581P - mRNA profiling as a biomarker of prognosis and response to first-line treatment in metastatic colorectal cancer: Discovery and validation of a gene expression signature in three randomized trials

Background

Comprehensive gene expression profiling can capture metastatic colorectal cancer (mCRC) biology more in depth than routine biomarkers in clinical practice. We looked for a mRNA expression signature in three randomized trials enrolling mCRC patients in their first line of treatment. In the phase II trials PANAMA and VALENTINO, RAS wild-type (wt) pts received induction with 5-Fluoruracil + oxaliplatin (FOLFOX) + anti-EGFR. In the phase III trial XELAVIRI, molecularly unselected patients (pts) received fluoropyrimidine (FP) + anti-VEGF ± irinotecan (IRI).

Methods

mRNA was isolated and gene expression analysis performed with a customized Nanostring PanCancer Progression Panel in 172 pts of the Full Analysis Set of PANAMA (discovery set), 326 pts of XELAVIRI, and 97 pts of VALENTINO (validation sets). Progression-free Survival (PFS), Overall Survival (OS) and Objective Response Rates (ORR) were assessed.

Results

A three-gene signature (VAV3, TDGF1, AGRN) identified 85 (49%) PANAMA low-risk pts with longer mPFS (HR: 0.69, 95% CI: 0.51-0.93, p=0.02), irrespective of other covariates (p_adj=0.004), and mOS (HR: 0.69, 95% CI: 0.49-0.97, p=0.03). In VALENTINO, low-risk pts were 59 (61%), with longer mPFS (HR: 0.61, 95% CI: 0.40-0.95, p=0.03; p_adj=0.03), and mOS (HR: 0.60, 95% CI: 0.37-0.99, p=0.04). In XELAVIRI, 240 low-risk pts (74%) were detected, demonstrating longer OS (HR: 0.71, 95% CI: 0.55-0.93, p=0.01), also after adjustment (p_adj=0.003). FP+IRI+anti-VEGF improved ORR (64 vs 39%, p=0.0001), PFS (HR: 0.70, 95% CI: 0.54-0.91, p=0.006) and OS (HR: 0.70, 95% CI: 0.53-0.91, p=0.009) versus FP+anti-VEGF in low-risk pts only. We confirmed these findings in the RAS wt subgroup (n=161) (p_ORR=0.03; p_OS<0.001; p_OSadj<0.001), including responsiveness to IRI (p_ORR<0.0001; p_PFS=0.002; p_OS=0.004), with an interaction for ORR (p=0.047).

Conclusions

We validated a prognostic gene expression signature in three randomized trials with different eligibility criteria and treatments, with consistency across RAS wt tumours, regardless of exposure to anti-EGFR or anti-VEGF. Adding IRI to FP was beneficial only in pts with the low-risk signature.

Clinical trial identification

PANAMA: NCT01991873 XELAVIRI: NCT01249638 VALENTINO: NCT02476045.

Editorial acknowledgement

Legal entity responsible for the study

Arbeitsgemeinschaft Internistische Onkologie (AIO): XELAVIRI and PANAMA; Istituto Nazionale Tumori (INT): VALENTINO.

Funding

Gene expression analyses were supported by AIO and INT. The conduct of the trials included was financed as follows: Istituto Nazionale Tumori: VALENTINO; AIO: XELAVIRI, PANAMA; Hoffman-La Roche: XELAVIRI; Amgen: VALENTINO, PANAMA.

Disclosure

V. Heinemann: Financial Interests, Personal, Advisory Board: Merck KGaA, Amgen, Roche, Pfizer, BMS, MSD, AstraZeneca, Novartis, Terumo, Oncosil, Nordic, Seagen, GSK, Takeda, Servier, Pierre Fabre, Taiho, Lilly Oncology, Servier, Sanofi, Bayer Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Merck KGaA, Amgen, Roche, Pfizer, BMS, MSD, AstraZeneca, Novartis, Terumo, Oncosil, Nordic, Seagen, GSK, Takeda, Servier, Pierre Fabre, Taiho, Lilly Oncology, Servier, Sanofi, Bayer Pharmaceuticals; Financial Interests, Personal, Other, Travel grant: Merck KGaA, Amgen, Roche, Pfizer, BMS, MSD, AstraZeneca, Novartis, Terumo, Oncosil, Nordic, Seagen, GSK, Takeda, Servier, Pierre Fabre, Taiho, Lilly Oncology, Servier, Sanofi, Bayer Pharmaceuticals; Financial Interests, Institutional, Research Funding: Merck, Amgen, Roche, Celgene, Boehringer Ingelheim, Sirtex Medical, Shire, Servier. F. Pietrantonio: Financial Interests, Personal, Advisory Board: AMGEN, Merck-Serono, MSD, Bayer, Astellas, Takeda, Ipsen, GSK, Johnson&Johnson, Rottapharm; Financial Interests, Personal, Invited Speaker: AMGEN, Merck-Serono, BMS, Lilly, Servier, Bayer, Pierre-Fabre, AstraZeneca, Astellas, Daiichi Sankyo, Takeda; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Incyte, Agenus; Financial Interests, Institutional, Coordinating PI: Lilly, Amgen. L. Fischer von W.: Financial Interests, Personal, Financially compensated role: Novartis, Roche Pharma AG, AstraZeneca, Pierre Fabre, Lilly GmbH. I. Na: Financial Interests, Institutional, Research Funding: Takeda and Octapharma. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, merck serono, lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi-Sankyo, Bristol-Myers Squibb, Astellas, GSK, Takeda, Bayer, Rottapharm; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GSK, Roche, Servier, Amgen, Bristol-Myers Squibb, Incyte, Lilly, Merck Serono, MSD, AstraZeneca; Financial Interests, Institutional, Coordinating PI: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol -Myers Squibb; Non-Financial Interests, Member of Board of Directors, Italian No-Profit Oncology Research Foundation supporting academic Clinical trials: GONO Foundation. F. Morano: Financial Interests, Personal, Invited Speaker: Servier, Pierre Fabre, Lilly; Financial Interests, Institutional, Research Grant: Incyte. M. Karthaus: Financial Interests, Personal, Other, Travel grant: Amgen. S. Fruehauf: Financial Interests, Personal, Advisory Board: Amgen. U. Graeven: Financial Interests, Personal, Stocks/Shares: Biontech; Financial Interests, Personal, Financially compensated role: Boehringer Ingelheim, Amgen, AstraZeneca, Bristol-Myers Squibb, MSD Oncology, sanofi Aventis GmbH, Fujifilm, Novartis, Cellrion, Ipsen; Financial Interests, Personal, Advisory Board: Amgen, MSD Oncology; Financial Interests, Institutional, Research Funding: Ipsen, Macrogenics; Financial Interests, Personal, Other, Travel grant: Boehringer Ingelheim, GSK. F. Kaiser: Financial Interests, Personal, Advisory Board: Astellas Pharma, GSK, MSD, Novartis, Sanofi, Pierre Fabre, Elsevier, Servier. S. Stintzing: Financial Interests, Personal, Advisory Board: Amgen, Bayer, Lilly, Pierre_Fabre, Merck KgaA, MSD, Roche, Sanofi, Taiho, Takeda; Financial Interests, Personal, Invited Speaker: Leo Pharma, AstraZeneca, Sysmex; Financial Interests, Institutional, Research Grant: Merck KGaA, Pierre-Fabre, Roche; Non-Financial Interests, Advisory Role: CV6. A. Stahler: Financial Interests, Personal, Advisory Board: BMS, Novocure; Financial Interests, Personal, Invited Speaker: Roche, Servier, Taiho Pharmaceuticals; Financial Interests, Personal, Other, Travel grant: Roche, Merck KGaA, MSD Sharp & Dohme, Pfizer, Lilly Oncology, Amgen. D.P. Modest: Financial Interests, Personal, Invited Speaker: Takeda, Taiho, Amgen, Servier, Merck, Onkowissen, MSD, AstraZeneca, PierreFabre, GSK, Medison, COR2ED, JE, 21up, Seagen; Financial Interests, Personal, Advisory Board: Amgen, Servier, Merck, MSD, Takeda, G1, Onkowissen, PierreFabre, AstraZeneca, Regeneron; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Coordinating PI: Servier. All other authors have declared no conflicts of interest.