In patients with KRAS wild-type metastatic colorectal cancer, outcomes were comparable whether patients received the epidermal growth factor receptor (EGFR) inhibitor panitumumab (Vectibix) or the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin). This was shown both in the first-line and second-line settings, in randomized phase II studies presented at the 2013 Gastrointestinal Cancers Symposium.
While bevacizumab is FDA-approved for the first-line treatment of patients with metastatic colorectal cancer in conjunction with a fluorouracil (5-FU)–based regimen or FOLFOX (leucovorin, 5-FU, oxaliplatin)/FOLFIRI (leucovorin, 5-FU, irinotecan), panitumumab is indicated as a monotherapy for the treatment of EGFR-expressing metastatic colorectal cancer with disease progression on or following FOLFOX/FOLFIRI regimens. In the European Union, panitumumab is indicated for wild-type KRAS metastatic colorectal cancer in the first- and second-line settings with FOLFOX and FOLFIRI, respectively, or in third-line treatment as a monotherapy.
The phase II PEAK study compared the drugs in 285 treatment-naive patients with metastatic unresectable KRAS wild-type colorectal cancer, in conjunction with modified FOLFOX6.1 The phase II SPIRITT trial evaluated both drugs paired with FOLFIRI for the second-line treatment of 182 patients with KRAS wild-type disease previously treated with bevacizumab.2 Both were labeled “estimation studies” and were not formal, hypothesis-testing trials. The senior author for both investigations was William Go, MD, PhD, Clinical Research Senior Medical Scientist in Hematology-Oncology at Amgen, Thousand Oaks, California.
“To our knowledge, the PEAK study is the first prospective trial comparing an anti-EGFR agent to bevacizumab in combination with an oxaliplatin-based regimen in KRAS wild-type patients with treatment-naive advanced colorectal cancer,” said Lee S. Schwartzberg, MD, Senior Partner and Medical Director of The West Clinic in Memphis.
Median progression-free survival was 10.9 months with panitumumab and 10.1 months with bevacizumab (hazard ratio [HR] = 0.87; P = .35). Median overall survival has not been reached with
panitumumab and was 25.4 months with bevacizumab (HR = 0.72; P = 0.14).
The overall response rates were 58% and 54%, and the resection rates were 13% and 11% for panitumumab and bevacizumab, respectively. Treatment exposure to the individual agents and number of cycles received were the same between the arms.
In the subgroup analysis of treatment hazard ratios, no clear differences were observed, although there was a suggestion that progression-free survival may be better with panitumumab among patients with three or more metastatic sites (HR = 0.52). For overall survival, patients who were young, with a high tumor burden and with high levels of lactate dehydrogenase—which often cluster together, he said—appeared to fare better with panitumumab as well, though these are hypothesis-generating observations only, according to Dr. Schwartzberg.
The safety profile in both treatment arms was similar to previous studies, and the treatment discontinuation rates due to adverse events were similar between the arms: 24% with panitumumab and 27% with bevacizumab. Grade 3/4 adverse events occurred in 86% and 76%, respectively.
“Based on these findings, I am very comfortable treating a KRAS wild-type patient with panitumumab first-line with FOLFOX,” Dr. Schwartzberg said.
Same Conclusion in Second-line Study
The drugs also were comparable in the second-line setting, reported J. Randolph Hecht, MD, Professor of Medicine and Director of the UCLA Gastrointestinal Oncology Program at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles. He presented the results of the SPIRITT trial, which enrolled 182 patients with KRAS wild-type colorectal cancer who had previously received bevacizumab and oxaliplatin-based treatment but no prior irinotecan or anti-EGFR therapy. The biologics were given along with FOLFIRI.
Median progression-free survival was 7.7 months with panitumumab and 9.2 months with bevacizumab (HR = 1.01). Median overall survival was 18.0 and 21.4 months, respectively (HR = 1.06), Dr. Hecht reported. Median progression-free survival and overall survival were both higher than was found in previous second-line treatment studies of these agents, he noted.
Twice as many bevacizumab-treated patients received subsequent anti-EGFR treatment vs panitumu-
mab-treated patients (54% vs 26%). Subsequent anti-VEGF therapy was received by 20% of the panitumumab arm and 24% of the bevacizumab arm.
Response rates were higher with panitumumab/FOLFIRI vs bevacizumab/FOLFIRI: 32% vs 19%. This difference, along with the difference in toxicity, can be used to guide treatment decisions, according to Dr. Hecht.
“These drugs are both reasonable options,” he commented. “Off study, my decision to use one or the other partly depends on the patient’s need to achieve a response. If the patient has a large tumor burden and is progressing rapidly, this is where I might use panitumumab. On the other hand, if I am concerned about skin toxicity, I may use bevacizumab.”
More toxicity attributed to known side effects of anti-EGFRs (skin toxicity, hypomagnesemia) was noted for panitumumab in the SPIRITT trial—30% of patients had skin toxicity of at least grade 3.
The worst of grade 3/4 adverse events were recorded for 78% of the panitumumab arm vs 65% of the bevacizumab arm, which did not appear to impact discontinuation rates (29% vs 25% rates of discontinuation due to adverse events, respectively). ■
Disclosure: Dr. Schwartzberg has served as aconsultant or advisor for Amgen. Dr. Hecht has received research funding from Amgen. Dr. Go is in a leadership position at and owns stock in Amgen.
1. Schwartzberg LS, Rivera F, Karthaus M, et al: PEAK (study 20070509): A randomized phase II study of mFOLFOX6 with either panitumumab or bevacizumab as first-line treatment in patients with unresectable wild-type KRAS metastatic colorectal cancer. 2013 Gastrointestinal Cancers Symposium. Abstract 446. Presented January 26, 2013.
2. Hecht JR, Cohn A, Dakhil S, et al: SPIRITT (study 2006014): A randomized phase II study of FOLFIRI with either panitumumab or bevacizumab as second-line treatment in patients with wild-type KRAS metastatic colorectal cancer. 2013 Gastrointestinal Cancers Symposium. Abstract 454. Presented January 26, 2013.
Two gastrointestinal cancer experts commented on the findings in interviews with The ASCO Post. Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, noted, “The PEAK and SPIRITT trial were decently designed, decently powered randomized phase II trials, and the results...