Phase 2 study of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type metastatic colorectal cancer: JACCRO CC-08

Abstract

Background Regorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC). Methods This Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses. Results Among 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4–60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group. Conclusions Irinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial. Clinical trial registration UMIN000010638

Biomarker-Guided Anti-EGFR Rechallenge Therapy in Metastatic Colorectal Cancer

“…Moreover, the mPFS of rechallenge therapy was longer in patients that responded to prior therapy with cetuximab/panitumumab (4.9 vs. 2.5 months). Similar results were observed in the JACCRO CC-08 study, in which 34 patients with KRAS WT mCRC received irinotecan and cetuximab as third line rechallenge treatment [ 14 ]. In the ITT population, mPFS and mOS were, respectively, 2.4 and 8.2 months.…”

“…However, in the absence of phase III randomized trials, there are several open questions, including the choice of the best rechallenge regimen, as well as the identification of predictive biomarkers of response to guide patient selection. The most used rechallenge regimen in prospective and retrospective trials is represented by the combination of irinotecan plus cetuximab [ 11 , 12 , 13 , 14 , 37 , 38 , 40 , 41 , 42 ]. The main advantage of this scheme is that both compounds are largely available in clinical practice.…”

“…In the CRICKET and CAVE mCRC trials, a period of at least 4 months after the discontinuation of EGFRi was required. Of note, post hoc subgroup analysis showed that a longer anti-EGFR-free interval was associated with better outcomes [ 14 , 38 , 39 ]. These data were not confirmed by the retrospective study by Rossini and colleagues [ 40 ].…”

“…The predictive role of liquid biopsy has been confirmed by two independent groups [ 13 , 15 ]. Sunakawa and colleagues reported a post hoc analysis of JACCRO CC-08 ( n = 34) and CC-09 ( n = 25) studies, which assessed rechallenge with irinotecan plus anti-EGFR mAbs for KRAS WT mCRC patients [ 13 , 14 ]. In 16 out of 59 patients, serial plasma samples were available for ctDNA analysis.…”

“…Recently, few studies have demonstrated that retreatment with anti-EGFR MAbs in the third or further lines of treatment in mCRC patients, which have previously obtained clinical benefit by first-line therapy with anti-EGFR MAbs plus chemotherapy, could lead to improved OS [ 11 , 12 , 13 , 14 , 15 ]. The rationale beyond this “rechallenge” strategy is that, after disease progression to first line EGFR-based chemotherapy, a treatment “holiday” from anti-EGFR drugs results in RAS mutant cancer cell decay, restoring the sensitivity of cancer cells to cetuximab or panitumumab [ 16 , 17 , 18 ].…”