Abstract CT088: Efficacy of anti-EGFR rechallenge in RAS and BRAF wt metastatic colorectal cancer: Clinical and translational results of the phase II CRICKET study by GONO
Authors: Rossini Daniele , Cremolini Chiara , Re Marzia Del , Lonardi Sara , Busico Adele , Rofi Eleonora , Garattini Silvio Ken , Tamburini Emiliano , Dell'Aquila Emanuela , Corsi Domenico , Bergamo Francesca , Barone Carlo , Masi Gianluca , Pucci Francesca , Cattaneo Monica , Pietrantonio Filippo , Perrone Federica , Tonini Giuseppe , Santini Daniele , Falcone Alfredo 
Published: August 2018

Abstract
Introduction CRICKET (NCT02296203) trial was designed to investigate the activity of the rechallenge with cetuximab (cet) and irinotecan (iri) as third-line treatment in RAS and BRAF wild-type mCRC patients (pts) with acquired resistance to 1st-line cet- and iri-based therapy. Recent data highlighted the clonal evolution and heterogeneity of acquired resistance to anti-EGFR treatments, and suggested the role of liquid biopsy as a reliable tool to track molecular events in circulating tumor DNA (ctDNA) and to properly inform treatment choices.
Materials and Methods: The primary endpoint was response rate (RR) according to RECIST v1.1. Setting p0 = 5%, and p1 = 20%, with 1-sided-α and β errors of 0.05 and 0.20, 27 patients were required. Null hypothesis would have been rejected if RECIST response had been observed in at least 4 patients. Main eligibility criteria included: RAS/RAF wild-type status in tissue samples; acquired resistance to 1st-line cet and iri-based regimen with at least RECIST partial response (PR), 1st-line PFS ≥6 months, and progression (PD) within 4 weeks after the last administration of cet; 2nd-line bevacizumab and oxaliplatin-based regimen. 3rd-line cet + iri was administered until PD. Liquid biopsies were collected at the rechallenge baseline. ctDNA was analyzed with ddPCR for specific RAS and BRAF mutations (mut), and then by means of ultra-deep next-generation sequencing (NGS) with Ion Torrent S5 XL (Thermo Fisher Scientific, Waltham, MA, USA).
Results: Between January 2015 and June 2017, 28 pts were enrolled in 9 centers. The primary endpoint was met. Six pts had PRs (RR: 21.4%) that were not confirmed in two consecutive evaluations in two cases, and 9 achieved disease stabilization (Disease Control Rate: 53.6%). Three patients were not evaluable for RECIST response. RAS mut were found in liquid biopsies collected at the rechallenge baseline in 12 (48%) out of 25 evaluable patients. No BRAF or PI3KCA mut were found. As shown in table 1, no RAS mut were detected in samples from patients who achieved a confirmed PR.
Conclusion: Rechallenge with cet + iri is active in some RAS and BRAF wild-type mCRC patients with acquired resistance to 1st-line iri- and cet-based therapy. Candidate patients' selection may be improved by treating only those who do not bear any RAS mut or other less frequent resistance mechanisms in ctDNA at the rechallenge baseline.
Partially funded by Merck Serono SpA.
Table 1PatientsRAS status on ctDNAObjective Response#1Wild-typeConfirmed PR#2KRAS G12DPD#3Wild-typeConfirmed PR#4Wild-typePD#5KRAS G12DSD#6Wild-typePD#7Wild-typeSD#9Wild-typeConfirmed PR#10Wild-typeUnconfirmed PR#11Wild-typePD#12KRAS G12DPD#13KRAS G12VPD#15NRAS Q61LSD#16Wild-typeSD#17KRAS G12V/ Q61HPD#18KRAS G12VPD#19Wild-typeConfirmed PR#21KRAS G12DSD#22KRAS G12VSD#23KRAS G12VPD#24KRAS G12DUnconfirmed PR#25KRAS G12DSD#26Wild-typeSD#27Wild-typePD#28Wild-typeSD
Citation Format: Daniele Rossini, Chiara Cremolini, Marzia Del Re, Sara Lonardi, Adele Busico, Eleonora Rofi, Silvio Ken Garattini, Emiliano Tamburini, Emanuela Dell'Aquila, Domenico Corsi, Francesca Bergamo, Carlo Barone, Gianluca Masi, Francesca Pucci, Monica Cattaneo, Filippo Pietrantonio, Federica Perrone, Giuseppe Tonini, Daniele Santini, Alfredo Falcone. Efficacy of anti-EGFR rechallenge in RAS and BRAF wt metastatic colorectal cancer: Clinical and translational results of the phase II CRICKET study by GONO [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT088.