511MO - Third line rechallenge with cetuximab (Cet) and irinotecan in circulating tumor DNA (ctDNA) selected metastatic colorectal cancer (mCRC) patients: The randomized phase II CITRIC trial

Background

In the management of mCRC after progression on irinotecan and oxaliplatin, therapeutic options offer marginal benefit, typically yielding response rates from 1-6%. Against this backdrop of therapeutic resistance, non-randomized clinical trials have pointed towards the potential efficacy of anti-EGFR rechallenge strategies in patients (pts) with RAS wild type (wt) mCRC, molecularly selected via liquid biopsy. Considering this clinical context, we conceived the CITRIC study, a multicenter, randomized, open-labeled, phase II study.

Methods

Pts with ECOG PS 0-1 and RAS wt mCRC who did benefit from anti-EGFR in the first line were eligible for molecular screening after progression on second line. RAS, BRAF V600E, and EGFR-ECD mutations (mut) were analyzed in ctDNA using the Oncomine Colon cfDNA Assay, Thermofisher. Pts with triple negative mutation status in ctDNA were randomized to Cet and irinotecan (arm A) or to investigator's choice (excluding anti-EGFR) (arm B). The primary endpoint was the overall response rate (ORR) according to RECIST 1.1.

Results

Between Aug 15, 2020 and Feb 5, 2024 114 pts were screened by liquid biopsy. RAS/BRAF/EGFR-ECD mut in ctDNA were detected in 28 pts (25%), and 58 pts were randomized. After a median follow up of 5.1 months (mo), 11 pts were still on treatment (5 pts in arm A and 6 pts in arm B). Median age was 61.9 years, and 23 pts (39.7%) were female. Median treatment duration was 3.8 mo and 2.1 mo in the Cet and control arm, respectively (p=.001). Partial response was observed in 3/31 pts in the Cet arm and in 0/27 pts in the control arm. ORR favored the Cet arm (9.7% vs 0%, p=.022). Disease control rate (DCR) was 71% (95% CI, 52.0 – 85.8%) in arm A and 33.3% (95% CI, 16.5 – 53.9%) in arm B (p=.008). No differences in toxicity were observed between arms unless for rash.

Conclusions

The CITRIC study is the first randomized trial assessing the efficacy of liquid biopsy for driving anti-EGFR rechallenge in the third line setting. Our preliminary results demonstrate the effectiveness of Cet rechallenge in terms of ORR and DCR and might be considered a treatment option for RAS/BRAF/EGFR-ECD wt ctDNA pts. We will present updated efficacy data at congress.

Clinical trial identification

EudraCT 2020-000443-31.

Editorial acknowledgement

Legal entity responsible for the study

Associació Per la Recerca Oncològica (APRO).

Funding

Merck.

Disclosure

C. Santos Vivas: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Invited Speaker: Amgen; Non-Financial Interests, Leadership Role, Clinical trial coordinator: Merck; Other, Travel Grant: Merck, MSD, Amgen. J. Vidal Barrull: Financial Interests, Personal, Invited Speaker: Merck Serono, Amgen, Pierre Fabre, Novartis; Financial Interests, Personal, Advisory Board: Merck Serono, Amgen, BMS, Pierre Fabre. C. Fernandez Rodriguez: Financial Interests, Personal, Invited Speaker: Roche, Merck, AstraZeneca. F. Salvà Ballabrera: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Invited Speaker: Sanofi, Merck, Servier, Roche, Terumo company. V. Alonso-Orduna: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Invited Speaker: Servier, Merck, Novartis. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Astellas, Bayer, BMS, Boerhringer, Esteve, Hutchmed, Ipsen, Midatech Pharma, MSD, Novartis, PharmaMar, Servier, Takeda; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Chair Elect: European Neuroendocrine Tumor Society (ENETS); Non-Financial Interests, Leadership Role, Past President, Member of the Executive Committee: Grupo Español de Tumores Neuroendocrinos (GETNE); Other, Honoraria received by spouse for advisory board or invited speaker roles: Abbvie, AstraZeneca, Bayer, Boehringer, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. N. Tarazona Llavero: Financial Interests, Personal, Advisory Board: Merck, Guardant Health, Grifols; Financial Interests, Personal, Invited Speaker: Merck, Pfizer, Servier, Amgen; Financial Interests, Institutional, Funding: Natera Inc, Guardant Health; Non-Financial Interests, Member: SEOM Committee. M.J. Safont Aguileria: Financial Interests, Personal, Advisory Board: Amgen, Servier; Financial Interests, Personal, Invited Speaker: Merck, Servier. F. Rivera Herrero: Financial Interests, Personal, Invited Speaker: Roche, MSD, BMS, Servier, Astellas, Amgen, Merck; Financial Interests, Personal, Advisory Board: MSD, BMS, Servier, Astellas, Amgen, AstraZeneca; Financial Interests, Institutional, Local PI: AstraZeneca, MSD, Novartis, Seagen, OBT, Inspirna. M.J. Ortiz Morales: Financial Interests, Institutional, Invited Speaker: Servier. J. Alcaide-Garcia: Financial Interests, Personal, Other, Congress support: MSD, Amgen; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Invited Speaker: Amgen, Servier, Merck, Pierre-Fabre. D. Paez: Financial Interests, Personal, Invited Speaker: MSD, Novartis, BMS; Financial Interests, Personal, Advisory Board: Amgen, Esteve, Ipsen; Financial Interests, Personal and Institutional, Research Grant: Merck. R. Alvarez Gallego: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Research Grant: Servier, BMS. R. Vera: Financial Interests, Personal, Advisory Board: Roche, Amgen, Sanofi; Financial Interests, Personal, Invited Speaker: Merck, Lilly, Bayer, Eisai, Servier, MSD. B. Bellosillo Paricio: Financial Interests, Personal, Advisory Board: Menarini, Janssen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Merck Serono, Roche, Thermofisher, Pfizer, BMS; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche. C. Montagut Viladot: Financial Interests, Personal, Advisory Board: Merck Serono, Roche; Financial Interests, Personal, Invited Speaker: Merck Serono, Pierre Fabre, Guardant Health, Amgen; Financial Interests, Institutional, Royalties: Biocartis; Financial Interests, Institutional, Coordinating PI: Merck-Serono; Non-Financial Interests, Member: TTD (Grupo Tratamiento Tumores Digestivos). All other authors have declared no conflicts of interest.