Molecular subtype-specific efficacy of anti-EGFR therapy in colorectal cancer is dependent on the chemotherapy backbone

Abstract

Background Patient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location. Methods Retrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively. Results When using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26–0.75, P = 0.003 and HR 0.12, 95% CI 0.04–0.36, P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 0.04–0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36–0.96, P = 0.034). Conclusions The subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy.

NSABP FC‐6: Surgical conversion rate in colorectal cancer patients with unresectable, KRAS wild‐type liver metastases receiving mFOLFOX7 plus cetuximab

“…Interestingly, in the remaining two of the paired samples (FC‐6‐0005 and FC‐6‐0006), the GEPs changed from the TA/enterocyte subtypes to stem‐like subtypes after FC‐6 treatment. It is worth noting that FC‐6‐0005 and FC‐6‐0006 switched from TA/enterocyte subtypes with good/intermediate outcomes to stem‐like with a very poor prognosis 29 and are associated with lack of efficacy to EGFR inhibitors when combined with an oxaliplatin chemotherapy backbone 30 …”

Efficacy of third-line anti-EGFR-based treatment versus regorafenib or trifluridine/tipiracil according to primary tumor site in RAS/BRAF wild-type metastatic colorectal cancer patients

“…CMS2 is an over-activated epithelial growth factor pathway with higher expression of EGFR and the EGFR-ligands amphiregulin and epiregulin, that are correlated to an increased response to EGFR inhibitor therapy in RAS/BRAF wt CRC (17) analyzing gene signature of 514 samples of patients enrolled in the FIRE-3 study, demonstrated that patients with CMS4 tumors had a longer OS when treated with cetuximab vs bevacizumab (18). In another molecular analysis of RAS/BRAF wt patients from the COIN and PICCOLO study, patients with CMS4 tumors showed a a longer OS and PFS when treated with anti-EGFR-based treatment vs chemotherapy alone (19).…”

“…Stintzing et al., analyzing gene signature of 514 samples of patients enrolled in the FIRE-3 study, demonstrated that patients with CMS4 tumors had a longer OS when treated with cetuximab vs bevacizumab ( 18 ). In another molecular analysis of RAS/BRAF wt patients from the COIN and PICCOLO study, patients with CMS4 tumors showed a a longer OS and PFS when treated with anti-EGFR-based treatment vs chemotherapy alone ( 19 ).…”

Receipt of Targeted Therapy and Survival Outcomes in Patients With Metastatic Colorectal Cancer

“…13 However, other studies have shown no survival benefits associated with EGFR inhibitor therapy in patients with a KRAS-WT tumor 14 or varying efficacy of EGFR inhibitors by chemotherapy backbone. 15 With VEGF inhibitors, a meta-analysis of 7 RCTs that included 2040 patients with mCRC reported that VEGF inhibitor therapy was associated with improved progression-free survival time, but not with overall survival. 16 Another study pooling data from 9 trials comprising 3914 patients noted that the addition of VEGF inhibitors to various chemotherapy regimens was associated with higher progression-free survival, as well as higher overall survival.…”

“…Furthermore, among patients with RAS- WT tumors, studies have shown survival advantage with the addition of EGFR inhibitors to a chemotherapy backbone, such as FOLFOX (folinic acid, fluorouracil, and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil, and irinotecan) . However, other studies have shown no survival benefits associated with EGFR inhibitor therapy in patients with a KRAS -WT tumor or varying efficacy of EGFR inhibitors by chemotherapy backbone …”