New FIRE-3 Analysis Shows Importance of Subsequent Therapies on mCRC Outcomes

Dominik P. Modest, MD

Sequence of therapies may be more significant versus single agents in treating patients with metastatic colorectal cancer (mCRC), according to an analysis of subsequent therapies in the FIRE-3 trial published in the Journal of Clinical Oncology.

In the analysis, choice, efficacy, and duration of second- and third-line therapies were evaluated in patients enrolled in the FIRE-3 trial with KRAS wild-type (exon 2) or RAS wild-type mCRC. Overall, patients who received cetuximab (Erbitux) as a first-line therapy followed by bevacizumab (Avastin) as a second-line therapy demonstrated improved progression-free and overall survival (OS) compared with patients who first received bevacizumab and subsequently cetuximab.

“Our data suggest that the sequence of drug application might be more important than exposure to single agents,” the authors noted. “In patients with RAS wild-type tumors, first-line application of anti—epidermal growth factor receptor–directed therapy may represent a favorable condition for promoting effective subsequent therapy, including antiangiogenic agents.”

In FIRE-3, a survival benefit was demonstrated with cetuximab combined with FOLFIRI over FOLFIRI plus bevacizumab in the first-line setting for patients with RAS wild-type mCRC. The median OS was 33.1 months with FOLFIRI plus cetuximab versus 25.6 months with bevacizumab, defined as a statistically significant difference of 7.5 months (hazard ratio [HR], 0.70; 95% CI, 0.53-0.92; P = .011). There was no difference with median progression-free survival (PFS) or response rate between the two arms.

Of the 592 patients in the intent-to-treat population, 414 (69.9%) received second-line and 256 (43.2%) received third-line therapies. In the subsequent treatment lines, 47.1% of patients who originally received FOLFIRI plus cetuximab (arm A) received bevacizumab, while 52.2% who originally received FOLFIRI plus bevacizumab (arm B) either received cetuximab or panitumumab. Oxaliplatin was subsequently administered in 55.9% of patients in arm A and 53.2% in arm B.

Second-line therapy was administered for a median duration of 5.0 months (arm A) versus 3.2 months (arm B; P <.001). PFS2nd was defined as the time from first application of second-line therapy to disease progression or death resulting from any cause. OS2nd was defined as the time from first application of second-line therapy to death resulting from any cause, and OS1 was calculated as the time from random assignment in FIRE-3 to death resulting from any cause. PFS2nd, OS2nd, and OS1 were assessed by the Kaplan-Meier method and compared using log-rank tests.

PFS2nd and OS2nd were both longer in KRAS wild-type patients who received first-line cetuximab than in those treated with frontline bevacizumab. In arm A, PFS2nd was 6.5 months versus 4.7 months in arm B (HR, 0.68; 95% CI, 0.54-0.85; P <.001). OS2nd was 16.3 months versus 13.2 months, respectively (HR, 0.70; 95% CI, 0.55-0.88; P = .0021).

Overall response rates were similar between the cetuximab (19.7%) and bevacizumab (20.9%) arms for KRAS wild-type (exon 2) patients.

For RAS wild-type patients, PFS2nd was 6.7 months in arm A and 4.8 months for arm B. OS2nd was 17.6 months for patients treated with frontline cetuximab and 14.8 months for patients who received first-line bevacizumab.

“These data indicate a significant reduction in population size with each successive treatment line and support the assumption that first-line therapy, addressing 100% of patients, remains the most important component of mCRC treatment,” the authors stated.

In both the KRAS and RAS populations, “no antibody crossover” (patients did not receive an antibody or continued on first-line antibody) versus antibody crossover in subsequent therapy lines attributed to a trend toward longer OS1 (KRAS: 30.8 vs 26.5 months; HR, 0.78; 95% CI, 0.60-1.03; P = .079; RAS: 32.9 vs 28.1 months; HR, 0.80; 95% CI, 0.58-1.11; P = .176). Similar findings were recorded for no oxaliplatin use in additional therapies versus oxaliplatin use.

“This finding supports our hypothesis that choice of second-line therapy per se does not determine OS. Stated differently, the effect of second-line therapy on OS in part depends on the previous regimen. Therefore, selection of first-line therapy remains the most important treatment decision, not only because it addresses the majority of patients, but also because it determines choice, duration, and efficacy of subsequent treatments,” the authors wrote in their conclusion.

Modest DP, Stintzing S, von Weikersthsl LF, et al. Impact of subsequent therapies on outcome of the FIRE-3/AIO KRK0306 trial: first-line therapy with FOLFIRI plus cetuximab or bevacizumab in patients with KRAS wild-type tumors in metastatic colorectal cancer [published online August 10, 2015]. J Clin Oncol. doi: 10.1200/JCO.2015.61.2887.