Carlson, Robert H.
ORLANDO, FL—The fully humanized anti-epidermal growth factor receptor monoclonal antibody panitumumab is approved in the United States and Europe as monotherapy for patients with chemorefractory metastatic colorectal cancer. The Gastrointestinal Cancers Symposium included several presentations about the drug, two of which focused on the safety profile.
A study examining data from five clinical trials of panitumumab, with 812 patients, showed a consistent safety profile across all studies. “This was as anticipated for an anti-EGFR antibody in combination with chemotherapy for metastatic colorectal cancer,” said Jean-Yves Douillard, MD, PhD, Professor and Director of Clinical Translational Research at the University Center Rene Gauducheau in Nantes, France, the study's first author.
Dr. Douillard noted that in Europe the drug is restricted to patients with wild-type KRAS, based on data showing that patients who have KRAS mutation do not benefit from addition of an EGFR inhibitor.
The safety data were collected from the following trials, all multicenter: 181, PRIME (203), 314, PRECEPT, and STEPP.
Patients in the two Phase III studies received FOLFOX or FOLFIRI every two weeks with or without panitumumab at 6.0 mg/kg every two weeks; in the Phase II studies, patients received FOLFIRI every two weeks plus panitumumab at 6.0 mg/kg every two weeks, or irinotecan every three weeks plus panitumumab every two weeks at 9.0 mg/kg.
In the five clinical trials, 763 patients with wild-type KRAS were randomly selected to receive chemotherapy plus panitumumab, and 49 patients with wild-type KRAS who were receiving chemotherapy plus panitumumab were further randomized to prophylactic or reactive skin treatment.
JEAN-YVES DOUILLARD,...Image Tools
Of all patients, 473 received FOLFIRI plus panitumumab, 322 received FOLFOX plus panitumumab, and 17 received irinotecan plus panitumumab.
Skin-related toxicity was seen in 37% of patients in the 181 trial, 36% in the PRIME (203) trial, 20% in the 314 trial, 28% in the PRECEPT trial, and 29% in the STEPP trial. Neutropenia occurred in 20%, 42%, 15%, 23%, and 16% of patients, respectively.
Diarrhea was experienced in 14%, 19%, 13%, 14% and 24% of patients respectively. There was one Grade 5 adverse event of diarrhea, and one Grade 5 adverse event of pulmonary embolism among all five trials.
The most frequent toxicity was skin toxicity, a class-related toxicity, seen at Grade 3–4 in one third of patients, Dr. Douillard reported. “We're now looking at the relationship between skin toxicity and outcome, as has been seen with rituximab.”
He also pointed out the very low rate of infusion-related reaction, five cases out of 823 patients and only Grade 3. “But patients were not receiving premedication in those trials, as opposed to patients receiving cetuximab, which is a mouse antibody—which means that panitumumab can be given safely in the outpatient setting, he said.
Well Tolerated as First-Line Therapy
In another report at the meeting, researchers from Germany, France, Austria, and Sweden found that the combination of panitumumab and the FOLFIRI regimen was well tolerated and showed activity as first-line treatment in patients with metastatic colorectal cancer regardless of KRAS-mutation status.
The objective of that study, the Phase-II 314 Trial, sponsored by Amgen Ltd., was to estimate the effect of KRAS mutation status on objective response rate, duration of response, and toxicity in the first-line setting.
Progression-free survival and time to disease progression both favored patients in the KRAS wild-type study arm.
Importantly, toxicity rates were quite similar between the study arms, said Claus-Henning Köhne, MD, Professor in the Department of Oncology/Hematology at University Clinic Oldenburg in Germany, who presented this primary analysis in a poster session.
Skin toxicity was seen in 29% of the KRAS wild-type group and 32% in the mutant-KRAS group; diarrhea in 23% and 22% respectively; and neutropenia in 16% and 20% of patients.
Complete responses were seen in only 2% of each study arm.
But partial responses were much more frequent—occurring in 54% and 36% of patients, respectively; the rate of stable disease was 34% and 52% respectively; and 7% of patients in each arm had progression of disease.
The median duration of response was 13.0 months in the wild-type KRAS group vs 7.4 months in the mutant-KRAS group; progression-free survival time was 8.9 and 7.2 months, respectively; and time to disease progression was 11.2 months and 7.3 months.
Dr. Köhne also said the resection rate was higher in the KRAS wild-type group (15%) vs the KRAS-mutant group (7%).
“These data are in line with those recently reported in a Phase III study of panitumumab in combination with FOLFOX in the first-line setting—PRIME Study, 203—and FOLFIRI in the second-line setting—181 trial,” he noted.
“In exploratory analysis, the combination of panitumumab with FOLFIRI in the KRAS wild-type population appears to show improvement in progression-free survival and time to disease progression, versus the KRAS mutant population.”
Because panitumumab is a fully human antibody, it is expected to have a low incidence of antibody responses. Researchers at Amgen, the drug's manufacturer, confirmed this in s study of patients receiving panitumumab in two Phase III clinical trials.
A poster study by Amgen researchers concluded that no evidence could be found of an impact on safety in the antibody-positive patients.
A Biacore-based immunoassay and an acid-dissociation ELISA were used to screen for anti panitumumab antibodies in patient serum samples.
All samples confirmed positive in either of these assays were subsequently tested for neutralizing activity in an epidermal carcinoma A431 cell-based bioassay that measured panitumumab-mediated reduction of EGFR phosphorylation in vitro.
Post-dose serum samples were available for immungenicity testing.
And in Study 181, the development of binding anti-panitumumab antibodies was detected in 0.4% of patients (2 of 501) by the Biacore assay; also in 0.4% (2 of 501) by ELISA assay; and in 0.8% (4 of 501) of patients by either study.
In the 203 trial, the development of binding anti panitumumab antibodies was detected in 1.5% of patients (7 of 468) by Biacore, also in 1.5% (7 of 470) by ELISA, and in 3.0% by either assay (14 of 470).
Neutralizing antibodies were not detected in post-dose samples from any patients in the 181 study, while they were detected in samples from 0.4% (2 of 470) in the 203 study.
The researchers (first author was Marta Starcevic, Senior Scientist in the Department of Clinical Immunology) concluded that the incidence of developing antibodies was very low in both studies, and similar for both wild-type and mutant subjects.
© 2010 Lippincott Williams & Wilkins, Inc.