FIRE-3 and ASPECCT: More Questions Arise for anti-EGFR Therapies in Colorectal Cancer
| Sep 30, 2013
Co-authored by Arnold DuBell, Ph.D., M.B.A., Associate Consultant
Two late-breaking abstracts during the colorectal cancer sessions at the 2013 European Cancer Congress were centered on the anti-EGFR therapies Erbitux® (cetuximab, Bristol-Myers Squibb/Eli Lilly/Merck KGaA) and Vectibix® (panitumumab, Amgen/Takeda). Although the data probably won’t immediately change clinical practice, questions continue to arise. If answered favorably, these therapies could conceivably be utilized more strongly in KRAS wild-type patients.
The first presentation was an update of the FIRE-3 data. This trial compared first-line FOLFIRI in combination with low-dose (5 mg/kg every two weeks) Avastin® (bevacizumab, Genentech/Roche/Chugai) or standard dose Erbitux in metastatic colorectal cancer patients with KRAS wild-type tumors. The data presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting indicated that the primary endpoint of an improvement in the response rate was not met (62% with Erbitux and 58% with Avastin, HR 1.18, p=0.183; Stinitzing, Abstract LBA 3506). There was also no difference in progression-free survival (PFS: 10.0 months versus 10.3 months, HR 1.06, p-0.547) but, surprisingly, there was a significant 3.7 month difference in overall survival in favor of Erbitux (OS: 28.7 months versus 25.0 months, HR 0.77, p=0.017). These data still perplex key opinion leaders – how can there be an improvement in overall survival in the absence of a response or PFS benefit?
This question was not directly addressed at the 2013 European Cancer Congress, but another one was: can these results be improved in patients with no RAS mutation? Although mutations in exon 2 of the KRAS gene are the most prevalent mutation type in colorectal cancer patients (approximately 40%) and constituted the intent-to-treat population in the FIRE-3 analysis, other RAS mutations, in particular NRAS or mutations in exons 3 and 4 of the KRAS gene constitute about 10% of metastatic CRC mutations. In a pre-planned exploratory analysis, neither the response rate (65.5% versus 59.6%, p=0.32) nor PFS (10.4 months versus 10.2 months, HR 0.93, p=0.54) were improved in RAS wild-type patients. However, the overall survival benefit was even stronger, with a 7.5 month survival advantage associated with Erbitux: 33.1 months versus 25.6 months, HR 0.70, p=0.011 (Heinemann, Abstract LBA17, ECCO 2013).
Will these new data matter? The discussant to this presentation, Dr. Tabernero, doesn’t recommend changes to current clinical practice until a biological explanation can be provided for the lack of a response rate or PFS benefit. Plenty of theories have been discussed, but to-date there has been no clear answer as to why this incongruous result was observed. This advice will be followed in the United States, where Avastin is strongly utilized by physicians even in KRAS wild-type patients. However, these new data could strengthen Erbitux’s position in Europe, where it is already preferred slightly over Avastin-based regimens in first-line KRAS wild-type patients (Kantar Health, CancerMPact® Treatment Architecture), even more so than after the release of the ASCO data. Dr. Tabernero predicts that two trials will ultimately decide this competition. The first is CALGB 80405, which is evaluating Avastin versus Erbitux in combination with either FOLFOX or FOLFIRI. The second is the GERCOR STRATEGIC-1 trial, which will evaluate two sequences. In arm A, patients will receive first-line Erbitux plus FOLFIRI followed by Avastin plus oxaliplatin-based chemotherapy. In Arm B, patients will receive Avastin plus oxaliplatin-based chemotherapy followed by second-line Avastin in combination with irinotecan-based chemotherapy, and then an anti-EGFR agent (Erbitux or Vectibix) as third-line therapy. The CALGB study is likely to have the greater impact in the U.S., whereas the GERCOR study may prove to have a more European/regional influence.
The second Late-Breaking Abstract in this colorectal cancer session was presentation of the ASPECCT trial (Price, Abstract LBA18, ECCO 2013). ASPECCT was a non-inferiority study which evaluated third-line Erbitux versus Vectibix in 999 metastatic colorectal cancer patients. The study achieved its primary endpoint of non-inferiority in overall survival (Vectibix, 10.4 months versus 10.0 months, HR 0.97, p=0.0007). Vectibix proved non-inferior to Erbitux in progression-free survival as well (4.1 months versus 4.4 months, HR 1.002). The possible advantage for Vectibix, if there is one, is found in an examination of the toxicity profile. Although there is no general change in the level of all toxicities (for example, grade 3: 36.3% versus 31.6%), the use of Vectibix was associated with a decreased incidence of infusion reactions (any grade, 2.8% versus 12.5%), owing to the humanized nature of this antibody).
This trial is unlikely to change clinical practice. Erbitux is strongly entrenched as the anti-EGFR therapy of choice in the U.S. and Europe, and will remain so based on this data. However, ASPECCT is important for another reason ― this trial will allow the conversion of Vectibix’s conditional approval in Europe to a full approval.
Two sets of data were presented at the European Cancer Congress. Although no changes in treatment practices are expected to arise from these data, enough questions should arise, especially from FIRE-3, to make physicians anticipate the arrival of the next set of data.