Anti-MEK-PI3K Drug Combination Reduces Lesions in Solid Tumors

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.