Susan London

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.

SAN FRANCISCO – Radium-223 chloride, the first alpha particle–emitting bone-targeted agent, is efficacious and safe for treating men with bone metastases of castration-resistant prostate cancer, according to a randomized, phase-III trial reported at the Genitourinary Cancers Symposium.

The 809 men in the ALSYMPCA trial had a 30% reduction in the risk of death and a nearly 40% reduction in the risk of a first clinical skeletal-related event if treated with radium-223 chloride, compared with placebo. The agent had a good safety profile as well, with low rates of myelosuppression and, thus far, no cases of secondary cancers.

Trial results were reported in a poster session by Dr. A. Oliver Sartor, Laborde Professor of Cancer Research at Tulane University, New Orleans, and medical director of the Tulane Cancer Center, and in an oral presentation by Dr. Chris Parker of the Royal Marsden NHS Foundation Trust in Sutton, England.

"We believe that this novel alpha pharmaceutical – the very first one to be tested in phase III in all of medicine – may provide a new standard of care for the treatment of patients with bone metastasis in advanced prostate cancer," Dr. Sartor said in a press briefing.

There is every reason to believe that radium-223 "will be very well received by the regulatory agencies, not only in the U.S. but also abroad," he predicted. In fact, it has been submitted for approval in the United States, where the Food and Drug Administration has agreed to fast-track status.

In the question-and-answer period following the oral presentation, Dr. Anthony V. D’Amico of the Dana-Farber Cancer Institute, Boston, said that the trial’s findings were "quite striking," but he questioned radium-223’s long-term safety, especially should the drug be eyed for treatment of less advanced cancer.

"Oftentimes, when we see a result like this, it then gets transferred back into earlier stages of disease. The one thing you can’t assess here are late effects, particularly leukemias and second cancers, like bone sarcomas, because patients die very quickly," he noted. "So caution would have to be thought of before one would administer such a drug even in a clinical trial in earlier settings when people have long life expectancies."

Another attendee asked about the ability to administer chemotherapy after a patient has been treated with radium-223, given that the agent might compromise bone marrow reserve; this in turn would influence decisions about the sequencing of treatment.

"Although we have seen that radium-223 has little effect on the full blood count, I don’t think that we can assume that the bone marrow reserve will be normal," Dr. Parker replied. "So it’s very important that we do collect data going forward on the safety and tolerability of chemotherapy after radium." To that end, data on patients in ALSYMPCA (A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases) subsequently given chemotherapy will be reported later this year.

Radiopharmaceuticals have not historically been widely used in metastatic prostate cancer, but radium-223 "is a different beast because of the survival benefit," Dr. Sartor noted in an interview during the poster session.

Additionally, because it was given in the trial along with best standard of care, it should be easy to combine with several commonly used therapies in this patient population. "Things like abiraterone and prednisone, I personally believe, will be incorporated very easily into this treatment schema," he commented. Data for various combinations will also be reported later this spring.

"Another issue with which I’m personally a little bit enamored is that when you utilize radiation, you actually enhance the epitopes that are important in some immunological therapies," Dr. Sartor added. "I believe that [radium-223] ... may play very well with immunotherapies. Now that’s a hypothesis, not a fact. But nevertheless, I want to see it tested."

Men were eligible for ALSYMPCA if they had symptomatic castration-resistant prostate cancer, had received docetaxel or were ineligible for or declined this chemotherapy, and had at least two bone metastases but no visceral metastases.

The docetaxel-naive population "perhaps constitutes about 40% of all men with castration-refractory disease. At the moment, there are no drugs approved in that setting that improve overall survival," Dr. Parker noted in his presentation. "So it’s a real unmet need present in that group of patients."

The men were assigned 2:1 to intravenous radium-223 or placebo given every 4 weeks, for a total of six treatments, each along with best standard of care, which could include secondary hormonal treatments, external beam radiation therapy, and steroids. (Treatments could not include chemotherapy, other experimental therapy, hemibody radiation, or other radiopharmaceuticals.)

Radium-223 chloride (Alpharadin, manufactured by Algeta in partnership with Bayer) mimics calcium and therefore targets new bone growth in and around bone metastases. Because of the short distance alpha particles travel, the agent results in highly localized tumor cell killing with minimal damage to nearby normal tissue.

"What you’re doing here is very different from all the other bone-targeted agents: You are actually killing cancer cells," Dr. Sartor commented. "The other bone-targeted agents – samarium, strontium, denosumab, and zoledronic acid are the four FDA-approved ones – none of them kill cancer cells like this one does. This is mechanistically distinct."

The men in the trial were 70 years old on average. More than 80% had at least six bone metastases, and more than 50% had bone pain requiring opioid analgesia. About half had received docetaxel.

In main results, radium-223 was associated with longer overall survival (14.0 vs. 11.2 months; hazard ratio [HR], 0.70; P = .002), the trial’s primary end point, a benefit that Dr. Sartor attributed to a reduction of disease burden in this population, whose only known disease was in bone. This finding in an interim analysis prompted early trial closure.

Radium-223 also prolonged the time to first skeletal-related events (13.5 vs. 8.4 months; HR, 0.61; P = .0005). Importantly, and in contrast to trials of zoledronic acid and denosumab, the events included were only clinical ones that came to attention because of signs or symptoms, as the trial did not use routine skeletal surveys, Dr. Parker noted. In addition, fractures were included only if they were pathologic.

Subgroup analyses showed perhaps the greatest reduction in these events among men receiving bisphosphonates (HR, 0.46). "Whilst one must interpret subgroup analyses with great caution, it’s interesting that radium-223 appears to be, if anything, more effective in the presence of bisphosphonates," he commented. "And there is a biologic rationale for that: If you are on a bisphosphonate, you have reduced osteoclast activity, and you could imagine that the radium-223 would be bound for longer. It also, of course, makes the point that radium-223 provides added value over and above bisphosphonates in terms of skeletal-related event prevention."

There also was significant improvement in rates of three of the four assessed skeletal-related events individually: pathologic bone fracture (HR, 0.45), spinal cord compression (HR, 0.44), and external beam radiation to bone (HR, 0.65).

The overall rate of grade 3 or 4 adverse events was lower with radium-223 than with placebo (51% vs. 59%). "You don’t often see phase-III trials with more adverse events in the control arm," Dr. Parker commented at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Rates of hematologic and nonhematologic adverse events of interest were generally similar in the two groups. Grade 3 or 4 neutropenia and thrombocytopenia were more common with radium-223 but still rare (2% and 4%). Also, there was a lower rate of grade 3 or 4 bone pain with the drug vs. placebo (18% vs. 23%).

Dr. Sartor disclosed that he is a consultant to Algeta ASA. Dr. Parker disclosed that he is a consultant to Algeta ASA and receives honoraria from Bayer.

SAN FRANCISCO – Radium-223 chloride, the first alpha particle–emitting bone-targeted agent, is efficacious and safe for treating men with bone metastases of castration-resistant prostate cancer, according to a randomized, phase-III trial reported at the Genitourinary Cancers Symposium.

The 809 men in the ALSYMPCA trial had a 30% reduction in the risk of death and a nearly 40% reduction in the risk of a first clinical skeletal-related event if treated with radium-223 chloride, compared with placebo. The agent had a good safety profile as well, with low rates of myelosuppression and, thus far, no cases of secondary cancers.

Trial results were reported in a poster session by Dr. A. Oliver Sartor, Laborde Professor of Cancer Research at Tulane University, New Orleans, and medical director of the Tulane Cancer Center, and in an oral presentation by Dr. Chris Parker of the Royal Marsden NHS Foundation Trust in Sutton, England.

"We believe that this novel alpha pharmaceutical – the very first one to be tested in phase III in all of medicine – may provide a new standard of care for the treatment of patients with bone metastasis in advanced prostate cancer," Dr. Sartor said in a press briefing.

There is every reason to believe that radium-223 "will be very well received by the regulatory agencies, not only in the U.S. but also abroad," he predicted. In fact, it has been submitted for approval in the United States, where the Food and Drug Administration has agreed to fast-track status.

In the question-and-answer period following the oral presentation, Dr. Anthony V. D’Amico of the Dana-Farber Cancer Institute, Boston, said that the trial’s findings were "quite striking," but he questioned radium-223’s long-term safety, especially should the drug be eyed for treatment of less advanced cancer.

"Oftentimes, when we see a result like this, it then gets transferred back into earlier stages of disease. The one thing you can’t assess here are late effects, particularly leukemias and second cancers, like bone sarcomas, because patients die very quickly," he noted. "So caution would have to be thought of before one would administer such a drug even in a clinical trial in earlier settings when people have long life expectancies."

Another attendee asked about the ability to administer chemotherapy after a patient has been treated with radium-223, given that the agent might compromise bone marrow reserve; this in turn would influence decisions about the sequencing of treatment.

"Although we have seen that radium-223 has little effect on the full blood count, I don’t think that we can assume that the bone marrow reserve will be normal," Dr. Parker replied. "So it’s very important that we do collect data going forward on the safety and tolerability of chemotherapy after radium." To that end, data on patients in ALSYMPCA (A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases) subsequently given chemotherapy will be reported later this year.

Radiopharmaceuticals have not historically been widely used in metastatic prostate cancer, but radium-223 "is a different beast because of the survival benefit," Dr. Sartor noted in an interview during the poster session.

Additionally, because it was given in the trial along with best standard of care, it should be easy to combine with several commonly used therapies in this patient population. "Things like abiraterone and prednisone, I personally believe, will be incorporated very easily into this treatment schema," he commented. Data for various combinations will also be reported later this spring.

"Another issue with which I’m personally a little bit enamored is that when you utilize radiation, you actually enhance the epitopes that are important in some immunological therapies," Dr. Sartor added. "I believe that [radium-223] ... may play very well with immunotherapies. Now that’s a hypothesis, not a fact. But nevertheless, I want to see it tested."

Men were eligible for ALSYMPCA if they had symptomatic castration-resistant prostate cancer, had received docetaxel or were ineligible for or declined this chemotherapy, and had at least two bone metastases but no visceral metastases.

The docetaxel-naive population "perhaps constitutes about 40% of all men with castration-refractory disease. At the moment, there are no drugs approved in that setting that improve overall survival," Dr. Parker noted in his presentation. "So it’s a real unmet need present in that group of patients."

The men were assigned 2:1 to intravenous radium-223 or placebo given every 4 weeks, for a total of six treatments, each along with best standard of care, which could include secondary hormonal treatments, external beam radiation therapy, and steroids. (Treatments could not include chemotherapy, other experimental therapy, hemibody radiation, or other radiopharmaceuticals.)

Radium-223 chloride (Alpharadin, manufactured by Algeta in partnership with Bayer) mimics calcium and therefore targets new bone growth in and around bone metastases. Because of the short distance alpha particles travel, the agent results in highly localized tumor cell killing with minimal damage to nearby normal tissue.

"What you’re doing here is very different from all the other bone-targeted agents: You are actually killing cancer cells," Dr. Sartor commented. "The other bone-targeted agents – samarium, strontium, denosumab, and zoledronic acid are the four FDA-approved ones – none of them kill cancer cells like this one does. This is mechanistically distinct."

The men in the trial were 70 years old on average. More than 80% had at least six bone metastases, and more than 50% had bone pain requiring opioid analgesia. About half had received docetaxel.

In main results, radium-223 was associated with longer overall survival (14.0 vs. 11.2 months; hazard ratio [HR], 0.70; P = .002), the trial’s primary end point, a benefit that Dr. Sartor attributed to a reduction of disease burden in this population, whose only known disease was in bone. This finding in an interim analysis prompted early trial closure.

Radium-223 also prolonged the time to first skeletal-related events (13.5 vs. 8.4 months; HR, 0.61; P = .0005). Importantly, and in contrast to trials of zoledronic acid and denosumab, the events included were only clinical ones that came to attention because of signs or symptoms, as the trial did not use routine skeletal surveys, Dr. Parker noted. In addition, fractures were included only if they were pathologic.

Subgroup analyses showed perhaps the greatest reduction in these events among men receiving bisphosphonates (HR, 0.46). "Whilst one must interpret subgroup analyses with great caution, it’s interesting that radium-223 appears to be, if anything, more effective in the presence of bisphosphonates," he commented. "And there is a biologic rationale for that: If you are on a bisphosphonate, you have reduced osteoclast activity, and you could imagine that the radium-223 would be bound for longer. It also, of course, makes the point that radium-223 provides added value over and above bisphosphonates in terms of skeletal-related event prevention."

There also was significant improvement in rates of three of the four assessed skeletal-related events individually: pathologic bone fracture (HR, 0.45), spinal cord compression (HR, 0.44), and external beam radiation to bone (HR, 0.65).

The overall rate of grade 3 or 4 adverse events was lower with radium-223 than with placebo (51% vs. 59%). "You don’t often see phase-III trials with more adverse events in the control arm," Dr. Parker commented at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Rates of hematologic and nonhematologic adverse events of interest were generally similar in the two groups. Grade 3 or 4 neutropenia and thrombocytopenia were more common with radium-223 but still rare (2% and 4%). Also, there was a lower rate of grade 3 or 4 bone pain with the drug vs. placebo (18% vs. 23%).

Dr. Sartor disclosed that he is a consultant to Algeta ASA. Dr. Parker disclosed that he is a consultant to Algeta ASA and receives honoraria from Bayer.

SAN FRANCISCO – Radium-223 chloride, the first alpha particle–emitting bone-targeted agent, is efficacious and safe for treating men with bone metastases of castration-resistant prostate cancer, according to a randomized, phase-III trial reported at the Genitourinary Cancers Symposium.

The 809 men in the ALSYMPCA trial had a 30% reduction in the risk of death and a nearly 40% reduction in the risk of a first clinical skeletal-related event if treated with radium-223 chloride, compared with placebo. The agent had a good safety profile as well, with low rates of myelosuppression and, thus far, no cases of secondary cancers.

Trial results were reported in a poster session by Dr. A. Oliver Sartor, Laborde Professor of Cancer Research at Tulane University, New Orleans, and medical director of the Tulane Cancer Center, and in an oral presentation by Dr. Chris Parker of the Royal Marsden NHS Foundation Trust in Sutton, England.

"We believe that this novel alpha pharmaceutical – the very first one to be tested in phase III in all of medicine – may provide a new standard of care for the treatment of patients with bone metastasis in advanced prostate cancer," Dr. Sartor said in a press briefing.

There is every reason to believe that radium-223 "will be very well received by the regulatory agencies, not only in the U.S. but also abroad," he predicted. In fact, it has been submitted for approval in the United States, where the Food and Drug Administration has agreed to fast-track status.

In the question-and-answer period following the oral presentation, Dr. Anthony V. D’Amico of the Dana-Farber Cancer Institute, Boston, said that the trial’s findings were "quite striking," but he questioned radium-223’s long-term safety, especially should the drug be eyed for treatment of less advanced cancer.

"Oftentimes, when we see a result like this, it then gets transferred back into earlier stages of disease. The one thing you can’t assess here are late effects, particularly leukemias and second cancers, like bone sarcomas, because patients die very quickly," he noted. "So caution would have to be thought of before one would administer such a drug even in a clinical trial in earlier settings when people have long life expectancies."

Another attendee asked about the ability to administer chemotherapy after a patient has been treated with radium-223, given that the agent might compromise bone marrow reserve; this in turn would influence decisions about the sequencing of treatment.

"Although we have seen that radium-223 has little effect on the full blood count, I don’t think that we can assume that the bone marrow reserve will be normal," Dr. Parker replied. "So it’s very important that we do collect data going forward on the safety and tolerability of chemotherapy after radium." To that end, data on patients in ALSYMPCA (A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases) subsequently given chemotherapy will be reported later this year.

Radiopharmaceuticals have not historically been widely used in metastatic prostate cancer, but radium-223 "is a different beast because of the survival benefit," Dr. Sartor noted in an interview during the poster session.

Additionally, because it was given in the trial along with best standard of care, it should be easy to combine with several commonly used therapies in this patient population. "Things like abiraterone and prednisone, I personally believe, will be incorporated very easily into this treatment schema," he commented. Data for various combinations will also be reported later this spring.

"Another issue with which I’m personally a little bit enamored is that when you utilize radiation, you actually enhance the epitopes that are important in some immunological therapies," Dr. Sartor added. "I believe that [radium-223] ... may play very well with immunotherapies. Now that’s a hypothesis, not a fact. But nevertheless, I want to see it tested."

Men were eligible for ALSYMPCA if they had symptomatic castration-resistant prostate cancer, had received docetaxel or were ineligible for or declined this chemotherapy, and had at least two bone metastases but no visceral metastases.

The docetaxel-naive population "perhaps constitutes about 40% of all men with castration-refractory disease. At the moment, there are no drugs approved in that setting that improve overall survival," Dr. Parker noted in his presentation. "So it’s a real unmet need present in that group of patients."

The men were assigned 2:1 to intravenous radium-223 or placebo given every 4 weeks, for a total of six treatments, each along with best standard of care, which could include secondary hormonal treatments, external beam radiation therapy, and steroids. (Treatments could not include chemotherapy, other experimental therapy, hemibody radiation, or other radiopharmaceuticals.)

Radium-223 chloride (Alpharadin, manufactured by Algeta in partnership with Bayer) mimics calcium and therefore targets new bone growth in and around bone metastases. Because of the short distance alpha particles travel, the agent results in highly localized tumor cell killing with minimal damage to nearby normal tissue.

"What you’re doing here is very different from all the other bone-targeted agents: You are actually killing cancer cells," Dr. Sartor commented. "The other bone-targeted agents – samarium, strontium, denosumab, and zoledronic acid are the four FDA-approved ones – none of them kill cancer cells like this one does. This is mechanistically distinct."

The men in the trial were 70 years old on average. More than 80% had at least six bone metastases, and more than 50% had bone pain requiring opioid analgesia. About half had received docetaxel.

In main results, radium-223 was associated with longer overall survival (14.0 vs. 11.2 months; hazard ratio [HR], 0.70; P = .002), the trial’s primary end point, a benefit that Dr. Sartor attributed to a reduction of disease burden in this population, whose only known disease was in bone. This finding in an interim analysis prompted early trial closure.

Radium-223 also prolonged the time to first skeletal-related events (13.5 vs. 8.4 months; HR, 0.61; P = .0005). Importantly, and in contrast to trials of zoledronic acid and denosumab, the events included were only clinical ones that came to attention because of signs or symptoms, as the trial did not use routine skeletal surveys, Dr. Parker noted. In addition, fractures were included only if they were pathologic.

Subgroup analyses showed perhaps the greatest reduction in these events among men receiving bisphosphonates (HR, 0.46). "Whilst one must interpret subgroup analyses with great caution, it’s interesting that radium-223 appears to be, if anything, more effective in the presence of bisphosphonates," he commented. "And there is a biologic rationale for that: If you are on a bisphosphonate, you have reduced osteoclast activity, and you could imagine that the radium-223 would be bound for longer. It also, of course, makes the point that radium-223 provides added value over and above bisphosphonates in terms of skeletal-related event prevention."

There also was significant improvement in rates of three of the four assessed skeletal-related events individually: pathologic bone fracture (HR, 0.45), spinal cord compression (HR, 0.44), and external beam radiation to bone (HR, 0.65).

The overall rate of grade 3 or 4 adverse events was lower with radium-223 than with placebo (51% vs. 59%). "You don’t often see phase-III trials with more adverse events in the control arm," Dr. Parker commented at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Rates of hematologic and nonhematologic adverse events of interest were generally similar in the two groups. Grade 3 or 4 neutropenia and thrombocytopenia were more common with radium-223 but still rare (2% and 4%). Also, there was a lower rate of grade 3 or 4 bone pain with the drug vs. placebo (18% vs. 23%).

Dr. Sartor disclosed that he is a consultant to Algeta ASA. Dr. Parker disclosed that he is a consultant to Algeta ASA and receives honoraria from Bayer.

SAN FRANCISCO – MDV3100, new oral inhibitor of androgen receptor signaling, reduces the risk of death by more than a third after a failure of docetaxel chemotherapy in men with progressive castration-resistant prostate cancer, according to results of the randomized AFFIRM trial.

Interim data for the trial, which was conducted in nearly 1,200 men, showed that those given the investigational drug lived 4.8 months longer than their counterparts who had been given a placebo, corresponding to a 37% reduced risk of death, lead investigator Dr. Howard I. Scher reported at the Genitourinary Cancers Symposium. This positive finding triggered early trial closure.

Additional analyses revealed that men treated with the drug were significantly more likely to have a soft tissue response and to have at least a halving of their prostate-specific antigen (PSA) level. At the same time, there was no increase in the rate of higher-grade adverse events; seizures (a potential concern from earlier research) occurred at low frequency.

"MDV3100 now joins the list of drugs demonstrating a survival benefit in a phase III trial post docetaxel," adding to abiraterone (Zytiga) and cabazitaxel (Jevtana), Dr. Scher maintained. "The risk-benefit ratio will likely position this as the frontline agent post docetaxel therapy."

"I’m not the [Food and Drug Administration], but I would say that when you see this kind of survival benefit and safety profile – and looking at a prior drug [investigation] that I had a privilege of leading – I would say that this should be approved relatively quickly," he commented in a press briefing.

"I have only one comment: wow! That’s very impressive," said Dr. Nicholas J. Vogelzang, the moderator of the briefing and the chair and medical director of the Developmental Therapeutics Committee of US Oncology. The median survival and dramatic rates of PSA reduction seen with MDV3100 are "unprecedented. This is going to definitely change the way we take care of patients every day in the office."

"This is a landmark study," Dr. Adam S. Kibel agreed in an interview at the meeting. "I think this is a drug that will be widely used, assuming it gets FDA approved."

Initially, MDV3100 is likely to be used in the postdocetaxel space, said, Dr. Kibel, chief of urology at Brigham and Women’s Hospital and the Dana Farber Cancer Institute and a professor at Harvard Medical School, all in Boston. "I imagine that it would probably be the first-line drug because it appears to have a little less side effect profile than abiraterone and certainly lower than cabazitaxel."

"The one tripper in there is, will insurance pay for it and how much is it going to cost?" said Dr. Kibel.

MDV3100 is also being tested in patients who have not yet received docetaxel. "I will be shocked if [those data] are not positive," he commented. And should it perform well there, "it will move prior to docetaxel, because it appears to be very well tolerated from the data presented."

The AFFIRM trial enrolled 1,199 men with castration-resistant prostate cancer who had experienced progression after receiving docetaxel – a population for whom there was no standard of care at the time the trial began, Dr. Scher noted. They were assigned in 2:1 ratio to once-daily treatment with MDV3100 (manufactured by Medivation) or placebo.

The first-in-class drug has a three-pronged mechanism of action, as well as some advantages over other antiandrogen agents, according to Dr. Scher, chief of the genitourinary oncology service and D. Wayne Calloway Chair in Urologic Oncology at the Memorial Sloan-Kettering Cancer Center in New York.

It "binds more tightly [to the androgen receptor] than the currently available agents, but is also unique in that it inhibits nuclear translocation [of the receptor] as well as the association of the receptor with DNA, inducing cell death," he explained.

The patients studied had a median age of 69 years. Most (90%) had bone metastases, and the large majority (70%) also had soft tissue metastases.

Main results showed that men given MDV3100 lived 18.4 months, whereas their counterparts given the placebo lived 13.6 months (hazard ratio, 0.63; P less than .0001). Stratified analyses showed similar benefit across most patient subgroups.

Men treated with the drug also had longer median radiographic progression free survival (8.3 vs. 2.9 months; HR, 0.40) and were more likely to have a soft tissue response on imaging (29% vs. 4%) and at least a halving of their PSA level (54% vs. 2%) (all P less than .0001).

There was no increase with MDV3100 in the rate of grade 3 or higher adverse events (45% vs. 53%) or the overall rate of treatment discontinuation due to adverse events (8% vs. 10%).

Seizures occurred in 0.6% of patients given the drug, compared with none of those given the placebo. "Obviously, these cases were studied very, very carefully. In four of the five cases, there were other potential confounders," including brain metastases and receipt of intravenous lidocaine for a biopsy, Dr. Scher noted. "This is an extremely low frequency, and considering this patient population who are symptomatic post docetaxel, for us, it’s really a nonissue."

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

Medivation Inc. sponsored the trial. Dr. Scher disclosed that he is a consultant to and receives research funding from Medivation. Dr. Vogelzang disclosed relationships with numerous companies. Dr. Kibel reported that he is a consultant to Dendreon and Sanofi-Aventis.

SAN FRANCISCO – MDV3100, new oral inhibitor of androgen receptor signaling, reduces the risk of death by more than a third after a failure of docetaxel chemotherapy in men with progressive castration-resistant prostate cancer, according to results of the randomized AFFIRM trial.

Interim data for the trial, which was conducted in nearly 1,200 men, showed that those given the investigational drug lived 4.8 months longer than their counterparts who had been given a placebo, corresponding to a 37% reduced risk of death, lead investigator Dr. Howard I. Scher reported at the Genitourinary Cancers Symposium. This positive finding triggered early trial closure.

Additional analyses revealed that men treated with the drug were significantly more likely to have a soft tissue response and to have at least a halving of their prostate-specific antigen (PSA) level. At the same time, there was no increase in the rate of higher-grade adverse events; seizures (a potential concern from earlier research) occurred at low frequency.

"MDV3100 now joins the list of drugs demonstrating a survival benefit in a phase III trial post docetaxel," adding to abiraterone (Zytiga) and cabazitaxel (Jevtana), Dr. Scher maintained. "The risk-benefit ratio will likely position this as the frontline agent post docetaxel therapy."

"I’m not the [Food and Drug Administration], but I would say that when you see this kind of survival benefit and safety profile – and looking at a prior drug [investigation] that I had a privilege of leading – I would say that this should be approved relatively quickly," he commented in a press briefing.

"I have only one comment: wow! That’s very impressive," said Dr. Nicholas J. Vogelzang, the moderator of the briefing and the chair and medical director of the Developmental Therapeutics Committee of US Oncology. The median survival and dramatic rates of PSA reduction seen with MDV3100 are "unprecedented. This is going to definitely change the way we take care of patients every day in the office."

"This is a landmark study," Dr. Adam S. Kibel agreed in an interview at the meeting. "I think this is a drug that will be widely used, assuming it gets FDA approved."

Initially, MDV3100 is likely to be used in the postdocetaxel space, said, Dr. Kibel, chief of urology at Brigham and Women’s Hospital and the Dana Farber Cancer Institute and a professor at Harvard Medical School, all in Boston. "I imagine that it would probably be the first-line drug because it appears to have a little less side effect profile than abiraterone and certainly lower than cabazitaxel."

"The one tripper in there is, will insurance pay for it and how much is it going to cost?" said Dr. Kibel.

MDV3100 is also being tested in patients who have not yet received docetaxel. "I will be shocked if [those data] are not positive," he commented. And should it perform well there, "it will move prior to docetaxel, because it appears to be very well tolerated from the data presented."

The AFFIRM trial enrolled 1,199 men with castration-resistant prostate cancer who had experienced progression after receiving docetaxel – a population for whom there was no standard of care at the time the trial began, Dr. Scher noted. They were assigned in 2:1 ratio to once-daily treatment with MDV3100 (manufactured by Medivation) or placebo.

The first-in-class drug has a three-pronged mechanism of action, as well as some advantages over other antiandrogen agents, according to Dr. Scher, chief of the genitourinary oncology service and D. Wayne Calloway Chair in Urologic Oncology at the Memorial Sloan-Kettering Cancer Center in New York.

It "binds more tightly [to the androgen receptor] than the currently available agents, but is also unique in that it inhibits nuclear translocation [of the receptor] as well as the association of the receptor with DNA, inducing cell death," he explained.

The patients studied had a median age of 69 years. Most (90%) had bone metastases, and the large majority (70%) also had soft tissue metastases.

Main results showed that men given MDV3100 lived 18.4 months, whereas their counterparts given the placebo lived 13.6 months (hazard ratio, 0.63; P less than .0001). Stratified analyses showed similar benefit across most patient subgroups.

Men treated with the drug also had longer median radiographic progression free survival (8.3 vs. 2.9 months; HR, 0.40) and were more likely to have a soft tissue response on imaging (29% vs. 4%) and at least a halving of their PSA level (54% vs. 2%) (all P less than .0001).

There was no increase with MDV3100 in the rate of grade 3 or higher adverse events (45% vs. 53%) or the overall rate of treatment discontinuation due to adverse events (8% vs. 10%).

Seizures occurred in 0.6% of patients given the drug, compared with none of those given the placebo. "Obviously, these cases were studied very, very carefully. In four of the five cases, there were other potential confounders," including brain metastases and receipt of intravenous lidocaine for a biopsy, Dr. Scher noted. "This is an extremely low frequency, and considering this patient population who are symptomatic post docetaxel, for us, it’s really a nonissue."

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

Medivation Inc. sponsored the trial. Dr. Scher disclosed that he is a consultant to and receives research funding from Medivation. Dr. Vogelzang disclosed relationships with numerous companies. Dr. Kibel reported that he is a consultant to Dendreon and Sanofi-Aventis.

SAN FRANCISCO – MDV3100, new oral inhibitor of androgen receptor signaling, reduces the risk of death by more than a third after a failure of docetaxel chemotherapy in men with progressive castration-resistant prostate cancer, according to results of the randomized AFFIRM trial.

Interim data for the trial, which was conducted in nearly 1,200 men, showed that those given the investigational drug lived 4.8 months longer than their counterparts who had been given a placebo, corresponding to a 37% reduced risk of death, lead investigator Dr. Howard I. Scher reported at the Genitourinary Cancers Symposium. This positive finding triggered early trial closure.

Additional analyses revealed that men treated with the drug were significantly more likely to have a soft tissue response and to have at least a halving of their prostate-specific antigen (PSA) level. At the same time, there was no increase in the rate of higher-grade adverse events; seizures (a potential concern from earlier research) occurred at low frequency.

"MDV3100 now joins the list of drugs demonstrating a survival benefit in a phase III trial post docetaxel," adding to abiraterone (Zytiga) and cabazitaxel (Jevtana), Dr. Scher maintained. "The risk-benefit ratio will likely position this as the frontline agent post docetaxel therapy."

"I’m not the [Food and Drug Administration], but I would say that when you see this kind of survival benefit and safety profile – and looking at a prior drug [investigation] that I had a privilege of leading – I would say that this should be approved relatively quickly," he commented in a press briefing.

"I have only one comment: wow! That’s very impressive," said Dr. Nicholas J. Vogelzang, the moderator of the briefing and the chair and medical director of the Developmental Therapeutics Committee of US Oncology. The median survival and dramatic rates of PSA reduction seen with MDV3100 are "unprecedented. This is going to definitely change the way we take care of patients every day in the office."

"This is a landmark study," Dr. Adam S. Kibel agreed in an interview at the meeting. "I think this is a drug that will be widely used, assuming it gets FDA approved."

Initially, MDV3100 is likely to be used in the postdocetaxel space, said, Dr. Kibel, chief of urology at Brigham and Women’s Hospital and the Dana Farber Cancer Institute and a professor at Harvard Medical School, all in Boston. "I imagine that it would probably be the first-line drug because it appears to have a little less side effect profile than abiraterone and certainly lower than cabazitaxel."

"The one tripper in there is, will insurance pay for it and how much is it going to cost?" said Dr. Kibel.

MDV3100 is also being tested in patients who have not yet received docetaxel. "I will be shocked if [those data] are not positive," he commented. And should it perform well there, "it will move prior to docetaxel, because it appears to be very well tolerated from the data presented."

The AFFIRM trial enrolled 1,199 men with castration-resistant prostate cancer who had experienced progression after receiving docetaxel – a population for whom there was no standard of care at the time the trial began, Dr. Scher noted. They were assigned in 2:1 ratio to once-daily treatment with MDV3100 (manufactured by Medivation) or placebo.

The first-in-class drug has a three-pronged mechanism of action, as well as some advantages over other antiandrogen agents, according to Dr. Scher, chief of the genitourinary oncology service and D. Wayne Calloway Chair in Urologic Oncology at the Memorial Sloan-Kettering Cancer Center in New York.

It "binds more tightly [to the androgen receptor] than the currently available agents, but is also unique in that it inhibits nuclear translocation [of the receptor] as well as the association of the receptor with DNA, inducing cell death," he explained.

The patients studied had a median age of 69 years. Most (90%) had bone metastases, and the large majority (70%) also had soft tissue metastases.

Main results showed that men given MDV3100 lived 18.4 months, whereas their counterparts given the placebo lived 13.6 months (hazard ratio, 0.63; P less than .0001). Stratified analyses showed similar benefit across most patient subgroups.

Men treated with the drug also had longer median radiographic progression free survival (8.3 vs. 2.9 months; HR, 0.40) and were more likely to have a soft tissue response on imaging (29% vs. 4%) and at least a halving of their PSA level (54% vs. 2%) (all P less than .0001).

There was no increase with MDV3100 in the rate of grade 3 or higher adverse events (45% vs. 53%) or the overall rate of treatment discontinuation due to adverse events (8% vs. 10%).

Seizures occurred in 0.6% of patients given the drug, compared with none of those given the placebo. "Obviously, these cases were studied very, very carefully. In four of the five cases, there were other potential confounders," including brain metastases and receipt of intravenous lidocaine for a biopsy, Dr. Scher noted. "This is an extremely low frequency, and considering this patient population who are symptomatic post docetaxel, for us, it’s really a nonissue."

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

Medivation Inc. sponsored the trial. Dr. Scher disclosed that he is a consultant to and receives research funding from Medivation. Dr. Vogelzang disclosed relationships with numerous companies. Dr. Kibel reported that he is a consultant to Dendreon and Sanofi-Aventis.

SAN FRANCISCO – A new 86-gene signature may add to metabolic imaging in guiding early treatment decisions for esophagogastric junction cancer, researchers reported.

The leptin gene, among others, stood out as having the potential to become a clinically useful biomarker in analyses that were presented at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Dr. Russell Petty of the University of Aberdeen (Scotland) and colleagues studied 182 patients with locally advanced or metastatic disease. The investigators performed FDG-PET (¹⁸fluorodeoxyglucose–positron emission tomography) imaging and CT imaging, as well as gene expression profiling, and immunohistochemistry of pretreatment tumor tissue.

Results showed that among a subgroup of 14 patients who had a PET metabolic response to the first cycle of neoadjuvant chemotherapy, a set of 86 genes in pretreatment tumor tissue distinguished those who had a radiologic response on CT after completing all cycles of that chemotherapy, compared with those who did not respond. In a variety of predictive models, this gene signature correctly predicted radiologic response in all cases.

"We have shown that gene expression profiling can subclassify FDG-PET metabolic responders into those patients that will and will not subsequently go on to have a [radiologic] response. We have also shown that combining molecular biomarkers and FDG-PET allows an optimization of response prediction," Dr. Petty said.

This is key, as PET alone has a poor positive predictive value in this setting, with only half of PET responders to neoadjuvant chemotherapy eventually showing a histopathologic response.

"While I suppose there is little doubt that if we used PET in this way to make treatment decisions, we would have a system that would be better than unstratified empirical treatment, what it still means is that quite significant proportions of our patients will go on to receive ineffective and intensely toxic therapy," he commented.

A subsequent gene enrichment and pathway analysis identified a half-dozen pathways that provided potential mechanistic explanations for the different tumor behavior. "Within the pathways identified, the adipocytokine-signaling pathway immediately caught our attention because of the strong known [epidemiologic] link between obesity and body weight, and esophagogastric adenocarcinoma," Dr. Petty noted.

Additional analyses specifically fingered the leptin gene (among others) and showed that among PET responders, leptin expression was higher in radiologic nonresponders than in responders (P = .026).

Yet, immunohistochemistry in an independent group of 154 patients showed that strong leptin staining was also associated with better survival (P = .021), an association that held up in multivariate analysis (hazard ratio, 0.85; P = .04).

In stratified analyses, patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, whereas those with leptin-negative tumors fared considerably better if they received this therapy (indeed, about as well as the positive group).

"Leptin in particular may be a molecular biomarker that is useful to combine with PET," Dr. Petty commented. "Leptin expression is associated with chemoresistance, but at the same time is also a favorable therapy-independent biomarker, so this combination of predictive and therapy-independent prognostic impacts mean that leptin has the potential to be a clinically useful biomarker."

"I really think that this is groundbreaking. ... The real future is here" when it comes to predicting treatment response in this cancer, as suggested by this study and others," session cochair Dr. Mark Krasna of the St. Joseph Medical Center in Towson, Md., commented in an interview. "The question now is, are we ready for prime time to adopt that throughout?"

At present, more research is needed, according to Dr. Krasna, such as the ongoing validation of the 86-gene signature and trials like CALGB (Cancer and Leukemia Group B) 80803 exploring response-adaptive treatment in this cancer. "I think those are the important things we can do today. We are ready for that," he concluded.

Dr. Petty and Dr. Krasna reported that they had no relevant conflicts of interest.

SAN FRANCISCO – A new 86-gene signature may add to metabolic imaging in guiding early treatment decisions for esophagogastric junction cancer, researchers reported.

The leptin gene, among others, stood out as having the potential to become a clinically useful biomarker in analyses that were presented at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Dr. Russell Petty of the University of Aberdeen (Scotland) and colleagues studied 182 patients with locally advanced or metastatic disease. The investigators performed FDG-PET (¹⁸fluorodeoxyglucose–positron emission tomography) imaging and CT imaging, as well as gene expression profiling, and immunohistochemistry of pretreatment tumor tissue.

Results showed that among a subgroup of 14 patients who had a PET metabolic response to the first cycle of neoadjuvant chemotherapy, a set of 86 genes in pretreatment tumor tissue distinguished those who had a radiologic response on CT after completing all cycles of that chemotherapy, compared with those who did not respond. In a variety of predictive models, this gene signature correctly predicted radiologic response in all cases.

"We have shown that gene expression profiling can subclassify FDG-PET metabolic responders into those patients that will and will not subsequently go on to have a [radiologic] response. We have also shown that combining molecular biomarkers and FDG-PET allows an optimization of response prediction," Dr. Petty said.

This is key, as PET alone has a poor positive predictive value in this setting, with only half of PET responders to neoadjuvant chemotherapy eventually showing a histopathologic response.

"While I suppose there is little doubt that if we used PET in this way to make treatment decisions, we would have a system that would be better than unstratified empirical treatment, what it still means is that quite significant proportions of our patients will go on to receive ineffective and intensely toxic therapy," he commented.

A subsequent gene enrichment and pathway analysis identified a half-dozen pathways that provided potential mechanistic explanations for the different tumor behavior. "Within the pathways identified, the adipocytokine-signaling pathway immediately caught our attention because of the strong known [epidemiologic] link between obesity and body weight, and esophagogastric adenocarcinoma," Dr. Petty noted.

Additional analyses specifically fingered the leptin gene (among others) and showed that among PET responders, leptin expression was higher in radiologic nonresponders than in responders (P = .026).

Yet, immunohistochemistry in an independent group of 154 patients showed that strong leptin staining was also associated with better survival (P = .021), an association that held up in multivariate analysis (hazard ratio, 0.85; P = .04).

In stratified analyses, patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, whereas those with leptin-negative tumors fared considerably better if they received this therapy (indeed, about as well as the positive group).

"Leptin in particular may be a molecular biomarker that is useful to combine with PET," Dr. Petty commented. "Leptin expression is associated with chemoresistance, but at the same time is also a favorable therapy-independent biomarker, so this combination of predictive and therapy-independent prognostic impacts mean that leptin has the potential to be a clinically useful biomarker."

"I really think that this is groundbreaking. ... The real future is here" when it comes to predicting treatment response in this cancer, as suggested by this study and others," session cochair Dr. Mark Krasna of the St. Joseph Medical Center in Towson, Md., commented in an interview. "The question now is, are we ready for prime time to adopt that throughout?"

At present, more research is needed, according to Dr. Krasna, such as the ongoing validation of the 86-gene signature and trials like CALGB (Cancer and Leukemia Group B) 80803 exploring response-adaptive treatment in this cancer. "I think those are the important things we can do today. We are ready for that," he concluded.

Dr. Petty and Dr. Krasna reported that they had no relevant conflicts of interest.

SAN FRANCISCO – A new 86-gene signature may add to metabolic imaging in guiding early treatment decisions for esophagogastric junction cancer, researchers reported.

The leptin gene, among others, stood out as having the potential to become a clinically useful biomarker in analyses that were presented at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Dr. Russell Petty of the University of Aberdeen (Scotland) and colleagues studied 182 patients with locally advanced or metastatic disease. The investigators performed FDG-PET (¹⁸fluorodeoxyglucose–positron emission tomography) imaging and CT imaging, as well as gene expression profiling, and immunohistochemistry of pretreatment tumor tissue.

Results showed that among a subgroup of 14 patients who had a PET metabolic response to the first cycle of neoadjuvant chemotherapy, a set of 86 genes in pretreatment tumor tissue distinguished those who had a radiologic response on CT after completing all cycles of that chemotherapy, compared with those who did not respond. In a variety of predictive models, this gene signature correctly predicted radiologic response in all cases.

"We have shown that gene expression profiling can subclassify FDG-PET metabolic responders into those patients that will and will not subsequently go on to have a [radiologic] response. We have also shown that combining molecular biomarkers and FDG-PET allows an optimization of response prediction," Dr. Petty said.

This is key, as PET alone has a poor positive predictive value in this setting, with only half of PET responders to neoadjuvant chemotherapy eventually showing a histopathologic response.

"While I suppose there is little doubt that if we used PET in this way to make treatment decisions, we would have a system that would be better than unstratified empirical treatment, what it still means is that quite significant proportions of our patients will go on to receive ineffective and intensely toxic therapy," he commented.

A subsequent gene enrichment and pathway analysis identified a half-dozen pathways that provided potential mechanistic explanations for the different tumor behavior. "Within the pathways identified, the adipocytokine-signaling pathway immediately caught our attention because of the strong known [epidemiologic] link between obesity and body weight, and esophagogastric adenocarcinoma," Dr. Petty noted.

Additional analyses specifically fingered the leptin gene (among others) and showed that among PET responders, leptin expression was higher in radiologic nonresponders than in responders (P = .026).

Yet, immunohistochemistry in an independent group of 154 patients showed that strong leptin staining was also associated with better survival (P = .021), an association that held up in multivariate analysis (hazard ratio, 0.85; P = .04).

In stratified analyses, patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, whereas those with leptin-negative tumors fared considerably better if they received this therapy (indeed, about as well as the positive group).

"Leptin in particular may be a molecular biomarker that is useful to combine with PET," Dr. Petty commented. "Leptin expression is associated with chemoresistance, but at the same time is also a favorable therapy-independent biomarker, so this combination of predictive and therapy-independent prognostic impacts mean that leptin has the potential to be a clinically useful biomarker."

"I really think that this is groundbreaking. ... The real future is here" when it comes to predicting treatment response in this cancer, as suggested by this study and others," session cochair Dr. Mark Krasna of the St. Joseph Medical Center in Towson, Md., commented in an interview. "The question now is, are we ready for prime time to adopt that throughout?"

At present, more research is needed, according to Dr. Krasna, such as the ongoing validation of the 86-gene signature and trials like CALGB (Cancer and Leukemia Group B) 80803 exploring response-adaptive treatment in this cancer. "I think those are the important things we can do today. We are ready for that," he concluded.

Dr. Petty and Dr. Krasna reported that they had no relevant conflicts of interest.

The 2012 Genitourinary Cancers Symposium, to be held Feb. 2-4, will feature potentially practice-changing data on two novel agents – MDV3100 and radium-223 chloride – in prostate cancer.

• Results of the phase III AFFIRM trial, to be reported in full Feb. 2, show that the investigational oral androgen–receptor signaling inhibitor MDV3100 prolongs overall survival in progressive castration-resistant prostate cancer after failure of docetaxel (Taxotere).

Men given this agent lived on average nearly 5 months longer than their counterparts given a placebo, according to a press preview of data by the American Society of Clinical Oncology (ASCO). There was no increase in rates of grade 3 or higher adverse events or serious adverse events with MDV3100. The rate of seizures was 0.6% with the drug and 0% with placebo.

• Results of the placebo-controlled phase III ALSYMPCA trial show that the first alpha-particle–emitting drug to target bone, radium-223 chloride (Alpharadin), prolonged overall survival by nearly 3 months (prompting early trial closure) and delayed the time to skeletal-related events by about 5 months in men with bone-only metastatic castration-resistant prostate cancer who had received or were not candidates for docetaxel.

Radium-223 chloride was well tolerated, and there were no cases of leukemia. The U.S. Food and Drug Administration has granted Fast Track status to this investigational agent.

In addition, two large observational studies using linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data, will likely add to the debate regarding the most cost-effective treatment for prostate cancer, and in particular, the pros and cons of various radiation therapy options.

• Investigators at the University of North Carolina at Chapel Hill and University of North Carolina Hospitals will report findings in more than 12,000 men with localized prostate cancer, showing a lower rate of subsequent cancer treatment with intensity-modulated radiation therapy (IMRT) vs. conformal radiation therapy; bowel toxicity and hip fracture were less common with the former, whereas erectile dysfunction was less common with the latter. In addition, proton therapy did not yield a significantly lower rate of subsequent cancer treatment vs. IMRT, and also had a higher rate of bowel toxicity.

• Investigators at the Cleveland Clinic and Kaiser Permanente will report outcomes after a median follow-up of 71 months in 137,427 men with prostate cancer of various stages, showing that of three common therapies – prostatectomy, external-beam radiation therapy (EBRT), and brachytherapy – EBRT was associated with the highest cumulative incidences of gastrointestinal and genitourinary therapy–related toxicity necessitating intervention and also was the most costly.

In another study of note, also being reported in full Feb. 2, researchers will present findings regarding the impact of vigorous exercise on gene expression in the prostate gland that may help explain its benefit in reducing progression.

• This study in a low-risk prostate cancer population under active surveillance has found that a set of 184 genes in normal prostate tissue are differentially expressed between men who exercise vigorously at least 3 hours a week and men who exercise less intensively, according to results to be presented in a poster session. A number of tumor suppressor genes were upregulated in the vigorous exercisers, and pathway analysis showed that the DNA repair and cell cycle pathways were positively modulated.

For ongoing coverage of these and other presentations at the ASCO Genitourinary Cancers Symposium, visit The Oncology Report.

The 2012 Genitourinary Cancers Symposium, to be held Feb. 2-4, will feature potentially practice-changing data on two novel agents – MDV3100 and radium-223 chloride – in prostate cancer.

• Results of the phase III AFFIRM trial, to be reported in full Feb. 2, show that the investigational oral androgen–receptor signaling inhibitor MDV3100 prolongs overall survival in progressive castration-resistant prostate cancer after failure of docetaxel (Taxotere).

Men given this agent lived on average nearly 5 months longer than their counterparts given a placebo, according to a press preview of data by the American Society of Clinical Oncology (ASCO). There was no increase in rates of grade 3 or higher adverse events or serious adverse events with MDV3100. The rate of seizures was 0.6% with the drug and 0% with placebo.

• Results of the placebo-controlled phase III ALSYMPCA trial show that the first alpha-particle–emitting drug to target bone, radium-223 chloride (Alpharadin), prolonged overall survival by nearly 3 months (prompting early trial closure) and delayed the time to skeletal-related events by about 5 months in men with bone-only metastatic castration-resistant prostate cancer who had received or were not candidates for docetaxel.

Radium-223 chloride was well tolerated, and there were no cases of leukemia. The U.S. Food and Drug Administration has granted Fast Track status to this investigational agent.

In addition, two large observational studies using linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data, will likely add to the debate regarding the most cost-effective treatment for prostate cancer, and in particular, the pros and cons of various radiation therapy options.

• Investigators at the University of North Carolina at Chapel Hill and University of North Carolina Hospitals will report findings in more than 12,000 men with localized prostate cancer, showing a lower rate of subsequent cancer treatment with intensity-modulated radiation therapy (IMRT) vs. conformal radiation therapy; bowel toxicity and hip fracture were less common with the former, whereas erectile dysfunction was less common with the latter. In addition, proton therapy did not yield a significantly lower rate of subsequent cancer treatment vs. IMRT, and also had a higher rate of bowel toxicity.

• Investigators at the Cleveland Clinic and Kaiser Permanente will report outcomes after a median follow-up of 71 months in 137,427 men with prostate cancer of various stages, showing that of three common therapies – prostatectomy, external-beam radiation therapy (EBRT), and brachytherapy – EBRT was associated with the highest cumulative incidences of gastrointestinal and genitourinary therapy–related toxicity necessitating intervention and also was the most costly.

In another study of note, also being reported in full Feb. 2, researchers will present findings regarding the impact of vigorous exercise on gene expression in the prostate gland that may help explain its benefit in reducing progression.

• This study in a low-risk prostate cancer population under active surveillance has found that a set of 184 genes in normal prostate tissue are differentially expressed between men who exercise vigorously at least 3 hours a week and men who exercise less intensively, according to results to be presented in a poster session. A number of tumor suppressor genes were upregulated in the vigorous exercisers, and pathway analysis showed that the DNA repair and cell cycle pathways were positively modulated.

For ongoing coverage of these and other presentations at the ASCO Genitourinary Cancers Symposium, visit The Oncology Report.

The 2012 Genitourinary Cancers Symposium, to be held Feb. 2-4, will feature potentially practice-changing data on two novel agents – MDV3100 and radium-223 chloride – in prostate cancer.

• Results of the phase III AFFIRM trial, to be reported in full Feb. 2, show that the investigational oral androgen–receptor signaling inhibitor MDV3100 prolongs overall survival in progressive castration-resistant prostate cancer after failure of docetaxel (Taxotere).

Men given this agent lived on average nearly 5 months longer than their counterparts given a placebo, according to a press preview of data by the American Society of Clinical Oncology (ASCO). There was no increase in rates of grade 3 or higher adverse events or serious adverse events with MDV3100. The rate of seizures was 0.6% with the drug and 0% with placebo.

• Results of the placebo-controlled phase III ALSYMPCA trial show that the first alpha-particle–emitting drug to target bone, radium-223 chloride (Alpharadin), prolonged overall survival by nearly 3 months (prompting early trial closure) and delayed the time to skeletal-related events by about 5 months in men with bone-only metastatic castration-resistant prostate cancer who had received or were not candidates for docetaxel.

Radium-223 chloride was well tolerated, and there were no cases of leukemia. The U.S. Food and Drug Administration has granted Fast Track status to this investigational agent.

In addition, two large observational studies using linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data, will likely add to the debate regarding the most cost-effective treatment for prostate cancer, and in particular, the pros and cons of various radiation therapy options.

• Investigators at the University of North Carolina at Chapel Hill and University of North Carolina Hospitals will report findings in more than 12,000 men with localized prostate cancer, showing a lower rate of subsequent cancer treatment with intensity-modulated radiation therapy (IMRT) vs. conformal radiation therapy; bowel toxicity and hip fracture were less common with the former, whereas erectile dysfunction was less common with the latter. In addition, proton therapy did not yield a significantly lower rate of subsequent cancer treatment vs. IMRT, and also had a higher rate of bowel toxicity.

• Investigators at the Cleveland Clinic and Kaiser Permanente will report outcomes after a median follow-up of 71 months in 137,427 men with prostate cancer of various stages, showing that of three common therapies – prostatectomy, external-beam radiation therapy (EBRT), and brachytherapy – EBRT was associated with the highest cumulative incidences of gastrointestinal and genitourinary therapy–related toxicity necessitating intervention and also was the most costly.

In another study of note, also being reported in full Feb. 2, researchers will present findings regarding the impact of vigorous exercise on gene expression in the prostate gland that may help explain its benefit in reducing progression.

• This study in a low-risk prostate cancer population under active surveillance has found that a set of 184 genes in normal prostate tissue are differentially expressed between men who exercise vigorously at least 3 hours a week and men who exercise less intensively, according to results to be presented in a poster session. A number of tumor suppressor genes were upregulated in the vigorous exercisers, and pathway analysis showed that the DNA repair and cell cycle pathways were positively modulated.

For ongoing coverage of these and other presentations at the ASCO Genitourinary Cancers Symposium, visit The Oncology Report.

SAN FRANCISCO – Adding the oral, investigational multikinase inhibitor regorafenib to best supportive care for metastatic colorectal cancer resulted in a modest but statistically significant increase in median overall survival in the phase III CORRECT trial.

The 760-patient study was stopped early, so that patients in a control group could receive the study drug, researchers reported at the Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Regorafenib added a median benefit of just 1.4 months, compared with placebo and best supportive care (6.4 months vs. 5.0 months; hazard ratio, 0.77; P = .0052), lead investigator Dr. Axel Grothey said. Though the time was short, he noted, all participants were running out of options, after the failure of standard therapies, including bevacizumab (Avastin) and epidermal growth factor receptor (EGFR) inhibitors in those who had KRAS wild-type tumors.

Regorafenib "identifies itself as a potential new standard of care in this patient population," and will move into earlier lines of therapy, said Dr. Grothey, professor of oncology at the Mayo Clinic in Rochester, Minn. Phase II studies are underway to evaluate the novel Bayer drug in combination with standard chemotherapy backbones such as 5-fluorouracil and irinotecan (Camptosar).

Discussant Dr. Herbert Hurwitz of the Duke Cancer Institute in Durham, N.C., said there is good reason to question why regorafenib worked in CORRECT, as the phase I data leading up to the trial were "relatively modest," and there was no phase II trial. "Rushing from phase I to phase III can work, but I would be cautious not to overinterpret the success of the regorafenib study, particularly when looking at the novel therapeutic classes," he advised.

To be eligible for the international CORRECT trial, patients had to have had progression while on or within 3 months after last receipt of approved standard therapies, which had to include a fluoropyrimidine, oxaliplatin (Eloxatin), irinotecan, bevacizumab, and, if they had KRAS wild-type disease, cetuximab (Erbitux) or panitumumab (Vectibix).

The patients had a median age of 61 years. A total of 60% had received four or more lines of prior therapy. Fifty-seven percent had tumors with a KRAS mutation.

The response rate was similar between regorafenib and placebo (1.0% vs. 0.4%), but regorafenib distinguished itself with a much higher disease-control rate than did placebo (45% vs. 15%). "So the strength of this drug is more in delaying tumor progression than inducing responses," Dr. Grothey said.

The median difference in progression-free survival (PFS) was again small, at just 0.2 months, but this corresponded to a 51% reduction in the risk of progression events (HR, 0.49; P less than .000001), he noted.

The progression-free survival curve "clearly identifies that the median difference in PFS does not fully reflect the efficacy of this drug in this patient population. These curves run together for about 50% of patients but then spread out wide. ... Clearly, the median does not reflect what’s happening," he elaborated.

Thus, "there is clearly a benefit for about 50% of patients, compared to the placebo-control."

The side effect profile was similar to that observed in the drug’s phase I trial and included grade 3 hand-foot skin reactions, fatigue, anorexia, and a class effect of hypertension that was controlled with dose reductions. The proportion of patients experiencing adverse events leading to treatment discontinuation was 8.2% with regorafenib and 1.2% with placebo.

"Efficacy in subgroup analyses are being conducted, with preliminary results that KRAS mutant and KRAS wild-type tumors benefit in a similar extent from the treatment," Dr. Grothey reported. "Further biomarker analyses and quality of life analyses are ongoing."

He suggested that regorafenib may have achieved the results it did in part because it was used as a single agent, whereas trials of other small-molecule kinase inhibitors such as gefitinib (Iressa), sorafenib (Nexavar), and PTK/ZK involved adding the agents to first- or second-line chemotherapy.

"This is not unheard of – that adding a kinase inhibitor to chemotherapy does not produce the desired result," he said, noting that the addition of sorafenib to FOLFOX chemotherapy actually appeared detrimental in patients with metastatic colorectal cancer.

Similarly, in his discussion, Dr. Hurwitz emphasized "that the clean design certainly helped." That is, the trial did not have the confounding effects of chemotherapy or any other anticancer therapy for that matter, did not allow cross-over, and studied a mature therapeutic drug class.

"The benefits in this study with regorafenib were indeed statistically significant. I would suggest that they are clinically meaningful for many, but not necessarily all, patients," Dr. Hurwitz commented. "The toxicity profile is acceptable but does require dose adjustment and monitoring of the patient."

"Regorafenib is likely to join the list of useful therapeutics for metastatic colorectal cancer," he predicted. However, as patients having a performance status of 2 were not included, outcomes in this group are unknown, he cautioned. "I would encourage efforts to further improve its toxicity profile and would suggest candidate biomarkers, which have been reported by multiple groups, be followed up with appropriate diligence."

Dr. Grothey reported that he is a consultant to Bayer. Dr. Hurwitz reported that he is a consultant to Bristol-Myers Squibb and Genentech/Roche; receives honoraria from Roche; and receives research funding from a dozen companies.

Patrice Wendling contributed to this report.

SAN FRANCISCO – Adding the oral, investigational multikinase inhibitor regorafenib to best supportive care for metastatic colorectal cancer resulted in a modest but statistically significant increase in median overall survival in the phase III CORRECT trial.

The 760-patient study was stopped early, so that patients in a control group could receive the study drug, researchers reported at the Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Regorafenib added a median benefit of just 1.4 months, compared with placebo and best supportive care (6.4 months vs. 5.0 months; hazard ratio, 0.77; P = .0052), lead investigator Dr. Axel Grothey said. Though the time was short, he noted, all participants were running out of options, after the failure of standard therapies, including bevacizumab (Avastin) and epidermal growth factor receptor (EGFR) inhibitors in those who had KRAS wild-type tumors.

Regorafenib "identifies itself as a potential new standard of care in this patient population," and will move into earlier lines of therapy, said Dr. Grothey, professor of oncology at the Mayo Clinic in Rochester, Minn. Phase II studies are underway to evaluate the novel Bayer drug in combination with standard chemotherapy backbones such as 5-fluorouracil and irinotecan (Camptosar).

Discussant Dr. Herbert Hurwitz of the Duke Cancer Institute in Durham, N.C., said there is good reason to question why regorafenib worked in CORRECT, as the phase I data leading up to the trial were "relatively modest," and there was no phase II trial. "Rushing from phase I to phase III can work, but I would be cautious not to overinterpret the success of the regorafenib study, particularly when looking at the novel therapeutic classes," he advised.

To be eligible for the international CORRECT trial, patients had to have had progression while on or within 3 months after last receipt of approved standard therapies, which had to include a fluoropyrimidine, oxaliplatin (Eloxatin), irinotecan, bevacizumab, and, if they had KRAS wild-type disease, cetuximab (Erbitux) or panitumumab (Vectibix).

The patients had a median age of 61 years. A total of 60% had received four or more lines of prior therapy. Fifty-seven percent had tumors with a KRAS mutation.

The response rate was similar between regorafenib and placebo (1.0% vs. 0.4%), but regorafenib distinguished itself with a much higher disease-control rate than did placebo (45% vs. 15%). "So the strength of this drug is more in delaying tumor progression than inducing responses," Dr. Grothey said.

The median difference in progression-free survival (PFS) was again small, at just 0.2 months, but this corresponded to a 51% reduction in the risk of progression events (HR, 0.49; P less than .000001), he noted.

The progression-free survival curve "clearly identifies that the median difference in PFS does not fully reflect the efficacy of this drug in this patient population. These curves run together for about 50% of patients but then spread out wide. ... Clearly, the median does not reflect what’s happening," he elaborated.

Thus, "there is clearly a benefit for about 50% of patients, compared to the placebo-control."

The side effect profile was similar to that observed in the drug’s phase I trial and included grade 3 hand-foot skin reactions, fatigue, anorexia, and a class effect of hypertension that was controlled with dose reductions. The proportion of patients experiencing adverse events leading to treatment discontinuation was 8.2% with regorafenib and 1.2% with placebo.

"Efficacy in subgroup analyses are being conducted, with preliminary results that KRAS mutant and KRAS wild-type tumors benefit in a similar extent from the treatment," Dr. Grothey reported. "Further biomarker analyses and quality of life analyses are ongoing."

He suggested that regorafenib may have achieved the results it did in part because it was used as a single agent, whereas trials of other small-molecule kinase inhibitors such as gefitinib (Iressa), sorafenib (Nexavar), and PTK/ZK involved adding the agents to first- or second-line chemotherapy.

"This is not unheard of – that adding a kinase inhibitor to chemotherapy does not produce the desired result," he said, noting that the addition of sorafenib to FOLFOX chemotherapy actually appeared detrimental in patients with metastatic colorectal cancer.

Similarly, in his discussion, Dr. Hurwitz emphasized "that the clean design certainly helped." That is, the trial did not have the confounding effects of chemotherapy or any other anticancer therapy for that matter, did not allow cross-over, and studied a mature therapeutic drug class.

"The benefits in this study with regorafenib were indeed statistically significant. I would suggest that they are clinically meaningful for many, but not necessarily all, patients," Dr. Hurwitz commented. "The toxicity profile is acceptable but does require dose adjustment and monitoring of the patient."

"Regorafenib is likely to join the list of useful therapeutics for metastatic colorectal cancer," he predicted. However, as patients having a performance status of 2 were not included, outcomes in this group are unknown, he cautioned. "I would encourage efforts to further improve its toxicity profile and would suggest candidate biomarkers, which have been reported by multiple groups, be followed up with appropriate diligence."

Dr. Grothey reported that he is a consultant to Bayer. Dr. Hurwitz reported that he is a consultant to Bristol-Myers Squibb and Genentech/Roche; receives honoraria from Roche; and receives research funding from a dozen companies.

Patrice Wendling contributed to this report.

SAN FRANCISCO – Adding the oral, investigational multikinase inhibitor regorafenib to best supportive care for metastatic colorectal cancer resulted in a modest but statistically significant increase in median overall survival in the phase III CORRECT trial.

The 760-patient study was stopped early, so that patients in a control group could receive the study drug, researchers reported at the Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Regorafenib added a median benefit of just 1.4 months, compared with placebo and best supportive care (6.4 months vs. 5.0 months; hazard ratio, 0.77; P = .0052), lead investigator Dr. Axel Grothey said. Though the time was short, he noted, all participants were running out of options, after the failure of standard therapies, including bevacizumab (Avastin) and epidermal growth factor receptor (EGFR) inhibitors in those who had KRAS wild-type tumors.

Regorafenib "identifies itself as a potential new standard of care in this patient population," and will move into earlier lines of therapy, said Dr. Grothey, professor of oncology at the Mayo Clinic in Rochester, Minn. Phase II studies are underway to evaluate the novel Bayer drug in combination with standard chemotherapy backbones such as 5-fluorouracil and irinotecan (Camptosar).

Discussant Dr. Herbert Hurwitz of the Duke Cancer Institute in Durham, N.C., said there is good reason to question why regorafenib worked in CORRECT, as the phase I data leading up to the trial were "relatively modest," and there was no phase II trial. "Rushing from phase I to phase III can work, but I would be cautious not to overinterpret the success of the regorafenib study, particularly when looking at the novel therapeutic classes," he advised.

To be eligible for the international CORRECT trial, patients had to have had progression while on or within 3 months after last receipt of approved standard therapies, which had to include a fluoropyrimidine, oxaliplatin (Eloxatin), irinotecan, bevacizumab, and, if they had KRAS wild-type disease, cetuximab (Erbitux) or panitumumab (Vectibix).

The patients had a median age of 61 years. A total of 60% had received four or more lines of prior therapy. Fifty-seven percent had tumors with a KRAS mutation.

The response rate was similar between regorafenib and placebo (1.0% vs. 0.4%), but regorafenib distinguished itself with a much higher disease-control rate than did placebo (45% vs. 15%). "So the strength of this drug is more in delaying tumor progression than inducing responses," Dr. Grothey said.

The median difference in progression-free survival (PFS) was again small, at just 0.2 months, but this corresponded to a 51% reduction in the risk of progression events (HR, 0.49; P less than .000001), he noted.

The progression-free survival curve "clearly identifies that the median difference in PFS does not fully reflect the efficacy of this drug in this patient population. These curves run together for about 50% of patients but then spread out wide. ... Clearly, the median does not reflect what’s happening," he elaborated.

Thus, "there is clearly a benefit for about 50% of patients, compared to the placebo-control."

The side effect profile was similar to that observed in the drug’s phase I trial and included grade 3 hand-foot skin reactions, fatigue, anorexia, and a class effect of hypertension that was controlled with dose reductions. The proportion of patients experiencing adverse events leading to treatment discontinuation was 8.2% with regorafenib and 1.2% with placebo.

"Efficacy in subgroup analyses are being conducted, with preliminary results that KRAS mutant and KRAS wild-type tumors benefit in a similar extent from the treatment," Dr. Grothey reported. "Further biomarker analyses and quality of life analyses are ongoing."

He suggested that regorafenib may have achieved the results it did in part because it was used as a single agent, whereas trials of other small-molecule kinase inhibitors such as gefitinib (Iressa), sorafenib (Nexavar), and PTK/ZK involved adding the agents to first- or second-line chemotherapy.

"This is not unheard of – that adding a kinase inhibitor to chemotherapy does not produce the desired result," he said, noting that the addition of sorafenib to FOLFOX chemotherapy actually appeared detrimental in patients with metastatic colorectal cancer.

Similarly, in his discussion, Dr. Hurwitz emphasized "that the clean design certainly helped." That is, the trial did not have the confounding effects of chemotherapy or any other anticancer therapy for that matter, did not allow cross-over, and studied a mature therapeutic drug class.

"The benefits in this study with regorafenib were indeed statistically significant. I would suggest that they are clinically meaningful for many, but not necessarily all, patients," Dr. Hurwitz commented. "The toxicity profile is acceptable but does require dose adjustment and monitoring of the patient."

"Regorafenib is likely to join the list of useful therapeutics for metastatic colorectal cancer," he predicted. However, as patients having a performance status of 2 were not included, outcomes in this group are unknown, he cautioned. "I would encourage efforts to further improve its toxicity profile and would suggest candidate biomarkers, which have been reported by multiple groups, be followed up with appropriate diligence."

Dr. Grothey reported that he is a consultant to Bayer. Dr. Hurwitz reported that he is a consultant to Bristol-Myers Squibb and Genentech/Roche; receives honoraria from Roche; and receives research funding from a dozen companies.

Patrice Wendling contributed to this report.

SAN FRANCISCO – Eagerly awaited results of the CO.20 trial in metastatic chemorefractory KRAS wild-type colorectal cancer are disappointing, showing no significant gain in the primary end point of overall survival from the addition of brivanib to cetuximab.

Patients in the phase III trial who received brivanib – an investigational oral inhibitor of signaling in the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) pathways – lived a median of about 9 months, compared with 8 months for those given placebo, Dr. Lillian L. Siu reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Adding brivanib did prolong progression-free survival and increase response rate, but the tradeoff was more toxicity, greater treatment discontinuation, and faster deterioration in quality of life, she said.

"There is good scientific rationale to investigate [brivanib] in combination with EGFR [epidermal growth factor receptor] inhibitors" such as cetuximab, commented Dr. Siu, a senior staff physician in the division of medical oncology and hematology at Princess Margaret Hospital, Toronto. The CO.20 trial, however, "did not meet its primary end point of overall survival," she said. Analyses assessing potential biomarkers are still ongoing.

"The median does not well reflect the overall benefit in progression-free survival by the nature of the curves, which tend to splay at the 50-percentile mark," pointed out discussant Dr. Herbert Hurwitz of the Duke Cancer Institute in Durham, N.C.

"The side effect profile for this study was unanticipatedly large," he maintained, and the increased toxicity was "clinically meaningful," leading to higher dropout and to "significant dose reductions in respect to brivanib, but also in respect to cetuximab, thereby compromising not only the value of the experimental drug, but of the standard drug as well." Thus, "the toxicity of this doublet likely confounded some of the efficacy results," he added.

The trial’s findings call into question the role in colorectal cancer of basic FGF (bFGF) as a mechanism of resistance to anti-VEGF therapy, suggested by early research. "Although this [trial] does not exclude a benefit, we need to rethink exactly what is the role, particularly given the diagnostic difficulty of assessing bFGF in both plasma and tissue," Dr. Hurwitz said.

"This data clearly will not lead to a regulatory approval" of brivanib, he concluded. "Data as monotherapy are not known, and data in trials in hepatocellular cancer are still ongoing."

To be eligible for the CO.20 trial, patients were required to have previously received a thymidylate synthase inhibitor (such as 5-fluorouracil or capecitabine) and to be intolerant of or have disease refractory to irinotecan and oxaliplatin. They could have received, at most, one prior therapy targeting VEGF but not any prior therapies targeting EGFR.

In all, 750 patients were assigned evenly to weekly cetuximab (Erbitux), an antibody to EGFR, plus either daily placebo or daily brivanib.

The patients had median age of about 64 years; nearly all (92%) had received more than three prior lines of chemotherapy in any setting (neoadjuvant, adjuvant, and/or metastatic), and a large share (41%) had received a prior therapy targeting VEGF.

Main results showed that, with a median follow-up of 19 months, there was no significant gain in median overall survival with brivanib-cetuximab compared with placebo-cetuximab in intention-to-treat analyses (8.8 vs. 8.1 months). The relative benefit was essentially the same in all patient subgroups.

Brivanib was associated with better progression-free survival (5.0 vs. 3.4 months; hazard ratio, 0.72; P less than .0001), a finding consistent across subgroups, and with a higher response rate (13.6% vs. 7.2%, P = .004).

The proportions of patients receiving at least 90% of the planned dose intensities of brivanib/placebo and cetuximab were lower in the brivanib group. "This was mainly due to dose reductions as well as omissions of these drugs," Dr. Siu noted.

The overall rate of grade 3 or worse nonhematologic toxicity was higher with brivanib than with placebo (78% vs. 53%). Fatigue, hypertension, gastrointestinal toxicity, and certain biochemical abnormalities were all more common with the drug. The rate of discontinuation as a result of adverse events was also higher with brivanib (22%) than with placebo (3%).

Finally, the median time to deterioration of quality of life was shorter with brivanib than with placebo for both global health (1.1 vs. 1.6 months, P = .02) and physical function (1.7 vs. 5.6 months, P less than .0001).

Dr. Siu reported that she receives research funding from Bristol-Myers Squibb. Dr. Hurwitz reported that he is a consultant to Bristol-Myers Squibb and Genentech/Roche; receives honoraria from Roche; and receives research funding from Acceleron Pharma, Amgen, Bristol-Myers Squibb, Cephalon, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi-Aventis, Threshold, and Tracon.

SAN FRANCISCO – Eagerly awaited results of the CO.20 trial in metastatic chemorefractory KRAS wild-type colorectal cancer are disappointing, showing no significant gain in the primary end point of overall survival from the addition of brivanib to cetuximab.

Patients in the phase III trial who received brivanib – an investigational oral inhibitor of signaling in the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) pathways – lived a median of about 9 months, compared with 8 months for those given placebo, Dr. Lillian L. Siu reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Adding brivanib did prolong progression-free survival and increase response rate, but the tradeoff was more toxicity, greater treatment discontinuation, and faster deterioration in quality of life, she said.

"There is good scientific rationale to investigate [brivanib] in combination with EGFR [epidermal growth factor receptor] inhibitors" such as cetuximab, commented Dr. Siu, a senior staff physician in the division of medical oncology and hematology at Princess Margaret Hospital, Toronto. The CO.20 trial, however, "did not meet its primary end point of overall survival," she said. Analyses assessing potential biomarkers are still ongoing.

"The median does not well reflect the overall benefit in progression-free survival by the nature of the curves, which tend to splay at the 50-percentile mark," pointed out discussant Dr. Herbert Hurwitz of the Duke Cancer Institute in Durham, N.C.

"The side effect profile for this study was unanticipatedly large," he maintained, and the increased toxicity was "clinically meaningful," leading to higher dropout and to "significant dose reductions in respect to brivanib, but also in respect to cetuximab, thereby compromising not only the value of the experimental drug, but of the standard drug as well." Thus, "the toxicity of this doublet likely confounded some of the efficacy results," he added.

The trial’s findings call into question the role in colorectal cancer of basic FGF (bFGF) as a mechanism of resistance to anti-VEGF therapy, suggested by early research. "Although this [trial] does not exclude a benefit, we need to rethink exactly what is the role, particularly given the diagnostic difficulty of assessing bFGF in both plasma and tissue," Dr. Hurwitz said.

"This data clearly will not lead to a regulatory approval" of brivanib, he concluded. "Data as monotherapy are not known, and data in trials in hepatocellular cancer are still ongoing."

To be eligible for the CO.20 trial, patients were required to have previously received a thymidylate synthase inhibitor (such as 5-fluorouracil or capecitabine) and to be intolerant of or have disease refractory to irinotecan and oxaliplatin. They could have received, at most, one prior therapy targeting VEGF but not any prior therapies targeting EGFR.

In all, 750 patients were assigned evenly to weekly cetuximab (Erbitux), an antibody to EGFR, plus either daily placebo or daily brivanib.

The patients had median age of about 64 years; nearly all (92%) had received more than three prior lines of chemotherapy in any setting (neoadjuvant, adjuvant, and/or metastatic), and a large share (41%) had received a prior therapy targeting VEGF.

Main results showed that, with a median follow-up of 19 months, there was no significant gain in median overall survival with brivanib-cetuximab compared with placebo-cetuximab in intention-to-treat analyses (8.8 vs. 8.1 months). The relative benefit was essentially the same in all patient subgroups.

Brivanib was associated with better progression-free survival (5.0 vs. 3.4 months; hazard ratio, 0.72; P less than .0001), a finding consistent across subgroups, and with a higher response rate (13.6% vs. 7.2%, P = .004).

The proportions of patients receiving at least 90% of the planned dose intensities of brivanib/placebo and cetuximab were lower in the brivanib group. "This was mainly due to dose reductions as well as omissions of these drugs," Dr. Siu noted.

The overall rate of grade 3 or worse nonhematologic toxicity was higher with brivanib than with placebo (78% vs. 53%). Fatigue, hypertension, gastrointestinal toxicity, and certain biochemical abnormalities were all more common with the drug. The rate of discontinuation as a result of adverse events was also higher with brivanib (22%) than with placebo (3%).

Finally, the median time to deterioration of quality of life was shorter with brivanib than with placebo for both global health (1.1 vs. 1.6 months, P = .02) and physical function (1.7 vs. 5.6 months, P less than .0001).

Dr. Siu reported that she receives research funding from Bristol-Myers Squibb. Dr. Hurwitz reported that he is a consultant to Bristol-Myers Squibb and Genentech/Roche; receives honoraria from Roche; and receives research funding from Acceleron Pharma, Amgen, Bristol-Myers Squibb, Cephalon, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi-Aventis, Threshold, and Tracon.

SAN FRANCISCO – Eagerly awaited results of the CO.20 trial in metastatic chemorefractory KRAS wild-type colorectal cancer are disappointing, showing no significant gain in the primary end point of overall survival from the addition of brivanib to cetuximab.

Patients in the phase III trial who received brivanib – an investigational oral inhibitor of signaling in the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) pathways – lived a median of about 9 months, compared with 8 months for those given placebo, Dr. Lillian L. Siu reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Adding brivanib did prolong progression-free survival and increase response rate, but the tradeoff was more toxicity, greater treatment discontinuation, and faster deterioration in quality of life, she said.

"There is good scientific rationale to investigate [brivanib] in combination with EGFR [epidermal growth factor receptor] inhibitors" such as cetuximab, commented Dr. Siu, a senior staff physician in the division of medical oncology and hematology at Princess Margaret Hospital, Toronto. The CO.20 trial, however, "did not meet its primary end point of overall survival," she said. Analyses assessing potential biomarkers are still ongoing.

"The median does not well reflect the overall benefit in progression-free survival by the nature of the curves, which tend to splay at the 50-percentile mark," pointed out discussant Dr. Herbert Hurwitz of the Duke Cancer Institute in Durham, N.C.

"The side effect profile for this study was unanticipatedly large," he maintained, and the increased toxicity was "clinically meaningful," leading to higher dropout and to "significant dose reductions in respect to brivanib, but also in respect to cetuximab, thereby compromising not only the value of the experimental drug, but of the standard drug as well." Thus, "the toxicity of this doublet likely confounded some of the efficacy results," he added.

The trial’s findings call into question the role in colorectal cancer of basic FGF (bFGF) as a mechanism of resistance to anti-VEGF therapy, suggested by early research. "Although this [trial] does not exclude a benefit, we need to rethink exactly what is the role, particularly given the diagnostic difficulty of assessing bFGF in both plasma and tissue," Dr. Hurwitz said.

"This data clearly will not lead to a regulatory approval" of brivanib, he concluded. "Data as monotherapy are not known, and data in trials in hepatocellular cancer are still ongoing."

To be eligible for the CO.20 trial, patients were required to have previously received a thymidylate synthase inhibitor (such as 5-fluorouracil or capecitabine) and to be intolerant of or have disease refractory to irinotecan and oxaliplatin. They could have received, at most, one prior therapy targeting VEGF but not any prior therapies targeting EGFR.

In all, 750 patients were assigned evenly to weekly cetuximab (Erbitux), an antibody to EGFR, plus either daily placebo or daily brivanib.

The patients had median age of about 64 years; nearly all (92%) had received more than three prior lines of chemotherapy in any setting (neoadjuvant, adjuvant, and/or metastatic), and a large share (41%) had received a prior therapy targeting VEGF.

Main results showed that, with a median follow-up of 19 months, there was no significant gain in median overall survival with brivanib-cetuximab compared with placebo-cetuximab in intention-to-treat analyses (8.8 vs. 8.1 months). The relative benefit was essentially the same in all patient subgroups.

Brivanib was associated with better progression-free survival (5.0 vs. 3.4 months; hazard ratio, 0.72; P less than .0001), a finding consistent across subgroups, and with a higher response rate (13.6% vs. 7.2%, P = .004).

The proportions of patients receiving at least 90% of the planned dose intensities of brivanib/placebo and cetuximab were lower in the brivanib group. "This was mainly due to dose reductions as well as omissions of these drugs," Dr. Siu noted.

The overall rate of grade 3 or worse nonhematologic toxicity was higher with brivanib than with placebo (78% vs. 53%). Fatigue, hypertension, gastrointestinal toxicity, and certain biochemical abnormalities were all more common with the drug. The rate of discontinuation as a result of adverse events was also higher with brivanib (22%) than with placebo (3%).

Finally, the median time to deterioration of quality of life was shorter with brivanib than with placebo for both global health (1.1 vs. 1.6 months, P = .02) and physical function (1.7 vs. 5.6 months, P less than .0001).

Dr. Siu reported that she receives research funding from Bristol-Myers Squibb. Dr. Hurwitz reported that he is a consultant to Bristol-Myers Squibb and Genentech/Roche; receives honoraria from Roche; and receives research funding from Acceleron Pharma, Amgen, Bristol-Myers Squibb, Cephalon, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi-Aventis, Threshold, and Tracon.

SAN FRANCISCO – The benefit of bevacizumab in some patients with advanced gastric cancer appears to vary by disease subtype, based on an exploratory analysis of data from the phase III AVAGAST trial.

The global trial randomized 774 patients to chemotherapy plus placebo or bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF). Results for the entire trial population, which were reported previously (J. Clin. Oncol. 2011;29:3968-76), showed no significant gain in overall survival from the addition of bevacizumab.

In the new analysis, presented at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology, investigators divided the patients according to three types of disease with distinct histology and clinical and environmental risk factors. About 10% of all patients had proximal (also known as type 1) disease, 50% had diffuse (type 2) disease, and 40% had distal (type 3) disease.

The main results showed that the addition of bevacizumab to chemotherapy was associated with a significant, one-third reduction in the risk of death for patients from Europe and the Americas who had diffuse or distal disease. Patients with proximal disease, and patients from the Asia-Pacific region with any disease type, did not show significant benefit.

Additionally, in the trial’s control arm, overall survival in patients from Europe and the Americas differed across the three types, with the diffuse type carrying the poorest prognosis. And levels of two biomarkers showing marginal correlation with bevacizumab efficacy – tumor neuropilin-1 (NRP-1) and plasma VEGF-A – varied across the types in ways that were consistent with the observed drug benefit.

"Gastric cancers really are more than one disease. The subtypes have different prognoses; they have different [bevacizumab] efficacy," said first author Dr. Manish A. Shah, a gastrointestinal oncologist with the Memorial Sloan-Kettering Cancer Center in New York. These subtypes "may form the basis of a new classification schema for gastric cancer."

In addition, the candidate biomarkers tumor NRP-1 and plasma VEGF-A may actually provide a rationale for gastric cancer and/or subtype-specific outcomes with bevacizumab, he said.

Discussant Dr. David H. Ilson agreed that etiologic and molecular data show that "these are likely biologically different diseases. The caveat from Dr. Shah’s analysis, however, is that this is a small, unplanned subset analysis and is at best hypothesis generating."

Numerous Asian trials of chemotherapy in gastric cancer have not found diffuse histology to be either prognostic or predictive, and Western trials have often not considered disease type, Dr. Ilson noted. Thus, "the potential prognostic and predictive impact of diffuse histology needs to be validated in other cohorts. And the potential bevacizumab biomarkers also require validation."

The need for further study of bevacizumab in gastric cancer in the West is debatable, according to Dr. Ilson, also of the Memorial Sloan-Kettering Cancer Center. "And I think an even bigger and overarching question is, Are agents targeting only one pathway really worth investigating? Should we be looking at multitargeted agents," or combining agents?

"The holy grail here, which never gets enough mention, is that we need to identify and validate biomarkers to direct therapy to the appropriate patient," he said.

In the unplanned, exploratory analysis, Dr. Shah and his team found that among patients from Europe and the Americas, the addition of bevacizumab improved overall survival significantly for those having diffuse disease (hazard ratio, 0.68) and marginally for those having distal disease (0.72). When these two groups were combined, the risk of death was reduced by one-third (0.67).

In an analysis of potential biomarkers of bevacizumab efficacy, survival benefit differed by tumor NRP-1 level (P = .06) – with only patients having below-median levels deriving benefit – and by plasma VEGF-A level (P = .07) – with only patients having above-median values deriving benefit.

Proximal tumors generally had higher tumor NRP-1 levels and lower plasma VEGF-A levels. By comparison, diffuse tumors had relatively low NRP-1 levels, and distal tumors had relatively high plasma VEGF-A levels.

"There is heterogeneity with these biomarkers across the different subtypes, and this is in support of the concept that subtypes are clinically meaningful," Dr. Shah commented. "Proximal tumors tend to have the worst profile, if you will, for bevacizumab."

Dr. Shah reported that he is a consultant to Genentech. Dr. Ilson reported that he receives research funding from Bayer, BMS-Imclone, Roche-Genentech, and Sanofi-Aventis.

SAN FRANCISCO – The benefit of bevacizumab in some patients with advanced gastric cancer appears to vary by disease subtype, based on an exploratory analysis of data from the phase III AVAGAST trial.

The global trial randomized 774 patients to chemotherapy plus placebo or bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF). Results for the entire trial population, which were reported previously (J. Clin. Oncol. 2011;29:3968-76), showed no significant gain in overall survival from the addition of bevacizumab.

In the new analysis, presented at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology, investigators divided the patients according to three types of disease with distinct histology and clinical and environmental risk factors. About 10% of all patients had proximal (also known as type 1) disease, 50% had diffuse (type 2) disease, and 40% had distal (type 3) disease.

The main results showed that the addition of bevacizumab to chemotherapy was associated with a significant, one-third reduction in the risk of death for patients from Europe and the Americas who had diffuse or distal disease. Patients with proximal disease, and patients from the Asia-Pacific region with any disease type, did not show significant benefit.

Additionally, in the trial’s control arm, overall survival in patients from Europe and the Americas differed across the three types, with the diffuse type carrying the poorest prognosis. And levels of two biomarkers showing marginal correlation with bevacizumab efficacy – tumor neuropilin-1 (NRP-1) and plasma VEGF-A – varied across the types in ways that were consistent with the observed drug benefit.

"Gastric cancers really are more than one disease. The subtypes have different prognoses; they have different [bevacizumab] efficacy," said first author Dr. Manish A. Shah, a gastrointestinal oncologist with the Memorial Sloan-Kettering Cancer Center in New York. These subtypes "may form the basis of a new classification schema for gastric cancer."

In addition, the candidate biomarkers tumor NRP-1 and plasma VEGF-A may actually provide a rationale for gastric cancer and/or subtype-specific outcomes with bevacizumab, he said.

Discussant Dr. David H. Ilson agreed that etiologic and molecular data show that "these are likely biologically different diseases. The caveat from Dr. Shah’s analysis, however, is that this is a small, unplanned subset analysis and is at best hypothesis generating."

Numerous Asian trials of chemotherapy in gastric cancer have not found diffuse histology to be either prognostic or predictive, and Western trials have often not considered disease type, Dr. Ilson noted. Thus, "the potential prognostic and predictive impact of diffuse histology needs to be validated in other cohorts. And the potential bevacizumab biomarkers also require validation."

The need for further study of bevacizumab in gastric cancer in the West is debatable, according to Dr. Ilson, also of the Memorial Sloan-Kettering Cancer Center. "And I think an even bigger and overarching question is, Are agents targeting only one pathway really worth investigating? Should we be looking at multitargeted agents," or combining agents?

"The holy grail here, which never gets enough mention, is that we need to identify and validate biomarkers to direct therapy to the appropriate patient," he said.

In the unplanned, exploratory analysis, Dr. Shah and his team found that among patients from Europe and the Americas, the addition of bevacizumab improved overall survival significantly for those having diffuse disease (hazard ratio, 0.68) and marginally for those having distal disease (0.72). When these two groups were combined, the risk of death was reduced by one-third (0.67).

In an analysis of potential biomarkers of bevacizumab efficacy, survival benefit differed by tumor NRP-1 level (P = .06) – with only patients having below-median levels deriving benefit – and by plasma VEGF-A level (P = .07) – with only patients having above-median values deriving benefit.

Proximal tumors generally had higher tumor NRP-1 levels and lower plasma VEGF-A levels. By comparison, diffuse tumors had relatively low NRP-1 levels, and distal tumors had relatively high plasma VEGF-A levels.

"There is heterogeneity with these biomarkers across the different subtypes, and this is in support of the concept that subtypes are clinically meaningful," Dr. Shah commented. "Proximal tumors tend to have the worst profile, if you will, for bevacizumab."

Dr. Shah reported that he is a consultant to Genentech. Dr. Ilson reported that he receives research funding from Bayer, BMS-Imclone, Roche-Genentech, and Sanofi-Aventis.

SAN FRANCISCO – The benefit of bevacizumab in some patients with advanced gastric cancer appears to vary by disease subtype, based on an exploratory analysis of data from the phase III AVAGAST trial.

The global trial randomized 774 patients to chemotherapy plus placebo or bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF). Results for the entire trial population, which were reported previously (J. Clin. Oncol. 2011;29:3968-76), showed no significant gain in overall survival from the addition of bevacizumab.

In the new analysis, presented at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology, investigators divided the patients according to three types of disease with distinct histology and clinical and environmental risk factors. About 10% of all patients had proximal (also known as type 1) disease, 50% had diffuse (type 2) disease, and 40% had distal (type 3) disease.

The main results showed that the addition of bevacizumab to chemotherapy was associated with a significant, one-third reduction in the risk of death for patients from Europe and the Americas who had diffuse or distal disease. Patients with proximal disease, and patients from the Asia-Pacific region with any disease type, did not show significant benefit.

Additionally, in the trial’s control arm, overall survival in patients from Europe and the Americas differed across the three types, with the diffuse type carrying the poorest prognosis. And levels of two biomarkers showing marginal correlation with bevacizumab efficacy – tumor neuropilin-1 (NRP-1) and plasma VEGF-A – varied across the types in ways that were consistent with the observed drug benefit.

"Gastric cancers really are more than one disease. The subtypes have different prognoses; they have different [bevacizumab] efficacy," said first author Dr. Manish A. Shah, a gastrointestinal oncologist with the Memorial Sloan-Kettering Cancer Center in New York. These subtypes "may form the basis of a new classification schema for gastric cancer."

In addition, the candidate biomarkers tumor NRP-1 and plasma VEGF-A may actually provide a rationale for gastric cancer and/or subtype-specific outcomes with bevacizumab, he said.

Discussant Dr. David H. Ilson agreed that etiologic and molecular data show that "these are likely biologically different diseases. The caveat from Dr. Shah’s analysis, however, is that this is a small, unplanned subset analysis and is at best hypothesis generating."

Numerous Asian trials of chemotherapy in gastric cancer have not found diffuse histology to be either prognostic or predictive, and Western trials have often not considered disease type, Dr. Ilson noted. Thus, "the potential prognostic and predictive impact of diffuse histology needs to be validated in other cohorts. And the potential bevacizumab biomarkers also require validation."

The need for further study of bevacizumab in gastric cancer in the West is debatable, according to Dr. Ilson, also of the Memorial Sloan-Kettering Cancer Center. "And I think an even bigger and overarching question is, Are agents targeting only one pathway really worth investigating? Should we be looking at multitargeted agents," or combining agents?

"The holy grail here, which never gets enough mention, is that we need to identify and validate biomarkers to direct therapy to the appropriate patient," he said.

In the unplanned, exploratory analysis, Dr. Shah and his team found that among patients from Europe and the Americas, the addition of bevacizumab improved overall survival significantly for those having diffuse disease (hazard ratio, 0.68) and marginally for those having distal disease (0.72). When these two groups were combined, the risk of death was reduced by one-third (0.67).

In an analysis of potential biomarkers of bevacizumab efficacy, survival benefit differed by tumor NRP-1 level (P = .06) – with only patients having below-median levels deriving benefit – and by plasma VEGF-A level (P = .07) – with only patients having above-median values deriving benefit.

Proximal tumors generally had higher tumor NRP-1 levels and lower plasma VEGF-A levels. By comparison, diffuse tumors had relatively low NRP-1 levels, and distal tumors had relatively high plasma VEGF-A levels.

"There is heterogeneity with these biomarkers across the different subtypes, and this is in support of the concept that subtypes are clinically meaningful," Dr. Shah commented. "Proximal tumors tend to have the worst profile, if you will, for bevacizumab."

Dr. Shah reported that he is a consultant to Genentech. Dr. Ilson reported that he receives research funding from Bayer, BMS-Imclone, Roche-Genentech, and Sanofi-Aventis.

SAN FRANCISCO – None of the common KRAS mutant alleles seen in metastatic colorectal cancer reliably predict benefit from panitumumab, new data show, suggesting that this agent should continue to be used only in patients with KRAS wild-type tumors.

Investigators led by Dr. Marc Peeters of Antwerp University Hospital in Edegem, Belgium, analyzed data from a trio of phase III randomized trials of panitumumab (Vectibix), an antibody to epidermal growth factor receptor (EGFR), in more than 1,400 patients.

Main results showed that there was no consistent difference in benefit across trials in terms of progression-free and overall survival for patients having the most common codon 12 and 13 KRAS mutant alleles, he reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In a pooled analysis, a significant association was seen only for the G12A mutant allele, whereby patients having this allele had poorer overall survival when panitumumab was added to their treatment.

"The take-home message based on this study: Patients with metastatic colorectal cancer harboring any of the most common codon 12 or 13 mutant KRAS alleles are unlikely to benefit from panitumumab treatment. Today, only metastatic colorectal cancer patients with wild-type KRAS tumors should be treated with EGFR antibodies," Dr. Peeters asserted.

Previous research (JAMA 2010;304:1812-20), has suggested that patients with the G13D KRAS mutant allele might still benefit from cetuximab, another antibody to EGFR, an attendee noted. Therefore, is it possible that there is some biological difference between panitumumab and cetuximab (Erbitux) when it comes to this allele?

"The results I presented here were based on a large data set treated with panitumumab and a very homogeneous population, which really shows ... that there is no benefit of treating patients with G13D with panitumumab," Dr. Peeters replied. "If you compare the results ... of data with cetuximab, this population is more heterogeneous than we studied in the panitumumab group.

"So it’s very difficult to draw final conclusions ... on standard of care of patients. My advice is still that patients with mutant tumors probably in general don’t benefit from treatment with EGFR antibodies, although from a scientific point of view, the discussion is still open and we have to search further [to see] if there is really a difference between the antibodies based on the results obtained in the literature," he added.

"And one of the studies that could answer this question is a head-to-head study that we are performing, where cetuximab is compared with panitumumab, and this might give us a better idea what is really the difference between the antibodies."

Session cochair Dr. George Fisher of the Stanford (Calif.) Cancer Center, maintained that the "door has been closed now" on potential benefit of anti-EGFR therapy in subsets of patients with KRAS-mutated colorectal cancer. "It’s hard for me to imagine that any mutations short of the very rare ones ... might be appropriate for EGFR inhibitors," he said in an interview.

However, even if inhibition of signaling in the EGFR pathway in these patients is not efficacious, there still might be a role for EGFR binding as it relates to antibody-dependent cell-mediated cytotoxicity, Dr. Fisher added. "There are a number of groups still working on that, and that would theoretically work even in KRAS mutants."

Panitumumab is approved by the Food and Drug Administration for the treatment of metastatic colorectal cancer. Its label indicates that it is not recommended for patients having common KRAS mutations.

The three trials included in the analysis tested addition of panitumumab to FOLFOX4 in the first-line setting (the PRIME trial, 301 patients), to FOLFIRI in the second-line setting (701 patients), and to best supportive care in the third-line setting (463 patients). In the new analysis, the investigators assessed the prognostic and predictive impact of six common KRAS mutant alleles: G12D, G12V, G13D, G12C, G12A, and G12S.

"Baseline demographics and clinical features were generally balanced between all mutant KRAS allele subgroups," Dr. Peeters noted.

In cross-trial analyses in which researchers looked just at the control arms to assess prognostic impact of the mutant alleles, none of the six alleles were consistently associated with better progression-free survival or overall survival, compared with all other mutant alleles.

When researchers looked at both arms in the trials to assess predictive impact of the mutant alleles, none of them were consistently associated with differential progression-free survival or overall survival if patients received added panitumumab instead of the control treatment.

In a single trial, G12V was associated with better overall survival and G13D was associated with poorer overall survival if patients received added panitumumab instead of the control treatment of FOLFOX4 alone, with a significant interaction term seen for each allele (P = .037 and P = .002, respectively).

In a pooled analysis of all three trials, only one mutant allele (G12) was significantly associated with overall survival, with poorer overall survival seen for patients having this allele if they received added panitumumab instead of the control treatment alone.

(The investigators also evaluated data from the CRYSTAL and OPUS trials, which tested addition of cetuximab to chemotherapy, and found that neither the G12V nor the G13D mutant allele significantly predicted benefit from the antibody in these trials.)

Dr. Peeters reported that he is a consultant to and receives honoraria and research funding from Amgen. Dr. Fisher reported that he owns stock in Seattle Genetics and receives research funding from Exelixis, FibroGen, Genentech, GlaxoSmithKline, Ispen, Merck, Newlink Genetics, Novartis, and Sanofi Aventis.

SAN FRANCISCO – None of the common KRAS mutant alleles seen in metastatic colorectal cancer reliably predict benefit from panitumumab, new data show, suggesting that this agent should continue to be used only in patients with KRAS wild-type tumors.

Investigators led by Dr. Marc Peeters of Antwerp University Hospital in Edegem, Belgium, analyzed data from a trio of phase III randomized trials of panitumumab (Vectibix), an antibody to epidermal growth factor receptor (EGFR), in more than 1,400 patients.

Main results showed that there was no consistent difference in benefit across trials in terms of progression-free and overall survival for patients having the most common codon 12 and 13 KRAS mutant alleles, he reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In a pooled analysis, a significant association was seen only for the G12A mutant allele, whereby patients having this allele had poorer overall survival when panitumumab was added to their treatment.

"The take-home message based on this study: Patients with metastatic colorectal cancer harboring any of the most common codon 12 or 13 mutant KRAS alleles are unlikely to benefit from panitumumab treatment. Today, only metastatic colorectal cancer patients with wild-type KRAS tumors should be treated with EGFR antibodies," Dr. Peeters asserted.

Previous research (JAMA 2010;304:1812-20), has suggested that patients with the G13D KRAS mutant allele might still benefit from cetuximab, another antibody to EGFR, an attendee noted. Therefore, is it possible that there is some biological difference between panitumumab and cetuximab (Erbitux) when it comes to this allele?

"The results I presented here were based on a large data set treated with panitumumab and a very homogeneous population, which really shows ... that there is no benefit of treating patients with G13D with panitumumab," Dr. Peeters replied. "If you compare the results ... of data with cetuximab, this population is more heterogeneous than we studied in the panitumumab group.

"So it’s very difficult to draw final conclusions ... on standard of care of patients. My advice is still that patients with mutant tumors probably in general don’t benefit from treatment with EGFR antibodies, although from a scientific point of view, the discussion is still open and we have to search further [to see] if there is really a difference between the antibodies based on the results obtained in the literature," he added.

"And one of the studies that could answer this question is a head-to-head study that we are performing, where cetuximab is compared with panitumumab, and this might give us a better idea what is really the difference between the antibodies."

Session cochair Dr. George Fisher of the Stanford (Calif.) Cancer Center, maintained that the "door has been closed now" on potential benefit of anti-EGFR therapy in subsets of patients with KRAS-mutated colorectal cancer. "It’s hard for me to imagine that any mutations short of the very rare ones ... might be appropriate for EGFR inhibitors," he said in an interview.

However, even if inhibition of signaling in the EGFR pathway in these patients is not efficacious, there still might be a role for EGFR binding as it relates to antibody-dependent cell-mediated cytotoxicity, Dr. Fisher added. "There are a number of groups still working on that, and that would theoretically work even in KRAS mutants."

Panitumumab is approved by the Food and Drug Administration for the treatment of metastatic colorectal cancer. Its label indicates that it is not recommended for patients having common KRAS mutations.

The three trials included in the analysis tested addition of panitumumab to FOLFOX4 in the first-line setting (the PRIME trial, 301 patients), to FOLFIRI in the second-line setting (701 patients), and to best supportive care in the third-line setting (463 patients). In the new analysis, the investigators assessed the prognostic and predictive impact of six common KRAS mutant alleles: G12D, G12V, G13D, G12C, G12A, and G12S.

"Baseline demographics and clinical features were generally balanced between all mutant KRAS allele subgroups," Dr. Peeters noted.

In cross-trial analyses in which researchers looked just at the control arms to assess prognostic impact of the mutant alleles, none of the six alleles were consistently associated with better progression-free survival or overall survival, compared with all other mutant alleles.

When researchers looked at both arms in the trials to assess predictive impact of the mutant alleles, none of them were consistently associated with differential progression-free survival or overall survival if patients received added panitumumab instead of the control treatment.

In a single trial, G12V was associated with better overall survival and G13D was associated with poorer overall survival if patients received added panitumumab instead of the control treatment of FOLFOX4 alone, with a significant interaction term seen for each allele (P = .037 and P = .002, respectively).

In a pooled analysis of all three trials, only one mutant allele (G12) was significantly associated with overall survival, with poorer overall survival seen for patients having this allele if they received added panitumumab instead of the control treatment alone.

(The investigators also evaluated data from the CRYSTAL and OPUS trials, which tested addition of cetuximab to chemotherapy, and found that neither the G12V nor the G13D mutant allele significantly predicted benefit from the antibody in these trials.)

Dr. Peeters reported that he is a consultant to and receives honoraria and research funding from Amgen. Dr. Fisher reported that he owns stock in Seattle Genetics and receives research funding from Exelixis, FibroGen, Genentech, GlaxoSmithKline, Ispen, Merck, Newlink Genetics, Novartis, and Sanofi Aventis.

SAN FRANCISCO – None of the common KRAS mutant alleles seen in metastatic colorectal cancer reliably predict benefit from panitumumab, new data show, suggesting that this agent should continue to be used only in patients with KRAS wild-type tumors.

Investigators led by Dr. Marc Peeters of Antwerp University Hospital in Edegem, Belgium, analyzed data from a trio of phase III randomized trials of panitumumab (Vectibix), an antibody to epidermal growth factor receptor (EGFR), in more than 1,400 patients.

Main results showed that there was no consistent difference in benefit across trials in terms of progression-free and overall survival for patients having the most common codon 12 and 13 KRAS mutant alleles, he reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In a pooled analysis, a significant association was seen only for the G12A mutant allele, whereby patients having this allele had poorer overall survival when panitumumab was added to their treatment.

"The take-home message based on this study: Patients with metastatic colorectal cancer harboring any of the most common codon 12 or 13 mutant KRAS alleles are unlikely to benefit from panitumumab treatment. Today, only metastatic colorectal cancer patients with wild-type KRAS tumors should be treated with EGFR antibodies," Dr. Peeters asserted.

Previous research (JAMA 2010;304:1812-20), has suggested that patients with the G13D KRAS mutant allele might still benefit from cetuximab, another antibody to EGFR, an attendee noted. Therefore, is it possible that there is some biological difference between panitumumab and cetuximab (Erbitux) when it comes to this allele?

"The results I presented here were based on a large data set treated with panitumumab and a very homogeneous population, which really shows ... that there is no benefit of treating patients with G13D with panitumumab," Dr. Peeters replied. "If you compare the results ... of data with cetuximab, this population is more heterogeneous than we studied in the panitumumab group.

"So it’s very difficult to draw final conclusions ... on standard of care of patients. My advice is still that patients with mutant tumors probably in general don’t benefit from treatment with EGFR antibodies, although from a scientific point of view, the discussion is still open and we have to search further [to see] if there is really a difference between the antibodies based on the results obtained in the literature," he added.

"And one of the studies that could answer this question is a head-to-head study that we are performing, where cetuximab is compared with panitumumab, and this might give us a better idea what is really the difference between the antibodies."

Session cochair Dr. George Fisher of the Stanford (Calif.) Cancer Center, maintained that the "door has been closed now" on potential benefit of anti-EGFR therapy in subsets of patients with KRAS-mutated colorectal cancer. "It’s hard for me to imagine that any mutations short of the very rare ones ... might be appropriate for EGFR inhibitors," he said in an interview.

However, even if inhibition of signaling in the EGFR pathway in these patients is not efficacious, there still might be a role for EGFR binding as it relates to antibody-dependent cell-mediated cytotoxicity, Dr. Fisher added. "There are a number of groups still working on that, and that would theoretically work even in KRAS mutants."

Panitumumab is approved by the Food and Drug Administration for the treatment of metastatic colorectal cancer. Its label indicates that it is not recommended for patients having common KRAS mutations.

The three trials included in the analysis tested addition of panitumumab to FOLFOX4 in the first-line setting (the PRIME trial, 301 patients), to FOLFIRI in the second-line setting (701 patients), and to best supportive care in the third-line setting (463 patients). In the new analysis, the investigators assessed the prognostic and predictive impact of six common KRAS mutant alleles: G12D, G12V, G13D, G12C, G12A, and G12S.

"Baseline demographics and clinical features were generally balanced between all mutant KRAS allele subgroups," Dr. Peeters noted.

In cross-trial analyses in which researchers looked just at the control arms to assess prognostic impact of the mutant alleles, none of the six alleles were consistently associated with better progression-free survival or overall survival, compared with all other mutant alleles.

When researchers looked at both arms in the trials to assess predictive impact of the mutant alleles, none of them were consistently associated with differential progression-free survival or overall survival if patients received added panitumumab instead of the control treatment.

In a single trial, G12V was associated with better overall survival and G13D was associated with poorer overall survival if patients received added panitumumab instead of the control treatment of FOLFOX4 alone, with a significant interaction term seen for each allele (P = .037 and P = .002, respectively).

In a pooled analysis of all three trials, only one mutant allele (G12) was significantly associated with overall survival, with poorer overall survival seen for patients having this allele if they received added panitumumab instead of the control treatment alone.

(The investigators also evaluated data from the CRYSTAL and OPUS trials, which tested addition of cetuximab to chemotherapy, and found that neither the G12V nor the G13D mutant allele significantly predicted benefit from the antibody in these trials.)

Dr. Peeters reported that he is a consultant to and receives honoraria and research funding from Amgen. Dr. Fisher reported that he owns stock in Seattle Genetics and receives research funding from Exelixis, FibroGen, Genentech, GlaxoSmithKline, Ispen, Merck, Newlink Genetics, Novartis, and Sanofi Aventis.

SAN FRANCISCO – Older and newer oral antiviral agents are similarly effective at preventing hepatocellular carcinoma in patients with chronic hepatitis B, according to a systematic review of 45 studies involving 9,330 patients.

The rate of hepatocellular carcinoma (HCC) was almost identical in patients given older drugs (lamivudine or adefovir) and patients given newer ones (entecavir, telbivudine, or tenofovir), ranging from just 0.012 to 0.017 per person-year of follow-up, Dr. Ashwani K. Singal reported at the annual meeting of the American Association for the Study of Liver Diseases.

"This is a surprising finding, that it doesn’t make a difference," he commented in an interview. "Whatever medication you use, the occurrence is similar – it’s low but it’s similar."

The surprise stems from the fact that the newer agents have a low rate of drug resistance and achieve continued suppression of hepatitis B virus DNA during prolonged therapy, Dr. Singal explained. And indeed, undetectable DNA at last follow-up was associated with a lower risk of HCC in the study.

He speculated that the apparent nonsuperiority of the newer agents in terms of this outcome may be related to the relatively small number of patients treated with them thus far. "Now that we have newer antiviral agents, maybe we need more larger studies done in a prospective fashion to see whether one is better than the other," he commented.

In addition to patients having detectable viral DNA at last follow-up, patients aged 50 years or older and patients having cirrhosis at the start of antiviral therapy had higher rates of HCC than did their respective counterparts. The take-home message is that "these populations should be more carefully followed up, even on treatment," maintained Dr. Singal, a gastroenterologist with the Mayo Clinic in Rochester, Minn.

The investigators conducted the systematic review because at least 10 additional studies, several involving the newer antivirals, have been published since the last large meta-analysis looking at this issue in 2010.

They identified studies of oral antiviral therapy among patients with chronic hepatitis B that were published in full in English, regardless of whether patients had cirrhosis or not, and were treatment naive or treatment experienced. But the studies had to have had a treatment duration of at least 12 months and a follow-up duration of at least 2 years. Patients coinfected with HIV or hepatitis C were excluded.

In contrast to the previous meta-analysis, the review used a statistical method that took into account the greater likelihood of detecting HCC with longer follow-up, Dr. Singal noted.

Overall, 42% of the patients had received lamivudine (Epivir), 32% had received adefovir (Hepsera), 10% had received tenofovir (Viread), 9% had received telbivudine (Tyzeka), and 7% had received entecavir (Baraclude).

Results of the review showed that the rate of HCC did not differ significantly with older vs. newer antiviral agents: It was at 0.013 per person-year of follow-up with lamivudine in controlled studies, 0.017 with lamivudine in uncontrolled studies, 0.015 with adefovir with or without lamivudine, and 0.012 with entecavir, telbivudine, or tenofovir.

But the rate was significantly higher in patients having detectable vs. undetectable viral DNA at last follow-up (0.019 vs. 0.01 per person-year of follow-up), patients aged 50 years or older vs. younger at the start of therapy (0.02 vs. 0.009), and patients with vs. without cirrhosis at the start of therapy (0.03 vs. 0.003).

Among those with cirrhosis, there was no difference according to whether the cirrhosis was compensated or decompensated. "The way I can explain that is before they get HCC, there are other things that kill these people: liver failure, bleeding, infections, those kind of things," commented Dr. Singal.

In the six studies having untreated control groups, all of which evaluated lamivudine, there was a significant 56% reduction in the risk of HCC for treated patients as compared with their untreated counterparts, confirming the marked benefit of antiviral therapy in general for reducing this outcome, he said.

"People say there are so many good drugs available now, the research on hepatitis B has almost come to a dead end," Dr. Singal concluded. "But I think there is still scope for doing research. For example ... most of the prospective studies on newer drugs are looking at 1-year outcomes of e antigen loss or surface antigen loss, but I think there should be ... longer follow-up and specifically aiming to look at whether newer drugs are different from older drugs when comparing hepatocellular carcinoma. That will have to be ... at least 5 or 7 years."

Dr. Singal reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Older and newer oral antiviral agents are similarly effective at preventing hepatocellular carcinoma in patients with chronic hepatitis B, according to a systematic review of 45 studies involving 9,330 patients.

The rate of hepatocellular carcinoma (HCC) was almost identical in patients given older drugs (lamivudine or adefovir) and patients given newer ones (entecavir, telbivudine, or tenofovir), ranging from just 0.012 to 0.017 per person-year of follow-up, Dr. Ashwani K. Singal reported at the annual meeting of the American Association for the Study of Liver Diseases.

"This is a surprising finding, that it doesn’t make a difference," he commented in an interview. "Whatever medication you use, the occurrence is similar – it’s low but it’s similar."

The surprise stems from the fact that the newer agents have a low rate of drug resistance and achieve continued suppression of hepatitis B virus DNA during prolonged therapy, Dr. Singal explained. And indeed, undetectable DNA at last follow-up was associated with a lower risk of HCC in the study.

He speculated that the apparent nonsuperiority of the newer agents in terms of this outcome may be related to the relatively small number of patients treated with them thus far. "Now that we have newer antiviral agents, maybe we need more larger studies done in a prospective fashion to see whether one is better than the other," he commented.

In addition to patients having detectable viral DNA at last follow-up, patients aged 50 years or older and patients having cirrhosis at the start of antiviral therapy had higher rates of HCC than did their respective counterparts. The take-home message is that "these populations should be more carefully followed up, even on treatment," maintained Dr. Singal, a gastroenterologist with the Mayo Clinic in Rochester, Minn.

The investigators conducted the systematic review because at least 10 additional studies, several involving the newer antivirals, have been published since the last large meta-analysis looking at this issue in 2010.

They identified studies of oral antiviral therapy among patients with chronic hepatitis B that were published in full in English, regardless of whether patients had cirrhosis or not, and were treatment naive or treatment experienced. But the studies had to have had a treatment duration of at least 12 months and a follow-up duration of at least 2 years. Patients coinfected with HIV or hepatitis C were excluded.

In contrast to the previous meta-analysis, the review used a statistical method that took into account the greater likelihood of detecting HCC with longer follow-up, Dr. Singal noted.

Overall, 42% of the patients had received lamivudine (Epivir), 32% had received adefovir (Hepsera), 10% had received tenofovir (Viread), 9% had received telbivudine (Tyzeka), and 7% had received entecavir (Baraclude).

Results of the review showed that the rate of HCC did not differ significantly with older vs. newer antiviral agents: It was at 0.013 per person-year of follow-up with lamivudine in controlled studies, 0.017 with lamivudine in uncontrolled studies, 0.015 with adefovir with or without lamivudine, and 0.012 with entecavir, telbivudine, or tenofovir.

But the rate was significantly higher in patients having detectable vs. undetectable viral DNA at last follow-up (0.019 vs. 0.01 per person-year of follow-up), patients aged 50 years or older vs. younger at the start of therapy (0.02 vs. 0.009), and patients with vs. without cirrhosis at the start of therapy (0.03 vs. 0.003).

Among those with cirrhosis, there was no difference according to whether the cirrhosis was compensated or decompensated. "The way I can explain that is before they get HCC, there are other things that kill these people: liver failure, bleeding, infections, those kind of things," commented Dr. Singal.

In the six studies having untreated control groups, all of which evaluated lamivudine, there was a significant 56% reduction in the risk of HCC for treated patients as compared with their untreated counterparts, confirming the marked benefit of antiviral therapy in general for reducing this outcome, he said.

"People say there are so many good drugs available now, the research on hepatitis B has almost come to a dead end," Dr. Singal concluded. "But I think there is still scope for doing research. For example ... most of the prospective studies on newer drugs are looking at 1-year outcomes of e antigen loss or surface antigen loss, but I think there should be ... longer follow-up and specifically aiming to look at whether newer drugs are different from older drugs when comparing hepatocellular carcinoma. That will have to be ... at least 5 or 7 years."

Dr. Singal reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Older and newer oral antiviral agents are similarly effective at preventing hepatocellular carcinoma in patients with chronic hepatitis B, according to a systematic review of 45 studies involving 9,330 patients.

The rate of hepatocellular carcinoma (HCC) was almost identical in patients given older drugs (lamivudine or adefovir) and patients given newer ones (entecavir, telbivudine, or tenofovir), ranging from just 0.012 to 0.017 per person-year of follow-up, Dr. Ashwani K. Singal reported at the annual meeting of the American Association for the Study of Liver Diseases.

"This is a surprising finding, that it doesn’t make a difference," he commented in an interview. "Whatever medication you use, the occurrence is similar – it’s low but it’s similar."

The surprise stems from the fact that the newer agents have a low rate of drug resistance and achieve continued suppression of hepatitis B virus DNA during prolonged therapy, Dr. Singal explained. And indeed, undetectable DNA at last follow-up was associated with a lower risk of HCC in the study.

He speculated that the apparent nonsuperiority of the newer agents in terms of this outcome may be related to the relatively small number of patients treated with them thus far. "Now that we have newer antiviral agents, maybe we need more larger studies done in a prospective fashion to see whether one is better than the other," he commented.

In addition to patients having detectable viral DNA at last follow-up, patients aged 50 years or older and patients having cirrhosis at the start of antiviral therapy had higher rates of HCC than did their respective counterparts. The take-home message is that "these populations should be more carefully followed up, even on treatment," maintained Dr. Singal, a gastroenterologist with the Mayo Clinic in Rochester, Minn.

The investigators conducted the systematic review because at least 10 additional studies, several involving the newer antivirals, have been published since the last large meta-analysis looking at this issue in 2010.

They identified studies of oral antiviral therapy among patients with chronic hepatitis B that were published in full in English, regardless of whether patients had cirrhosis or not, and were treatment naive or treatment experienced. But the studies had to have had a treatment duration of at least 12 months and a follow-up duration of at least 2 years. Patients coinfected with HIV or hepatitis C were excluded.

In contrast to the previous meta-analysis, the review used a statistical method that took into account the greater likelihood of detecting HCC with longer follow-up, Dr. Singal noted.

Overall, 42% of the patients had received lamivudine (Epivir), 32% had received adefovir (Hepsera), 10% had received tenofovir (Viread), 9% had received telbivudine (Tyzeka), and 7% had received entecavir (Baraclude).

Results of the review showed that the rate of HCC did not differ significantly with older vs. newer antiviral agents: It was at 0.013 per person-year of follow-up with lamivudine in controlled studies, 0.017 with lamivudine in uncontrolled studies, 0.015 with adefovir with or without lamivudine, and 0.012 with entecavir, telbivudine, or tenofovir.

But the rate was significantly higher in patients having detectable vs. undetectable viral DNA at last follow-up (0.019 vs. 0.01 per person-year of follow-up), patients aged 50 years or older vs. younger at the start of therapy (0.02 vs. 0.009), and patients with vs. without cirrhosis at the start of therapy (0.03 vs. 0.003).

Among those with cirrhosis, there was no difference according to whether the cirrhosis was compensated or decompensated. "The way I can explain that is before they get HCC, there are other things that kill these people: liver failure, bleeding, infections, those kind of things," commented Dr. Singal.

In the six studies having untreated control groups, all of which evaluated lamivudine, there was a significant 56% reduction in the risk of HCC for treated patients as compared with their untreated counterparts, confirming the marked benefit of antiviral therapy in general for reducing this outcome, he said.

"People say there are so many good drugs available now, the research on hepatitis B has almost come to a dead end," Dr. Singal concluded. "But I think there is still scope for doing research. For example ... most of the prospective studies on newer drugs are looking at 1-year outcomes of e antigen loss or surface antigen loss, but I think there should be ... longer follow-up and specifically aiming to look at whether newer drugs are different from older drugs when comparing hepatocellular carcinoma. That will have to be ... at least 5 or 7 years."

Dr. Singal reported that he had no relevant conflicts of interest.