Exploratory pooled analysis evaluating the effect of sequence of biological therapies on overall survival in patients with RAS wild-type metastatic colorectal carcinoma

Marc Peeters, Frédéric Forget, Meinolf Karthaus, Manuel Valladares-Ayerbes, Alberto Zaniboni, Gaston Demonty, Xuesong Guan, Fernando Rivera, Marc Peeters, Frédéric Forget, Meinolf Karthaus, Manuel Valladares-Ayerbes, Alberto Zaniboni, Gaston Demonty, Xuesong Guan, Fernando Rivera

Abstract

Background: The aim of this study was to evaluate the optimal sequence of targeted therapies (epidermal growth factor receptor inhibitors (EGFRi) and vascular endothelial growth factor inhibitors (VEGFi)), combined with chemotherapy, in patients with RAS wild-type (WT) metastatic colorectal carcinoma (mCRC). Exploratory analyses of overall survival (OS) for patients treated with either first-line panitumumab (EGFRi) and second-line VEGFi therapy, or first-line bevacizumab (VEGFi) and second-line EGFRi, were conducted.

Methods: Patients from PEAK (NCT00819780), PRIME (NCT00364013) and Study 181 (NCT00339183), with RAS WT or RAS WT/BRAF WT tumours, were included in the analyses. OS data were pooled for patients receiving first-line panitumumab (PEAK and PRIME) or first-line bevacizumab (PEAK and 181), followed by second-line VEGFi or EGFRi, respectively.

Results: Overall, 104 RAS WT patients were included (n=66 panitumumab→VEGFi, n=38 bevacizumab→EGFRi). At the time of final data analysis, 63.6% versus 92.1% of patients in the panitumumab→VEGFi versus bevacizumab→EGFRi arms had died; median OS was 36.8 versus 27.8 months, respectively (HR 0.65; 95% CI 0.42 to 1.03). The OS HR for patients with RAS WT/BRAF WT mCRC overall was 0.58 (95% CI 0.36 to 0.95) and was 0.56 (95% CI 0.30 to 1.04) in those with left-sided tumours.

Conclusion: Although numbers are small, these exploratory analyses suggest a trend towards improved OS for first-line panitumumab plus chemotherapy followed by second-line VEGFi, compared with first-line bevacizumab followed by second-line EGFRi in patients with RAS WT and RAS WT/BRAF WT mCRC. Large prospective randomised trials are needed to further evaluate the optimum sequence of EGFRi/VEGFi in mCRC.

Keywords: epidermal growth factor receptor; metastatic colorectal cancer; targeted agents; treatment sequence; vascular endothelial growth factor.

Conflict of interest statement

Competing interests: MP has received research funding from Amgen, Roche and Sirtex, and honoraria from Amgen, Merck Serono, Roche, Sanofi Aventis, Servier, and Sirtex. FF has received research grants from Amgen and acted on advisory boards/received honoraria from Novartis and Nutricia. MK has consulting/advisory roles and has participated in steering committees for Amgen and received travel/accommodation/expenses from Amgen. MVA has acted on advisory boards and received research funding from Amgen, Merck Serono, Roche and Sanofi. GD is an employee of Amgen (Europe) and owns restricted shares in Amgen. XG is an employee of Amgen and owns restricted shares in Amgen. FR has acted on advisory boards and/or received research funding from Amgen, Bayer, Celgene, Lilly, Merck Serono, Merck Sharp & Dohme, Roche, Sanofi, and Servier. AZ has no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Schema of the exploratory analyses (RAS wild-type population). EGFRi, epidermal growth factor receptor inhibitor; FOLFIRI, folinic acid, 5-fluorouracil and irinotecan; FOLFOX, 5-fluorouracil, leucovorin and oxaliplatin; OS, overall survival; PEAK, Panitumumab Efficacy in combination with mFOLFOX6 Against bevacizumab plus mFOLFOX6 in mCRC subjects with KRAS WT tumours; PRIME, Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy; R, randomisation; VEGFi, vascular endothelial growth factor inhibitor.
Figure 2
Figure 2
Kaplan-Meier analysis of overall survival in patients receiving panitumumab→VEGFi (PEAK and PRIME) versus bevacizumab→EGFRi (PEAK and 181) in the (A) RAS wild-type and (B) RAS wild-type/BRAF wild-type populations. Bev, bevacizumab; EGFRi, epidermal growth factor receptor inhibitor; PEAK, Panitumumab Efficacy in combination with mFOLFOX6 Against bevacizumab plus mFOLFOX6 in mCRC subjects with KRAS WT tumours; PRIME, Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy; Pmab, panitumumab; VEGFi, vascular endothelial growth factor inhibitor.

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