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
Germani MM., Borelli B., Hashimoto T., Nakamura Y., Oldani S., Battaglin F., Bergamo F., Salvatore L., Stahler A., Antoniotti C., Shitara K., Venook A., Oki E., Muro K., Ugolini C., Soeda J., Lonardi S., Pietrantonio F., Lenz H-J., Modest DP., Yoshino T., Cremolini C.
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 adj PFS = .02, P adj OS = .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 int ORR = .81; P int PFS = .95; P int OS = .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.