Impact of Human Epidermal Growth Factor Receptor 2 in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab or Anti-EGFRs: Exploratory Analysis of Eight Randomized Trials

Abstract

Purpose: Human epidermal growth factor receptor 2 (HER2) amplification/overexpression (HER2-pos) is detected in 5% of RAS/BRAF wild-type metastatic colorectal cancers (mCRCs). Its prognostic/predictive role in terms of benefit from anti-EGFR/bevacizumab (bev) is debated. Similarly, the role of activating HER2 mutations (mut) is unclear.

Methods: We collected individual data of 1,604 patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) RAS/BRAF wild-type untreated mCRC with HER2 amplification/expression status available enrolled in eight randomized clinical trials (RCT; TRIBE2, TRIPLETE, VALENTINO, ATEZOTRIBE, PANDA, PANAMA, PARADIGM, and CALGB/SWOG80405). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were assessed with respect to HER2 amplification/expression and HER2 mutational status and according to biologics (anti-EGFR/bev).

Results: Patients with HER2-pos were 81 (5%). HER2-pos patients experienced shorter PFS (median PFS [mPFS]: 9.8 v 12.2 months, hazard ratio [HR], 1.31, P = .02) and OS (median OS [mOS]: 28.0 v 34.9 months, HR, 1.37, P = .01), also after adjustment for covariates (P_adjPFS = .02, P_adjOS = .048). ORR was similar between HER2-pos and HER2-negative (HER2-neg) tumors (75% v 72%, odds ratio [OR], 1.21, P = .47). We found no interaction between HER2 amplification/expression status and biologics' effect in terms of PFS (P_int = .76), OS (P_int = .76), and ORR (P_int = .64). In left-sided HER2-pos tumors, outcomes were similar with chemotherapy plus bev/anti-EGFRs in terms of PFS (9.8 v 9.3 months, HR, 0.73, P = .29), OS (29.8 v 28.0 months, HR, 1.29, P = .40), and ORR (59% v 79%, OR, 0.39, P = .10). HER2-mutant tumors (2% of patients with HER2-neg tumors) showed shorter OS than HER2 wild-type ones (mOS: 23.7 v 34.4 months, HR, 1.56, P = .04) with no differential effect of biologics (P_intORR = .81; P_intPFS = .95; P_intOS = .92).

Conclusion: To our knowledge, this is the largest analysis of HER2 status in patients with untreated mCRC enrolled in RCT. Waiting for targeted approaches, HER2-pos and mut do not predict benefit from bev/anti-EGFRs and should be regarded as negative prognostic factors in pMMR/MSS RAS/BRAF wild-type mCRC.

FIG 1.

Flow diagram. dMMR, deficient mismatch repair; FOLFOXIRI, fluorouracil/leucovorin plus oxaliplatin plus irinotecan; FU+LV, fluorouracil + leucovorin; HER2, human epidermal growth factor receptor 2; MSI, microsatellite; MSI-H, MSI instability; MSS, MSI stable; pMMR, proficient mismatch repair; wt, wild-type.

FIG 2.

(A) ORR, (B) PFS, and (C) OS according to HER2 expression/amplification status. HER2-neg, human epidermal growth factor receptor 2–negative; HER2-pos, human epidermal growth factor receptor 2–positive; HR, hazard ratio; (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival; OR, odds ratio; ORR, objective response rate; pop, population.

FIG 3.

(A) ORR, (B) PFS, and (C) OS according to HER2 expression/amplification status and monoclonal antibody received. Anti-EGFRs, antiepidermal growth factor receptors; bev, bevacizumab; HER2-neg, human epidermal growth factor receptor 2–negative; HER2-pos, human epidermal growth factor receptor 2–positive; HR, hazard ratio; (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival; OR, odds ratio; ORR, objective response rate; pop, population.

FIG 4.

(A) ORR, (B) PFS, and (C) OS according to HER2 mutational status in HER2-negative tumors. HER2-neg, human epidermal growth factor receptor 2–negative; HR, hazard ratio; (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival; mut, mutant; OR, odds ratio; ORR, objective response rate; pop, population.

FIG 5.

(A) ORR, (B) PFS, and (C) OS according to HER2 mutational status in HER2-negative tumors and monoclonal antibody received. Anti-EGFRs, antiepidermal growth factor receptors; bev, bevacizumab; HER2-neg, human epidermal growth factor receptor 2–negative; HR, hazard ratio; (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival; mut, mutant; NA, not assessable; OR, odds ratio; ORR, objective response rate; pop, population; wt, wild-type.

FIG A1.

(A) ORR, (B) PFS, and (C) OS according to HER2 expression/amplification status in patients treated with doublets only. HER2-neg, human epidermal growth factor receptor 2–negative; HER2-pos, human epidermal growth factor receptor 2–positive; HR, hazard ratio; (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival; OR, odds ratio; ORR, objective response rate; pop, population.

FIG A2.

(A) ORR, (B) PFS, and (C) OS according to HER2 expression/amplification status and primary tumor origin. HER2-neg, human epidermal growth factor receptor 2–negative; HER2-pos, human epidermal growth factor receptor 2–positive; HR, hazard ratio, (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival; NA, not assessable; OR, odds ratio; ORR, objective response rate; pop, population.

FIG A3.

(A) ORR, (B) PFS, and (C) OS according to HER2 expression/amplification status and monoclonal antibody received with HER2-pos tumors being only those with higher presumed HER2 dependency. Anti-EGFRs, antiepidermal growth factor receptors; bev, bevacizumab; HER2-neg, human epidermal growth factor receptor 2–negative; HER2-pos, human epidermal growth factor receptor 2–positive; HR, hazard ratio; (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival; OR, odds ratio; ORR, objective response rate; pop, population.