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

Human epidermal growth factor receptor 2 (HER2) amplification/overexpression (HER2-pos) is detected in 5% of <i>RAS/BRAF</i> 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 <i>HER2</i> mutations (mut) is unclear. We collected individual data of 1,604 patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) <i>RAS/BRAF</i> 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 <i>HER2</i> mutational status and according to biologics (anti-EGFR/bev). Patients with HER2-pos were 81 (5%). HER2-pos patients experienced shorter PFS (median PFS [mPFS]: 9.8 <i>v</i> 12.2 months, hazard ratio [HR], 1.31, <i>P</i> = .02) and OS (median OS [mOS]: 28.0 <i>v</i> 34.9 months, HR, 1.37, <i>P</i> = .01), also after adjustment for covariates (<i>P</i>_adjPFS = .02, <i>P</i>_adjOS = .048). ORR was similar between HER2-pos and HER2-negative (HER2-neg) tumors (75% <i>v</i> 72%, odds ratio [OR], 1.21, <i>P</i> = .47). We found no interaction between HER2 amplification/expression status and biologics' effect in terms of PFS (<i>P</i>_int = .76), OS (<i>P</i>_int = .76), and ORR (<i>P</i>_int = .64). In left-sided HER2-pos tumors, outcomes were similar with chemotherapy plus bev/anti-EGFRs in terms of PFS (9.8 <i>v</i> 9.3 months, HR, 0.73, <i>P</i> = .29), OS (29.8 <i>v</i> 28.0 months, HR, 1.29, <i>P</i> = .40), and ORR (59% <i>v</i> 79%, OR, 0.39, <i>P</i> = .10). <i>HER2</i>-mutant tumors (2% of patients with HER2-neg tumors) showed shorter OS than <i>HER2</i> wild-type ones (mOS: 23.7 <i>v</i> 34.4 months, HR, 1.56, <i>P</i> = .04) with no differential effect of biologics (<i>P</i>_intORR = .81; <i>P</i>_intPFS = .95; <i>P</i>_intOS = .92). 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 <i>RAS/BRAF</i> wild-type mCRC.