114P - Comprehensive genomic profiling by liquid biopsy captures tumor heterogeneity and identifies cancer vulnerabilities in patients with RAS/BRAFV600E wild type metastatic colorectal cancer in the CAPRI 2-GOIM trial

Background

Emerging evidence supports tumor tissue-based comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC). Data on liquid biopsy-based circulating tumor DNA (ctDNA) CGP are scarce and mainly retrospective. Prospective comparison between the two tests is not currently available.

Methods

The CAPRI 2-GOIM trial investigates efficacy and safety of ctDNA-driven, cetuximab-based, sequence of three treatment lines in patients with RAS/BRAFV600E wild type (WT) mCRC, as determined by local laboratory. Before first-line therapy, CGP is performed with FoundationOne (F1) CDx and F1 Liquid (F1L) CDx (324 genes) on tumor tissue DNA and plasma ctDNA, respectively.

Results

For 2/207 (0.96%) patients, no ctDNA was detected by F1L CDx. No patient displayed tumor fraction (TF) below 1%, whereas elevated ctDNA (TF≥10%) was detected among 140/205 (68.3%) patients. 1013 genomic variants were identified. F1L CDx found KRAS, NRAS or BRAFV600E alterations in 19 patients, whose tumors were classified as RAS/BRAFV600E WT by local laboratory. Both F1 CDx and F1L CDx were available for 164/205 (80%) patients. Concordance of 61.4% between the two tests was observed. Concordance increased to 72.7% for F1L CDx with TF ≥10%. Concordance for genes involved in anti-EGFR resistance was found in 137/164 (83%) patients, increasing to 91.5% for F1L CDx with TF ≥10%. A higher number of genomic alterations was detected by F1L CDx compared with F1 CDx, including 6 cases with KRAS and NRAS alterations. Overall, 109/205 (53.2%) patients displayed at least one actionable genomic alteration (I to IIIB), according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT).

Conclusions

Baseline liquid biopsy-based CGP is feasible, has high concordance with tumor tissue-based CGP, could better recapitulate tumor heterogeneity, and is clinically informative by identifying additional actionable genomic alterations in approximately half of RAS/BRAF^V600E WT mCRC patients.

Editorial acknowledgement

Giuseppe Colucci.

Clinical trial identification

NCT05312398.

Legal entity responsible for the study

Gruppo Oncologico dell'Italia Meridionale (GOIM).

Funding

Partially funded by Merck.

Disclosure

D. Ciardiello: Financial Interests, Personal, Other, Travel support: Merck KGaA, Sanofi, BMS. S. Napolitano: Financial Interests, Personal, Other, Travel support: Novartis, Amgen. E. Martinelli: Financial Interests, Personal, Invited Speaker: Merck-Serono, Bayer, Merck S.p.a., ESMO; Financial Interests, Personal, Invited Speaker, Advisory board and invited speaker and travel grant: Pierre-Fabre; Financial Interests, Personal, Invited Speaker, Advisory board and Invited speakers: Incyte; Financial Interests, Personal, Invited Speaker, Advisory board and invited speaker: Servier, Roche; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Invited Speaker, Travel grant: AstraZeneca; Financial Interests, Personal, Invited Speaker, Advisory board: MSD. E. Maiello: Financial Interests, Personal, Expert Testimony: AstraZeneca, Merck KGaA, Lily, Roche, Eisai, Pfizer. A. Avallone: Financial Interests, Personal, Expert Testimony: Amgen, AstraZeneca, Merck Sharp & Dome, Eisai, BMS. R. Bordonaro: Financial Interests, Personal, Invited Speaker: Novartis, Sanofi, AstraZeneca, Amgen, Roche, Pfizer, BMS, Janssen-Cilag, Bayer. N. Fazio: Financial Interests, Personal, Other, Steering committee: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Merck, MSD, Novartis, Ipsen; Financial Interests, Institutional, Invited Speaker: Astellas, MSD, Beigene, Nucana, Ipsen, FibroGen, ITM, Boehringer; Financial Interests, Institutional, Research Grant: Ipsen, Novartis, Merck; Non-Financial Interests, Personal, Other, Steering committee: SPARC Europe; Non-Financial Interests, Personal, Member of Board of Directors: ENETS; Non-Financial Interests, Personal, Other, Member of the NET Faculty: ESMO; Non-Financial Interests, Personal, Other, Internal reviewer of NET guidelines: AIOM. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Advisory Board, Advisory Board: Menarini, Gilead; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Personal, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Personal, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Personal, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Personal, Officer, Editor of Chief of ESMO Open: ESMO; Non-Financial Interests, Personal, Leadership Role, Until the end of 2024: EUSOMA. F. Ciardiello: Financial Interests, Personal, Advisory Board: Roche, Merck Serono, Servier, Pierre Fabre, Pfizer; Financial Interests, Institutional, Research Grant: Merck Serono, Roche, Amgen; Financial Interests, Institutional, Invited Speaker: Pfizer, Pierre Fabre, Servier. G. Martini: Financial Interests, Personal, Invited Speaker: Incyte, Servier, Pierre Fabre. All other authors have declared no conflicts of interest.