FROM THE JOURNAL OF CLINICAL ONCOLOGY
(FRONTLINE MEDICAL NEWS) – The sequence of antibody agents may affect overall survival for individuals with metastatic colorectal cancer (mCRC) according to new analysis of data from a large clinical trial comparing two antibody therapies used in conjunction with a standard systemic regime.
Tumor biology may be modified when antibody therapies are used, affecting the tumor’s susceptibility to later therapies, said Dr. Dominik Modest of the University Hospital Grosshadern (Munich), and his coauthors.
Individuals with mCRC were studied in the FIRE-3 trial, an open-label, randomized phase III clinical trial of cetuximab or bevacizumab in combination with FOLFIRI (fluorouracil plus folinic acid in combination with irinotecan) for patients with metastatic colorectal cancer (n = 592, KRAS exon 2 wild-type and n = 400, RAS wild-type). First-line use of cetuximab, an anti–epidermal growth factor receptor (anti-EGFR) agent, was compared head-to-head with first-line use of bevacizumab, an anti–vascular endothelial growth factor (anti-VEGF) agent.
For this population with advanced disease, the study protocol permitted use of an extensive array of second-, third-, and later-line therapies, as well as tumor-directed surgery and radiation therapy. Thus, a subset of FIRE-3 patients in each arm received first one antibody therapy, then the other, allowing investigators to explore the effect of agent sequence.
Though the analysis was predetermined, investigators were interested in explaining an earlier finding from FIRE-3: The cetuximab arm patients had significantly prolonged overall survival (OS) compared with the bevacizumab arm, despite no significant difference in progression-free survival (PFS) or response rate between the treatment arms in either the KRAS exon 2 wild-type intention-to-treat population, or the RAS wild-type group.
On analysis, patients who crossed over to receive oxaliplatin-based chemotherapy plus cetuximab or panitumumab after initial bevacizumab (n = 38) were compared with those who received oxaliplatin-based chemotherapy in combination with bevacizumab after initial cetuximab (n = 67). PFS after second-line therapy was slightly longer for patients who received initial cetuximab (6.3 vs. 5.7 months for KRAS exon 2 wild-type group and 7.3 vs. 5.8 months for RAS wild-type group), though the differences were not statistically significant.
However, overall survival after second-line therapy was significantly longer for the intention-to-treat population when cetuximab was the initial treatment (16.3 months vs. 13.2 months, P = .0021), as was PFS after second line therapy (6.5 vs. 4.7 months, P less than 0.001).
“Taken together, it seems that the sequential application of anti-EGFR agents followed by second-line anti-VEGF therapy achieves more favorable results than the reverse sequence,” said Dr. Modest and his associates. Particularly for patients witth RAS wild-type tumors, “first-line application of anti EGFR–directed therapy may therefore represent an optimal condition for effective subsequent therapy including antiangiogenic agents,” they said.
Dr. Modest and his coauthors cautioned that although poststudy treatment analysis was predefined for FIRE-3, their findings are observational and should not replace prospectively randomized trials designed to compare cancer therapy sequences.
The study was sponsored by Merck KGaA. The study authors report multiple financial disclosures for various pharmaceutical companies.
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