Cabozantinib Hits Metastatic Kidney Cancer

CHICAGO – The investigational tyrosine kinase inhibitor cabozantinib showed "encouraging" activity against metastatic, treatment-refractory renal cell carcinoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

Cabozantinib was associated with a 28% objective response rate and a median progression-free survival of 14.7 months, among 25 patients with metastatic renal cell carcinoma, one-third of whom had been treated with at least four prior systemic therapies. Median overall survival had not been reached at a median 14.7 months of follow-up in the drug-drug interaction study, said Dr. Toni K. Choueiri, director of the kidney cancer center at the Dana-Farber Cancer Institute in Boston.

One patient with symptomatic metastatic bone lesions had partial resolution of the lesions on a bone scan, and was able to substantially reduce narcotic use by 7 weeks and continue on a reduced dose through week 25. A second patient with bone metastases and pain at baseline had complete resolution of pain by 4 weeks, and has remained pain free for more than 90 weeks on study, Dr. Choueiri said.

"The safety profile was somewhat similar to other TKIs [tyrosine kinase inhibitors], with manageable adverse events, with an extended treatment period over 600-plus days," he said.

Cabozantinib, also known as XL184, is a small-molecule inhibitor of the c-MET and vascular endothelial growth factor (VEGF) receptor 2 pathways. Up to 25% of patients with renal cell carcinoma have disease that is refractory to anti-VEGF therapies, but may be susceptible to cabozantinib, with its ability to overcome resistance to VEGF through blockage of the c-MET kinase pathway.

In addition, nearly one-third of patients develop metastases to bone, which are generally resistant to existing therapies and are prognostic of poor survival; hence the rationale for testing cabozantinib in this population, Dr. Choueiri said.

A total of 25 patients with metastatic kidney cancer in whom prior therapies had failed received cabozantinib at a dose of 140 mg daily with a single dose of rosiglitazone (Avandia) as part of a phase I study to test drug-drug interactions.

Most of the patients (22) had previously received anti-VEGF therapy, 15 had received therapy directed against mTOR (mammalian target of rapamycin), 13 had received anti-VEGF and anti-mTOR agents in combination, 5 had received cytokine therapy, and 3 had undergone chemotherapy. Four patients had bone metastases.

At last follow-up, 7 patients remained on study and 18 had discontinued, 8 for progressive disease, 6 for adverse events, and 4 at the patient’s request.

Of the 21 patients evaluable for a postbaseline RECIST assessment, 7 had a confirmed partial response, 13 had stable disease, and 1 had disease progression. A total of 18 patients met the criteria for disease control (partial responses plus stable disease) at 16 weeks.

The median duration of response is not yet estimable, Dr. Choueiri said. Of the 21 patients with one or more postbaseline scans, 19 had some degree of tumor regression, ranging from about a 5% shrinkage to a decline of more than 60%.

The most frequently occurring grade 3 or 4 adverse events were fatigue in four patients, diarrhea in three, hypophosphatemia in nine, and hyponatremia in five. There were no drug-related deaths.

Investigators are planning an evaluation of cabozantinib at a dose of 60 mg daily as first-line therapy for renal cell carcinoma, Dr. Choueiri said.

"I think overall [with] cabozantinib, it is rational to think of it as a synergistic approach to VEGF and c-MET blockade," said Dr. Lauren C. Harshman, an oncologist at Stanford (Calif.) University. Dr. Harshman was the invited discussant but was not involved in the study.

She noted that while cabozantinib has "intriguing preliminary efficacy," the toxicities – primarily fatigue, diarrhea, and nausea – were similar to those seen in trials of the drug for prostate cancer, and required discontinuations in nearly one-fourth of patients.

"A big question will be whether a lower dose can achieve the same efficacy," she said.

The study was funded by Exelixis, maker of cabozantinib. Dr. Choueiri has received research funding from the company. Dr. Harshman has received research funding from Bristol-Myers Squibb.

CHICAGO – The investigational tyrosine kinase inhibitor cabozantinib showed "encouraging" activity against metastatic, treatment-refractory renal cell carcinoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

Cabozantinib was associated with a 28% objective response rate and a median progression-free survival of 14.7 months, among 25 patients with metastatic renal cell carcinoma, one-third of whom had been treated with at least four prior systemic therapies. Median overall survival had not been reached at a median 14.7 months of follow-up in the drug-drug interaction study, said Dr. Toni K. Choueiri, director of the kidney cancer center at the Dana-Farber Cancer Institute in Boston.

One patient with symptomatic metastatic bone lesions had partial resolution of the lesions on a bone scan, and was able to substantially reduce narcotic use by 7 weeks and continue on a reduced dose through week 25. A second patient with bone metastases and pain at baseline had complete resolution of pain by 4 weeks, and has remained pain free for more than 90 weeks on study, Dr. Choueiri said.

"The safety profile was somewhat similar to other TKIs [tyrosine kinase inhibitors], with manageable adverse events, with an extended treatment period over 600-plus days," he said.

Cabozantinib, also known as XL184, is a small-molecule inhibitor of the c-MET and vascular endothelial growth factor (VEGF) receptor 2 pathways. Up to 25% of patients with renal cell carcinoma have disease that is refractory to anti-VEGF therapies, but may be susceptible to cabozantinib, with its ability to overcome resistance to VEGF through blockage of the c-MET kinase pathway.

In addition, nearly one-third of patients develop metastases to bone, which are generally resistant to existing therapies and are prognostic of poor survival; hence the rationale for testing cabozantinib in this population, Dr. Choueiri said.

A total of 25 patients with metastatic kidney cancer in whom prior therapies had failed received cabozantinib at a dose of 140 mg daily with a single dose of rosiglitazone (Avandia) as part of a phase I study to test drug-drug interactions.

Most of the patients (22) had previously received anti-VEGF therapy, 15 had received therapy directed against mTOR (mammalian target of rapamycin), 13 had received anti-VEGF and anti-mTOR agents in combination, 5 had received cytokine therapy, and 3 had undergone chemotherapy. Four patients had bone metastases.

At last follow-up, 7 patients remained on study and 18 had discontinued, 8 for progressive disease, 6 for adverse events, and 4 at the patient’s request.

Of the 21 patients evaluable for a postbaseline RECIST assessment, 7 had a confirmed partial response, 13 had stable disease, and 1 had disease progression. A total of 18 patients met the criteria for disease control (partial responses plus stable disease) at 16 weeks.

The median duration of response is not yet estimable, Dr. Choueiri said. Of the 21 patients with one or more postbaseline scans, 19 had some degree of tumor regression, ranging from about a 5% shrinkage to a decline of more than 60%.

The most frequently occurring grade 3 or 4 adverse events were fatigue in four patients, diarrhea in three, hypophosphatemia in nine, and hyponatremia in five. There were no drug-related deaths.

Investigators are planning an evaluation of cabozantinib at a dose of 60 mg daily as first-line therapy for renal cell carcinoma, Dr. Choueiri said.

"I think overall [with] cabozantinib, it is rational to think of it as a synergistic approach to VEGF and c-MET blockade," said Dr. Lauren C. Harshman, an oncologist at Stanford (Calif.) University. Dr. Harshman was the invited discussant but was not involved in the study.

She noted that while cabozantinib has "intriguing preliminary efficacy," the toxicities – primarily fatigue, diarrhea, and nausea – were similar to those seen in trials of the drug for prostate cancer, and required discontinuations in nearly one-fourth of patients.

"A big question will be whether a lower dose can achieve the same efficacy," she said.

The study was funded by Exelixis, maker of cabozantinib. Dr. Choueiri has received research funding from the company. Dr. Harshman has received research funding from Bristol-Myers Squibb.

CHICAGO – The investigational tyrosine kinase inhibitor cabozantinib showed "encouraging" activity against metastatic, treatment-refractory renal cell carcinoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

Cabozantinib was associated with a 28% objective response rate and a median progression-free survival of 14.7 months, among 25 patients with metastatic renal cell carcinoma, one-third of whom had been treated with at least four prior systemic therapies. Median overall survival had not been reached at a median 14.7 months of follow-up in the drug-drug interaction study, said Dr. Toni K. Choueiri, director of the kidney cancer center at the Dana-Farber Cancer Institute in Boston.

One patient with symptomatic metastatic bone lesions had partial resolution of the lesions on a bone scan, and was able to substantially reduce narcotic use by 7 weeks and continue on a reduced dose through week 25. A second patient with bone metastases and pain at baseline had complete resolution of pain by 4 weeks, and has remained pain free for more than 90 weeks on study, Dr. Choueiri said.

"The safety profile was somewhat similar to other TKIs [tyrosine kinase inhibitors], with manageable adverse events, with an extended treatment period over 600-plus days," he said.

Cabozantinib, also known as XL184, is a small-molecule inhibitor of the c-MET and vascular endothelial growth factor (VEGF) receptor 2 pathways. Up to 25% of patients with renal cell carcinoma have disease that is refractory to anti-VEGF therapies, but may be susceptible to cabozantinib, with its ability to overcome resistance to VEGF through blockage of the c-MET kinase pathway.

In addition, nearly one-third of patients develop metastases to bone, which are generally resistant to existing therapies and are prognostic of poor survival; hence the rationale for testing cabozantinib in this population, Dr. Choueiri said.

A total of 25 patients with metastatic kidney cancer in whom prior therapies had failed received cabozantinib at a dose of 140 mg daily with a single dose of rosiglitazone (Avandia) as part of a phase I study to test drug-drug interactions.

Most of the patients (22) had previously received anti-VEGF therapy, 15 had received therapy directed against mTOR (mammalian target of rapamycin), 13 had received anti-VEGF and anti-mTOR agents in combination, 5 had received cytokine therapy, and 3 had undergone chemotherapy. Four patients had bone metastases.

At last follow-up, 7 patients remained on study and 18 had discontinued, 8 for progressive disease, 6 for adverse events, and 4 at the patient’s request.

Of the 21 patients evaluable for a postbaseline RECIST assessment, 7 had a confirmed partial response, 13 had stable disease, and 1 had disease progression. A total of 18 patients met the criteria for disease control (partial responses plus stable disease) at 16 weeks.

The median duration of response is not yet estimable, Dr. Choueiri said. Of the 21 patients with one or more postbaseline scans, 19 had some degree of tumor regression, ranging from about a 5% shrinkage to a decline of more than 60%.

The most frequently occurring grade 3 or 4 adverse events were fatigue in four patients, diarrhea in three, hypophosphatemia in nine, and hyponatremia in five. There were no drug-related deaths.

Investigators are planning an evaluation of cabozantinib at a dose of 60 mg daily as first-line therapy for renal cell carcinoma, Dr. Choueiri said.

"I think overall [with] cabozantinib, it is rational to think of it as a synergistic approach to VEGF and c-MET blockade," said Dr. Lauren C. Harshman, an oncologist at Stanford (Calif.) University. Dr. Harshman was the invited discussant but was not involved in the study.

She noted that while cabozantinib has "intriguing preliminary efficacy," the toxicities – primarily fatigue, diarrhea, and nausea – were similar to those seen in trials of the drug for prostate cancer, and required discontinuations in nearly one-fourth of patients.

"A big question will be whether a lower dose can achieve the same efficacy," she said.

The study was funded by Exelixis, maker of cabozantinib. Dr. Choueiri has received research funding from the company. Dr. Harshman has received research funding from Bristol-Myers Squibb.