Maintenance therapy following an anti-EGFR-based induction regimen in metastatic colorectal cancer (mCRC): A network meta-analysis of clinical trials.

Abstract

128 Background: A fluoropyrimidine with or without bevacizumab is often used in clinical practice as maintenance therapy after a first-line chemotherapy + bevacizumab induction in mCRC. However, the role of maintenance following an anti-EGFR-based induction and the optimal regimen are not well established. Methods: We searched PubMed and conferences’ proceedings for clinical trials assessing maintenance therapy after first-line treatment for RAS WT mCRC. Two independent reviewers excluded single-arm studies and retrospective reports from trials that were not designed to assess maintenance therapy. We used the method of Guyot et. al. to obtain the individual patient data, followed by a Cox procedure to derive the survival hazard ratios (HR) from studies that did not report that value. Safety analysis included grade 3-4 asthenia, neuropathy, neutropenia, rash, and diarrhea. We performed a random-effects bayesian network metanalysis using the package “GeMTC R Package” to compare all treatment strategies included (anti-EGFR, anti-EGFR + chemotherapy [CT], CT alone, and observation). The risk of bias was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. Results: The systematic review retrieved 145 studies from which 142 were excluded. Two additional studies were found in the Conferences’ Proceedings review. Consequently, 5 studies were included in this NMA. In terms of Progression-Free Survival (PFS), there was a benefit of anti-EGFR and anti-EGFR+CT versus CT alone (HR 0.63 [95%CrI 0.31-1.30] and 0.72 [95%CrI 0.41-1.30], respectively). The rank probability of anti-EGFR being the best option considering PFS was 61%. In terms of Overall Survival (OS), the benefit of anti-EGFR and anti-EGFR+CT versus CT alone was statistically weak (HR 0.92 [95%CrI 0.54-1.50] and 0.84 [95%CrI 0.57-1.20], respectively). The rank probability of anti-EGFR+CT be the best option in terms of OS was 51%. Comparing anti-EGFR versus anti-EGFR+CT resulted in no statistically significant difference. Anti-EGFR-containing regimens increased the rate of rash and diarrhea compared to CT alone (RR 11.23 and 1.23, respectively). The risk of bias was average low, except for the unclear risk of selection bias linked to unpublished studies. Conclusions: Anti-EGFR±CT maintenance therapy improves PFS and OS compared to CT alone or observation in RAS WT mCRC, with manageable safety profile.

Current concepts of anti-EGFR targeting in metastatic colorectal cancer

“…To summarize these different approaches and often conflicting results, a recent metanalysis was performed and revealed a PFS and even OS benefit for continuation of an EGFR-based doublette or active maintenance with EGFR + 5+FU over 5-FU or EGFR inhibitor monotherapy or observation ( 103 ). These findings were confirmed by a further meta-analysis of a larger real-world cohort and individual patient data pooled observations from the PANAMA and VALENTINO trial ( 104 – 107 ).…”

New developments in targeted therapy for metastatic colorectal cancer

“…Maintenance therapy with EGFR antibodies has been shown to improve PFS in some studies 20 , 21 ; however, it remains unclear whether they should be used alone or with fluoropyrimidines. 22 , 23 While fluoropyrimidine-based therapy has been used as maintenance for mCRC, the recent PANAMA trial has established a modest PFS improvement with the addition of panitumumab to maintenance fluoropyrimidine over fluoropyrimidine alone (8.8 versus 5.7 months, p = 0.014).…”

“…The result has been recently reported, showing that four-drug regimen did not improve PFS (12.7 versus 12.3 months, p = 0.277) nor ORR (73% versus 76%, p = 0.526) over the three-drug regimen, with notably higher rates of grade 3-4 adverse events (AEs) (69% versus 57%). 19 Maintenance therapy with EGFR antibodies has been shown to improve PFS in some studies 20,21 ; however, it remains unclear whether they should be used alone or with fluoropyrimidines. 22,23 While fluoropyrimidine-based therapy has been used as maintenance for mCRC, the recent PANAMA trial has established a modest PFS improvement with the addition of panitumumab to maintenance fluoropyrimidine over fluoropyrimidine alone (8.8 versus 5.7 months, p = 0.014).…”