Role of maintaining the TKI backbone in oncogene-driven NSCLC after progression

Tyrosine kinase inhibitors (TKIs) have marked a turning point in the treatment of oncogene-addicted non-small cell lung cancer (NSCLC), offering unprecedented efficacy. Yet, most tumors eventually develop resistance and progress, often prompting discontinuation of the targeted agent and a switch to non-targeted therapies such as chemotherapy. We explored current evidence on maintaining inhibition of the oncogenic driver beyond progression in a narrative literature review through August 24, 2026, including clinical trials, retrospective analyses, case reports, case series, and preclinical models. Among all drivers, only EGFR-mutated NSCLC provided phase II/III evidence supporting maintenance of driver inhibition beyond progression. Combinations of EGFR-directed therapies with chemotherapy or MET inhibitors were associated with improved response rates and progression-free survival (PFS) compared with chemotherapy or MET inhibitor monotherapy, although these trials had several limitations. ALK and KRAS G12C evidence was limited to early-phase trials with small cohorts and modest clinical signals, while the remaining drivers (RET, METex14, NTRK, HER2, ROS1, BRAF, and EGFR exon 20) evidence was largely preclinical or anecdotal, making continuation experimental. Co-occurring resistance mechanisms, heterogeneous tumor evolution, and potential additive toxicity complicate interpretation of the backbone's contribution to clinical benefit. Continuation should therefore not be applied routinely but tailored to the pattern and site of progression, re-biopsy findings, CNS disease control, expected toxicity, and patient preferences. Given the rarity of many oncogenic drivers and the challenges of conducting adequately powered randomized trials, definitive data may remain available for several resistance scenarios.