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The MARIPOSA and FLAURA2 phase 3 trials have established that combination regimens of amivantamab plus lazertinib and osimertinib plus platinum-pemetrexed, respectively, extend both progression-free and overall survival compared with osimertinib monotherapy. Each carries substantially greater toxicity, treatment complexity, and cost. No validated, prospective framework exists to guide first-line selection between combination and single-agent strategies. Decision-making is currently anchored to trial eligibility criteria and institutional norms rather than individualized risk stratification. This review synthesizes evidence from landmark trials, molecular biomarker analyses, and real-world cohort studies to propose a practical risk-adapted algorithm integrating tumor biology, molecular co-alterations, patient performance status, comorbidities, logistical feasibility, and treatment preference. Patients with biologically high-risk features, including liver metastases, baseline central nervous system (CNS) involvement, circulating tumor DNA (ctDNA) elevation, or heavy disease burden, may derive the greatest absolute benefit from combination therapy.\n                    <jats:italic>TP53<\/jats:italic>\n                    co-mutation warrants consideration but should be interpreted as a prognostic marker rather than a definitive treatment-selection criterion given conflicting predictive data across trials. The subcutaneous (SC) formulation of amivantamab, demonstrated in PALOMA-3 to reduce infusion-related reactions and administration time relative to the intravenous formulation, may improve the tolerability and logistical feasibility of MARIPOSA-based therapy, though prospective comparative evidence across formulations remains limited. Prospective biomarker-driven trials are needed to validate treatment selection; until that evidence matures, individualized shared decision-making guided by the proposed algorithm is the most defensible clinical approach.\n                  <\/jats:p>","DOI":"10.1007\/s12032-026-03338-y","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T06:51:30Z","timestamp":1787986290000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Risk-adapted first-line therapy selection in advanced EGFR-mutant NSCLC: a practical clinical algorithm integrating tumor biology and patient factors"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2698-0128","authenticated-orcid":false,"given":"Ashish","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3648-6553","authenticated-orcid":false,"given":"Joecelyn Kirani","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harendra","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hareesha Rishab","family":"Bharadwaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"issue":"5","key":"3338_CR1","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1093\/jnci\/dji055","volume":"97","author":"H Shigematsu","year":"2005","unstructured":"Shigematsu H, Lin L, Takahashi T, et al. 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All content was independently reviewed, verified, and edited by the authors. The authors take full responsibility for the accuracy and integrity of all content presented in this manuscript.","order":4,"name":"Ethics","label":"AI disclosure","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This narrative review adheres to the general principles of good narrative review practice. REMARK criteria for prognostic biomarker reporting have been referenced where applicable [\n                      \n                      ]. Transparent reporting of evidence quality, study limitations, and evidence grading has been incorporated throughout the manuscript.","order":5,"name":"Ethics","label":"Compliance with reporting guidelines","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"258"}}