Kidney Cancer Patients May Need Higher Axitinib Dose

SAN FRANCISCO – Some patients with metastatic renal cell carcinoma may need a higher-than-standard dose of the newly approved antiangiogenic agent axitinib to achieve optimal benefit, according to a secondary analysis of data from the phase III AXIS trial.

Progression-free survival and adverse event rates were essentially the same for patients who continued on the standard dose of 5 mg twice daily of axitinib or less when compared with patients who tolerated the standard dose well enough to advance to a higher one – up to twice as high – lead investigator Dr. Brian I. Rini reported at the Genitourinary Cancers Symposium here.

These findings are consistent with pharmacokinetic data from the phase II trial leading up to AXIS, which suggested that some patients simply need a higher dose of axitinib – an inhibitor of signaling in the vascular endothelial growth factor receptor (VEGFR) pathway – to achieve the same blood level of the drug, according to Dr. Rini, a urologic oncologist at the Cleveland Clinic Taussig Cancer Institute.

"Clearly, there is interpatient variability in the pharmacokinetics of axitinib, and therefore, dose increases to greater than 5 mg twice daily are likely required to optimize both exposure and clinical efficacy in this setting," he said.

An ongoing front-line trial is looking more closely at the issue by testing safety-based dose escalation in a randomized way, he added; results are likely to be reported at the main American Society of Clinical Oncology meeting later this year.

The analysis also found that a response to prior sunitinib (Sutent) did not affect progression-free survival with axitinib, but it did with sorafenib (Nexavar), the trial’s comparator drug, which also inhibits VEGFR signaling, as well as signaling in other pathways. Yet, for both trial drugs, longer progression-free survival on prior sunitinib portended longer progression-free survival with the trial drug.

Discussant Dr. Daniel Cho of Beth Israel Deaconess Medical Center in Boston noted that some might wonder whether axitinib’s superiority in the AXIS trial was due in part to lack of dose escalation of sorafenib, but data on the feasibility of dose escalating that agent are mixed. "It could very well be that the kind of more focused toxicity of the more novel TKIs [tyrosine kinase inhibitors], which allows them to be dose escalated, is a major advantage for these drugs," he commented.

The finding of longer progression-free survival with both trial drugs in patients faring better on prior sunitinib raises an important question relevant to treatment decisions, according to Dr. Cho: "Can a longer progression-free survival on your first VEGF TKI be helpful in determining the next line of therapy?"

"On one hand, you could hypothesize that patients who are on the VEGF TKI longer in the first-line setting represent a group that is more VEGF sensitive and should receive a VEGF TKI as the second-line treatment instead of an mTOR [mammalian target of rapamycin] inhibitor; on the other hand, this group could just sort of represent a group of people whose tumors are growing slower," he explained.

"Other efforts to correlate the response to first-line treatment with response to second-line treatment have largely been negative. ... This remains a critical issue, and a lot of work needs to be done on this subject."

Patients were eligible for the AXIS trial if they had metastatic clear-cell renal cell carcinoma and had experienced a failure of certain first-line therapies; in slightly more than half of patients, that first-line therapy was sunitinib.

The 723 patients were randomized evenly to axitinib (starting at 5 mg twice daily with optional, stepwise dose escalation up to 10 mg twice daily, safety measures permitting) or sorafenib (400 mg twice daily). Axitinib (Inlyta, manufactured by Pfizer) had not yet been approved by the Food and Drug Administration as a second-line treatment for advanced renal cell carcinoma; sorafenib (Nexavar, manufactured by Bayer) had already been approved for treating advanced disease.

Main results of AXIS, previously reported, showed significantly longer progression-free survival with axitinib than with sorafenib in the trial population as a whole (Lancet 2011;376:1931-9).

The new analysis showed that 37% of patients in the axitinib arm had dose escalation of the drug above the starting dose of 5 mg twice daily.

Progression-free survival was essentially the same for patients who did and did not have an axitinib dose escalation – and in both cases, higher than that with sorafenib. Additionally, rates of grade 3 or worse adverse events and serious adverse events were similar between the axitinib groups that did and did not have dose escalation.

These findings are in keeping with the phase II data, which showed first that dose escalation reduced the proportion of patients having subtherapeutic axitinib blood levels, and second that patients achieving therapeutic blood levels had progression-free survival about twice as long as that in their counterparts who did not achieve these levels.

"Dose titration with axitinib serves to normalize plasma exposure. ... We’re not increasing their drug levels above what patients at 5 mg get, but rather their drug levels are catching up to what some patients are able to achieve without titration," Dr. Rini explained.

Thus, in AXIS, "as you would expect from the pharmacokinetic data in which there is normalization of axitinib drug levels for both of these groups, they have roughly equivalent clinical outcomes, both of which were superior to sorafenib in the second-line setting."

The new analysis also showed that with axitinib, progression-free survival was essentially the same for prior sunitinib responders and nonresponders; in contrast, with sorafenib, it tended to be longer for prior sunitinib responders.

For both trial drugs, progression-free survival on prior sunitinib appeared to influence progression-free survival on the trial drug. For example, in the axitinib group, it was 40% longer for patients whose duration of prior sunitinib response was at least 9 months vs. shorter than that (6.3 vs. 4.5 months).

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Pfizer sponsored the AXIS trial. Dr. Rini disclosed that he is a consultant to and receives research funding from Pfizer. Dr. Cho disclosed that he has no relevant conflicts of interest.

SAN FRANCISCO – Some patients with metastatic renal cell carcinoma may need a higher-than-standard dose of the newly approved antiangiogenic agent axitinib to achieve optimal benefit, according to a secondary analysis of data from the phase III AXIS trial.

Progression-free survival and adverse event rates were essentially the same for patients who continued on the standard dose of 5 mg twice daily of axitinib or less when compared with patients who tolerated the standard dose well enough to advance to a higher one – up to twice as high – lead investigator Dr. Brian I. Rini reported at the Genitourinary Cancers Symposium here.

These findings are consistent with pharmacokinetic data from the phase II trial leading up to AXIS, which suggested that some patients simply need a higher dose of axitinib – an inhibitor of signaling in the vascular endothelial growth factor receptor (VEGFR) pathway – to achieve the same blood level of the drug, according to Dr. Rini, a urologic oncologist at the Cleveland Clinic Taussig Cancer Institute.

"Clearly, there is interpatient variability in the pharmacokinetics of axitinib, and therefore, dose increases to greater than 5 mg twice daily are likely required to optimize both exposure and clinical efficacy in this setting," he said.

An ongoing front-line trial is looking more closely at the issue by testing safety-based dose escalation in a randomized way, he added; results are likely to be reported at the main American Society of Clinical Oncology meeting later this year.

The analysis also found that a response to prior sunitinib (Sutent) did not affect progression-free survival with axitinib, but it did with sorafenib (Nexavar), the trial’s comparator drug, which also inhibits VEGFR signaling, as well as signaling in other pathways. Yet, for both trial drugs, longer progression-free survival on prior sunitinib portended longer progression-free survival with the trial drug.

Discussant Dr. Daniel Cho of Beth Israel Deaconess Medical Center in Boston noted that some might wonder whether axitinib’s superiority in the AXIS trial was due in part to lack of dose escalation of sorafenib, but data on the feasibility of dose escalating that agent are mixed. "It could very well be that the kind of more focused toxicity of the more novel TKIs [tyrosine kinase inhibitors], which allows them to be dose escalated, is a major advantage for these drugs," he commented.

The finding of longer progression-free survival with both trial drugs in patients faring better on prior sunitinib raises an important question relevant to treatment decisions, according to Dr. Cho: "Can a longer progression-free survival on your first VEGF TKI be helpful in determining the next line of therapy?"

"On one hand, you could hypothesize that patients who are on the VEGF TKI longer in the first-line setting represent a group that is more VEGF sensitive and should receive a VEGF TKI as the second-line treatment instead of an mTOR [mammalian target of rapamycin] inhibitor; on the other hand, this group could just sort of represent a group of people whose tumors are growing slower," he explained.

"Other efforts to correlate the response to first-line treatment with response to second-line treatment have largely been negative. ... This remains a critical issue, and a lot of work needs to be done on this subject."

Patients were eligible for the AXIS trial if they had metastatic clear-cell renal cell carcinoma and had experienced a failure of certain first-line therapies; in slightly more than half of patients, that first-line therapy was sunitinib.

The 723 patients were randomized evenly to axitinib (starting at 5 mg twice daily with optional, stepwise dose escalation up to 10 mg twice daily, safety measures permitting) or sorafenib (400 mg twice daily). Axitinib (Inlyta, manufactured by Pfizer) had not yet been approved by the Food and Drug Administration as a second-line treatment for advanced renal cell carcinoma; sorafenib (Nexavar, manufactured by Bayer) had already been approved for treating advanced disease.

Main results of AXIS, previously reported, showed significantly longer progression-free survival with axitinib than with sorafenib in the trial population as a whole (Lancet 2011;376:1931-9).

The new analysis showed that 37% of patients in the axitinib arm had dose escalation of the drug above the starting dose of 5 mg twice daily.

Progression-free survival was essentially the same for patients who did and did not have an axitinib dose escalation – and in both cases, higher than that with sorafenib. Additionally, rates of grade 3 or worse adverse events and serious adverse events were similar between the axitinib groups that did and did not have dose escalation.

These findings are in keeping with the phase II data, which showed first that dose escalation reduced the proportion of patients having subtherapeutic axitinib blood levels, and second that patients achieving therapeutic blood levels had progression-free survival about twice as long as that in their counterparts who did not achieve these levels.

"Dose titration with axitinib serves to normalize plasma exposure. ... We’re not increasing their drug levels above what patients at 5 mg get, but rather their drug levels are catching up to what some patients are able to achieve without titration," Dr. Rini explained.

Thus, in AXIS, "as you would expect from the pharmacokinetic data in which there is normalization of axitinib drug levels for both of these groups, they have roughly equivalent clinical outcomes, both of which were superior to sorafenib in the second-line setting."

The new analysis also showed that with axitinib, progression-free survival was essentially the same for prior sunitinib responders and nonresponders; in contrast, with sorafenib, it tended to be longer for prior sunitinib responders.

For both trial drugs, progression-free survival on prior sunitinib appeared to influence progression-free survival on the trial drug. For example, in the axitinib group, it was 40% longer for patients whose duration of prior sunitinib response was at least 9 months vs. shorter than that (6.3 vs. 4.5 months).

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Pfizer sponsored the AXIS trial. Dr. Rini disclosed that he is a consultant to and receives research funding from Pfizer. Dr. Cho disclosed that he has no relevant conflicts of interest.

SAN FRANCISCO – Some patients with metastatic renal cell carcinoma may need a higher-than-standard dose of the newly approved antiangiogenic agent axitinib to achieve optimal benefit, according to a secondary analysis of data from the phase III AXIS trial.

Progression-free survival and adverse event rates were essentially the same for patients who continued on the standard dose of 5 mg twice daily of axitinib or less when compared with patients who tolerated the standard dose well enough to advance to a higher one – up to twice as high – lead investigator Dr. Brian I. Rini reported at the Genitourinary Cancers Symposium here.

These findings are consistent with pharmacokinetic data from the phase II trial leading up to AXIS, which suggested that some patients simply need a higher dose of axitinib – an inhibitor of signaling in the vascular endothelial growth factor receptor (VEGFR) pathway – to achieve the same blood level of the drug, according to Dr. Rini, a urologic oncologist at the Cleveland Clinic Taussig Cancer Institute.

"Clearly, there is interpatient variability in the pharmacokinetics of axitinib, and therefore, dose increases to greater than 5 mg twice daily are likely required to optimize both exposure and clinical efficacy in this setting," he said.

An ongoing front-line trial is looking more closely at the issue by testing safety-based dose escalation in a randomized way, he added; results are likely to be reported at the main American Society of Clinical Oncology meeting later this year.

The analysis also found that a response to prior sunitinib (Sutent) did not affect progression-free survival with axitinib, but it did with sorafenib (Nexavar), the trial’s comparator drug, which also inhibits VEGFR signaling, as well as signaling in other pathways. Yet, for both trial drugs, longer progression-free survival on prior sunitinib portended longer progression-free survival with the trial drug.

Discussant Dr. Daniel Cho of Beth Israel Deaconess Medical Center in Boston noted that some might wonder whether axitinib’s superiority in the AXIS trial was due in part to lack of dose escalation of sorafenib, but data on the feasibility of dose escalating that agent are mixed. "It could very well be that the kind of more focused toxicity of the more novel TKIs [tyrosine kinase inhibitors], which allows them to be dose escalated, is a major advantage for these drugs," he commented.

The finding of longer progression-free survival with both trial drugs in patients faring better on prior sunitinib raises an important question relevant to treatment decisions, according to Dr. Cho: "Can a longer progression-free survival on your first VEGF TKI be helpful in determining the next line of therapy?"

"On one hand, you could hypothesize that patients who are on the VEGF TKI longer in the first-line setting represent a group that is more VEGF sensitive and should receive a VEGF TKI as the second-line treatment instead of an mTOR [mammalian target of rapamycin] inhibitor; on the other hand, this group could just sort of represent a group of people whose tumors are growing slower," he explained.

"Other efforts to correlate the response to first-line treatment with response to second-line treatment have largely been negative. ... This remains a critical issue, and a lot of work needs to be done on this subject."

Patients were eligible for the AXIS trial if they had metastatic clear-cell renal cell carcinoma and had experienced a failure of certain first-line therapies; in slightly more than half of patients, that first-line therapy was sunitinib.

The 723 patients were randomized evenly to axitinib (starting at 5 mg twice daily with optional, stepwise dose escalation up to 10 mg twice daily, safety measures permitting) or sorafenib (400 mg twice daily). Axitinib (Inlyta, manufactured by Pfizer) had not yet been approved by the Food and Drug Administration as a second-line treatment for advanced renal cell carcinoma; sorafenib (Nexavar, manufactured by Bayer) had already been approved for treating advanced disease.

Main results of AXIS, previously reported, showed significantly longer progression-free survival with axitinib than with sorafenib in the trial population as a whole (Lancet 2011;376:1931-9).

The new analysis showed that 37% of patients in the axitinib arm had dose escalation of the drug above the starting dose of 5 mg twice daily.

Progression-free survival was essentially the same for patients who did and did not have an axitinib dose escalation – and in both cases, higher than that with sorafenib. Additionally, rates of grade 3 or worse adverse events and serious adverse events were similar between the axitinib groups that did and did not have dose escalation.

These findings are in keeping with the phase II data, which showed first that dose escalation reduced the proportion of patients having subtherapeutic axitinib blood levels, and second that patients achieving therapeutic blood levels had progression-free survival about twice as long as that in their counterparts who did not achieve these levels.

"Dose titration with axitinib serves to normalize plasma exposure. ... We’re not increasing their drug levels above what patients at 5 mg get, but rather their drug levels are catching up to what some patients are able to achieve without titration," Dr. Rini explained.

Thus, in AXIS, "as you would expect from the pharmacokinetic data in which there is normalization of axitinib drug levels for both of these groups, they have roughly equivalent clinical outcomes, both of which were superior to sorafenib in the second-line setting."

The new analysis also showed that with axitinib, progression-free survival was essentially the same for prior sunitinib responders and nonresponders; in contrast, with sorafenib, it tended to be longer for prior sunitinib responders.

For both trial drugs, progression-free survival on prior sunitinib appeared to influence progression-free survival on the trial drug. For example, in the axitinib group, it was 40% longer for patients whose duration of prior sunitinib response was at least 9 months vs. shorter than that (6.3 vs. 4.5 months).

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Pfizer sponsored the AXIS trial. Dr. Rini disclosed that he is a consultant to and receives research funding from Pfizer. Dr. Cho disclosed that he has no relevant conflicts of interest.