506O - Evaluation of risk of disease progression in first-line therapy of unresected metastatic colorectal cancer to guide intervals of radiological assessment: An analysis of eleven randomized trials by AIO and GONO

Background

We evaluated the distribution and risk of disease progression (PD) in first-line therapy of unresected metastatic colorectal cancer (mCRC) patients (pts) receiving chemotherapy + biologics. The aim of the analysis is to provide guidance for the timing of disease reassessments during first-line therapy.

Methods

Individual data of 2845 pts from TRIBE, MOMA, TRIBE2, VALENTINO, ATEZOTRIBE, TRIPLETE, FIRE-3, XELAVIRI, PANAMA, FIRE-4 and FIRE-4.5 were analyzed. The frequency and risk of PD events were calculated for individual time points during therapy. RAS/BRAF profiling, tumor sidedness and therapy were used to identify subgroups for risk assessment. Lastly, a nomogram to predict the risk of PD within the first 8 months (mo) of therapy was built.

Results

In the overall population, the maximum density of PD events was observed at 7.4 mo with a median PFS of 9.4 mo. Based on bimonthly restaging, the highest risk of PD was 23% at 14 mo in RAS/BRAF WT pts (n=1702), 25% at 10 mo in RAS MUT pts (n=964) and 35% at 8 mo BRAF MUT pts (n=179). Left-sided RAS/BRAFWT pts exposed to anti-EGFRs (n=997) had a plateau of the PD risk between 12-18 mo, with a maximum risk of 22% at 14 mo. Pts with RASMUT or right-sided and RASWT tumors treated with triplet (n=451) or doublets + bev (n=636) had an increase in the risk of PD at 8 mo (21% and 18%, respectively) and its maximum at 14 and 16 mo, (27% and 30% respectively). Among pts with BRAF MUT tumors the highest risk of PD with both the triplet (n=96) and doublets + bev (n=83) was at 8 mo (34% and 37%, respectively). ECOG-PS, primary tumor sidedness and its resection, peritoneal mts and RAS/BRAF status were associated with the risk of PD at 8 mo. A nomogram built on these features showed consistency across a training (C-index: 0.64) and a validation set (C-index: 0.61) of 1339 and 1506 pts of different trials, respectively.

Conclusions

The distribution of PD events does not follow a Gaussian pattern with the highest density prior to the median PFS suggesting that tumor assessments should focus on the interval between 6-10 mo. The nomogram might be helpful to identify subgroups of pts in which could be sound to diversify timings of tumor restaging.

Clinical trial identification

TRIBE: NCT00719797 MOMA: NCT02271464 TRIBE2: NCT02339116 VALENTINO: NCT02476045 ATEZOTRIBE: NCT03721653 TRIPLETE: NCT03231722 FIRE-3: NCT00433927 XELAVIRI: NCT01249638 PANAMA: NCT01991873 FIRE-4: NCT02934529 FIRE-4.5: NCT04034459.

Editorial acknowledgement

Legal entity responsible for the study

Gruppo Oncologico del Nord Ovest (GONO): TRIBE, MOMA, TRIBE2, ATEZOTRIBE, TRIPLETE; Istituto Nazionale Tumori: VALENTINO; Arbeitsgemeinschaft Internistische Onkologie (AIO): FIRE-3, XELAVIRI, PANAMA, FIRE-4, FIRE-4.5.

Funding

This post-hoc analysis was supported by GONO and AIO Foundations. The conduct of the trials included in this analysis was financially supported as follows: GONO: TRIBE, MOMA, TRIBE2, ATEZOTRIBE, TRIPLETE; Istituto Nazionale Tumori: VALENTINO; AIO: FIRE-3, XELAVIRI, PANAMA, FIRE-4, FIRE-4.5; Hoffman-La Roche: TRIBE, MOMA, TRIBE2, ATEZOTRIBE, XELAVIRI; Amgen: VALENTINO, TRIPLETE, PANAMA; Merck KGaA: FIRE-3, FIRE-4, FIRE-4.5.

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. D. Rossini: Financial Interests, Personal, Invited Speaker: Amgen, Pierre Fabre, Sanofi, Takeda. L. Fischer von Weikersthal: Financial Interests, Personal, Financially compensated role: Novartis, Roche Pharma AG, AstraZeneca, Pierre Fabre, Lilly GmbH. F. Morano: Financial Interests, Personal, Invited Speaker: Servier, Pierre Fabre, Lilly; Financial Interests, Institutional, Research Grant: Incyte. K. Heinrich: Financial Interests, Personal, Advisory Board: Servier (Inst); Financial Interests, Personal, Financially compensated role: Roche Pharma AG, Taiho Pharmaceutical; Financial Interests, Personal, Other, Travel grant: Amgen, Lilly, Servier, Merck KGaA. 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. F. Bergamo: Financial Interests, Personal, Invited Speaker: Lilly, BMS, MSD, Eisai, Bayer, Amgen; Financial Interests, Personal, Advisory Board: Servier, AAA; Other, Congress: Bayer, Ipsen, AAA. F. Kaiser: Financial Interests, Personal, Advisory Board: Astellas Pharma, GSK, MSD, Novartis, Sanofi, Pierre Fabre, Elsevier, Servier. L. Salvatore: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, Servier; Financial Interests, Personal, Financially compensated role: Amgen, AstraZeneca, Bayer, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, Servier; Financial Interests, Personal, Other, Travel Grant: Bayer, Celgene, Merck Serono, Pierre Fabre, Sanofi, Servier. L. Weiss: Financial Interests, Personal, Invited Speaker: Roche, Servier; Financial Interests, Personal, Advisory Board: Roche, Servier; Financial Interests, Personal, Other, Travel grant: Amgen, Merck. A.A. Prete: Financial Interests, Personal, Other, Grant: Bayer. G. Masi: Financial Interests, Ownership Interest: Terumo (Inst); Financial Interests, Institutional, Research Grant: Terumo (Inst), Terumo (Inst); Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, MSD Oncology, Roche, Roche. 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. C. Cremolini: Financial Interests, Personal, Advisory Board: Roche, MSD, Amgen, Pierre Fabre, Nordic Pharma, Takeda; Financial Interests, Personal, Invited Speaker: Bayer, Servier, Merck Serono; Financial Interests, Institutional, Coordinating PI: Roche, Bayer, Servier, Merck; Financial Interests, Institutional, Local PI: Seagen, Hutchinson. 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.