Cetuximab retreatment in patients with metastatic colorectal cancer who exhibited a clinical benefit in response to prior cetuximab: A retrospective study

Abstract

Clinical benefits of cetuximab retreatment in patients with metastatic colorectal (mCRC) have been reported. In the present study, the effect of cetuximab retreatment on predictive markers was investigated by evaluating the clinical benefit of initial cetuximab treatment prior to cetuximab retreatment. Between November 2012 and March 2017, 14 patients with KRAS proto-oncogene GTPase exon 2 wild-type mCRC who exhibited a clinical benefit (confirmed stable disease for at least 6 months or a clinical response) to an initial cetuximab-based regimen, who received multiple lines of chemotherapy following disease progression and ultimately received a second cetuximab and irinotecan regimen, were retrospectively analyzed. For retreatment, patients received bi-weekly irinotecan (120–150 mg/m2) combined with cetuximab (400 mg/m2 as an initial dose, followed by 250 mg/m2, weekly). The median age of the 14 patients (11 males, 3 females) was 68 years (32–77). The median progression-free survival (PFS) following prior cetuximab-based therapy was 6.6 months (range, 4.1–18.4). Initial cetuximab treatment was administered as a first-line treatment in 11 patients, a second-line treatment in 1 patient and a third-line treatment in 2 patients. The median interval time between the last cycle of initial cetuximab-based therapy and the first cycle of cetuximab retreatment was 13.1 months (range, 6.0–37.1). The objective response rate of cetuximab retreatment was 21.4% and the median PFS was 4.4 months (95% confidence interval, 1.4–5.6). The Spearman's correlation coefficient for the PFS following retreatment and duration of initial cetuximab-based regimens demonstrated a more marked correlation compared with that between the PFS following retreatment and the interval time between the two regimens (r=0.45, P=0.11 vs. r=0.08, P=0.79). Cetuximab retreatment may provide clinical benefit to patients with mCRC who were good responders with longer periods of initial cetuximab-based therapy.

Relationships among KRAS mutation status, expression of RAS pathway signaling molecules, and clinicopathological features and prognosis of patients with colorectal cancer

“…These amino acid mutations impair GTPase hydrolase activity and maintain the protein in an activated state, which results in continuous signaling to downstream effectors, even in the absence of extracellular stimulation. In our study, we detected a KRAS mutation rate of 30.9%, which is consistent with previous reports of 30%-40% in China[28] and was lower than those (30%-50%) observed in other countries[27,29-31].…”

“…In this manner, the mutant KRAS gene results in a constitutively active GTP-bound state and the activation of downstream pro-proliferative signaling pathways[25,26]. The most common oncogenic mutations in CRCs are point mutations at positions 12, 13, and 61 of KRAS , with approximately 90% being in codons 12 and 13[22-27]. These amino acid mutations impair GTPase hydrolase activity and maintain the protein in an activated state, which results in continuous signaling to downstream effectors, even in the absence of extracellular stimulation.…”

Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…Due to few efficacious options in later lines of therapy, there has been considerable interest in the possibility of retreating with a systemic therapy used during an earlier line of treatment. Most studies that have reported on this approach have been retrospective, detailing institutional experiences retreating with chemotherapeutics [31][32][33] or targeted therapies (eg, epidermal growth factor receptor [EGFR] inhibitors) 31,[34][35][36][37][38] and concluded that a retreatment approach was feasible, based on response and/or toxicity data. However, these studies were mainly small and did not differentiate between patients who stopped therapy due to progression compared with other reasons, limiting the quality of these data.…”

Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer

“…Outcomes were better in patients who benefited in the first-line setting with cetuximab, and, notably, in those with a longer interval between the last dose of cetuximab and progression on second-line therapy. 16 – 18 Moreover, the prospective phase II Cricket trial demonstrated an ORR of 21.5% with cetuximab-based re-challenge treatment, with higher PFS and OS when patients selected by ctDNA analysis did not present RAS mutation in plasma. 19 This, and the previous results, strongly support the value of ctDNA-based selection of patients for the sequential use of cetuximab or panitumumab in refractory patients.…”