A Phase II Study of High-Dose Cetuximab plus Irinotecan in Colorectal Cancer Patients with KRAS Wild-Type Tumors Who Progressed after Standard Dose of Cetuximab plus Irinotecan

Abstract

Objectives: We conducted a phase II clinical trial of high-dose cetuximab plus irinotecan in KRAS wild-type patients who progressed on standard-dose cetuximab plus irinotecan. Methods: Patients who progressed within 4 weeks from receiving a minimum of 6 weeks of standard-dose cetuximab plus irinotecan were included in this study. Cetuximab was administered at 500 mg/m²/week and irinotecan was administered at the same dose/schedule on which each individual patient had previously progressed. The study was closed early after having met its primary end point. Results: Twenty patients were treated. The regimen was found to be efficacious, with 9 patients achieving disease control lasting more than 12 weeks. The median progression-free survival and overall survival were 2.8 and 6.6 months, respectively. The toxicity profile was favorable, with the exception of grade 3–4 hypomagnesemia which was noted in 25% of patients. Conclusions: High-dose cetuximab plus irinotecan rechallenge can re-elicit clinical benefits in patients who have previously failed cetuximab plus irinotecan treatment. The clinical benefits are modest and may be related to cetuximab rechallenge rather than cetuximab dose escalation.

Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-EGFR response

“…In addition a longer interval length between prior and retreatment anti-EGFR therapy demonstrated a non-significant trend favoring an increased likelihood of obtaining a clinical benefit from anti-EGFR retreatment. This study lends support to the notion of anti-EGFR retreatment in metastatic CRC, however the magnitude of benefit from retreatment appears less than previously reported [ 8 , 9 ].…”

“…Another phase II prospective study by Fora et al . reported benefit from EGFR retreatment with a higher dose of cetuximab (500 mg/m2 weekly) in combination with irinotecan in 20 KRAS-wt metastatic CRC patients who had previously progressed on both agents [ 9 ]. A clinical benefit was seen in 9 patients (1 PR and 8 SD) and in an exploratory analysis patients treated >2 months from prior cetuximab progression had an improved PFS, p = 0.02).…”

“…Success with a retreatment strategy utilizing targeted therapy has been reported with other agents in different types of cancer, such as trastuzumab in breast cancer [ 5 ] and sunitinib in gastrointestinal stromal tumor [ 6 ]. Recent small studies have suggested a benefit from a retreatment strategy in colorectal cancer with the use of anti-EGFR therapy [ 7 – 9 ]. In a phase II study by Santini et al .…”

Resistance to anti-epidermal growth factor receptor in metastatic colorectal cancer: What does still need to be addressed?

“…In addition, a retrospective trial by Feng and colleagues demonstrated how patients that had progressed to a FOLFOX or FOLFIRI plus cetuximab first line had better PFS, OS and disease control rate if in second line received a switched chemotherapy regimen (FOLFOX or FOLFIRI, depending on first line) plus cetuximab, than those patients receiving chemotherapy alone [90]. Thus, mechanisms of resistance occur after the onset of progression, but tumors seem to strongly depend on EGFR activation [91]. Accordingly, the proof of concept, prospective, CAPRI 2-GOIM trial will recruit patients with RAS and BRAF WT mCRC treated as follows: patients whose tumors are RAS WT will receive a continuum treatment with cetuximab-based treatment lines (with FOLFIRI, FOLFOX and irinotecan, respectively); for those patients with a RAS mutation detected after PD to first line FOLFIRI-cetuximab, a FOLFOX bevacizumab treatment will be provided as second line.…”

Current Options for Third-line and Beyond Treatment of Metastatic Colorectal Cancer. Spanish TTD Group Expert Opinion

“…44,45 Different studies try to provide evidence about the potential use of re-administering anti-EGFR agents and thus, various strategies and combinations with chemotherapeutic agents, have been tested. [46][47][48][49][50] In a phase II randomized trial, Cremolini et al 51 evaluated the role of the treatment with cetuximab and irinotecan in a total of 29 patients with RAS and BRAF wt mCRC who had progressed to a first-line irinotecan-and cetuximab-based therapy. The study found a response rate of 21% (95% CI, 10%-40%) and a disease control rate (DCR) of 54% (95% CI, 6%-70%), showing that this rechallenge strategy with may be active in patients with acquired resistance to this therapy.…”