The prognostic and predictive role of HER2 amplification/overexpression and <i>HER2</i> mutations in metastatic colorectal cancer treated with first-line chemotherapy plus bevacizumab/anti-EGFRs: An individual patient data pooled analysis of eight ra

3537 Background: HER2 amplification/overxpression (HER2-pos) is detected in the 5% of RAS/BRAF wild-type (wt) metastatic colorectal cancers (mCRC) and is associated with poor efficacy of EGFR blockade in preclinical models. Whether HER2-pos is a prognostic and/or predictive biomarker of benefit from anti-EGFRs/bevacizumab (bev) in mCRC patients (pts) is still debated. Similarly, the role of activating HER2 mutations (mut) is unclear. Methods: We collected individual patient data from 8 randomized clinical trials (RCTs) in the first-line treatment of mCRC: TRIBE2, TRIPLETE, VALENTINO, ATEZOTRIBE, PANDA, PANAMA, PARADIGM and CALGB/SWOG80405. Only pts with RAS/BRAF wt pMMR mCRC with available HER2 status by means of immunohistochemistry ± in situ hybridization and/or Next-generation sequencing on tumor or circulating DNA and treated with triplet or doublets + bev or an anti-EGFR were included. The prognostic and predictive impact of HER2-pos and HER2 mut was assessed in terms of PFS, OS and ORR. Results: 1604 pts were eligible. 81 (5%) tumours were HER2-pos. HER2-pos was associated with shorter PFS (mPFS: 9.8 vs 12.2 months (mos), HR: 1.31, p = 0.02) and OS (mOS: 28.0 vs 34.9 mos, HR: 1.37, p = 0.01), and similar ORR (77 vs 72%, p = 0.47) compared to HER2-neg pts. P-values adjusted for clinically meaningful covariates (p adj ) were p adj PFS = 0.075 and p adj OS = 0.036. We found no interaction between HER2-pos and treatment effect according to the use of bev vs anti-EGFRs in terms of PFS (p int = 0.76), OS (p int = 0.76) and ORR (p int = 0.64). Similar findings were reported restricting the analysis to pts treated with doublets (N = 1465), and to those with left-sided tumors (N = 1315). In the HER2-pos subgroup (N = 69) of pts with left-sided RAS/BRAF wild-type pMMR tumors no difference between chemotherapy/bev and chemotherapy/anti-EGFR was reported in terms of PFS (mPFS: 9.8 vs 9.3 mos, HR: 0.73, p = 0.30), OS (mOS: 29.8 vs 28.0 mos, HR: 1.29, p = 0.40), and ORR (59% vs 79%, p = 0.10). Activating HER2 mut were found in 27 (2%) out of 1408 HER2-neg tumors with HER2 mutational status available. Pts with HER2 mut tumors had a shorter OS (median: 23.7 vs 34.4 mos, HR: 1.56, p = 0.04) than HER2 wt. No interaction between HER2 mutational status and treatment effect was evident, with no significantly different PFS (mPFS: 9.4 vs 5.7 mos, HR: 0.88, p = 0.76) and OS (mOS: 20.9 vs 23.7 mos, HR: 1.04, p = 0.93) in the HER2 mut subgroup between bev and anti-EGFRs. Conclusions: This is the largest analysis of HER2 status in untreated mCRC pts enrolled in RCTs. Waiting for targeted approaches, HER2-pos is an independent negative prognostic factor and does not predict benefit between bev/anti-EGFRs also in left-sided tumors. HER2 mut may exert a negative prognostic impact in HER2-neg RAS/BRAF wt pMMR mCRC.