The Battle Between Avastin and Erbitux in Colorectal Cancer Heats Up with the FIRE-3 Results at ASCO 2013
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| Jun 1, 2013
Co-authored by Josh Garcia, Associate Consultant
Another year and the 2013 American Society of Clinical Oncology (ASCO) conference provides more intriguing clinical data to shape the future of oncology therapy. One of the hottest presentations this year (pun intended) is the results from a German cooperative group-sponsored FIRE-3 study (n=592), comparing first-line FOLFIRI in combination with low-dose (5 mg/kg every two weeks) Avastin (bevacizumab, Roche/Genentech) or standard dose Erbitux (cetuximab, Bristol Myers Squibb, Eli Lilly, Merck KGaA) in metastatic colorectal cancer (mCRC) patients with KRAS wild-type tumors. Both targeted agents have previously shown to significantly improve PFS compared with chemotherapy alone, and both have demonstrated a strong trend to OS benefit in previous first-line studies. In the absence of comparative data between the two agents, the current practice patterns have evolved based on safety profile, cost of therapy, order of market entry, and KRAS status. With Avastin the primary biologic option in mCRC patients with a KRAS mutation, the question remained which option was superior in KRAS wild-type tumors. Prospective head-to-head studies were required to compare these two agents in order to definitively answer the question of which agent is the better option in first-line mCRC.
The FIRE-3 results did not disappoint but questions remain after some potentially conflicting results (Stinitzing, Abstract LBA3506). The primary endpoint was overall response rate, which was not significantly different in either arm (62.0% with Erbitux and 58% with Avastin, HR=1.18, p=0.183), but there was a trend to benefit in the Erbitux arm, as well as a higher percentage of complete responses (4.4% versus 1.4%). However, the most interesting conundrum was the fact that there was no difference in progression-free survival with the curves being superimposable (PFS: 10.0 months versus 10.3 months, HR=1.06, p=0.547) but there was a statistically significant benefit in median overall survival (mOS: 28.7 months with Erbitux and 25.0 months with Avastin, HR=0.77, p=0.017). It is the OS Kaplan-Meier curve that tells the full story. The curves begin to separate around 18 months, well after the 10-month PFS median, and the curves continue to separate past the median OS where the superiority of Erbitux arm becomes far more pronounced and is evidently durable.
The immediate question becomes: how can an agent that appears similar in terms of response and identical in terms of PFS, generate such a strong OS benefit? The trial was well balanced, there were no new safety signals. Duration of therapy and rates of liver resection were comparable. Unfortunately, the answer is not yet available though the investigator did offer the possibility of depth of response as an explanation. It is possible that tumor shrinkage was greater with Erbitux, which would not necessarily effect the measurement of PFS but could allow for more effective subsequent lines of therapy due to the smaller tumor size. As evidence, the speaker offered an analysis of the CRYSTAL study that originally evaluated Erbitux in combination with front-line chemotherapy. The analysis was also presented at ASCO this year and suggested tumor volume shrinkage (rather than the strict RECIST response criteria) could predict a strong OS benefit, but not necessarily effect the time to progression (Mansmann, Abstract 3630). A similar analysis will be performed on the FIRE-3 results in the near future.
One final question that remains is: How will the FIRE-3 results influence U.S. and EU physicians? FIRE-3 could be viewed favorably in Europe where first-line use of Erbitux for KRAS wild-type mCRC patients is utilized to a greater extent. FIRE-3 will likely further increase this practice. Conversely in the U.S., Avastin has been highly entrenched as the preferred first-line biologic to use in combination with first-line chemotherapy for nearly a decade. Additionally, U.S. physicians prefer to use FOLFOX in the first line in combination with Avastin, so they may not see the FIRE-3 study as accurately depicting their first-line treatment of choice. However, in late 2013, results are anticipated from the CALGB 80405 study, which has a very similar design as the FIRE-3 study, evaluating Avastin versus Erbitux in the front line colorectal cancer. In this study patients will be allowed to be given FOLFOX or FOLFIRI as the combination chemotherapy, which likely means that this study will be more influential on the U.S. market, compared with FIRE-3. With the CALGB 80405 trial being initiated around the same time as the FIRE-3 study, the oncology community will not have to wait long to digest the full results and implications from both of these studies.