Cetuximab Fails First-Line in Gastric Cancer

VIENNA – Adding cetuximab to first-line chemotherapy for gastric cancer was associated with a worse benefit-to-risk ratio in the open-label, randomized, con-trolled, phase III EXPAND trial.

Investigators reported that progression-free survival was nonsignificantly decreased in patients who had received cetuximab (Erbitux) in addition to capecitabine (Xeloda) and cisplatin treatment vs. those just receiving the chemotherapy doublet. Progression-free survival, which was the primary end point, was 4.4 months versus 5.6 months, respectively, with a hazard ratio (HR) of 1.09 (P = .3158).

There was also no benefit in overall survival or objective response rates. Overall survival was 9.4 months vs. 10.7 months (HR = 1.0; P = .96). The best objective response rates were 30% and 29%, respectively.

"Unfortunately, there was no benefit from adding cetuximab to chemotherapy [consisting of] capecitabine and cisplatin as first-line treatment for advanced gastric cancer," said Dr. Florian Lordick, who presented the findings at the European Society for Medical Oncology Congress.

"The results are consistent across subgroups," added Dr. Lordick, of the University Cancer Center Leipzig in Germany.

This is not the first disappointment seen with the use of an epidermal growth factor receptor (EGFR) inhibitor in gastric cancer. Recently reported results of the REAL-3 trial showed that panitumumab (Vectibix) was also not of benefit when added to standard chemotherapy for esophagogastric cancer.

Cetuximab also failed to show a benefit in patients when added to adjuvant oxaliplatin-containing chemotherapy for advanced metastatic colorectal cancer in the PETACC8 trial.

It is approved by the Food and Drug Administration in combination with irinotecan-containing regimens against EGFR-expressing metastatic colorectal cancer.

In the EXPAND study, 870 patients with unresected, advanced adenocarcinoma of the stomach gastric or gastroesophageal junction were rand-omized to receive cisplatin (80 mg/m² on day 1) and capecitabine (1,000 mg/m² twice daily, starting the evening of day 1 until the morning of day 15) with or without additional cetuximab (400 mg/m² initial dose, then 250 mg/m² per week).

The median age of enrolled patients was 59-60 years. Three quarters of participants were men and the main tumor site was the stomach in about a third of the cases with almost all patients having metastatic disease.

"Interestingly, the rate of hematologic adverse events was somewhat lower in the chemotherapy plus cetuximab arm," Dr. Lordick said. Compared with chemotherapy only, the rates of grade 3/4 neutropenia were 22% with cetuximab and 32% without. Grades 3/4 anemia occurred in 9% vs. 11% of patients, respectively.

"This is in contrast to other studies that have been performed in colorectal cancer, head and neck cancer, and lung cancer, where usually an increase of hematologic toxicity is seen with the administration of cetuximab in combination with chemotherapy," Dr. Lordick observed.

Nonhematologic adverse events, however, were more common in the cetuximab-containing vs. cetuximab-free arm, including grade 3 or 4 skin reactions (13% vs. 0%), diarrhea (8% vs. 4%), hand-foot syndrome (7% vs. 2%), hypomagnesemia (11% vs. 1%), and hypokalemia (13% vs. 9%).

Patients given the cetuximab-containing regimen also had a slightly higher rate of grade 3/4 cardiac adverse events (6.7% vs. 4.1 %).

"This study confirms a little bit what we heard at ASCO in the REAL-3 trial," said Dr. Arnaud D. Roth of Geneva University Hospital. Dr. Roth, who was not involved in the EXPAND study, noted that it was a well-designed and -conducted study and although negative, provided an excellent opportunity to conduct translational research.

However, Dr. Roth disagreed that this was the right setting to learn much more about anti-EGFRs and gastric cancer. Nevertheless, gaining access to the data and biospecimens was important and "a moral obligation" considering the patients who had given their consent for their participation in the trial.

"The good news is that tissue is available from 97% of patients and biomarker analysis is ongoing," Dr. Lordick said prior to Dr. Roth’s comments.

The study was funded by Merck KGaA. Dr. Lordick has received research funding and honoraria from Merck KGaA, GlaxoSmithKline, and Fresenius Biotech, and advisory fees from Amgen, Ganymed GmbH, Ribological GmbH, and Roche. Dr. Roth has acted as an adviser for Merck.

VIENNA – Adding cetuximab to first-line chemotherapy for gastric cancer was associated with a worse benefit-to-risk ratio in the open-label, randomized, con-trolled, phase III EXPAND trial.

Investigators reported that progression-free survival was nonsignificantly decreased in patients who had received cetuximab (Erbitux) in addition to capecitabine (Xeloda) and cisplatin treatment vs. those just receiving the chemotherapy doublet. Progression-free survival, which was the primary end point, was 4.4 months versus 5.6 months, respectively, with a hazard ratio (HR) of 1.09 (P = .3158).

There was also no benefit in overall survival or objective response rates. Overall survival was 9.4 months vs. 10.7 months (HR = 1.0; P = .96). The best objective response rates were 30% and 29%, respectively.

"Unfortunately, there was no benefit from adding cetuximab to chemotherapy [consisting of] capecitabine and cisplatin as first-line treatment for advanced gastric cancer," said Dr. Florian Lordick, who presented the findings at the European Society for Medical Oncology Congress.

"The results are consistent across subgroups," added Dr. Lordick, of the University Cancer Center Leipzig in Germany.

This is not the first disappointment seen with the use of an epidermal growth factor receptor (EGFR) inhibitor in gastric cancer. Recently reported results of the REAL-3 trial showed that panitumumab (Vectibix) was also not of benefit when added to standard chemotherapy for esophagogastric cancer.

Cetuximab also failed to show a benefit in patients when added to adjuvant oxaliplatin-containing chemotherapy for advanced metastatic colorectal cancer in the PETACC8 trial.

It is approved by the Food and Drug Administration in combination with irinotecan-containing regimens against EGFR-expressing metastatic colorectal cancer.

In the EXPAND study, 870 patients with unresected, advanced adenocarcinoma of the stomach gastric or gastroesophageal junction were rand-omized to receive cisplatin (80 mg/m² on day 1) and capecitabine (1,000 mg/m² twice daily, starting the evening of day 1 until the morning of day 15) with or without additional cetuximab (400 mg/m² initial dose, then 250 mg/m² per week).

The median age of enrolled patients was 59-60 years. Three quarters of participants were men and the main tumor site was the stomach in about a third of the cases with almost all patients having metastatic disease.

"Interestingly, the rate of hematologic adverse events was somewhat lower in the chemotherapy plus cetuximab arm," Dr. Lordick said. Compared with chemotherapy only, the rates of grade 3/4 neutropenia were 22% with cetuximab and 32% without. Grades 3/4 anemia occurred in 9% vs. 11% of patients, respectively.

"This is in contrast to other studies that have been performed in colorectal cancer, head and neck cancer, and lung cancer, where usually an increase of hematologic toxicity is seen with the administration of cetuximab in combination with chemotherapy," Dr. Lordick observed.

Nonhematologic adverse events, however, were more common in the cetuximab-containing vs. cetuximab-free arm, including grade 3 or 4 skin reactions (13% vs. 0%), diarrhea (8% vs. 4%), hand-foot syndrome (7% vs. 2%), hypomagnesemia (11% vs. 1%), and hypokalemia (13% vs. 9%).

Patients given the cetuximab-containing regimen also had a slightly higher rate of grade 3/4 cardiac adverse events (6.7% vs. 4.1 %).

"This study confirms a little bit what we heard at ASCO in the REAL-3 trial," said Dr. Arnaud D. Roth of Geneva University Hospital. Dr. Roth, who was not involved in the EXPAND study, noted that it was a well-designed and -conducted study and although negative, provided an excellent opportunity to conduct translational research.

However, Dr. Roth disagreed that this was the right setting to learn much more about anti-EGFRs and gastric cancer. Nevertheless, gaining access to the data and biospecimens was important and "a moral obligation" considering the patients who had given their consent for their participation in the trial.

"The good news is that tissue is available from 97% of patients and biomarker analysis is ongoing," Dr. Lordick said prior to Dr. Roth’s comments.

The study was funded by Merck KGaA. Dr. Lordick has received research funding and honoraria from Merck KGaA, GlaxoSmithKline, and Fresenius Biotech, and advisory fees from Amgen, Ganymed GmbH, Ribological GmbH, and Roche. Dr. Roth has acted as an adviser for Merck.

VIENNA – Adding cetuximab to first-line chemotherapy for gastric cancer was associated with a worse benefit-to-risk ratio in the open-label, randomized, con-trolled, phase III EXPAND trial.

Investigators reported that progression-free survival was nonsignificantly decreased in patients who had received cetuximab (Erbitux) in addition to capecitabine (Xeloda) and cisplatin treatment vs. those just receiving the chemotherapy doublet. Progression-free survival, which was the primary end point, was 4.4 months versus 5.6 months, respectively, with a hazard ratio (HR) of 1.09 (P = .3158).

There was also no benefit in overall survival or objective response rates. Overall survival was 9.4 months vs. 10.7 months (HR = 1.0; P = .96). The best objective response rates were 30% and 29%, respectively.

"Unfortunately, there was no benefit from adding cetuximab to chemotherapy [consisting of] capecitabine and cisplatin as first-line treatment for advanced gastric cancer," said Dr. Florian Lordick, who presented the findings at the European Society for Medical Oncology Congress.

"The results are consistent across subgroups," added Dr. Lordick, of the University Cancer Center Leipzig in Germany.

This is not the first disappointment seen with the use of an epidermal growth factor receptor (EGFR) inhibitor in gastric cancer. Recently reported results of the REAL-3 trial showed that panitumumab (Vectibix) was also not of benefit when added to standard chemotherapy for esophagogastric cancer.

Cetuximab also failed to show a benefit in patients when added to adjuvant oxaliplatin-containing chemotherapy for advanced metastatic colorectal cancer in the PETACC8 trial.

It is approved by the Food and Drug Administration in combination with irinotecan-containing regimens against EGFR-expressing metastatic colorectal cancer.

In the EXPAND study, 870 patients with unresected, advanced adenocarcinoma of the stomach gastric or gastroesophageal junction were rand-omized to receive cisplatin (80 mg/m² on day 1) and capecitabine (1,000 mg/m² twice daily, starting the evening of day 1 until the morning of day 15) with or without additional cetuximab (400 mg/m² initial dose, then 250 mg/m² per week).

The median age of enrolled patients was 59-60 years. Three quarters of participants were men and the main tumor site was the stomach in about a third of the cases with almost all patients having metastatic disease.

"Interestingly, the rate of hematologic adverse events was somewhat lower in the chemotherapy plus cetuximab arm," Dr. Lordick said. Compared with chemotherapy only, the rates of grade 3/4 neutropenia were 22% with cetuximab and 32% without. Grades 3/4 anemia occurred in 9% vs. 11% of patients, respectively.

"This is in contrast to other studies that have been performed in colorectal cancer, head and neck cancer, and lung cancer, where usually an increase of hematologic toxicity is seen with the administration of cetuximab in combination with chemotherapy," Dr. Lordick observed.

Nonhematologic adverse events, however, were more common in the cetuximab-containing vs. cetuximab-free arm, including grade 3 or 4 skin reactions (13% vs. 0%), diarrhea (8% vs. 4%), hand-foot syndrome (7% vs. 2%), hypomagnesemia (11% vs. 1%), and hypokalemia (13% vs. 9%).

Patients given the cetuximab-containing regimen also had a slightly higher rate of grade 3/4 cardiac adverse events (6.7% vs. 4.1 %).

"This study confirms a little bit what we heard at ASCO in the REAL-3 trial," said Dr. Arnaud D. Roth of Geneva University Hospital. Dr. Roth, who was not involved in the EXPAND study, noted that it was a well-designed and -conducted study and although negative, provided an excellent opportunity to conduct translational research.

However, Dr. Roth disagreed that this was the right setting to learn much more about anti-EGFRs and gastric cancer. Nevertheless, gaining access to the data and biospecimens was important and "a moral obligation" considering the patients who had given their consent for their participation in the trial.

"The good news is that tissue is available from 97% of patients and biomarker analysis is ongoing," Dr. Lordick said prior to Dr. Roth’s comments.

The study was funded by Merck KGaA. Dr. Lordick has received research funding and honoraria from Merck KGaA, GlaxoSmithKline, and Fresenius Biotech, and advisory fees from Amgen, Ganymed GmbH, Ribological GmbH, and Roche. Dr. Roth has acted as an adviser for Merck.