Could Cetuximab Maintenance Play a Role in RAS Wild-Type Metastatic CRC?

Maintenance therapy with cetuximab (Erbitux) after FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus cetuximab induction therapy led to better outcomes for patients with RAS wild-type metastatic colorectal cancer (CRC) in a phase II randomized trial, yet it failed to reach the study’s prespecified threshold for success.

At 6 months after randomization, more patients assigned to maintenance therapy with the EGFR inhibitor were alive and without progressive disease compared with an observation group (39% vs 6%), falling short of the primary endpoint goal of 50%, reported Valérie Boige, MD, PhD, of the Gustave Roussy Institute Department of Cancer Medicine in Villejuif, France, and colleagues in JAMA Network Open.

The trial wasn’t powered for comparisons between groups, but over a median follow-up of 40.5 months, numerically higher median progression-free survival (PFS) and overall survival (OS) were observed in the cetuximab arm:

• PFS: 5.3 months (95% CI 3.7-7.4) and 2.0 months (95% CI 1.8-2.7)
• OS: 24.8 months (95% CI 18.7-30.4) and 19.7 months (95% CI 13.3-24.4)

During the maintenance phase, 30 of 67 patients in the cetuximab group (44.8%) experienced at least one grade 3 or higher adverse event related or unrelated to study medication, with rash (11.9%) and diarrhea (6%) reported most frequently.

“Although this randomized clinical trial did not meet its primary endpoint, maintenance cetuximab after induction FOLFIRI plus cetuximab appeared feasible and was associated with longer PFS, OS, and chemotherapy-free intervals than observation,” wrote Boige and colleagues.

In explaining the rationale behind the study, the investigators pointed out that the optimal maintenance strategy after induction chemotherapy with EGFR inhibition for patients with RAS wild-type, metastatic CRC remains uncertain.

They recruited 214 patients (median age 67 years, 65.9% male) from 35 French sites. Among those patients, 139 had an objective response or stable disease after eight cycles of FOLFIRI plus cetuximab and were randomized 1:1 to biweekly cetuximab or observation.

On disease progression, re-induction with FOLFIRI and cetuximab was recommended for 16 weeks and was followed by further maintenance or observation according to the original randomization group.

In the cetuximab group, the objective response rate during maintenance and after first rechallenge was 17.5% (11 of 63 patients) and 10.9% (five of 46), respectively; those rates were 4.8% (three of 63 patients) and 25.9% (14 of 54), respectively, in the observation group.

Median time to strategy failure was 8.7 months (95% CI 7.5-15.0) in the cetuximab group and 10.1 months (95% CI 7.3-10.9) in the observation group.

In an exploratory multivariate analysis, any tumor-activating mutation in mitogen activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization, regardless of treatment group (HR 1.63, 95% CI 1.01-2.62, P=0.04).

“Maintenance cetuximab or treatment breaks after first-line combination FOLFIRI cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor,” the authors observed.

In a commentary accompanying the study, Federica Morano, MD, and Filippo Pietrantonio, MD, both of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, called the study results “disappointing.”

They suggested that a “thorough understanding of the biology underlying anti-EGFR resistance is of paramount importance, especially when it comes to identifying the best strategy (i.e., continuation, treatment break, or drug deescalation) after achieving maximum response in the first-line setting.”

“Although novel findings are improving our understanding of this complex scenario, the clinical decision of treatment deescalation or treatment break should involve a comprehensive and dynamic evaluation of both patient and tumor’s characteristics, as well as the achievement of an optimal cytoreduction, thus supporting a more individualized approach for the choice of treatment duration and intensity,” Morano and Pietrantonio concluded.