Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials

Abstract

Importance: Metastatic colorectal cancer (mCRC) is heterogeneous, and primary tumors arising from different regions of the colon are clinically and molecularly distinct.

Objective: To examine the prognostic and predictive value of primary tumor location in patients with RAS wild-type (wt) mCRC treated with first-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab in the Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial and FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer (FIRE-3) trial.

Design, setting, and participants: In this retrospective analysis patients with RAS wt metastatic colorectal cancer from the CRYSTAL and FIRE-3 trials were classified as having left-sided or right-sided mCRC, defined, respectively, as patients whose tumors originated in the splenic flexure, descending colon, sigmoid colon, or rectum vs appendix, cecum, ascending colon, hepatic flexure, or transverse colon.

Main outcomes and measures: Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were assessed according to tumor location and treatment arm.

Results: In the RAS wt populations of the CRYSTAL and FIRE-3 trials, patients with left-sided tumors (n = 142 and n = 157, respectively) had markedly superior PFS, OS, and ORR compared with patients with right-sided tumors (n = 33 and n = 38, respectively). Among CRYSTAL and FIRE-3 study patients with RAS wt left-sided tumors, FOLFIRI plus cetuximab significantly improved OS relative to the respective comparators (FOLFIRI and FOLFIRI plus bevacizumab); in contrast, in RAS wt patients with poor-prognosis right-sided tumors, limited efficacy benefits were observed upon the addition of cetuximab to FOLFIRI in CRYSTAL, and comparable outcomes were observed between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab arms of FIRE-3. A significant interaction was observed between primary tumor location and treatment for OS (CRYSTAL: hazard ratio [HR], 1.95; 95% CI, 1.09-3.48 and FIRE-3: HR, 0.40; 95% CI, 0.23-0.70) within the RAS wt populations of both studies in multivariable models that also included sex, prior adjuvant therapy, and BRAF mutational status.

Conclusions and relevance: In the RAS wt populations of CRYSTAL and FIRE-3, patients with left-sided tumors had a markedly better prognosis than those with right-sided tumors. First-line FOLFIRI plus cetuximab clearly benefitted patients with left-sided tumors (vs FOLFIRI or FOLFIRI plus bevacizumab, respectively), whereas patients with right-sided tumors derived limited benefit from standard treatments.

Trial registration: clinicaltrials.gov Identifiers: CRYSTAL, NCT00154102, and FIRE-3, NCT00433927.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Tejpar has received honoraria from Merck KGaA, Bayer, Sanofi, and Roche; provided consulting for Merck KGaA, Bayer, Sanofi, Boehringer, and Roche; participated in speakers bureaus for Roche, Merck KGaA, and Sanofi; and received research funding from Sanofi and Bayer. Dr Stintzing has received honoraria from Amgen, Roche, Bayer, Merck KGaA, and Sanofi; provided consulting for Amgen, Roche, Bayer, Merck KGaA, and Sanofi; and received travel accommodations from Amgen, Roche, Bayer, Merck KGaA, and Sanofi. Dr Ciardiello has provided consulting for Merck KGaA, Bayer, Lilly, Roche, and AstraZeneca; and received research funding from Bayer and Merck KGaA. Dr Tabernero has provided consulting for Amgen, Boehringer Ingelheim, Celgene, Chugia, Imclone, Lilly, Merck, Merck KGaA, Millennium, Novartis, Roche, Sanofi, Symphogen, and Tahio. Dr Van Cutsem has received research funding from Amgen, Bayer, Boehringer, Celgene, Ipsen, Merck, Roche, and Sanofi. Mr Beier is an employee of Merck KGaA. Ms Esser is an employee of Merck KGaA and reports stock ownership. Dr Lenz has received honoraria from Merck KGaA and provided consulting for Merck KGaA. Dr Heinemann has received honoraria from Merck, Amgen, Roche, Sanofi, Baxalta, and SIRTEX; provided consulting for Merck, Amgen, Roche, Sanofi, Baxalta, Servier, and SIRTEX; participated in speakers bureaus for Merck, Amgen, Roche, Sanofi, Baxalta, and SIRTEX; received research funding from Merck, Amgen, Roche, Pfizer, and Sanofi; and received travel accommodations from Merck, Roche, Baxalta, and SIRTEX. No other disclosures are reported.

Figures

Figure 1.. Survival Characteristics of CRYSTAL Study Patients

A, Progression-free survival (PFS) and (B) overall survival (OS) for RAS wild-type (wt) CRYSTAL study patients, stratified based on tumor location. P values derive from a log-rank test, stratified by region and Eastern Cooperative Oncology Group performance status. FOLFIRI indicates fluorouracil, leucovorin, and irinotecan; HR, hazard ratio; mCRC, metastatic colorectal cancer.

Figure 2.. Survival Characteristics of FIRE-3 Study Patients

A, Progression-free survival (PFS) and (B) overall survival (OS) for RAS wild-type (wt) FIRE-3 study patients, stratified based on tumor location. P values derive from a log-rank test, stratified by region and Eastern Cooperative Oncology Group performance status. FOLFIRI indicates fluorouracil, leucovorin, and irinotecan; HR, hazard ratio; mCRC, metastatic colorectal cancer.