517P - Circulating tumor DNA driving anti-EGFR rechallenge therapy in metastatic colorectal cancer: The RASINTRO prospective multicenter study

Background

In RAS wild-type (WT) metastatic colorectal cancer (mCRC), preliminary data have suggested that circulating tumor DNA (ctDNA) may select patients (pts) for anti-EGFR rechallenge therapy. Furthermore, early variation in ctDNA concentration may predict treatment efficacy but has never been evaluated for anti-EGFR rechallenge therapy.

Methods

RASINTRO is a prospective multicenter study evaluating anti-EGFR rechallenge strategy in third and later line treatment in RAS/BRAFWT mCRC. Pts were required to have received prior anti-EGFR-based therapy continued until progression of disease, and at least one line of interval treatment before anti-EGFR rechallenge. Liquid biopsies for ctDNA analysis were collected before the first (C1), second (C2) and third (C3) cycle of anti-EGFR rechallenge therapy, and at disease progression. The primary endpoint was the PFS according to RAS/BRAF status on ctDNA at C1 with an expected HR of 0.50 in favor of the RAS/BRAF WT subgroup.

Results

Among 74 patients screened between November 2017 to March 2020, 62 were enrolled: male, 66.1%; median age, 66.1 years; ECOG PS 0-1, 85.2%; median number of previous lines of therapy, 3; panitumumab or cetuximab rechallenge alone (66.2%) or with chemotherapy (33.8%). In pts with RAS/BRAF WT on ctDNA at C1 (n=42, 67.7%), the median PFS (3.3 vs 1.9 months: HR=0.43; 95%CI, 0.24-0.75; P<0.01) and OS (7.9 vs 4.9 months: HR=0.46; 95%CI, 0.25-0.85; P=0.01) were significantly longer as compared to those with RAS/BRAF mutated (n=20, 32.3%). Among the 34 pts with RAS/BRAF WT at C1 and available blood samples at C2 and/or C3, a significantly longer median PFS (4.2 vs 2.8 months; HR=0.42; 95%CI, 0.20-0.87; P=0.01) and OS (9.7 vs 4.2 months; HR=0.44; 95%CI, 0.20-0.97; P=0.03) were observed for those experienced an early decrease of more than 50% in ctDNA concentration (n=17). Results of ctDNA at disease progression to analyze the mechanism of resistance will be presented at the meeting.

Conclusions

This study showed that anti-EGFR rechallenge therapy in the third and later lines is more effective in patients with RAS/BRAF WT on ctDNA, and for those who experienced an early decrease over 50% of ctDNA concentration.

Clinical trial identification

NCT03259009.

Editorial acknowledgement

Legal entity responsible for the study

Association des Gastro-Entérologues Oncologues - Gastroenterologists Oncologists Association (AGEO).

Funding

Amgen.

Disclosure

A. Zaanan: Financial Interests, Personal and Institutional, Funding: Amgen provided financial support for RASINTRO study: Amgen; Financial Interests, Personal, Advisory Board: Astellas, Merck, Sanofi, Servier, Bayer, BeiGene, MSD, BMS, Pierre Fabre, AstraZeneca, Daiichi Sankyo. L. Evesque: Financial Interests, Personal, Advisory Board: Servier, Amgen, MSD, Merck, Astellas. P. Artru: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Roche, Servier, Pierre Fabre, BMS, Merck Serono, Takeda; Financial Interests, Personal, Invited Speaker: Amgen. T. Lecomte: Financial Interests, Personal, Advisory Board: Sanofi, Merck Serono, Servier, Amgen, Ipsen, Pierre Fabre, AstraZeneca, Deciphera, Bayer. O. Bouche: Financial Interests, Personal, Advisory Board: Amgen, Merck, Apmonia Therapeutics, Deciphera, Astellas, Takeda; Financial Interests, Personal, Invited Speaker: Servier, Pierre Fabre, Bayer. R. Coriat: Financial Interests, Personal, Invited Speaker: AAA, Novartis; Financial Interests, Personal, Advisory Board: Bayer, Merck, BMS. A. Lievre: Financial Interests, Personal, Invited Speaker: Amgen, Astellas, AstraZeneca, BMS, Esteve, Pierre Fabre Oncologie, Servier, Viatris; Financial Interests, Personal, Advisory Board: Astellas, BMS, Bayer, Servier; Financial Interests, Institutional, Research Grant, RePERSO trial: Bayer; Financial Interests, Institutional, Coordinating PI, SOCRATE trial (FFCD promotion): Lilly; Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Bayer, Incyte, Lilly; Non-Financial Interests, Other, Travel and meeting registration: Bayer, Pierre Fabre, Servier, Viatris. R. Cohen: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Exeliom Biosciences, Enterome Biosciences; Financial Interests, Personal, Invited Speaker: Pierre Fabre, MSD Oncology, Servier, AstraZeneca; Financial Interests, Personal, Research Grant: Servier Institute. J. Bachet: Financial Interests, Personal, Other, consultancy: Abbvie; Financial Interests, Personal, Other, Consultancy: Acobiom; Financial Interests, Personal, Invited Speaker: Amgen, Leo Pharma, Viatris; Financial Interests, Personal, Advisory Board: Bayer, Biomunex, BMS, GSK, Merck Serono, MSD, Pierre Fabre, Servier, Takeda; Financial Interests, Institutional, Research Grant: Daichi, AstraZeneca, Roche. J. Taieb: Financial Interests, Personal, Advisory Board: MSD, Astellas, Merck, Servier, Pierre Fabre, Amgen, BMS, Novartis, Pfizer, Sanofi, Rottapharm, Takeda; Financial Interests, Personal, Invited Speaker: Amgen, BMS, Merck, MSD, Novartis; Financial Interests, Personal, Invited Speaker, Symposia: Astellas; Financial Interests, Personal, Other, Steering Committee of clinical trial: Novartis; Non-Financial Interests, Leadership Role, President of the Scientific Committee of the ARCAD foundation until end 2022: Arcad Foundation; Non-Financial Interests, Leadership Role, Chair of the ARCAD pancreas research group: ARCAD Foundation; Non-Financial Interests, Leadership Role, Member of the Administrative Council, the Scientific Committee, the Executive Board and Responsible for the International Relationships /Partnership for FFCD in the Prodige Intergroup: Federation Francophone de Cancerologie Digestive (FFCD); Non-Financial Interests, Other, Steering Committee of clinical trials: Pfizer, Servier. P. Laurent-Puig: Financial Interests, Personal, Invited Speaker: Amgen, Sanofi; Financial Interests, Personal, Advisory Board: Biocartis, Pierre Fabre; Financial Interests, Personal, Ownership Interest: Methys DX; Financial Interests, Institutional, Research Grant, PI of translational research: Federation Francophone de Cancerologie Digestive; Non-Financial Interests, Leadership Role: President of Canceropole Ile de France. All other authors have declared no conflicts of interest.