Brivanib Disappoints in KRAS Wild-Type Colorectal Cancer

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.