Survival Benefit Observed With Cetuximab in RAS Wild-Type Colorectal Cancer

Volker Heinemann, MD, PhD

Cetuximab (Erbitux) plus FOLFIRI may offer a survival advantage over FOLFIRI plus bevacizumab (Avastin) in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer who do not have RAS mutations (ie, “all-RAS wild-type tumors”), according to a preplanned analysis of the FIRE-3 study. The data were presented at the 2013 European Cancer Congress (ECC) by Volker Heinemann, MD, PhD, professor of Medical Oncology at the University of Munich in Germany.

“The exclusion of patients with RAS mutations identifies a population which is more likely to benefit from cetuximab,” Heinemann said. “Overall survival was markedly superior, with a gain of about 7.5 months, in the all-RAS wild-type patients receiving first-line therapy with cetuximab. No benefit was observed when patients with RAS-mutant tumors were treated with FOLFIRI plus cetuximab as compared to FOLFIRI plus bevacizumab.”

The RAS category includes both KRAS and NRAS genes. “Upfront determination of RAS mutation status appears highly recommendable in patients with metastatic disease,” Heinemann said.

The FIRE-3 study was a randomized, multicenter trial comparing the efficacy of FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus cetuximab with FOLFIRI plus bevacizumab as first-line treatment in patients with KRAS wild-type metastatic colorectal cancer. In the primary analysis, the two regimens were comparable in terms of objective response rate (ORR, the primary endpoint) and progression-free survival (PFS), but overall survival (OS) was significantly longer—a gain of 3.7 months (P = .017)—in the FOLFIRI/cetuximab arm, though approximately 40% of patients crossed over to the opposite treatment arm.

In a preplanned analysis presented at ECC 2013, the effect of various mutations within the KRAS wild-type (exon 2) population of 592 patients was evaluated. These included mutations in KRAS (exon 3 [codon 59/61], exon 4 [codon 117/146]), NRAS (exon 2 [codon 12/13], exon 3 [codon 59/61], exon 4 [codon 117/146]), and BRAF (V600E). Approximately 15% of patients were found to harbor mutations beyond KRAS exon 2 mutations.

The analysis involved 342 RAS wild-type patients and 178 RAS mutant patients, which included the 113 initially found to be KRAS exon 2 mutant plus the 65 additional newly identified patients. The new mutated groups were comparable to the main study’s intent-to-treat population. The subgroups were compared for ORR, PFS, and OS.

RAS wild-type patients had a median OS of 33.1 months with FOLFIRI plus cetuximab, versus 25.6 months with FOLFIRI plus bevacizumab, a statistically significant difference of 7.5 months (hazard ratio [HR] = 0.70; 95% CI, 0.53-0.92; P = .011). In RAS-mutant patients, however, this difference between the regimens was not observed, as median OS was 16.4 months and 20.6 months, respectively, (HR = 1.20; P = 0.57).

There was no difference between the arms in median PFS for the RAS wild-type patients—about 10 months with either treatment (P = .54)—but for RAS-mutated patients, PFS was longer in the bevacizumab arm—12.2 months vs. 6.1 months (P = .004).

“If you look back at the whole group of RAS and KRAS mutant patients (n = 178) you can see this effect is not so clear anymore—7.5 versus 10.1 months—and you lose significance (P = .085),” he noted.

ORR within both the RAS wild-type and RAS-mutant patients was similar between the arms. In the wild-type population, response rates were 65.5% with cetuximab and 59.6% with bevacizumab (P = .32), while rates within the mutant population were 38.2% and 58.1%, respectively (P = .14), and the KRAS exon 2 mutant plus RAS mutant population (n = 178) were 38.0 and 51.2% (P = 0.097).

Commenting on the study, Josep Tabernero, MD, head of Gastrointestinal Tumors at Vall d’Hebron University in Barcelona, Spain, suggested that, lacking more information about subsequent treatment, clinicians should not alter practice based on the study’s findings.

He was especially concerned that other key endpoints were not significantly different between the treatments. “It is difficult to understand how a treatment that does not increase response rate and progression-free survival may have a big impact on overall survival. This is surprising in the field of cancer,” he said. “It is difficult to compare these regimens when we don’t completely understand what is happening—especially which treatments patients received in the second- and third-line setting.”

Stintzing S, Jung A, Rossius L, et al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract LBA17.

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