No Panitumumab Benefit Seen in Colorectal Cancer with KRAS Mutations

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.