Tumour location and efficacy of first-line EGFR inhibitors in KRAS/RAS wild-type metastatic colorectal cancer: retrospective analyses of two phase II randomised Spanish TTD trials

Manuel Benavides, Eduardo Díaz-Rubio, Alfredo Carrato, Albert Abad, Carmen Guillén, Pilar Garcia-Alfonso, Silvia Gil, María Teresa Cano, María José Safont, Cristina Gravalos, José Luis Manzano, Antonio Sánchez, Julia Alcaide, Rafael López, Bartomeu Massutí, Javier Sastre, Eva Martínez, Pilar Escudero, Miguel Méndez, Enrique Aranda, Manuel Benavides, Eduardo Díaz-Rubio, Alfredo Carrato, Albert Abad, Carmen Guillén, Pilar Garcia-Alfonso, Silvia Gil, María Teresa Cano, María José Safont, Cristina Gravalos, José Luis Manzano, Antonio Sánchez, Julia Alcaide, Rafael López, Bartomeu Massutí, Javier Sastre, Eva Martínez, Pilar Escudero, Miguel Méndez, Enrique Aranda

Abstract

Purpose: Metastatic colorectal cancer (mCRC) is a group of distinct diseases, with clinical and molecular differences between right-sided and left-sided tumours driving varying prognosis.

Methods: Patients with KRAS/RAS-wild type (wt) mCRC treated in first line with epidermal growth factor receptor inhibitors (EGFR-Is) (cetuximab or panitumumab) plus oxaliplatin or irinotecan-based chemotherapy from two phase II randomised trials conducted by the Spanish Cooperative for the Treatment of Digestive Tumours group were included in this retrospective study. The main objective was to analyse the prognostic effect of primary tumour location on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).

Results: Patients with KRAS-wt right-sided tumours (n=52) had significantly lower efficacy as compared with patients with KRAS-wt left-sided tumours (n=209); confirmed ORR (25% vs 47%, respectively; OR 0.4, 95% CI 0.2 to 0.8, p=0.004); and shorter median PFS (7.2 vs 9.9 months; HR 0.6, 95% CI 0.4 to 0.9, p=0.0157) and OS (13.6 vs 27.7 months; HR 0.5, 95% CI 0.3 to 0.7, p<0.0001). Similar results were observed in the RAS-wt populations. The further classification of left-sided tumours as colon or rectum delivered similar survival outcomes, as well as a tendency to diminished ORR in patients with rectum tumours.

Conclusion: We observed significantly improved efficacy outcomes in patients with KRAS/RAS-wt mCRC treated with first-line EGFR-I plus chemotherapy in left-sided primary tumours as compared with right-sided primary tumours.

Trial registration numbers: NCT01161316 and NCT00885885.

Keywords: cetuximab; metastatic colorectal cancer; panitumumab; primary tumour location; sidedness.

© Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.

Figures

Figure 1
Figure 1
Patient disposition for (A) KRAS and (B) RAS wt populations. wt, wild type; mt, mutant type.
Figure 2
Figure 2
Analyses of survival by primary tumour location. (A, B) Kaplan-Meier estimates of the probability of PFS in the KRAS and RAS wt populations, respectively. (C, D) Kaplan-Meier estimates of the probability of OS in the KRAS and RAS wt populations, respectively, in patients with right-sided (blue line) and left-sided (red line) tumours. OS, overall survival; PFS, progression-free survival; wt, wild type.

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