 women with BRCA1, 367 with BRCA2, and 1,986 who were BRCA negative.

The 5-year survival was 36% in those with no mutation, 46% of those with the BRCA1 mutation, and 61% of those with the BRCA2 mutation, after adjustment for stage, grade, histology, and age at diagnosis, said Ms. Bolton, a predoctoral fellow at the National Cancer Institute.

The difference in survival between the BRCA1 mutation carriers and those with no mutation was modest, although not statistically significant (hazard ratio, 0.84). However, the difference between the BRCA2 mutation carriers and both the noncarriers and the BRCA1 mutation carriers (after adjustment for age at diagnosis) did reach statistical significance (HR, 0.57 and 0.69, respectively).

Even after the exclusion of all but high-grade, advanced-stage serous cases, the survival differences persisted, Ms. Bolton reported.

A possible explanation for the differences, based on in vitro work and some retrospective trials, may lie in patients’ responses to chemotherapy; those with the BRCA2 mutation may have an improved response, but unidentified biological differences among BRCA1 carriers, BRCA2 carriers, and noncarriers could also be driving the association, she said.

The BRCA1 and BRCA2 mutation carriers in this study did not differ in regard to tumor stage, grade, or histology. Compared with noncarriers, however, BRCA1 carriers were younger and BRCA2 carriers were older at diagnosis.

Furthermore, compared with noncarriers, BRCA1 and BRCA2 carriers were more likely to present with advanced-stage disease, high-grade disease, and serous disease.

"The findings don’t have any immediate impact on clinical practice, but they do have important implications [for both] clinical prediction and also trial design, particularly for clinical trials," Ms. Bolton said, noting that although germline mutations in the BRCA1 and BRCA2 genes (which are important in DNA damage repair and have distinct yet complementary functions) are rare in the general population, they are present in 10%-15% of those with ovarian cancer.

Indeed, the findings – which "may be a very faint silver lining" for mutation carriers with a terrible disease that still has terrible survival – do speak to the possibility that women with these mutations need to be identified in the setting of ovarian cancer, as the presence of mutations will affect thinking about treatment, said Dr. Judy E. Garber, the new AACR president and director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston. Dr. Garber moderated a press briefing where Ms. Bolton discussed her findings,

Ms. Bolton had no relevant disclosures.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell's presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn't appear to be the case. "We're very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell's presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We've been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell's presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn't appear to be the case. "We're very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell's presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We've been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell's presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn't appear to be the case. "We're very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell's presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We've been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Endobronchial dysplasia appears useful as a biomarker for measuring the success of lung cancer chemoprevention, investigators reported at the annual meeting of the American Association for Cancer Research.

Bronchoscopies, along with biopsies of standard endobronchial sites and any other abnormal appearing areas, were performed at baseline and at 6 months after randomization to treatment with iloprost (Ventavis) or placebo in a phase II chemoprevention trial involving 152 former or current smokers with at least a 20 pack-year history.

Former smokers who received iloprost, an oral prostacyclin analog approved for the treatment of primary pulmonary hypertension, had significant improvements on several measures of endobronchial dysplasia, while current smokers had no improvement, Dr. Paul Bunn reported.

The findings demonstrate that iloprost, which has been shown to prevent the development of lung cancer in various murine models involving cigarette-smoke exposure, also might have the same effect in humans and thus deserves further study for this purpose, Dr. Bunn and his coauthors concluded.

The results also demonstrate that endobronchial dysplasia could serve as a biomarker for effectiveness of chemopreventive treatment– much as cholesterol does in patients being treated with statins to prevent cardiovascular disease, according to Dr. Bunn, executive director of the International Association for the Study of Lung Cancer. He is also the James Dudley endowed professor of lung cancer research at the cancer center at the University of Colorado, Aurora.

In the current study, baseline histology was significantly worse in current smokers than in former smokers (average biopsy scores of 3.0 vs. 2.1, respectively, with a score of 4 indicating mild dysplasia). Former smokers experienced a 0.41-point improvement in average biopsy score (P = .010), a 1.10-point improvement in their worst baseline biopsy score (P = .002), and a 12.5% improvement in dysplasia index (P = .006), which was the percentage of biopsies with a score of at least 4, said Dr. Bunn.

"The histologic improvement in the treated patients who were former smokers was larger than the magnitude of the difference between current and former smokers," he said.

For example, the baseline dysplasia index in current and former smokers was 46% and 31%, respectively, but the pre- and post-treatment dysplasia index in former smokers was 43% and 19.6%, respectively.

Study participants had an average 30 pack-year history of smoking, and at least mild cytologic atypia on sputum cytology, but no previous history of cancer. Iloprost was given in escalating doses across the 6-month treatment period and was well tolerated. The treatment and placebo groups were well-matched for age, tobacco exposure and baseline histology, and there was no difference in dropout rate or serious adverse events between the treatment and placebo groups, Dr. Bunn noted.

Although antismoking campaigns are working – and about half of all smokers have quit, those who quit remain at greater risk for developing lung cancer than are nonsmokers; about half of all cases of lung cancer are in former smokers, and it is important to find effective chemopreventive measures for these individuals, he said.

Dr. Bunn discussed off-label use of iloprost for chemoprevention of lung cancer. He had no other disclosures.

ORLANDO – Endobronchial dysplasia appears useful as a biomarker for measuring the success of lung cancer chemoprevention, investigators reported at the annual meeting of the American Association for Cancer Research.

Bronchoscopies, along with biopsies of standard endobronchial sites and any other abnormal appearing areas, were performed at baseline and at 6 months after randomization to treatment with iloprost (Ventavis) or placebo in a phase II chemoprevention trial involving 152 former or current smokers with at least a 20 pack-year history.

Former smokers who received iloprost, an oral prostacyclin analog approved for the treatment of primary pulmonary hypertension, had significant improvements on several measures of endobronchial dysplasia, while current smokers had no improvement, Dr. Paul Bunn reported.

The findings demonstrate that iloprost, which has been shown to prevent the development of lung cancer in various murine models involving cigarette-smoke exposure, also might have the same effect in humans and thus deserves further study for this purpose, Dr. Bunn and his coauthors concluded.

The results also demonstrate that endobronchial dysplasia could serve as a biomarker for effectiveness of chemopreventive treatment– much as cholesterol does in patients being treated with statins to prevent cardiovascular disease, according to Dr. Bunn, executive director of the International Association for the Study of Lung Cancer. He is also the James Dudley endowed professor of lung cancer research at the cancer center at the University of Colorado, Aurora.

In the current study, baseline histology was significantly worse in current smokers than in former smokers (average biopsy scores of 3.0 vs. 2.1, respectively, with a score of 4 indicating mild dysplasia). Former smokers experienced a 0.41-point improvement in average biopsy score (P = .010), a 1.10-point improvement in their worst baseline biopsy score (P = .002), and a 12.5% improvement in dysplasia index (P = .006), which was the percentage of biopsies with a score of at least 4, said Dr. Bunn.

"The histologic improvement in the treated patients who were former smokers was larger than the magnitude of the difference between current and former smokers," he said.

For example, the baseline dysplasia index in current and former smokers was 46% and 31%, respectively, but the pre- and post-treatment dysplasia index in former smokers was 43% and 19.6%, respectively.

Study participants had an average 30 pack-year history of smoking, and at least mild cytologic atypia on sputum cytology, but no previous history of cancer. Iloprost was given in escalating doses across the 6-month treatment period and was well tolerated. The treatment and placebo groups were well-matched for age, tobacco exposure and baseline histology, and there was no difference in dropout rate or serious adverse events between the treatment and placebo groups, Dr. Bunn noted.

Although antismoking campaigns are working – and about half of all smokers have quit, those who quit remain at greater risk for developing lung cancer than are nonsmokers; about half of all cases of lung cancer are in former smokers, and it is important to find effective chemopreventive measures for these individuals, he said.

Dr. Bunn discussed off-label use of iloprost for chemoprevention of lung cancer. He had no other disclosures.

ORLANDO – Endobronchial dysplasia appears useful as a biomarker for measuring the success of lung cancer chemoprevention, investigators reported at the annual meeting of the American Association for Cancer Research.

Bronchoscopies, along with biopsies of standard endobronchial sites and any other abnormal appearing areas, were performed at baseline and at 6 months after randomization to treatment with iloprost (Ventavis) or placebo in a phase II chemoprevention trial involving 152 former or current smokers with at least a 20 pack-year history.

Former smokers who received iloprost, an oral prostacyclin analog approved for the treatment of primary pulmonary hypertension, had significant improvements on several measures of endobronchial dysplasia, while current smokers had no improvement, Dr. Paul Bunn reported.

The findings demonstrate that iloprost, which has been shown to prevent the development of lung cancer in various murine models involving cigarette-smoke exposure, also might have the same effect in humans and thus deserves further study for this purpose, Dr. Bunn and his coauthors concluded.

The results also demonstrate that endobronchial dysplasia could serve as a biomarker for effectiveness of chemopreventive treatment– much as cholesterol does in patients being treated with statins to prevent cardiovascular disease, according to Dr. Bunn, executive director of the International Association for the Study of Lung Cancer. He is also the James Dudley endowed professor of lung cancer research at the cancer center at the University of Colorado, Aurora.

In the current study, baseline histology was significantly worse in current smokers than in former smokers (average biopsy scores of 3.0 vs. 2.1, respectively, with a score of 4 indicating mild dysplasia). Former smokers experienced a 0.41-point improvement in average biopsy score (P = .010), a 1.10-point improvement in their worst baseline biopsy score (P = .002), and a 12.5% improvement in dysplasia index (P = .006), which was the percentage of biopsies with a score of at least 4, said Dr. Bunn.

"The histologic improvement in the treated patients who were former smokers was larger than the magnitude of the difference between current and former smokers," he said.

For example, the baseline dysplasia index in current and former smokers was 46% and 31%, respectively, but the pre- and post-treatment dysplasia index in former smokers was 43% and 19.6%, respectively.

Study participants had an average 30 pack-year history of smoking, and at least mild cytologic atypia on sputum cytology, but no previous history of cancer. Iloprost was given in escalating doses across the 6-month treatment period and was well tolerated. The treatment and placebo groups were well-matched for age, tobacco exposure and baseline histology, and there was no difference in dropout rate or serious adverse events between the treatment and placebo groups, Dr. Bunn noted.

Although antismoking campaigns are working – and about half of all smokers have quit, those who quit remain at greater risk for developing lung cancer than are nonsmokers; about half of all cases of lung cancer are in former smokers, and it is important to find effective chemopreventive measures for these individuals, he said.

Dr. Bunn discussed off-label use of iloprost for chemoprevention of lung cancer. He had no other disclosures.

ORLANDO – Endobronchial dysplasia appears useful as a biomarker for measuring the success of lung cancer chemoprevention, investigators reported at the annual meeting of the American Association for Cancer Research.

Bronchoscopies, along with biopsies of standard endobronchial sites and any other abnormal appearing areas, were performed at baseline and at 6 months after randomization to treatment with iloprost (Ventavis) or placebo in a phase II chemoprevention trial involving 152 former or current smokers with at least a 20 pack-year history.

Former smokers who received iloprost, an oral prostacyclin analog approved for the treatment of primary pulmonary hypertension, had significant improvements on several measures of endobronchial dysplasia, while current smokers had no improvement, Dr. Paul Bunn reported.

The findings demonstrate that iloprost, which has been shown to prevent the development of lung cancer in various murine models involving cigarette-smoke exposure, also might have the same effect in humans and thus deserves further study for this purpose, Dr. Bunn and his coauthors concluded.

The results also demonstrate that endobronchial dysplasia could serve as a biomarker for effectiveness of chemopreventive treatment– much as cholesterol does in patients being treated with statins to prevent cardiovascular disease, according to Dr. Bunn, executive director of the International Association for the Study of Lung Cancer. He is also the James Dudley endowed professor of lung cancer research at the cancer center at the University of Colorado, Aurora.

In the current study, baseline histology was significantly worse in current smokers than in former smokers (average biopsy scores of 3.0 vs. 2.1, respectively, with a score of 4 indicating mild dysplasia). Former smokers experienced a 0.41-point improvement in average biopsy score (P = .010), a 1.10-point improvement in their worst baseline biopsy score (P = .002), and a 12.5% improvement in dysplasia index (P = .006), which was the percentage of biopsies with a score of at least 4, said Dr. Bunn.

"The histologic improvement in the treated patients who were former smokers was larger than the magnitude of the difference between current and former smokers," he said.

For example, the baseline dysplasia index in current and former smokers was 46% and 31%, respectively, but the pre- and post-treatment dysplasia index in former smokers was 43% and 19.6%, respectively.

Study participants had an average 30 pack-year history of smoking, and at least mild cytologic atypia on sputum cytology, but no previous history of cancer. Iloprost was given in escalating doses across the 6-month treatment period and was well tolerated. The treatment and placebo groups were well-matched for age, tobacco exposure and baseline histology, and there was no difference in dropout rate or serious adverse events between the treatment and placebo groups, Dr. Bunn noted.

Although antismoking campaigns are working – and about half of all smokers have quit, those who quit remain at greater risk for developing lung cancer than are nonsmokers; about half of all cases of lung cancer are in former smokers, and it is important to find effective chemopreventive measures for these individuals, he said.

Dr. Bunn discussed off-label use of iloprost for chemoprevention of lung cancer. He had no other disclosures.

ORLANDO – Endobronchial dysplasia appears useful as a biomarker for measuring the success of lung cancer chemoprevention, investigators reported at the annual meeting of the American Association for Cancer Research.

Bronchoscopies, along with biopsies of standard endobronchial sites and any other abnormal appearing areas, were performed at baseline and at 6 months after randomization to treatment with iloprost (Ventavis) or placebo in a phase II chemoprevention trial involving 152 former or current smokers with at least a 20 pack-year history.

Former smokers who received iloprost, an oral prostacyclin analog approved for the treatment of primary pulmonary hypertension, had significant improvements on several measures of endobronchial dysplasia, while current smokers had no improvement, Dr. Paul Bunn reported.

The findings demonstrate that iloprost, which has been shown to prevent the development of lung cancer in various murine models involving cigarette-smoke exposure, also might have the same effect in humans and thus deserves further study for this purpose, Dr. Bunn and his coauthors concluded.

The results also demonstrate that endobronchial dysplasia could serve as a biomarker for effectiveness of chemopreventive treatment– much as cholesterol does in patients being treated with statins to prevent cardiovascular disease, according to Dr. Bunn, executive director of the International Association for the Study of Lung Cancer. He is also the James Dudley endowed professor of lung cancer research at the cancer center at the University of Colorado, Aurora.

In the current study, baseline histology was significantly worse in current smokers than in former smokers (average biopsy scores of 3.0 vs. 2.1, respectively, with a score of 4 indicating mild dysplasia). Former smokers experienced a 0.41-point improvement in average biopsy score (P = .010), a 1.10-point improvement in their worst baseline biopsy score (P = .002), and a 12.5% improvement in dysplasia index (P = .006), which was the percentage of biopsies with a score of at least 4, said Dr. Bunn.

"The histologic improvement in the treated patients who were former smokers was larger than the magnitude of the difference between current and former smokers," he said.

For example, the baseline dysplasia index in current and former smokers was 46% and 31%, respectively, but the pre- and post-treatment dysplasia index in former smokers was 43% and 19.6%, respectively.

Study participants had an average 30 pack-year history of smoking, and at least mild cytologic atypia on sputum cytology, but no previous history of cancer. Iloprost was given in escalating doses across the 6-month treatment period and was well tolerated. The treatment and placebo groups were well-matched for age, tobacco exposure and baseline histology, and there was no difference in dropout rate or serious adverse events between the treatment and placebo groups, Dr. Bunn noted.

Although antismoking campaigns are working – and about half of all smokers have quit, those who quit remain at greater risk for developing lung cancer than are nonsmokers; about half of all cases of lung cancer are in former smokers, and it is important to find effective chemopreventive measures for these individuals, he said.

Dr. Bunn discussed off-label use of iloprost for chemoprevention of lung cancer. He had no other disclosures.

ORLANDO – Endobronchial dysplasia appears useful as a biomarker for measuring the success of lung cancer chemoprevention, investigators reported at the annual meeting of the American Association for Cancer Research.

Bronchoscopies, along with biopsies of standard endobronchial sites and any other abnormal appearing areas, were performed at baseline and at 6 months after randomization to treatment with iloprost (Ventavis) or placebo in a phase II chemoprevention trial involving 152 former or current smokers with at least a 20 pack-year history.

Former smokers who received iloprost, an oral prostacyclin analog approved for the treatment of primary pulmonary hypertension, had significant improvements on several measures of endobronchial dysplasia, while current smokers had no improvement, Dr. Paul Bunn reported.

The findings demonstrate that iloprost, which has been shown to prevent the development of lung cancer in various murine models involving cigarette-smoke exposure, also might have the same effect in humans and thus deserves further study for this purpose, Dr. Bunn and his coauthors concluded.

The results also demonstrate that endobronchial dysplasia could serve as a biomarker for effectiveness of chemopreventive treatment– much as cholesterol does in patients being treated with statins to prevent cardiovascular disease, according to Dr. Bunn, executive director of the International Association for the Study of Lung Cancer. He is also the James Dudley endowed professor of lung cancer research at the cancer center at the University of Colorado, Aurora.

In the current study, baseline histology was significantly worse in current smokers than in former smokers (average biopsy scores of 3.0 vs. 2.1, respectively, with a score of 4 indicating mild dysplasia). Former smokers experienced a 0.41-point improvement in average biopsy score (P = .010), a 1.10-point improvement in their worst baseline biopsy score (P = .002), and a 12.5% improvement in dysplasia index (P = .006), which was the percentage of biopsies with a score of at least 4, said Dr. Bunn.

"The histologic improvement in the treated patients who were former smokers was larger than the magnitude of the difference between current and former smokers," he said.

For example, the baseline dysplasia index in current and former smokers was 46% and 31%, respectively, but the pre- and post-treatment dysplasia index in former smokers was 43% and 19.6%, respectively.

Study participants had an average 30 pack-year history of smoking, and at least mild cytologic atypia on sputum cytology, but no previous history of cancer. Iloprost was given in escalating doses across the 6-month treatment period and was well tolerated. The treatment and placebo groups were well-matched for age, tobacco exposure and baseline histology, and there was no difference in dropout rate or serious adverse events between the treatment and placebo groups, Dr. Bunn noted.

Although antismoking campaigns are working – and about half of all smokers have quit, those who quit remain at greater risk for developing lung cancer than are nonsmokers; about half of all cases of lung cancer are in former smokers, and it is important to find effective chemopreventive measures for these individuals, he said.

Dr. Bunn discussed off-label use of iloprost for chemoprevention of lung cancer. He had no other disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin’s syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin’s syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin’s syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin’s syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin’s syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin’s syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin's syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin's syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin's syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.