First-line anti-EGFR monoclonal antibodies in panRAS wild-type metastatic colorectal cancer: A systematic review and meta-analysis

•Anti-EGFRs confer overall survival gain in RAS wild-type mCRC.•Anti-EGFRs provide clear benefit in PFS and ORR when added to chemotherapy alone.•Anti-EGFRs provide benefit in OS but not PFS and ORR versus chemotherapy plus bevacizumab.•Both anti-EGFRs and bevacizumab are valid first-line options in RAS wild-type patients.•Further translational studies are needed for the goal of treatment personalization.

SummaryBackgroundThe use of anti-EGFR monoclonal antibodies (MoAbs) is restricted in Europe to RAS wild-type metastatic colorectal cancer (mCRC) patients. While up today these targeted agents have been mainly chosen as salvage treatment in later lines, their use in first-line in combination with chemotherapy is highly debated.MethodsMEDLINE/PubMed, Cochrane Library, ASCO University, ESMO/ECCO conferences were searched for randomized controlled trials (RCTs) comparing first-line anti-EGFR MoAbs cetuximab or panitumumab plus chemotherapy to chemotherapy alone or with bevacizumab in patients with RAS wild-type colorectal cancer. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.ResultsSeven eligible RCTs were identified. In the overall RAS wild-type population (N = 2719), anti-EGFR MoAbs significantly improved OS (HR = 0.81; 95%CI, 0.71–0.92; p = 0.002), PFS (HR = 0.77; 95%CI, 0.60–0.98; p = 0.03) and objective response rate (ORR) (RR = 1.33; 95%CI, 1.09–1.62; p = 0.004). The addition of an anti-EGFR MoAb to chemotherapy alone improved PFS (p < 0.001) and ORR (p < 0.001) with a trend toward longer OS (p = 0.07). As compared to bevacizumab, anti-EGFR MoAbs significantly improved OS (HR = 0.80; 95%CI, 0.69–0.92; p = 0.003), but not PFS (HR = 0.94; 95%CI, 0.74–1.19; p = 0.59) or ORR (RR = 1.10; 95%CI, 0.97–1.25; p = 0.12). No significant differences were found with respect to the chemotherapy backbone (oxaliplatin- versus irinotecan-based).ConclusionsThe choice of an anti-EGFR MoAb as first-line biologic is a valid option in RAS wild-type patients candidate to a doublet with infusional 5-FU. While attempting to further refine molecular selection, clinical considerations are crucial in planning the treatment strategy.