Oral mucositis risk with EGFR tyrosine kinase inhibitor monotherapies and combination regimens in non-small cell lung cancer: a systematic review and network meta-analysis

Introduction and aims Oral mucositis (OM) impairs quality of life, necessitates dose modification, and disrupts treatment continuity in patients receiving EGFR tyrosine kinase inhibitors (EGFR-TKIs), yet comparative OM risks across monotherapies and combination regimens remain poorly defined. Methods PubMed, Embase, Web of Science, the Cochrane Library, and ClinicalTrials.gov were searched from inception to June 13, 2026, for phase II or III randomized controlled trials. Bayesian random-effects network meta-analyses estimated odds ratios (ORs) with 95% credible intervals (CrIs) for any-grade and grade ≥3 OM. Treatments were ranked using the surface under the cumulative ranking curve (SUCRA). Results Sixty-three trials involving 21,845 participants were included. Compared with chemotherapy, higher odds of any-grade OM were observed with afatinib plus cetuximab (OR 11.97, 95% CrI 2.27–65.45), afatinib (OR 9.73, 95% CrI 3.75–26.50), dacomitinib (OR 5.12, 95% CrI 1.71–16.00), and erlotinib plus chemotherapy (OR 2.84, 95% CrI 1.27–6.53), with low-, high-, moderate-, and very-low-certainty evidence, respectively; for grade ≥3 OM, with afatinib plus cetuximab (OR 13.91, 95% CrI 1.55–199.26), afatinib (OR 8.80, 95% CrI 1.37–100.11), and mobocertinib (OR 8.12, 95% CrI 1.14–97.77), all supported by moderate-certainty evidence. Afatinib plus cetuximab ranked highest for both outcomes (SUCRA, 89.0% and 91.6%). Second-generation EGFR-TKIs generally ranked higher, whereas the third-generation agents osimertinib and furmonertinib ranked lower. Combination regimens often yielded higher point estimates than matched monotherapies, but most comparisons were inconclusive. Conclusions OM risk varies substantially across EGFR-TKI regimens. Higher-risk regimens warrant strengthened baseline oral assessment, patient education, and monitoring during treatment. Given limited head-to-head evidence for novel agents/combinations and imprecision in some estimates, findings warrant further validation in standardized prospective studies. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420261449930 , identifier CRD420261449930.