Background

The FOxTROT trial has reported advantages of neoadjuvant chemotherapy (NAC) in locally advanced CC and also reported the embedded phase II which tested the addition of panitumumab (pan) to NAC in KRAS-wt pts. Here we present detailed results of neoadjuvant FOLFOX +/- pan with extended hypothesis-led biomarker testing, to reflect current pan use.

Methods

Pts had operable CC; CT-predicted stage T3-4, N0-2, M0, and KRAS-wt. KRAS-wt pts who had been allocated to NAC could optionally be sub-randomized 1:1 to 6 weeks FOLFOX ± pan during the NAC phase. All pts received FOLFOX post-op. RAS/RAF were tested by NGS; EREG/AREG (EGFR receptor ligands) by RNAseq. Primary endpoint of this exploratory analysis is RFS in RAS/BRAF-wt pts; secondary endpoints include safety, histological downstaging, DFS, CC specific survival, and test impact of primary tumor location (PTL) and EREG/AREG expression on pan effect.

Results

Biomarker data was available for 232(83%) pts randomised; 22(9.5%) were RAS mut; 41/210(19.5%) BRAF-mut. In 169 RAS/BRAF-wt pts with a median 42 month follow up, RFS was 88.1% in pts treated with FOLFOX+pan compared with 79.2% with FOLFOX (HR=0.51,p=0.09). Effect size was stronger in pts with high EREG/AREG (RFS HR=0.29,p=0.04), and for CC-specific survival (see table). Pan did not result in greater pathological response (TRG 1-3 16.4% vs 22.4%,p=0.27) or downstaging compared with FOLFOX. Pan was associated with higher rates of grade 3 diarrhoea (8% vs 3%) and rash (22% vs 2%), and trend towards more post-operative complications than FOLFOX alone.

Table: 552O

Conclusions

In this exploratory analysis, neoadjuvant FOLFOX+ pan showed promising activity in RAS/BRAF-wt pts compared with FOLFOX alone in pts with operable CC. Further pt selection with EREG/AREG appears beneficial. No impact on tumour regression was seen with pan. Further testing and safety assessment is warranted.

Clinical trial identification

ISRCTN 87163246.

Legal entity responsible for the study

The authors.

Funding

Amgen.

Disclosure

J. Seligmann: Financial Interests, Personal, Other, Travel: Bristol Myers Squibb; Financial Interests, Personal, Other, CME activities: GI Connect; Financial Interests, Personal, Invited Speaker: Merck Serono, Pierre Fabre, Servier; Financial Interests, Personal, Advisory Board: Pierre Fabre, Seagan, Ventana, Zentalis, AstraZeneca, Elevate Oncology, Merck Serono; Financial Interests, Institutional, Other, Research Funding: Pierre Fabre Medicament; Financial Interests, Personal, Other, Review of guidelines, consultancy: Roche Diagnostics; Financial Interests, Personal, Other, travel: Servier. All other authors have declared no conflicts of interest.

Background

CAIRO5 aimed to find the optimal systemic induction regimen to convert initially unresectable CRLM to local treatment.Previously, we showed that for patients with right-sided and/or RAS/BRAFV600E mutated tumours PFS was significantly longer and complete local treatment (R0/R1 resection and/or ablation) higher with FOLFOXIRI vs FOLFOX/FOLFIRI, both plus bevacizumab. For patients with left-sided and RAS/BRAFV600E wild-type tumours these parameters were not different between adding panitumumab vs bevacizumab to FOLFOX/FOLFIRI.

Methods

Patients with right-sided and/or RAS/BRAFV600E mutated tumours randomly received FOLFOX/FOLFIRI-bevacizumab (arm A) or FOLFOXIRI-bevacizumab (arm B), and with left-sided and RAS/BRAFV600E wild-type tumours FOLFOX/FOLFIRI-bevacizumab (arm C) or FOLFOX/FOLFIRI-panitumumab (arm D). Resectability was assessed by an expert panel of surgeons and radiologists at baseline and 2-monthly thereafter. Patients were stratified by potentially resectable vs permanently unresectable, serum LDH, irinotecan vs oxaliplatin, and BRAFV600E mutation status (arm A/B). Overall survival (OS, secondary endpoint) was compared with a stratified log-rank test and hazard ratios were calculated with a Cox proportional hazards model.

Results

Between November 2014 and January 2022, 530 patients were randomised in 47 centres, 148/146/118/118 in arms A/B/C/D. 9 ineligible patients were excluded. Median follow up was 57 months. Median OS in arm A vs B was 23.6 vs 24.1 months (HR 0.92, 95% CI 0.70 – 1.20, p=0.52) with 229 events. Median OS in arm C vs D was 40.4 vs 38.3 months (HR 1.02, 95% CI 0.72 – 1.46, p=0.89) with 134 events. Recurrence within 6 months after complete local treatment occurred in 26 (49%) vs 29 (39%) patients in arm A vs B (p=0.28), and 28 (42%) vs 26 (39%) patients in arm C vs D (p=0.73).

Conclusions

In patients with initially unresectable CRLM, OS was not different between FOLFOXIRI-bevacizumab and FOLFOX/FOLFIRI-bevacizumab for right-sided and/or RAS/BRAFV600E mutated tumours, nor between adding panitumumab vs bevacizumab to FOLFOX/FOLFIRI for left-sided and RAS/BRAFV600E wild-type tumours.

Clinical trial identification

NCT02162563, EudraCT 2013-005435-24.

Legal entity responsible for the study

Dutch Colorectal Cancer Group.

Funding

This study was supported by unrestricted grants from Roche and Amgen. The funders had no role in the design, conduct and submission of the study, nor the decision to submit the abstract for publication.

Disclosure

C.J.A. Punt: Financial Interests, Institutional, Advisory Board: Nordic Group BV. J.W. de Groot: Financial Interests, Advisory Role: BMS. All other authors have declared no conflicts of interest.

Background

Whether KRAS and BRAFV600E mutations are prognostic in stage III CC remains controversial and has never been clearly analyzed in the subgroup of MSI-H patients (pts) due to sample size limitations. The prognostic value of individual KRAS mutations has also not been widely studied.

Methods

We studied the prognostic impact of individual KRAS exon 2 and BRAFV600E mutations in pts with surgically resected stage III CC who participated in 7 clinical trials from the ACCENT/IDEA databases. Associations between mutations and time to recurrence (TTR), overall survival (OS) and survival after recurrence (SAR) were assessed by Cox model, stratified by study and adjusted for sex, age, performance status, T and N stage, disease grade, and primary tumor location. The prognostic value of individual KRAS exon 2 submutations (G12A, G12C, G12D, G12R, G12S, G12V, G13D and others) was also analyzed.

Results

8286 pts were included, 11.6% were MSI-H (N=967) with 5 yr recurrence rates of 24.1% for MSI-H and 30.3% for MSS subgroups. BRAFV600E, KRAS exon 2 mutants or double wild type represented 40.6%, 18.1% and 41.3% of the MSI-H group and 7.8%, 38.6% and 53.7% of the MSS group, respectively. In the MSS group, 5y TTR rates of 61.7%, 66.4% and 73.2% emerged in pts with BRAFV600E , KRAS exon 2 mutants and in double wild-type pts, respectively, (adjHR: 1.34 and 1.32, both p<0.001), while in the MSI group shorter TTR in mutated subgroups was not seen with 5y TTR rates of 76.1%, 75.8% and 75.6%, respectively (adjHR: 1.01 and 0.98, both p>0.05). Similar results were found for OS. However, SAR was significantly shorter for pts with tumors harboring a KRAS exon 2 or BRAFV600E mutation in both MSS (adjHR: 1.16 and 2.05; both p<0.0001) and MSI (adjHR: 1.76 and 2.00; both p<0.05) pts. No major differences were noted in the prognostic value of KRAS exon 2 submutations.

Conclusions

In the largest analysis of the association of KRAS exon 2 and BRAFV600E mutations and disease outcome in resected stage III CC, either mutation was associated with significantly shorter DFS, OS and SAR in MSS tumors, but only with shorter SAR in MSI-H tumors. In addition, all KRAS codon 12 and 13 mutations had similar prognostic value.

Clinical trial identification

IDEA France: NCT00958737 PMID: 29620995 C07: NCT00004931 PMID: 17470851 C89803: PMID: 17687149 PETACC3: PMID: 19451425 C08: PMID: 20940184 PETACC8: EudraCT 2005-003463-23 PMID: 24928083 N0147: NCT00079274 PMID: 22474202

Legal entity responsible for the study

ACCENT group.

Funding

Has not received any funding.

Disclosure

J. Taieb: Financial Interests, Personal, Advisory Board: MSD, Merck, Servier, Pierre Fabre, Amgen, Bristol Myers Squibb, Novartis, Pfizer; Financial Interests, Personal, Expert Testimony: Astellas; Financial Interests, Personal, Invited Speaker: Amgen, Bristol Myers Squibb, Merck, MSD, 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). F.A. Sinicrope: Financial Interests, Personal, Advisory Board: Roche, Eisai, Guardant Health; Financial Interests, Institutional, Royalties: Roche/Ventana Medical Systems. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Pierre Fabre, GSK, Roche, Astellas; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb. T. George: Financial Interests, Personal, Advisory Board: Pfizer Oncology, Tempus Labs; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, AZ, Lilly, Bayer, Incyte, Ipsen, Seagen, Genentech, Astellas, GSK, BioMed Valley Discoveries, Amgen, OncoC4, Jounce. R. Goldberg: Financial Interests, Personal, Other, DMC: AstraZeneca, Bayer, Inspirna, Sorrento; Financial Interests, Personal, Advisory Board, New drug development advice: Compass Therapeutics; Financial Interests, Personal, Other, New drug development advice: AbbVie; Financial Interests, Personal, Expert Testimony, expert witness in patent law trial: Taiho; Financial Interests, Personal, Advisory Board, Device development advice: Focal Medical; Financial Interests, Personal, Other, DMS: IQVIA; Financial Interests, Personal, Other, Drug development advice: Eisai, Innovative Cellular Therapeutics, Merck, Modulation Therapeutics, Takeda; Financial Interests, Personal, Advisory Board, drug development advice: GSK; Financial Interests, Personal, Advisory Board, genetic testing advice: Haystack Oncology; Financial Interests, Personal, Other, DMC and drug development advice: G1 Therapeutics; Financial Interests, Personal, Stocks/Shares, stock options: Compass Therapeutics, Focus Medical, Haystack Oncology; Non-Financial Interests, Other, Board member of an advocacy group: Fight Colorectal Cancer; Non-Financial Interests, , Leadership Role, Associate Group Chair, NCI funded cooperative oncology group: Alliance for Clinical Trials in Oncology. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Invited Speaker: Ono Pharmaceutical Co., Ltd, Sanofi K.K., Daiichi Sankyo Co., Ltd., MSD K.K., Pfizer Japan Inc., Eisai Co., Ltd.; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Ono Pharmaceutical Co., Ltd., Amgen K.K., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Roche Diagnostics K.K.; Financial Interests, Personal, Research Grant: FALCO Biosystems Ltd.. E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; Financial Interests, Institutional, Research Grant: Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. T. André: Financial Interests, Personal, Advisory Board, Advosiry Board on February 12, 2021: Astellas pharma; Financial Interests, Personal, Advisory Board, Advisory Board on February 2021: Kaleido Biosciences; Financial Interests, Personal, Invited Speaker, and advisory board 2021: Amgen; Financial Interests, Personal, Invited Speaker, Invited speaker in a symposuim december 2020: AstraZeneca; Financial Interests, Personal, Advisory Board, and consultant fees and consultant contract 2021 and 2022: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory board in Janaury 2020 : Clovis; Financial Interests, Personal, Advisory Board, Advisory board in January 2020: Gritstone Oncology; Financial Interests, Personal, Advisory Board, Advisory board 2020: Haliodx; Financial Interests, Personal, Advisory Board, and consultant fees/consultant contract and invited speaker: MSD Oncology; Financial Interests, Personal, Invited Speaker, and other: Pierre Fabre; Financial Interests, Personal, Invited Speaker, in an symposuim in 2020: Roche; Financial Interests, Personal, Invited Speaker, in a meeting in 2019: Ventana; Financial Interests, Personal, Invited Speaker, In a educational meeting in 2019: Sanofi; Financial Interests, Personal, Advisory Board, in a symposuim in 2020: Servier; Financial Interests, Personal, Expert Testimony, Consultant with personnal fees and invited speaker: Servier; Financial Interests, Personal, Advisory Board, in 2019: GSK; Financial Interests, Personal, Invited Speaker, in 2020 and 2021: GSK; Financial Interests, Personal, Invited Speaker, Virtual symposuimLecture: 1 MSI-H CRC: Implementation of Immunotherapy in clinical practice (30 minutes) – (this will be pre-recorded)Q&A – Live Q&A – (10 minutes) (on July 2, 2021): MSD Oncology; Financial Interests, Personal, Invited Speaker, June 2022 : Sanofi; Financial Interests, Personal, Advisory Board, Contract 2021, 2022, 2023 : Merck & Co., Inc; Financial Interests, Personal, Advisory Board, Contrat 2019, 2020, 2021, 2022 : Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Contract 2021 : Gritstone Oncologie; Financial Interests, Personal, Invited Speaker, June 2022 and June 2023 during ESMO GI meeting: Seagen; Financial Interests, Personal, Invited Speaker, Contract of consulting 2021 and 2022 and 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, September 2022: GSK, Seagen; Financial Interests, Personal, Invited Speaker, Contract of consulting 2022 and 2023: GSK; Financial Interests, Personal, Invited Speaker, Contract of consulting 2022: Nordic Pharma; Financial Interests, Personal, Invited Speaker, October 2022: Merck Serono; Financial Interests, Personal, Other, Educational in 2022: Roche; Financial Interests, Personal, Other, Contract of consulting 2020, 2021, 2022,2023: Servier; Financial Interests, Personal, Advisory Board, 2023 : Aptide Health, Glilead; Financial Interests, Institutional, Other, Investigator and scientific committee president: Gercor Academic group; Financial Interests, Institutional, Invited Speaker, PI Garnet study: GSK; Financial Interests, Institutional, Invited Speaker, Keynote 164 and 171 and 811 and C08: MSD; Financial Interests, Institutional, Invited Speaker, Bristol Myers Squibb CA209-8HW, Bristol Myers Squibb CA209-142, Bristol Myers Squibb CA209-577: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, SPOTLIGHT study: Astellas; Financial Interests, Personal, Invited Speaker, and international PI (trial chair Solstice study): Servier; Financial Interests, Personal, Invited Speaker, MOUNTAINEER and MOUNTAINEER-03 study (PI for France) 2022, 2023: Seagen; Non-Financial Interests, Invited Speaker, Investigator: Gercor group; Non-Financial Interests, Invited Speaker, President since October 2022: ARCAD Foundation . P. Laurent-Puig: Financial Interests, Personal, Invited Speaker: Amgen, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Biocartis, Pierre Fabre; Financial Interests, Personal, Ownership Interest: Methys DX; Financial Interests, Institutional, Research Grant: Federation Francophone de Cancerologie Digestive; Non-Financial Interests, Leadership Role: President of Canceropole Ile de France. Q. Shi: Financial Interests, Personal, Advisory Board: Regeneron Pharmaceuticals, Inc., Kronos Bio; Financial Interests, Personal, Advisory Board, DSMB: Hoosier Cancer Research Network, Yiviva Inc., Mirati Therapeutics Inc; Financial Interests, Institutional, Research Grant: Genentech, Bristol Myers Squibb, Novartis, Johnson & Johnson. All other authors have declared no conflicts of interest.

Background

Aspirin is an inexpensive, readily available treatment globally with the potential to be an effective adjuvant therapy to prevent recurrence of colorectal cancer (CRC) after completing standard primary treatment. This landmark study conducted entirely in the Asia-Pacific region, where incidence of CRC is increasing, is the first international Phase III double-blind placebo-controlled trial to report the activity of aspirin in the secondary prevention of CRC (NCT 00565708).

Methods

Patients with Dukes’ C and high-risk Dukes’ B CRC were randomised to Aspirin 200mg daily or placebo for 3 years after surgery and completion of standard adjuvant therapy (including 3+ months of chemotherapy) and followed for 5+ years. The primary endpoint was Disease-Free Survival (DFS). The primary analysis used a stratified Cox model, with those commencing study treatment (modified intention to treat (mITT) and with all events up to 31/03/2023. Secondary endpoints included overall survival (OS) and DFS in the colon cancer group. Translational biomarker studies are ongoing.

Results

Between 25/02/2009 and 31/03/2021, 1587 participants were randomised from 66 centres across 10 Asia-Pacific countries and 1550 were included in the mITT analysis: 791 on aspirin and 759 placebo. Of these, 897 were males; 271 Dukes’ B colon cancers, 769 Dukes’ C colon cancers and 510 rectal cancers. Estimated DFS at 5 years was 77% (95% CI 74-80%) and 75% (95% CI 71-78%) for aspirin and placebo respectively with an estimated hazard ratio (HR) of 0.91 (95% CI 0.73-1.13, p=0.38). Overall survival showed HR favouring aspirin of 0.75 (95% CI 0.53-1.07, p=0.11). In the colon cancer group, the HR for DFS was 0.86 (95% CI 0.66 - 1.13, p=0.28). Adverse events were low in both arms and aspirin was well tolerated.

Conclusions

Our study did not show a significant DFS or OS benefit of aspirin therapy as an additional adjuvant therapy for patients with colorectal cancer. Nevertheless, results are still consistent with a more moderate, yet still worthwhile benefit for the global populations, and results from ongoing studies are awaited. Analysis of special subpopulations predicted to benefit from aspirin in ASCOLT and other trials, may also be critical.

Clinical trial identification

NCT00565708.

Editorial acknowledgement

NIL / Not applicable

Legal entity responsible for the study

National Cancer Centre Singapore.

Funding

National Medical Research Council, Singapore National Cancer Cancer Singapore Research Fund SinghealthFoundation, Singapore National Health and Medical Research Council, Australia Lee Foundation, Singapore Lee Kim TahFoundation, Singapore SilentFoundation, Singapore Rising Tide Foundation, Switzerland Bayer AG (Study Drug only).

Disclosure

All authors have declared no conflicts of interest.

Background

Retrospective studies demonstrated an impressive prognostic impact of circulating tumor DNA (ctDNA, LB) positivity on colon cancer (CC) relapse after radical resection as proxy of minimal residual disease (MRD). Initial evidence is accumulating that in some patients (pts) adjuvant treatment does not clear ctDNA and this associates with relapse. With these premises we designed the PEGASUS trial to prove the feasibility of using LB to guide the post-surgical and post-adjuvant clinical management of Stage-IIT4N0/III CC pts.

Methods

LB was performed using Guardant Reveal assay (v L1.2). In the post-surgical phase, LB+ pts received 3 months (mos) of CAPOX and LB- pts 6 mos of CAPE. To mitigate the risk of false negatives a LB was repeated after one cycle of CAPE and treatment escalated to CAPOX if LB+. At the end of adjuvant treatments, LB was repeated: CAPOX-treated pts were switched to FOLFIRI if LB+ or de-escalated to CAPE if LB-; CAPE-treated pts received CAPOX if LB+ or started the standard follow-up phase if LB-. Primary endpoint was the number of post-surgery false negative cases, defined as pts with two consecutive LB- experiencing disease relapse (accepted <14 relapses).

Results

From July 2020 to July 2022, 135 pts were included in 11 cancer centers in Italy and Spain. At data cut-off, median follow-up was 20,8 months, with data completeness of 91% in LB- and 92% in LB+. Post-surgery ctDNA was detected in 35/135 pts (26%), of which 12 (34%) experienced relapses, while 9 out of 100 LB- pts (9%) relapsed, being defined as false negatives. ctDNA+ was associated with a clear increase in the risk of relapse (HR 4.37, log rank P=0.0003). After 3 months of CAPOX, 11/35 LB+ pts were converted to LB- (31%), but 8/11 relapsed or LB re-positivized. Of the 23 LB+ pts receiving FOLFIRI after CAPOX, 12 remained LB+ (52%) among which 6 relapsed, while 11 were converted to LB- remaining relapse-free at the time of analysis (48%), thus suggesting an effect of FOLFIRI in the MRD setting.

Conclusions

LB may be used to guide the post-surgical clinical management of CC pts by reducing unnecessary toxicity and by improving the response to standard chemotherapy. Ongoing and newly designed randomized trials trials will define the clinical utility of LB for MRD in colon cancer.

Clinical trial identification

IFOM-CPT005/2019/PO004 EudraCT 2019-002074-32 NCT04259944.

Legal entity responsible for the study

IFOM - the AIRC Institute of Molecular Oncology.

Funding

Guardant Health.

Disclosure

S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol-Myers Squibb; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GSK, Roche, Astellas; Financial Interests, Institutional, Coordinating PI: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol -Myers Squibb. F. Pietrantonio: Financial Interests, Personal, Advisory Board: Amgen, Merck-Serono, MSD, Bayer, Organon, Astellas; Financial Interests, Personal, Invited Speaker: Amgen, Merck-Serono, BMS, Lilly, Servier, Bayer, Pierre-Fabre, AstraZeneca, Astellas; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Incyte, Agenus. N. Tarazona Llavero: Financial Interests, Personal, Advisory Board: Merck, Guardant Health; Financial Interests, Personal, Invited Speaker: Merck, Pfizer, Servier, Amgen; Financial Interests, Institutional, Funding: Natera Inc; Non-Financial Interests, Member: SEOM Committee. 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). A. Sartore Bianchi: Financial Interests, Personal, Advisory Board: Amgen, Servier, Novartis; Financial Interests, Personal, Invited Speaker: Bayer, Guardant Health, Pierre Fabre. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La - Roche, Servier, Amgen, Merck Serono, Sanofi, Bayer, Pierre Fabre, MSD, Takeda; Financial Interests, Personal, Invited Speaker: Organon, Novartis, Pfizer; Financial Interests, Personal, Other, Educational training: Seagen International GmbH; Financial Interests, Institutional, Funding: Hoffmann-La Roche Ltd, Sanofi Aventis Recherche & Développement, Amgen Inc., Boehringer Ingelheim, Novartis Farmacéutica SA, Bristol-Myers Squibb International Corporation, BeiGene, HalioDX SAS, Janssen-Cilag SA, Merck Health KGAA, Merck Sharp & Dohme de España SA, PharmaMar SA, Servier, Taiho Pharma USA Inc, Hutchison MediPharma International, Menarini, Merus NV, Pfizer, Mirati, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Celgene International SARL, Debiopharm International SA, Genentech Inc, MedImmune; Non-Financial Interests, Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM); Non-Financial Interests, Other, Speaker of the ESMO Academy: European Society for Medical Oncology (ESMO); Non-Financial Interests, Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy: American Society of Clinical Oncology (ASCO); Other, Travel, accommodations, expenses.: Roche, Merck Serono, Sanofi, Amgen, Array BioPharma, Servier, Bristol-Myers Squibb. C. Santos Vivas: Financial Interests, Personal, Advisory Board: Sanofi, Amgen, Pierre-Fabre; Financial Interests, Personal, Other, Travel and accommodation: Merck KGaA, Merck. M. Mandalà: Financial Interests, Personal, Advisory Board: MSD, Novartis, Sanofi, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: Sun Pharma. S. Tamberi: Financial Interests, Personal, Advisory Board: Gilead, AstraZeneca. M.S. Sciallero: Financial Interests, Personal, Invited Speaker: MSD; Other, Travel/accomodation expenses: Amgen, PFIZER, SELGENE, TRIPLE-A. A. Cervantes: Financial Interests, Institutional, Advisory Board: MerckSerono, Amgen, Roche, Transgene, AnHeart Therapeutics, AbbVie, GSK; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck Serono, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor in Chief: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, BeiGene, Bayer, AstraZeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda, Affimed, Roche, Seamless, Gilead, Janssen, F. STAR Therapeutics, Ribon Therapeutics; Non-Financial Interests, Other, Scientific Director: INCLIVA Biomedical Research Institute. A. Bardelli: Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: Guardant Health, Inivata; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: Inivata, Neophore; Financial Interests, Personal, Advisory Board, Roche/Genentech Global CRC Advisory Board: Roche; Financial Interests, Personal, Stocks/Shares, Stock shareholder: Neophore, Kither; Financial Interests, Institutional, Research Grant, Receipt of grants/research supports: Neophore, AstraZeneca, Boehringer Ingelheim. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, Array Biopharma Inc, Debiopharm International SA, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb International Corporation, Celgene International SARL, F. Hoffmann-La Roche Ltd, Merck, Sharp & Dohme de España, SA, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Leadership Role, External Scientific Committee: IdiSNA –Universidad de Navarra, Institute for Health Research INCLIVA – Clinical Hospital of Valencia; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Principal Investigator, Clinical Trials & Research: AstraZeneca Pharmaceutics LP, Array Biopharma Inc., BeiGene, Boehringer Ingelheim, F. Hoffmann-La Roche Ltd, Debiopharm International SA, Bristol-Myers Squibb International Corporation, Celgene International SARL, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Menarini, Janssen-Cilag International NV, MedImmune, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System; Other, President: Oncology Master Plan – Catalonia Department of Health. S. Siena: Financial Interests, Personal, Advisory Board, Advisory Board Member: Agenus, AstraZeneca, BMS, Checkmab, Daiichi Sankyo, GSK, Novartis, Seagen, T-One-Therapeutics. All other authors have declared no conflicts of interest.