First-Line Cetuximab Combo Validated in RAS Wild-Type Colorectal Cancer

Tianshu Liu, MD

The addition of cetuximab (Erbitux) to standard FOLFOX-4 chemotherapy in the first-line treatment of patients with RAS wild-type metastatic colorectal cancer (mCRC) significantly improved survival outcomes in a phase III clinical trial that builds upon the regimen’s efficacy, particularly for Asian patients, and may help pave the way for its approval in China.

The randomized, multicenter TAILOR trial, which was conducted in nearly 400 Chinese patients, demonstrated that the cetuximab plus FOLFOX-4 regimen resulted in a median progression-free survival (PFS) of 9.2 months compared with 7.4 months in similar patients receiving only FOLFOX-4, according to findings presented at the 2016 World Congress on Gastrointestinal (GI) Cancer.¹ Those results translated into a 31% decrease in the risk of disease progression (HR, 0.69; P = .004)

Overall survival (OS) was also significantly improved with cetuximab/FOLFOX-4, with these patients showing median OS of 20.7 months versus 17.8 months in FOLFOX-4—treated patients, for a 24% reduction in the risk of death with the cetuximab regimen (HR, 0.76; P = .02).

The findings mark the first time that the cetuximab/FOLFOX-4 regimen—although established in the United States—has been studied in a randomized trial Chinese population with RAS wild-type mCRC, researchers indicated.¹ It also represents the first time the combination has been prospectively validated for RAS wild-type disease in a clinical trial.

“TAILOR is the first prospective trial evaluating an anti-EGFR antibody in the first-line in patients with RAS wild-type metastatic colorectal cancer,” said Tianshu Liu, MD, of Zhongshan Hospital, which is affiliated with Fudan University in Shanghai, in presenting the results. “The aim of the study was to confirm the efficacy and safety results of FOLFOX-4 plus cetuximab compared with FOLFOX-4 alone that were demonstrated in the phase III CRYSTAL trial and the randomized phase II OPUS trial.”

Those trials helped establish cetuximab plus FOLFOX-4 as an effective first-line treatment regimen for patients with RAS wild-type mCRC, said Liu.

Liu said the TAILOR results support the approval of this treatment in China. “Currently, the first-line treatment options for patients with wild-type RAS metastatic colorectal cancer in China are limited,” said Liu.

In the United States, the FDA initially approved cetuximab in 2004 as a second-line treatment for patients with EGFR-expressing mCRC in combination with irinotecan.²

In 2012, that approval was refined and expanded to include first-line treatment of patients with KRAS wild-type mCRC in combination with FOLFIRI (irinotecan, 5-fluorouracil [5-FU], and leucovorin). The decision was based on retrospective analyses of the CRYSTAL trial, which combined cetuximab with FOLFIRI, and the OPUS trial, which added the targeted agent to FOLFOX-4 (folinic acid, 5-FU, and oxaliplatin).²

In their conference poster, investigators noted that the CRYSTAL and OPUS trials enrolled predominantly Caucasian patents.¹ Additionally, they pointed out that international consensus guidelines recommend FOLFOX as the preferred initial therapy for Asian patients.³

TAILOR randomized 193 patients to standard FOLFOX-4 plus cetuximab, and 200 patients to FOLFOX-4 until the occurrence of disease progression or unacceptable toxicity. Cetuximab was administered at at 400 mg/m² on day 1 and then 250 mg/m² every week. The FOLFOX-4 regimen consisted of oxaliplatin 85 mg/m² on day 1 every 2 weeks; folinic acid at 200 mg/m² on days 1 and 2 every 2 weeks; 5-FU at 400 mg/m² bolus, then 22 hours’ continuous infusion of 600 mg/m² per day on days 1 and 2 every 2 weeks.

Baseline characteristics were balanced between treatment arms. The median age of participants was 56 years and about 26% of patients in each arm had previously received adjuvant chemotherapy. Fourteen percent of the patients in the cetuximab/FOLFOX-4 arm had ≥3 metastatic disease sites (n = 40), compared with 28.5% (n = 57) in the FOLFOX-4 group.

The primary endpoint was PFS by RECIST 1.0, as assessed by an independent review committee, and key secondary endpoints included OS, best overall response rate (ORR), and safety/tolerability.

Compared with patients receiving FOLFOX-4 alone, patients treated with cetuximab plus FOLFOX-4 demonstrated a best ORR of 61.1% versus 39.5%, odds ratio (OR) 2.41 (P <.001), respectively.

“The best overall response rate is in line with that observed in other international trials of cetuximab and FOLFOX,” said Liu.

Patients in the cetuximab plus FOLFOX-4 arm received a higher cumulative chemotherapy dose than patients receiving FOLFOX-4 only. “The higher cumulative dose most likely reflects longer dosing due to prolonged PFS time,” Liu explained.

The incidence of treatment-related adverse events was higher in the cetuximab/FOLFOX-4 arm than it was in the FOLFOX-4 group for (61.9% vs 43.2%, respectively) and leukopenia (26.8% vs 21.1%, respectively), which study investigators associated with the higher cumulative dose of chemotherapy they had received.

“The safety profile of cetuximab plus FOLFOX observed in TAILOR is similar to that seen in previous randomized clinical trials, and there were no unexpected safety findings,” Liu stated.

The results of the TAILOR trial illustrate the importance of biomarkers to guide therapy, said one of the researchers involved in an earlier cetuximab study.

“As the first prospective trial evaluating first-line cetuximab in RAS wild-type patients, these results from TAILOR demonstrate the value and importance of RAS biomarker testing in order to determine the appropriate targeted therapy for individual patients, based on their tumor’s genetic makeup,” said Carsten Bokemeyer, MD, of the University Medical Center in Hamburg-Eppendorf, Germany, who was the primary investigator of the OPUS study but was not involved in the TAILOR trial.

The study was sponsored by Merck KGaA, the German-based company that has licensed marketing rights to cetuximab outside the United States and Canada. Lilly markets the drug in the United States.

References

1. Qin S, Xu J, Wang L, et al. First-line FOLFOX-4 ± cetuximab in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC): the open-label, randomized phase 3 TAILOR trial. Presented at: 18th World Congress on Gastrointestinal Cancer; June 29-July 2, 2016; Barcelona, Spain. LBA-05.
2. National Cancer Institute. FDA approval for cetuximab. http://goo.gl/y6Rn0m. Updated July 2, 2013. Accessed July 2, 2016.
3. Cheng AL, Li J, Vaid AK, et al. Adaptation of international guidelines for metastatic colorectal cancer: an Asian consensus. Clin Colorectal Cancer. 2014;13(3):145-155.

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Although cetuximab plus either FOLFOX or FOLFIRI is now recommended as first-line therapy for patients with RAS wild-type mCRC by the National Comprehensive Cancer Network and European Society for Medical Oncology clinical guidelines, and has been authorized in 90 countries, it is not yet approved in China.