Regorafenib Anticipated to Show Survival Advantage in Colorectal Cancer

Phase III data on regorafenib, the first small-molecule kinase inhibitor to demonstrate a significant survival advantage in colorectal cancer, will be presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium opening Jan. 19.

Other noteworthy studies include a reanalysis of the phase III RADIANT-2 trial suggesting that everolimus (Afinitor) may be of greater benefit in neuroendocrine tumors than previously shown, and research that could improve the early detection of esophageal and pancreatic cancer.

CORRECT Trial in Colorectal Cancer

Investigators will present results on Jan. 21 from the phase III CORRECT trial showing that the oral, investigational multikinase inhibitor, regorafenib, plus best supportive care, significantly increased median overall survival by 29% in 760 patients whose metastatic colorectal cancer progressed after standard therapies (hazard ratio 0.773; P value = .0051).

This added a median benefit of just 1.4 months compared with placebo and best supportive care (6.4 months vs. 5.0 months), but lead investigator Dr. Axel Grothey pointed out during a press briefing that the patients were running out of options after failing all standard therapies including bevacizumab and epidermal growth factor receptor inhibitors if they had KRAS-wild type tumors.

The response rate was similar between regorafenib and placebo (1.6% vs. 0.4%), but where regorafenib distinguished itself was in a much higher disease-control rate than placebo (44% vs. 15%).

The median difference in progression-free survival was again small, at just 1.2 months, but this corresponded to a 51% reduction in the risk of progression (HR 0.493; P less than .000001), said Dr. Grothey, professor of oncology at Mayo Clinic in Rochester, Minn. "There is clearly a benefit for about 50% of patients compared to the placebo-control," he said.

The side effect profile was similar to that observed in the 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 trial was stopped based on the preliminary results from the preplanned interim analysis to allow patients on placebo to cross over to treatment with regorafenib.

Dr. Grothey said regorafenib "identifies itself as a potential new standard of care in this patient population," and that it will move into earlier lines of therapy. Phase II studies are underway to evaluate the agent in combination with standard chemotherapy backbones such as 5FU and irinotecan.

Presscast moderator Dr. Morten S. Kahlenberg, medical director of Surgical Oncology Associates of South Texas in San Antonio, called results from the late-breaking abstract exciting and very noteworthy, particularly in such a heavily pretreated population, and agreed that the research lays the groundwork for further study to evaluate whether regorafenib could "possibly become a component of standard therapies for colorectal cancer."

Dr. Grothey 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.

RADIANT-2 Reanalysis

On Jan. 20, Dr. James C. Yao, deputy chair of gastrointestinal medical oncology at M.D. Anderson Cancer Center in Houston, will present a reanalysis of the phase III RADIANT-2 trial in patients with advanced nonpancreatic neuroendocrine tumors.

The analysis identified several prognostic factors that could help physicians better identify which patients should be treated. It could also explain why the addition of everolimus to standard therapy with octreotide LAR (Sandostatin LAR Depot) delayed progression by a median of 5.1 months, but just missed statistical significance.

In multivariate analysis, significant prognostic factors included WHO performance status, bone involvement, lung as primary site, and, most notably, baseline levels of chromogranin A, a secretory protein present in neuroendocrine tissue.

Patients with elevated chromogranin A (CgA) had a significantly shorter progression-free survival of 11.3 months vs. 26.8 for those with nonelevated chromogranin A.

At baseline, there was a significant imbalance in mean and median CgA levels between patients receiving everolimus plus octreotide and those given octreotide alone, he said.

An exploratory analysis that adjusted for these prognostic indicators indicated that everolimus had a significant benefit, changing the reduction in risk of neuroendocrine progression from 23% as originally reported to 38% (HR 0.62). A larger trial, RADIANT-4, is planned to confirm these results, Dr. Yao said.

Dr. Kahlenberg said the results provide clinicians with additional insights on how to determine which patients would benefit from everolimus therapy. "In that providers are really limited by the small number of successful therapies for neuroendocrine tumors, your study is that much more meaningful," he added.

Flagging Patients at High Risk for Esophageal Cancer

Investigators at the University of Pittsburgh will present data on Jan. 19 describing the use of three optical biomarkers to improve early identification of patients at high risk for esophageal cancer.

The biomarkers were derived using a novel microscopy technique called spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to evaluate tissue samples taken during conventional endoscopic surveillance of 60 patients with Barrett’s esophagus. SL-QPM measures nano-scale changes in the nuclear structure of cells in the esophageal lining.

All three biomarkers – nuclear optical path length, intranuclear uniformity, and intranuclear entropy – were able to distinguish patients with nondysplastic Barrett’s esophagus from those with high-grade dysplasia or esophageal adenocarcinoma. When combined, they had a sensitivity of 89% and specificity of 76%, for an overall accuracy of 86%.

Lead author Dr. Randall E. Brand, professor of medicine at the university, said the biomarkers provide a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium, and could potentially simplify surveillance by identifying patients who warrant intensive surveillance.

"Further, we think this may be useful in monitoring patients after ablative therapy or in determining surveillance frequency," he said.

Barrett’s esophagus affects about 1% of the U.S. population, and is typically monitored by obtaining multiple random biopsies of the esophagus every 1 to 3 years. Notably, the incidence of esophageal adenocarcinoma in the United States is rising faster than any other type of cancer, with the National Cancer Institute reporting an estimated 16,980 new cases and 14,710 deaths in 2011.

"The ability to have an additional test in patients who may harbor malignancy or a precancerous condition like high-grade dysplasia in the background of Barrett’s is indeed very, very noteworthy, and has a very real chance of modifying how this patient population is followed and treated," Dr. Kahlenberg told reporters.

Markers Promising for Finding Early Pancreatic Cancer

Finally, three abstracts to be presented at the meeting discuss the use of the monoclonal antibody PAM4 to identify patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for 90% of all patients with pancreatic cancer.

David V. Gold, Ph.D., lead author of abstract 151 to be presented on Jan. 20, said that in a blinded analysis involving about 600 patients, the PAM4 immunoassay confirmed the presence of PDAC in 76% of 298 patients with known PDAC, and that it detected two-thirds of stage I patients. Specificity was high.

The results confirm a prior study in which the immunoassay correctly identified about 80% of roughly 60 patients with known PDAC, and provide a rationale for longitudinal surveillance of patients at high risk for PDAC including those with a history of familial pancreatic cancer or with new-onset diabetes, according to Dr. Gold of the Garden State Cancer Center in Belleville, N.J.

The second abstract (no. 164) reports improved detection rates when the PAM4 immunoassay is combined with the cancer antigen 19-9 test, which is widely used to monitor pancreatic cancer progression.

The final abstract (no. 188) provides detailed specificity analyses for the PAM4 antibody itself. Currently, there is no approved test for the detection and diagnosis of pancreatic cancer.

Dr. Grothey disclosed a consultant/advisory role for Bayer. His coauthors reported financial relationships with several pharmaceutical firms. Dr. Kahlenberg reported honoraria from Genentech. Dr. Yao reported a consultant/advisory role for Ipsen, Pfizer, and Endo Pharmaceuticals; honoraria from Novartis; and research funding from Novartis and Genentech. His coauthors reported several financial relationships including employment with Novartis. Dr. Brand reported no conflicts of interest. Dr. Gold reported no conflicts. His coauthor Dr. David Goldenberg reported employment/leadership and stock ownership with Immunomedics.

Phase III data on regorafenib, the first small-molecule kinase inhibitor to demonstrate a significant survival advantage in colorectal cancer, will be presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium opening Jan. 19.

Other noteworthy studies include a reanalysis of the phase III RADIANT-2 trial suggesting that everolimus (Afinitor) may be of greater benefit in neuroendocrine tumors than previously shown, and research that could improve the early detection of esophageal and pancreatic cancer.

CORRECT Trial in Colorectal Cancer

Investigators will present results on Jan. 21 from the phase III CORRECT trial showing that the oral, investigational multikinase inhibitor, regorafenib, plus best supportive care, significantly increased median overall survival by 29% in 760 patients whose metastatic colorectal cancer progressed after standard therapies (hazard ratio 0.773; P value = .0051).

This added a median benefit of just 1.4 months compared with placebo and best supportive care (6.4 months vs. 5.0 months), but lead investigator Dr. Axel Grothey pointed out during a press briefing that the patients were running out of options after failing all standard therapies including bevacizumab and epidermal growth factor receptor inhibitors if they had KRAS-wild type tumors.

The response rate was similar between regorafenib and placebo (1.6% vs. 0.4%), but where regorafenib distinguished itself was in a much higher disease-control rate than placebo (44% vs. 15%).

The median difference in progression-free survival was again small, at just 1.2 months, but this corresponded to a 51% reduction in the risk of progression (HR 0.493; P less than .000001), said Dr. Grothey, professor of oncology at Mayo Clinic in Rochester, Minn. "There is clearly a benefit for about 50% of patients compared to the placebo-control," he said.

The side effect profile was similar to that observed in the 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 trial was stopped based on the preliminary results from the preplanned interim analysis to allow patients on placebo to cross over to treatment with regorafenib.

Dr. Grothey said regorafenib "identifies itself as a potential new standard of care in this patient population," and that it will move into earlier lines of therapy. Phase II studies are underway to evaluate the agent in combination with standard chemotherapy backbones such as 5FU and irinotecan.

Presscast moderator Dr. Morten S. Kahlenberg, medical director of Surgical Oncology Associates of South Texas in San Antonio, called results from the late-breaking abstract exciting and very noteworthy, particularly in such a heavily pretreated population, and agreed that the research lays the groundwork for further study to evaluate whether regorafenib could "possibly become a component of standard therapies for colorectal cancer."

Dr. Grothey 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.

RADIANT-2 Reanalysis

On Jan. 20, Dr. James C. Yao, deputy chair of gastrointestinal medical oncology at M.D. Anderson Cancer Center in Houston, will present a reanalysis of the phase III RADIANT-2 trial in patients with advanced nonpancreatic neuroendocrine tumors.

The analysis identified several prognostic factors that could help physicians better identify which patients should be treated. It could also explain why the addition of everolimus to standard therapy with octreotide LAR (Sandostatin LAR Depot) delayed progression by a median of 5.1 months, but just missed statistical significance.

In multivariate analysis, significant prognostic factors included WHO performance status, bone involvement, lung as primary site, and, most notably, baseline levels of chromogranin A, a secretory protein present in neuroendocrine tissue.

Patients with elevated chromogranin A (CgA) had a significantly shorter progression-free survival of 11.3 months vs. 26.8 for those with nonelevated chromogranin A.

At baseline, there was a significant imbalance in mean and median CgA levels between patients receiving everolimus plus octreotide and those given octreotide alone, he said.

An exploratory analysis that adjusted for these prognostic indicators indicated that everolimus had a significant benefit, changing the reduction in risk of neuroendocrine progression from 23% as originally reported to 38% (HR 0.62). A larger trial, RADIANT-4, is planned to confirm these results, Dr. Yao said.

Dr. Kahlenberg said the results provide clinicians with additional insights on how to determine which patients would benefit from everolimus therapy. "In that providers are really limited by the small number of successful therapies for neuroendocrine tumors, your study is that much more meaningful," he added.

Flagging Patients at High Risk for Esophageal Cancer

Investigators at the University of Pittsburgh will present data on Jan. 19 describing the use of three optical biomarkers to improve early identification of patients at high risk for esophageal cancer.

The biomarkers were derived using a novel microscopy technique called spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to evaluate tissue samples taken during conventional endoscopic surveillance of 60 patients with Barrett’s esophagus. SL-QPM measures nano-scale changes in the nuclear structure of cells in the esophageal lining.

All three biomarkers – nuclear optical path length, intranuclear uniformity, and intranuclear entropy – were able to distinguish patients with nondysplastic Barrett’s esophagus from those with high-grade dysplasia or esophageal adenocarcinoma. When combined, they had a sensitivity of 89% and specificity of 76%, for an overall accuracy of 86%.

Lead author Dr. Randall E. Brand, professor of medicine at the university, said the biomarkers provide a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium, and could potentially simplify surveillance by identifying patients who warrant intensive surveillance.

"Further, we think this may be useful in monitoring patients after ablative therapy or in determining surveillance frequency," he said.

Barrett’s esophagus affects about 1% of the U.S. population, and is typically monitored by obtaining multiple random biopsies of the esophagus every 1 to 3 years. Notably, the incidence of esophageal adenocarcinoma in the United States is rising faster than any other type of cancer, with the National Cancer Institute reporting an estimated 16,980 new cases and 14,710 deaths in 2011.

"The ability to have an additional test in patients who may harbor malignancy or a precancerous condition like high-grade dysplasia in the background of Barrett’s is indeed very, very noteworthy, and has a very real chance of modifying how this patient population is followed and treated," Dr. Kahlenberg told reporters.

Markers Promising for Finding Early Pancreatic Cancer

Finally, three abstracts to be presented at the meeting discuss the use of the monoclonal antibody PAM4 to identify patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for 90% of all patients with pancreatic cancer.

David V. Gold, Ph.D., lead author of abstract 151 to be presented on Jan. 20, said that in a blinded analysis involving about 600 patients, the PAM4 immunoassay confirmed the presence of PDAC in 76% of 298 patients with known PDAC, and that it detected two-thirds of stage I patients. Specificity was high.

The results confirm a prior study in which the immunoassay correctly identified about 80% of roughly 60 patients with known PDAC, and provide a rationale for longitudinal surveillance of patients at high risk for PDAC including those with a history of familial pancreatic cancer or with new-onset diabetes, according to Dr. Gold of the Garden State Cancer Center in Belleville, N.J.

The second abstract (no. 164) reports improved detection rates when the PAM4 immunoassay is combined with the cancer antigen 19-9 test, which is widely used to monitor pancreatic cancer progression.

The final abstract (no. 188) provides detailed specificity analyses for the PAM4 antibody itself. Currently, there is no approved test for the detection and diagnosis of pancreatic cancer.

Dr. Grothey disclosed a consultant/advisory role for Bayer. His coauthors reported financial relationships with several pharmaceutical firms. Dr. Kahlenberg reported honoraria from Genentech. Dr. Yao reported a consultant/advisory role for Ipsen, Pfizer, and Endo Pharmaceuticals; honoraria from Novartis; and research funding from Novartis and Genentech. His coauthors reported several financial relationships including employment with Novartis. Dr. Brand reported no conflicts of interest. Dr. Gold reported no conflicts. His coauthor Dr. David Goldenberg reported employment/leadership and stock ownership with Immunomedics.

Phase III data on regorafenib, the first small-molecule kinase inhibitor to demonstrate a significant survival advantage in colorectal cancer, will be presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium opening Jan. 19.

Other noteworthy studies include a reanalysis of the phase III RADIANT-2 trial suggesting that everolimus (Afinitor) may be of greater benefit in neuroendocrine tumors than previously shown, and research that could improve the early detection of esophageal and pancreatic cancer.

CORRECT Trial in Colorectal Cancer

Investigators will present results on Jan. 21 from the phase III CORRECT trial showing that the oral, investigational multikinase inhibitor, regorafenib, plus best supportive care, significantly increased median overall survival by 29% in 760 patients whose metastatic colorectal cancer progressed after standard therapies (hazard ratio 0.773; P value = .0051).

This added a median benefit of just 1.4 months compared with placebo and best supportive care (6.4 months vs. 5.0 months), but lead investigator Dr. Axel Grothey pointed out during a press briefing that the patients were running out of options after failing all standard therapies including bevacizumab and epidermal growth factor receptor inhibitors if they had KRAS-wild type tumors.

The response rate was similar between regorafenib and placebo (1.6% vs. 0.4%), but where regorafenib distinguished itself was in a much higher disease-control rate than placebo (44% vs. 15%).

The median difference in progression-free survival was again small, at just 1.2 months, but this corresponded to a 51% reduction in the risk of progression (HR 0.493; P less than .000001), said Dr. Grothey, professor of oncology at Mayo Clinic in Rochester, Minn. "There is clearly a benefit for about 50% of patients compared to the placebo-control," he said.

The side effect profile was similar to that observed in the 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 trial was stopped based on the preliminary results from the preplanned interim analysis to allow patients on placebo to cross over to treatment with regorafenib.

Dr. Grothey said regorafenib "identifies itself as a potential new standard of care in this patient population," and that it will move into earlier lines of therapy. Phase II studies are underway to evaluate the agent in combination with standard chemotherapy backbones such as 5FU and irinotecan.

Presscast moderator Dr. Morten S. Kahlenberg, medical director of Surgical Oncology Associates of South Texas in San Antonio, called results from the late-breaking abstract exciting and very noteworthy, particularly in such a heavily pretreated population, and agreed that the research lays the groundwork for further study to evaluate whether regorafenib could "possibly become a component of standard therapies for colorectal cancer."

Dr. Grothey 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.

RADIANT-2 Reanalysis

On Jan. 20, Dr. James C. Yao, deputy chair of gastrointestinal medical oncology at M.D. Anderson Cancer Center in Houston, will present a reanalysis of the phase III RADIANT-2 trial in patients with advanced nonpancreatic neuroendocrine tumors.

The analysis identified several prognostic factors that could help physicians better identify which patients should be treated. It could also explain why the addition of everolimus to standard therapy with octreotide LAR (Sandostatin LAR Depot) delayed progression by a median of 5.1 months, but just missed statistical significance.

In multivariate analysis, significant prognostic factors included WHO performance status, bone involvement, lung as primary site, and, most notably, baseline levels of chromogranin A, a secretory protein present in neuroendocrine tissue.

Patients with elevated chromogranin A (CgA) had a significantly shorter progression-free survival of 11.3 months vs. 26.8 for those with nonelevated chromogranin A.

At baseline, there was a significant imbalance in mean and median CgA levels between patients receiving everolimus plus octreotide and those given octreotide alone, he said.

An exploratory analysis that adjusted for these prognostic indicators indicated that everolimus had a significant benefit, changing the reduction in risk of neuroendocrine progression from 23% as originally reported to 38% (HR 0.62). A larger trial, RADIANT-4, is planned to confirm these results, Dr. Yao said.

Dr. Kahlenberg said the results provide clinicians with additional insights on how to determine which patients would benefit from everolimus therapy. "In that providers are really limited by the small number of successful therapies for neuroendocrine tumors, your study is that much more meaningful," he added.

Flagging Patients at High Risk for Esophageal Cancer

Investigators at the University of Pittsburgh will present data on Jan. 19 describing the use of three optical biomarkers to improve early identification of patients at high risk for esophageal cancer.

The biomarkers were derived using a novel microscopy technique called spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to evaluate tissue samples taken during conventional endoscopic surveillance of 60 patients with Barrett’s esophagus. SL-QPM measures nano-scale changes in the nuclear structure of cells in the esophageal lining.

All three biomarkers – nuclear optical path length, intranuclear uniformity, and intranuclear entropy – were able to distinguish patients with nondysplastic Barrett’s esophagus from those with high-grade dysplasia or esophageal adenocarcinoma. When combined, they had a sensitivity of 89% and specificity of 76%, for an overall accuracy of 86%.

Lead author Dr. Randall E. Brand, professor of medicine at the university, said the biomarkers provide a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium, and could potentially simplify surveillance by identifying patients who warrant intensive surveillance.

"Further, we think this may be useful in monitoring patients after ablative therapy or in determining surveillance frequency," he said.

Barrett’s esophagus affects about 1% of the U.S. population, and is typically monitored by obtaining multiple random biopsies of the esophagus every 1 to 3 years. Notably, the incidence of esophageal adenocarcinoma in the United States is rising faster than any other type of cancer, with the National Cancer Institute reporting an estimated 16,980 new cases and 14,710 deaths in 2011.

"The ability to have an additional test in patients who may harbor malignancy or a precancerous condition like high-grade dysplasia in the background of Barrett’s is indeed very, very noteworthy, and has a very real chance of modifying how this patient population is followed and treated," Dr. Kahlenberg told reporters.

Markers Promising for Finding Early Pancreatic Cancer

Finally, three abstracts to be presented at the meeting discuss the use of the monoclonal antibody PAM4 to identify patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for 90% of all patients with pancreatic cancer.

David V. Gold, Ph.D., lead author of abstract 151 to be presented on Jan. 20, said that in a blinded analysis involving about 600 patients, the PAM4 immunoassay confirmed the presence of PDAC in 76% of 298 patients with known PDAC, and that it detected two-thirds of stage I patients. Specificity was high.

The results confirm a prior study in which the immunoassay correctly identified about 80% of roughly 60 patients with known PDAC, and provide a rationale for longitudinal surveillance of patients at high risk for PDAC including those with a history of familial pancreatic cancer or with new-onset diabetes, according to Dr. Gold of the Garden State Cancer Center in Belleville, N.J.

The second abstract (no. 164) reports improved detection rates when the PAM4 immunoassay is combined with the cancer antigen 19-9 test, which is widely used to monitor pancreatic cancer progression.

The final abstract (no. 188) provides detailed specificity analyses for the PAM4 antibody itself. Currently, there is no approved test for the detection and diagnosis of pancreatic cancer.

Dr. Grothey disclosed a consultant/advisory role for Bayer. His coauthors reported financial relationships with several pharmaceutical firms. Dr. Kahlenberg reported honoraria from Genentech. Dr. Yao reported a consultant/advisory role for Ipsen, Pfizer, and Endo Pharmaceuticals; honoraria from Novartis; and research funding from Novartis and Genentech. His coauthors reported several financial relationships including employment with Novartis. Dr. Brand reported no conflicts of interest. Dr. Gold reported no conflicts. His coauthor Dr. David Goldenberg reported employment/leadership and stock ownership with Immunomedics.